35980975 the alkaloids chemistry and physiology volume 16 1977 isbn 0124695167

8/12/2019 35980975 the Alkaloids Chemistry and Physiology Volume 16 1977 IsBN 0124695167

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THE ALKALOIDS

Chemistry and Physiology

VOLUME XVI



This Page Intentionally Left Blank



THE ALIMLOIDSChemistry and Physiology

E d i t e d by

R . H . F. MANSKE

Department of Chemistry, University of Waterloo

Waterloo, Ontario, Canad a

VOLUME XVI

1977

ACADEMIC PRESS 0 N E W YORK 0 SAN FRANCISCO 0 LONDON

A Subsidiary of Harcourt Brace Jovanovich, Publishers



COPYRIGHT 977, B Y ACADEMICRESS,NC.ALL RIGHTS RESERVED.

NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR

TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC

OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR A N Y

INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT

PERMISSION IN WRITING FROM THE PUBLISHER.

ACADEMIC PRESS, INC.111 Fifth Avenue. New York, New York 10003

United Kingdo m Edi t ion publ ished byACADEMIC PRESS, INC. (LONDON) LTD.24/28 Oval Road, London NWl

Library of Congress Cataloging in Publication Data

Manske, Richard Helrnuth Fred,

The alkaloids.

Vols. 8-16 edited by R. H. F. Manske.

Includes bibliographical references.

1. Alkaloids. 2. Alkaloids-Physiological effect.

I. Holrnes, Henry Lavergne, joint author. 11. Title:

Thru physiology. [DNLM: 1. Alkaloids. QV628 M288al

ISBN 0-12-469516-7

QD421.M3 547 .I 2 50-5522

PRINTED IN THE UNITED STATES OF AMERICA



CONTENTS

LISTOF CONTRIBUTORS.. ix

PREFACE xi

CONTENTSF PREVIOUSOLUMES.. xiii

Chapter 1 Plant Systematics and AlkaloidsDAVIDS. SEIGLER

I . Introduction 1

11. Data to Be Utilized 3

UI. Application of the Dat a t iological Problems 8

V.

1V. Alkaloids in Lower Vascular Plant s and Gymnosperms

Alkaloids in the Angiosperms

References 73

Chapter 2 The Tropane Alkaloids

ROBERT . CLARKE

I. Introduction

11. New Tropane A1

107

153

IX. Analytical Methods

References

Chapter 3. Nuphar Alkaloids

JERZY. WR~BEL

I. Introduction

11 C,, Alkaloids 181

111 Sulfur-Containing C,, Alkaloids

IV. Mass Spectrometry.V. Total Synthesis of C,, Nuphar Alkaloids 211

VI. Biosynthesis

213

V



vi CONTENTS

Chapter 4. Celestraceae Alkaloids

ROGERM. SMITH

I. Introduction11. Occurrence and Isolation

111. Structures of Esters of Nicot AcidIV. Structures of Diesters of Substituted Nicotinic Acids

VI. BiosynthesisVII. Biological Properties

References

V. Structures of Related Sesquiterpene

I.11.

111.

IV.V.

VIVII

VIII.

Chapter 5. The Bisbenzylisoquinoline AlkaloidsOccurrence Structure and Pharmacology

M. P. CAVAK. T. BUCK nd K. L. STUART

IntroductionStructure RevisionsNew AlkaloidsKnown Alkaloids from New SourcesMethods and TechniquesPharmacology

Appendix

Bisbenzylisoquinoline Alkal ated by Molecular Wei gh t..

References

Chapter 6. Syntheses of Bisbenzylisoquinoline Alkaloids

MAURICE HAMMAnd VASSILST. GEORGIEV

I. Introduction

11. Dauricine-Type Alkaloids111. Magnolamine-Type AlkaloidsIV. Berbamine Oxyacanthine Type _ _

V . Thalicberine-Type AlkaloidsVI. Trilobine Isotrilobine TypeA

VII. Menisarine-Type AlkaloidsVIII. Tiliacorine-Type Alkaloids

IX. Liensinine-Type Alkaloids

XI. Miscellaneous SynthesesX K Syntheses Using Phenolic Oxidative Coupling

XIII. Synthesis Using Electrolytic OxidationXIV. Use of Pentafluorophenyl Cop

X. Curine-Chondocurine-Type Alkaloids_

215

216

219

227

241

245

246

246

250

251

257

297

297

300

301

304312

319

320

336

341

348

354

357

359

361

363

381

383

387

387

389



CONTENTS vii

Chapter 7. The Hasubanan Alkaloids

YASUONUSUSHInd TOSHIROBUKA

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11. Occurrence and Physical Constants of the Hasubanan

III. Structure Elucidations . . . . . . . . . . . . . . . ... . . .. . . . . .IV. Synthesis of the Hasubanan Skeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

VI.

V. Synthesis of Hasubanan Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . .

Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 8. The Monoterpene Alkaloids

GEOFFREY A. CORDEU

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

II. Isolation and Structure Elucidation of the Monoterpene Alkaloids . . . . . .111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids . . . . . . . . . . .IV. Pharmacology of the Monoterpene Alkaloids . . . . . . . . . . . . . . . .. . . . . . .V. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chapter 9. Alkaloids Unclassified and of Unknown Structure

R. H . F. MANSKE

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

II. Plants and Their Contained Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

393

395

395

414

419

427

428

432

432

470

499

502

502

511

511

551

SUBJECT NDE X. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557



LIST O F CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

K. T. BUCK,Depar tmen t of Chemistry, University of Pennsylvania,Phi ladelphia , Pennsylvania (249)

M. P. CAVA,Depar tmen t of Chemistry, University of Pennsylvania,Philadelphia, Pennsylvania (249)

ROBERT . CLARKE, terling-W inthrop R esearch In sti tu te , Rensselaer,New York (83)

GEOFFREY. CORDELL, epar tm ent of Pharmacognosy an d Pharmacol-ogy, College of Pharm acy , Univers i ty of Illinois at the MedicalCe nter, Chicago, Illinois (431)

VASSILST. GEORGIEV, SV Pharm aceutical Corporation, Tuckahoe,New York (319)

TOSHIROBUKA,epa r tmen t of Pharm aceutical Sciences, Kyoto Uni-

versity , Sakyo-ku Kyoto, Ja p a n (393)YASUONUBUSHI,epa r tmen t of Pha rm aceu tical Sciences, Kyoto U ni-

versity , Sakyo-ku Kyoto, Ja p a n (393)

R. H. F. MANSKE, epar tment of Chemistry, University of Waterloo,Water loo, Ontario , C ana da (511)

DAVIDS. SEIGLER: epa r tmen t of Botany, Th e U niversi ty of Illinois,Urbana, I l l inois (1)

MAURICEHAMMA, epar tm ent of Chem istry , The Pennsylvania State

University , Universi ty P ar k, Pennsylvania (319)ROGERM. SMITH,School of N atu ral Resources, Th e Universi ty of the

So uth Pacific, Su va , Fiji (215)

K. L. STUART, epa r tm ent of Chem istry, University of th e W est Indies,Kingston, Jam aica (249)

JERZY T. W R ~ B E L ,epa r tmen t of Chemistry, University of Warsaw,W arsaw, Poland (181)

* Present address: Calle Peria 3166-9”A,Buenos Aires, Argentina.

ix



PREFACE

The literature dealing with alkaloids shows no obvious signs ofabatement. The classic methods of the organic chemist employed in

structural determinations have evolved into spectral methods, and

chemical reactions are involved largely in confirmatory and peripheral

studies. Inasmuch as the spectral methods have become largelystandardized we incline to limit the details in these volumes.

Many new and already known alkaloids have been isolated from new

and from previously examined sources. Novel syntheses are a promi-

nent feature of recent publications. We attempt to review timely topics

related to alkaloids.

R. H. F. MANSKE

x1



CONTENTS OF PREVIOUS VOLUMES

Contents of V o l u m e ICHAPTER

1

2 . . . . . . . . . . .3. The Pyrrolidine Alkaloids BY LEOMARION. . . . . . . . .4. Senecio Alkaloids BY NEISONJ .LEONARD . . . . . . . . .5. The Pyridine Alkaloids BY LEOMARION . . . . . . . . .6. The Chemistry of the Tropane Alkaloids BY H.L. HOLMES . . . .7. The Strychnos Alkaloids BY H.L. HOLMES . . . . . . . . .

Sources of Alkaloids and Their Isolation BY R.H.F.MANSKE

Alkaloids i n the Plant BY W . 0 JAMES

. . .

8.1.

8.11.

9.10

11

1 2

13

14

15

16

17

18

1920.2 1.

22.23.24.

Contents of V o l u m e 11

The Morphine Alkaloids I BY H .L.HOLMES . . . . . . . .The Morphine Alkaloids BY H . L. HOLMESND (IN PART) GILBERTTORKSinomenine BY H. L. HOLMES . . . . . . . . . . . .Colchicine BY J .W . COOK ND J . D . LOUDON . . . . . . . .Alkaloids of the Amaryllidaceae BY J W . COOK ND J.D . LOUDON. .Acridine Alkaloids BY J.R .PRICE . . . . . . . . . . .The Indole Alkaloids BY LEOMARION . . . . . . . . . .The Erythrina Alkaloids BY LEOMARION . . . . . . . . .The Strychnos Alkaloids .Part 11BY H. L. HOLMES . . . . . .

Contents of V o l u m e III

The Chemistry of the Cinchona Alkaloids BY RICHARD . TURNERND

. . . . . . . . . . . . . . .Quinoline Alkaloids Other than Those of Cinchona BY H .T.OPENSHAW

The Quinazoline Alkaloids BY H.T OPENSHAW . . . . . . .

Lupine Alkaloids BY NELSON.LEONARD . . . . . . . . .The Imidazole Alkaloids BY A.R. BATCERSBYND H.T. OPENSHAW .The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOGND

0 EGER . . . . . . . . . . . . . . . . . .P-Phenethylamines B Y L .RETI . . . . . . . . . . . .Ephreda Bases BY L. RETI . . . . . . . . . . . . .TheIpecac Alkaloids BY MAURICE-MARIEANOT . . . . . .

R. B.WOODWARD

Contents of V o l u m e N

25. . . . . .26. Simple Isoquinoline Alkaloids BY L.RETI . . . . . . . . .

27. Cactus Alkaloids BY L.RETI . . . . . . . . . . . . .28. The Benzylisoquinoline Alkaloids BY ALFRED URGER . . . . .

The Biosynthesis of Isoquinolines BY R. H.F. MANSKE

1

15

91

107

165

271

375

1

161

219

261

331

353

369

499

513

1

65

101

119201

247

313

339

363

17

23

29

xiii



XiV CONTENTS OF PREVIOUS VOLUMES

CHAPTER

29

ASHFORD . . . . . . . . . . . . . . . . . . 7730 . The Aporphine Alkaloids B Y R .H.F.MANSKE . . . . . . . 119

31. The Protopine Alkaloids B Y R. H.F.MANSKE . . . . . . . . 147

32 Phthalideisoquinoline Alkaloids B Y JAROSLAVTANEK AND R. H. FMANSKE . . . . . . . . . . . . . . . . . . 167

34 . The Cularine Alkaloids BY R.H .F .MANSKE . . . . . . . . 249

36. The Erythrophleum Alkaloids BY G DALMA . . . . . . . . 265

The Protoberberine Alkaloids BY R. H. F. MANSKE N D WALTERR.

33. Bisbenzylisoquinoline Alkaloids BY MARSHALLULKA . . . . . 199

35 . a-Naphthaphenanthridine Alkaloids BY R.H.F.MANSKE . . . . 253

37 . The Aconitum and Delphinium Alkaloids BY E . S.STERN . . . . 275

Contents of Volume V

38 .39

40

41.42

43

44

45

46 .47 .48.

1.2.3.4.5.6.7.8.9.

10

11.12

1314

15.16.17.

Narcotics and Analgesics BY HUGOKRUEGER . . . . . . . .Cardioactive Alkaloids BY E.L.MCCAWLEY . . . . . . . .

Respiratory Stimulant s BY MICHAEL.DALLEMAGNE . . . . .

Antimalarials B Y L. H. SCHMIDT . . . . . . . . . . .Uterine Stimulants B Y A. K .REYNOLDS . . . . . . . . .Alkaloids as Local Anesthetics BY THOMAS CARNEY . . . . .Pressor Alkaloids BY K . K. CHEN . . . . . . . . . . .

Mydriatic Alkaloids BY H. R. ING . . . . . . . . . . .Curare-like Effects BY L.E CRAIG . . . . . . . . . . .The Lycopodium Alkaloids BY R .H.F.MANSKE . . . . . . .Minor Alkaloids of Unknown Structure BY R.H. F .MANSKE . . .

Contents of Volume VI

Alkaloids in the Pla nt BY K .MOTHES . . . . . . . . . .

The Pyrrolidine Alkaloids BY LEOMARION. . . . . . . . .

Senecio Alkaloids B Y NELSON LEONARD . . . . . . . . .The Pyridine Alkaloids B Y LEOMARION . . . . . . . . .

The Tropane Alkaloids B Y G.FODOR . . . . . . . . . .

The Strychnos Alkaloids BY J B . HENDRICKSON . . . . . . .The Morphine Alkaloids BY GILBERTTORK . . . . . . . .Colchicine and Related Compounds BY W. C.WILDMAN . . . . .Alkaloids of the Amaryllidaceae B Y W. C.WILDMAN. . . . . .

Contents of Volume V I I

The Indole Alkaloids B Y J .E . SAXTON . . . . . . . . . .

The Erythrina Alkaloids BY V .BOEKELHEIDE

Quinoline Alkaloids Other than Those of Cinchona BY H .T.OPENSHAW

The Quinazoline Alkaloids B Y H. T. OPENSHAW . . . . . . .Lupine Alkaloids B Y NEWON LEONARD . . . . . . . . .Steroid Alkaloids: The Holarrhena Group B Y 0 JEGERND V . PRELOGSteroid Alkaloids: The Solanum Group B Y V .PRELQGND 0 JEGER .

Steroid Alkaloids: Veratrum Group BY 0 JE GE RND V .PRELOG . .

. . . . . . . .

1

79

109

141

163

211

229

243

265

259

301

1

31

35

123

145

179219

247

289

1

201

229

247253

319

343363



CONTENTS OF P R E V IOU S V OL U ME S xv

CHAFTER18. . . . . . . . .

19. . . . . . . . .20. Phthalideisoquinoline Alkaloids BY JAROSLAVTAN~K . . . . .2 1 Bisbenzylisoquinoline Alkaloids BY MARSHALLULKA . . . . .22 . The Diterpenoid Alkaloids from Aconitum, Delphinium, and Garrya

. . . . . . . . . . . . . .23 . The Lycopodium Alkaloids BY R.H.F. MANSKE . . . . . . .24 . Minor Alkaloids of Unknown Structure BY R. H .F MANSKE . . .

The Ipecac Alkaloids B Y R.H .F MANSKE

Isoquinoline Alkaloids BY R. H.F. MANSKE

Species BY E .S STERN

1

2 .3 .4 .5 .6 .7.8 .9 .

10.11.

12.13.

1 4

15.

16.17 .18.

1 9

20 .21 .2 2 .

Contents of V o l u m e V I I I

The Simple Bases BY J .E . SAXTON

Alkaloids of the Calabar Bean B Y E . COXWORTH

The Carboline Alkaloids B Y R.H.F MANSKE . . . . . . . .The Quinazolinocarbolines B Y R.H .F.MANSKE . . . . . . .Alkaloids of Mitragyna and Ourouparia Species B Y J E.SAXTON .Alkaloids of Gelsemium Species BY J .E . SAXTON . . . . . .Alkaloids ofPicralima nitida BY J.E .SAXTON . . . . . . .

Alkaloids ofAlstonia Species BY J .E . SAXTON . . . . . . .

The Chemistry of the 2,2 -Indolylquinuclidine Alkaloids BY W . I. TAYLOR

The Pentaceras and the Eburnamine (HunteriabVicamine Alkaloids

. . . . . . . . . . . . . . . .The Vinca Alkaloids BY W . I. TAYLOR . . . . . . . . . .RauwolfiaAlkaloids with Special Reference to the Chemistry of Reserpine

B Y ESCHLITTLER . . . . . . . . . . . . . .The Alkaloids ofdspidosperma, Diplorrhyncus,Kopsia, Ochrosia, Pleio-

Alkaloids of Calabash Curare andStrychnos Species BY A.R.BATTERSBY

. . . . . . . . . . . . . . .

. . . . . . . . . . .

. . . . . . .

The Zboga and Voacanga Alkaloids B Y W .I .TAYLOR . . . . . .

BY W . I .TAYLOR

c a r p , and Related Genera BY B.GILBERT . . . . . . . .

AND H. F.HODSON

The Alkaloids of Calycanthaceae B Y R.H .F MANSKE . . . . .Strychnos Alkaloids BY G.F SMITH . . . . . . . . . . .Alkaloids ofHaplophyton cimicidum B Y J .E . SAXTON . . . . .

The Alkaloids of Geissospermum Species BY R. H . F MANSKE ND W .ASHLEY ARRISON . . . . . . . . . . . . . . .

Alkaloids ofPsuedocinchona and Yohimbe B Y R .H.F.MANSKE . .The Ergot Alkaloids BY A.STOLLND A. HOFMA" . . . . . .The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR . . . . . .

Contents of V o l u m e I X

1 The Aporphine Alkaloids BY MAURICE HAMMA . . . . . . .2 . . . . . . . . .

3 . Phthalideisoquinoline Alkaloids BY JAROSLAVT A N ~ K . . . . .4 . Bisbenzylisoquinoline and Related Alkaloids BY M. CURCUMELLI-

RODWTAMOND MARSHALLULKA . . . . . . . . . .5 . Lupine Alkaloids B Y FERDINANDOHLMANNND DIETERSCHUMANN6 . Quinoline Alkaloids Other tha n Those of Cinchona BY H.T.OPENSHAW

TheProtoberberine Alkaloids BY P. W .JEFFS

4194 2 3433439

473505509

1

2747555993

119159203238

250272

287

336

515581592673

679694726789

14 1

117

133175223



xvi CONTENTS OF PREVIOUS VOLUMES

CHAPTER7. The Tropane Alkaloids BY G.FODOR . . . . . . . . . .

8. Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V. ERN+AND F.SORM . . . . . . . . . . . . . . . .9. The Steroid Alkaloids: The Salamandra Group BY GERHARDABERMEHL

10 Nuphar Alkaloids BY J .T.WROBEL . . . . . . . . . . .11 The Mesembrine Alkaloids B Y A.POPELAKND G. LETFENBAUER . .12. The Erythrina Alkaloids B Y RICHARD . HILL . . . . . . . .13. Tylophora Alkaloids BY T.R. GOVINDACHARI . . . . . . .14. The Galbul imima Alkaloids BY E.RITCHIE ND W C.TAYLOR . . .15. The Stemona Alkaloids BY 0 .E .EDWARDS . . . . . . . .

1

2.

3.4.5.

6.

7.8.9.

10

11.12.13.14

1.2.3.4.5.6.7.8.

9.

10.11

12.

Contents of Volum e X

Steroid Alkaloids: The Solanun Group BY KLAUS CHRIEBER . .The Steroid Alkaloids: The Veratrum Group BY S .MORRISKUPCHANN D

ARNOLDW.BY . . . . . . . . . . . . . . . .

Erythrophleum Alkaloids B Y ROBERT . MORIN . . . . . . .The Lycopodium Alkaloids BY D.B .MACLEAN . . . . . . .

Alkaloids of the Calabar Bean BY B.ROBINSON . . . . . . .The Benzylisoquinoline Alkaloids B Y VENANCIODEULOFEU, ORGE

. . . . . . . . . .

The Cularine Alkaloids BY R.H.F.MANSKE . . . . . . . .Papaveraceae Alkaloids B Y R. H.F.MANSKE . . . . . . . .a-Naphthaphenanthridine Alkaloids BY R. H.F. MANSKE . . . .The Simple Indole Bases BY J E.SAXTON . . . . . . . .Alkaloids of Picralima nitida BY J .E . SAXTON . . . . . . .Alkaloids of M i t m g y m and Ourouparia Species BY J . E. SAXTON . .Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE

The Taxus Alkaloids BY B. LYTHGOE . . . . . . . . . .

COMIN. ND MARCELO.VERNENGO

Contents of Vo lum e XIThe Distribution of Indole Alkaloids in Plants BY V.SNIECKUS

The Ajmaline-Sarpagine Alkaloids BY W . I.TAYLORThe 2,2 -Indolylquinuclidine Alkaloids BY W . I TAYLORThe Iboga and Voacanga Alkaloids BY W . I.TAYLORThe Vinca Alkaloids BY W.I.TAYLORThe Eburnamine-Vincamine Alkaloids BY W. I.TAYLORYohimbirw and Related Alkaloids BY H . J . MONTEIROAlkaloids of Calabash Curare and Strychnos Species BY A. R. BATTERSBY

. . . . . . . . . . . . . . .

The Alkaloids of Aspidosperma, Ochrosia, Pleiocarpa, Melodinus, and. . . . . . . . . . .

The Amaryllidaceae Alkaloids BY W . C.WILDMAN . . . . . .Colchicine and Related Compounds BY W .C WILDMANND B.A.PURSEY

The Pyridine Alkaloids BY W . A.AYER ND T. E. HABGOOD . . .

. . .

. . . . . .. . . . .

. . . . . .. . . . . . . . . .

. . . . .

. . . . .

ANDHF.HODSON

Related Genera BY B. GILBERT

269

305

427

441

467

483

517

529

545

1

193

287

306

383

402

463467

485

491

501

521

545

597

I

41

73

79

99

125

145

189

205

307

407

459



CONTENTS OF PREVIOUS VOLUMES xvii

Contents of Volume XI1

CHAFTER

The Diterpene Alkaloids: General Introduction B Y S. W. PELLETIERND

L. H. KEITH . . . . . . . . . . . . . . . . . .1. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species:

The C,,-Diterpene Alkaloids BY S. W. PELLETIERND L. H. KEITH2. Diterpene Alkaloids from Aconitum, Delphinium, and Garrya Species:

The Go-DiterpeneAlkaloids BY S. W. PELLETIERND L. H. KEITH3. Alkaloids ofA l s t on i a Species BY J. E. SAXTON . . . . . . .4. Senecio Alkaloids BY FRANK. WARREN . . . . . . . . .5. Papaveraceae Alkaloids B Y F. SANTAVY . . . . . . . . .6. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE

7. The Forensic Chemistry of Alkaloids B YE.G. C. CLARKE . . . .

Contents of Volume XI I I

1. The Morphine Alkaloids B Y K. W. BENTLEY . . . . . . . .2. The Spirobenzylisoquinoline Alkaloids BY MAURICE HAMMA . . .3. The Ipecac Alkaloids BY A. BROSSI,S. TEITEL, ND G. V. PARRY . .4. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . .

5. The Galbulirnima Alkaloids BY E. RITCHIEAND W. C. TAYLOR . . .6. The Carbazole Alkaloids BY R. S. KAPIL . . . . . . . . .7. Bisbenylisoquinoline and Related Alkaloids B Y M. CURCUMELLI-RODC+

8. The Tropane Alkaloids BY G. FODOR . . . . . . . . . .9. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE

STAMO . . . . . . . . . . . . . . . . . . .

2.

3.

4.

5.

6.

7.

8.9.

10.

11.

12.

Contents of Volume X NSteroid Alkaloids: The Veratrum and B w u s Groups BY J. TOMKOND

2. VOTICKP . . . . . . . . . . . . . . . . .Oxindole Alkaloids BY JASJIT. BINDRA . . . . . . . . .Alkaloids of M i t r a g y m and Related Genera BY J. E. SAXTON . . .Alkaloids ofP i c r a l i m a and Alstonia Species BY J . E. SAXTON . . .The Cinchona Alkaloids BY M. R. USKOKOVICND G. GRETHE . . .The Oxoaporphine Alkaloids BY MAURICEHAMMAND R. L. CASTENSONPhenethylisoquinoline Alkaloids B Y TETSUJI KAMETANI ND MASUO

KOIZUMI . . . . . . . . . . . . . . . . . .

Elaeocarpus Alkaloids BY S. R. JOHNSND J. A. LAMBERTON . . .The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . . .TheCancentrine Alkaloids BY RUSSELLRODRIGO . . . . . .The Securinega Alkaloids BY V . SNIECKUS . . . . . . . .Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE

xv

2

136

207

246

333

455

514

1

165

189

213

227273

303

351

397

1

83

123

157

181

225

265

325347

407

425507



xviii CONTENTS OF PREVIOUS VOLUMES

Contents of V o lu m e X V

CHAPTER

1 . The Ergot Alkaloids BY P. A. STADLERND P . SWTZ . . . . . . 1

2.

MASAHIRATA . . . . . . . . . . . . . . . . 41

3. The Amaryllidaceae A l k a l o i d s ~ ~IAUDIOFUGANTI . . . . . 83

4. The Cyclopeptide Alkaloids BY R. TSCHESCHEND E. U. KAUBMANN 1655. The Pharmacology and Toxicology of the Papaveraceae Alkaloids

B Y V . PREININCER . . . . . . . . . . . . . . . 207

6. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE 263

The Daphniphyllum Alkaloids BY SHOSUKE AMAMURAND YOGHI-



-CHAPTER 1-

PLANT SYSTEMATICS A N D ALKALOIDS

DAVIDS. SEICILER

T h e University of I ~ ~ i n o i s

Urbana, Illinois

I. Introduction ........................................................A. What Is Plan t Systematics ? .......................................B. Major Goals of Plant Systematics ..................................

11. Da ta t o Be Utilized .................................................A. Relationship of Chemical Da ta to Botanical Data ....................B. Rationale for Using Chemical Data.. ...............................C. Botanical and Chemical Literature .................................D. Documentation of Pl an t Materials. . . . . . . . . .

111. Application of the Data to Biological Problems .A. N ature and Sources of Variation in Plants. ..B. Basic Pathways of Alkaloid Biosynthesis ....

IV. Alkaloids in Lower Vascular Plants and Gymnos

V. Alkaloids in the Angiosperms .........................................A. Introduction .....................................................B. The Magnoliopsida (Dicotyledonous Plants) ..........................

ida (Monocotyledonous Plants) .................................................................................

1

22

3

3

3

6

7

8

8

14

20

22

24

65

73

22

I. Introduction

Many scientists, both chemical and biological, have sought t o corre-late chemical characters (i.e., the presence of certain types of compounds)

with various botanical entities. I n the past, several factors have limited

the success of such efforts, and it is only in recent years that such

correlations have been applied to many plant groups. My purpose in

this article is to review several of these earlier attempts as well as to

examine current thinking in this area of endeavor. Several new ideas

concerning the placement of selected plant groups within taxonomic

systems will be discussed, and in addition, certain enigmatic problems

that as yet cannot be clearly resolved will be posed as subjects forfuture investigation. As background to these discussions, I will first

describe the nature and goals of plant systematics to provide the reader

with the necessary perspective to understand the needs of that science.



1. PLANT SYSTEMATICS 3

plant taxa , (b) provide an inventory of plant taxa via local, regional,

and continental floras, and (c) provide a classification scheme that

at tempts to express natural or phylogenetic relationships and to providean understanding of evolutionary processes and relationships ( 5 ) . n the

subsequent parts of this chapter, I will present and discuss ways in

which chemical data and in particular alkaloid chemical data can be

utilized in meeting these goals.

11. Data to Be Utilized

A. RELATIONSHIPF CHEMICAL ATA O BOTANICALATA

As both morphological and chemical features are determined by

genetics, the structure of a molecule must be as much a character as

any other (7) . Further , all the “characters” of a plant must be related

and self-consistent. Thus, it is scarcely surprising that new cytological,

numerical, and chemical data have provided valuable complementary

information about the placement of groups within the taxonomic

system rather than upsetting the results of extensive morphological

investigations. How did these two types of characters arise and how do

they differ Z

In the course of evolution the fate of any change in the genetic

material of an organism will in large part depend on the function of the

products produced. For example, changes in respiratory proteins, such

as cytochromes, are unlikely t o survive, whereas changes in t he enzymes

that produce alkaloids or other secondary metabolic products are more

likely to persist. The evolution of morphological and chemical features

of an organism must be interrelated, but significantly, the forces of

natural selection do not have the same effect on each type of genetic

expression. These differences in selection are very important from a

systematic standpoint because evolution of chemical constituents

differs from morphological evolution, making the examination of both

morphological and chemical characters an extremely valuable approach

to the study of evolutionary problems (8).Because the structure of any

compound is determined by a series of biosynthetic steps, each of which

is under differing selective forces, not only may the structure of the

compound itself be useful, but the biochemical pathway by which it has

arisen may be of systematic significance.

B. RATIONALEOR USING HEMICALDATA

The two major groups of compounds that have been applied to

t,axonomic problems involve basically different approaches and appear



4 DAVID S . SEIGLER

to be useful in different manners. To date, these applications involve

niacromolecules (in particular proteins) and micromolecules (mostly

secondary metabolic compounds such as terpenes, flavonoids, alkaloids,cyanogenic and other glycosides, amino acids, and lipids of various

When one utilizes macromolecules, he is examining the primary

products of plant DNA and changes in amino acids within the protein

reflect changes in the base sequence of the DNA. Initial studies of

protein sequencing, especially those studies involving cytochrome C,

indicate that th is dat a provides valuable information about phylogeny

and relationships a t the higher taxonomic categorical levels (families,

orders, classes). Cytochrome c, which occurs in both animals and plants,has been sequenced in several species of animals (9).The fossil record

for animals generally confirms information derived from these phylogen-

etic studies. The number of similarities in amino acids in particular

positions in cytochrome c molecules from different animals makes itstatistically improbable that they could have arisen from more than a

single ancestral type with an ancestral cytochrorne c molecule. By

tracing the differences in amino acid substitutions it is possible to

relate various groups of animals, as successive groups after a modifica-

tion carry the changed cytochrome c molecule.In plants, especially flowering plants, there is no extensive fossil

record and much of the current knowledge of relationships and phy-

logeny in this group is based on extrapolation of studies of morphological

data. To date, relatively few plant cytochromes have been studied, but

in the few that have been investigated, it is apparent from the number

of similarities of amino acid sequences that plant and animal G Y ~ O -

chromes are related. It is also evident that the sequences of amino

acids in genera of the same family me more similar to each other than

to those of other families and that families thought to be closely

related by morphological evidence generally resemble each other more

closely than less related families. The evolutionary history of plant

groups, as well as of animals, appears to be recorded in this and other

proteins.

Much recent work has established that micromolecular chemical

data can also provide valuable insight into evolutionary processes ( 8 ) .

Chemical studies of secondary products have proved useful in resolving

many problems of specification and evolution but in contrast t o protein

sequencing data have generally been applied to the study of lowertaxonomic categories, i.e., problems at the species and genus level

(10,1 1 ) . However, as will be pointed out, they may also be of value a t

higher taxonomic levels.

To understand how secondary compounds can be useful for the study

types).



6 DAVID S. SEIGLER

lipid compounds for surface coatings as long as the necessary physical

properties are met ; but at tractants for specific pollinators or diterpenes

with hormonal activities must be precisely synthesized (7 ) . Many plantproducts arise by simple processes such as removal of activating groups

(as phosphate or coenzyme A ) or from oxidations, reductions, or

methylations of easily modified groups (7) . In some cases the relative

amounts of products produced may simply reflect the rates of two

enzymes operating on a common precursor. Highly probable reactions,

such as the introduction of an hydroxyl group orthoor para to an existing

one in a phenol, occur frequently in nature. These types of changes

are usually of only minor importance in considering the taxonomic

significance of secondary compounds.

Other reaction sequences are reversible or are controlled by feedback

inhibition controls such that when a given compound disappears it

disappears without a trace or causes accumulation of a compound far

removed in the sequence. For example, polyketide chains, probably as

coenzyme A esters, are rapidly reversible to their initial units unless

some chemically irreversible stage is reached such as reduction or

cyclization (7) . In the fungus Penicillium islandicum which produces

polyketide anthraquinones, mutation simply leads to the complete

absence of these compounds.

We have limited knowledge as to what pathways may be available in

advanced plant groups as we can only see the products of those path-

ways that the plant utilizes a t a particular time. Several lines of work

suggest that many plants are capable of carrying out complex reactions

or reaction series but lack precursors or particular enzymes under

normal situations. For example, when plants of Nicotiana are fed

thebaine and certain other precursors of morphine they are able to

perform several biosynthetic steps and produce morphine (14) hich is

not known to occur naturally in the genus. Interestingly, this conversion

cannot be made by some species of Papaver, although other species of

the genus contain thebaine and morphine.

In assessing the importance of a particular change as an evolutionary

step i t is necessary to decide on the probability of its occurrence.As a

general rule, the more difficult the reactions and the less available the

building blocks or the more reaction steps required in a definite sequence

to give rise to a compound, the rarer will be its convergent formation

C . BOTANICALND CHEMICALLITERATURE

Many earlier publications were based on mass collections of materials,

often gathered from large geographical areas and/or of uncertain origin.

(14).



1. PLAXT SYSTEMATICS 7

Frequently, only the major constituents-those that were poisonous,

crystallized readily, or had other easily detectable properties-were

examined. These facts must be considered by those who intend to applythe information to a taxonomic problem. Another difficulty in utilizing

chemical data from the literature is a lack of reliability of certain

structure determinations and in particular the identification of plant

products by such physical properties as gas-liquid chromatography

retention time, paper and thin-layer chromatography R, values, color

reactions, and spot tests. Misidentification of compounds by wet

chemical methods is not uncommon in the older literature before

advanced spectral methods became available and must always be

considered.One of the most serious problems in utilizing literature data is that

almost no chemical reports are supported by adequately vouchered

plant materials. Proper vouchering records would make it possible to

examine the original materials and allow comparison with other

collections in order to ascertain whether (a) the material was correctly

identified and (b) certain phenomena, such as hybridization, intro-

gression, or subspecific variations exist. It would also permit subsequent

workers to determine the presence of fungi, lichens, algae, insects, etc.,

that may be involved in the production of certain secondary compounds.

If a small portion of the actual materials utilized for the research is also

preserved, it would permit later analysis for foreign contaminants.

I n other cases, careful perusal of the botanical literature will reveal

that taxonomists have placed taxa of various rank incorrectly. These

incorrect placements may range from questionable or aberrant species

in a genus to the realignment of entire orders of plants. Chemical data

can assist in resolving problems of this type, but they sometimes provide

enigmatic results until sufficient information is available to allow a

reassignment of the taxa involved.

One must look carefully and critically a t all reported data t o be sure

both chemical and botanical portions of the work have been done and

interpreted correctly before applying the data to a problem under

investigation.

D. DOCUMENTATIONF PLANT ATERIALS

As mentioned in the preceding section, many early reports of alka-

loids and other secondary compounds are suspect because accurate

techniques required for assignment of complex structures were notavailable. Nonetheless, the major problem in using these data for

systematic studies is not the reliability of the chemicaldata but the

identity of the plant materials th at were examined ( 1 5 ) .



1 . PLANT SYSTEMATICS 9

conclusions based on a meager amount of data in comparison to what

was actually needed. Recent combined chemical and morphological

investigations have used this information more fully and proved that,instead of being troublesome, the study of chemical and morphological

variation actually provides a key to the solution of many problems ofbiological speciation, hybridization, and introgression.*

Relationship between plant taxa is established by “ ummarizing”

the similarities between groups of organisms and contrasting their

differences. We consider two plants to be closely related if they have

many common characters and only distantly so (orat higher categorical

levels) if the differences outweigh the similarities. In contrast to this,

the name of the game in evolution is change and the ability to maintainvariability. Few natural populations are without measurable variation;

that is, plants from interbreeding groups that share a gene pool have

phenotypic and genotypic differences that can be seen even by inexperi-

enced observers. How do these variations arise and how are they

maintained

Each individual plant must possess the ability to respond to its

environment, but this variation must remain within the limits set by the

genetic makeup of the taxon ( 1 2 , 1‘7). Thus, phenotypic expression is

determined by both genotypic composition and reaction to a specific

environment. Some characters are little changed by environment--e.g.,

leaf arrangement or floral structure-and these have been considered

“good characters” or to be “genetically fixed.” Other characters are

known to vary radically and are said to be “phenotypically plastic.”

Examples of characters of this type are leaf shape, stem height, and time

of flowering. The effects of environment are superimposed on and may

obscure genotypic variability; further, it is the phenotype produced by

both that is is exposed to the pressures of natural selection. Davis and

Heywood ( 1 7 ) have listed a number of important physical factors in

determining the appearance of a plant in nature. Among these are light,

seasonal variation, elevational differences, terrestrial versus epiphytic

state, photoperiodism, temperature, temperature periodic effects,

water (heterophylly), wind, soil (e.g., halophytes), and biotic factors

such as fungal and bacterial infection, ant habitation, galls, grazing

and browsing, fire, and trampling.

The population is considered by many to be the basic evolutionary

* Introgression is the process by which the genes of one taxon are mixed with thegenes of another by hybridization of the two taxa followed by backcrossing of th e

hybrid plants with either of the two parents. Even when hybrids are not significant in

relative numbers, they can allow gene flow and mixing, producing increased variability

of the two paren tal types.



1. PLANT SYSTEMATICS 1 1

entiate into a series of populations that may have gradually accrued

differences (clinal variation) or stepwise variations associated with

ecological differences (ecotypic variation) ( 1 7 ) .If the differences between populations increases sufficiently, and

especially if reproductive barriers arise, these differentiating populations

may be recognized as species. Stebbins ( 1 2 ) considers four major

factors in speciation: (a) mutation, (b ) genetic recombination, (c)

natural selection, and (d) isolation. In small, often peripheral popula-

tions, chance may play a greater role in speciation because the proba-

bility of loss of a particular character is greater; recessive genes are

more likely to appear and become homozygous, and the genetic nature

of the population may be determined by the “founders” or “survivors”of a period of catastrophic selection. These phenomena explain many of

the variational patterns observed in the distribution and occurrence

of secondary plant compounds, especially at the lower taxonomic

ranks, and although they have mostly been examined by means of

morphological characters, much evidence suggests that evolution and

speciation may be studied or measured by chemical characters as well.

In the preceding discussion, variation of morphological characters has

been considered. There is no reason to think that variation in chemical

characters has not occurred and is not maintained in a similar manner.

I n contrast to morphological features, however, th e specific structures

an d steps of biosynthetic pathways are easier to quantify and generally

simpler in terms of genetic control (at least in principle).

Secondary compounds are affected by environmental as well as

genetic factors (18 , 19). In a study of alkaloids of the genus Baptisia

(Leguminosae), Cranmer studied the variation of lupine alkaloids

during the development of individual plants in different populations of

Baptisia leucophaea Nutt. ( 2 0 ) . Individual plants in each population

exhibited considerable quantitative variation, while plants from different

populations were similar at similar stages of development. However,

there was striking variation in the specific alkaloids produced, the

relative amounts of each, and in the total quantity of alkaloids present

a t any given time in development. Nowacki encountered similar

variation in lupine alkaloids in the genus Lup inus ( 2 1 ) .

A number of workers have examined the genetics of alkaloid produc-

tion by the study of hybrid plants (1 4 , 21 -25 ) . These results indicate

that the genetic mechanisms that control alkaloid synthesis are complex

and that hybridization and introgression can produce significant

variations in the alkaloid content of plants within a population. Many

past workers have been unaware of natural hybridization and, because

these plants are occasionally indistinguishable f r om the parental species,



12 DAVID S. SEIGLER

have not been able to interpret th e alkaloid patterns observed ( 1 4 , 15).

Hybridization and introgression in the genus Baptis ia has been ex-

tensively studied by workers a t the University of Texas. Several pop-ulations that contained all possible hybrid combinations, plants

derived from back-crossing these plants with the parental plants, and

the parental plants were examined. The status of these plants was

established by independent methods; subsequently the alkaloid

chemistry was examined. The dat a indicated that the hybrid plants not

only failed to exhibit the alkaloid chemistry of the parent species either

singly or combined, but also showed some striking quantitative

variation among individual hybrid plants. Mabry concludes that this

variation is extremely useful and represents one of the best availabletechniques for detecting and documenting natural hybridization and

introgression ( 2 6 ) .Extensive variation can occur in the different parts of an individual

plant ( 2 7 ) .Changes associated with the reproductive parts of a plant

are often striking; these organs also exhibit the greatest amount of

morphological change during a plant’s growth and development.

Cranmer and co-workers ( 2 0 , 28) observed that in Baptis ia species

alkaloids often showed greater variation between organs of plants from

a single species than between the same organs for different species. Thetotal yield of alkaloids from different organs was also shown to vary

significantly. The most thoroughly investigated plants in this regard

are medicinally important ones such as Papaver somniferum L. and

solanaceous plants of the genera Nicot iana, Atropa , H yoscyamus, and

D a t u m ( 2 7 ) .

At the present time our lack of knowledge of the specific enzymology

of the synthesis of secondary metabolites prevents direct comparison of

many of the pathways involved in various taxa. Examination and

comparisons must frequently be restricted to those systems ascertained

to be related by other reasoning, such as a knowledge of the structures

of other compounds derived from and part of the biosynthetic pathways

in the same and related species of plants.

Secondary compounds have classically been viewed as waste or

excretion products ( l a ) , ut a body of information is accumulating that

suggests that many have important coevolutionary defensive and

attractive roles (29-31) as well as primary metabolic importance

(32-34) . The forces of natural selection seldom operate on a single

organism but on a total biological system. This is undoubtedly onereason convergence in the evolution of both morphological and chemical

characters is observed.

It is well known, for example, that certain habitats are occupied by




plants that possess similar morphological features (12 , 27, 35-38). It

has not been definitely established, but i t appears that various chemical

components of plants can be seiected to produce convergence of chemi-cal types. One example that confirms this possibility is that Am m oden-dron conollyi Bge., a legume native to Central Asia, contains the

alkaloids ammodendrine (1) nd sparteine (2),and another plant from

C O C H ,

1

that area, Anabasis aphylla L. , a member of the Chenopodiaceae,

contains similar alkaloids such as lupinine (3),phyllin (a),and anabasin

( 5 ) . n the legume, cadaverine (and hence lysine) serves as a precursor

3

0

4 5

for both types, whereas in Anabas i s , the quinolizidine alkaloids are

formed as in legumes but anabasine is derived from nicotinic acid as in

Nicot iana. Thus, what might appear to be a close similarity is in reality

an analogous route to the same compounds ( 1 4 ) .

In another example, three species of the genus Hymenoxys (Com-

positae), H . scuposa (DC.) K. F. Parker, H . acaulis (Pursh) K. F.Parker, and H . ives ianu (Greene) K. F. Parker, contain more than

thirty flavonoids. The patterns of distribution of these compounds are

correlated more strongly with population positions along an east-west

gradient extending from Arizona to Texas than with the diagnostic

morphological features of the species. The biochemical parallelism

observed for populations of different species in the same region suggests

the action of common selective forces (39).It has been observed that

small, isolated island populations of mainland taxa usually have fewer

and simpler compounds than their mainland ancestors. This may be

because of lowered selection by predation or because island habitats

have different environmental requirements ( 3 5 ) .



14 DAVID S. SEIQLER

B. BASICPATHWAYSF ALKALOIDIOSYNTHESIS

In the preceding section we have surveyed some of the ways inwhich variation originates and is maintained in plants. A knowledge

of these variations is extremely important in systematic studies at the

lower taxonomic levels (genus-species), but when one wishes to establish

relationships at higher ranks, e.g., at the family, order, and subclass

level, it is necessary to survey as many taxa and individuals as possible

to reduce the effects of these variations. That is, we need to know what

morphological features are produced and what biosynthetic pathways

exist in a particular group of taxa to compare them. This is made more

difficult by our imperfect knowledge of biosynthetic pathways, but, bycareful observation of their products, we can establish certain relation-

ships. In this chapter we will mostly consider the application of

alkaloids to systematic problems. Other secondary compound data can

prove equally usable and should also be considered in a complete study

of the relationship of systematics and secondary compounds. I have

necessarily addressed those problems for which alkaloid data appear to

be most helpful or promising and have not pursued certain relationships

that may be more clearly established by other chemical and mor-

phological data.In this section I will survey some of the fundamental and widespread

pathways of alkaloid biosynthesis. Studies of many of these compounds

have proven useful a t lower taxonomic ranks but, due to the widespread

appearance and presumably simple biosynthetic origin, are not as

valuable for delineating the higher categorical levels, although in a few

cases compounds that appear to be very simple are observed to have

limited distributions.

The simplest alkaloids are several amines derived from common

amino acids such as phenylalanine, tyrosine, histidine, tryptophan,lysine, ornithine, and anthranilic acid. Alkaloids containing simple

aromatic moieties and some of their simply derived relations have been

reviewed (40-46) . These simple amines arise by decarboxylation of the

corresponding amino acids, often with subsequent methylation,

hydroxylation, and addition of other groups. They are widely distrib-

uted, and their presence is usually not of taxonomic significance at the

higher taxonomic ranks. These compounds are important because they

are frequently beginning points for the synthesis of more complex

alkaloids.Phenylalanine gives rise to phenylethylamine (6) and the corre-

sponding methylated compound (7), hile tyrosine produces the corre-

sponding compounds tyramine (8) and N-methyltyrosine (9). In the

Gramineae tyramine is converted to hordenine (lo),which is widespread




in 1

6 7 8

is family ,ut not restricted to it . Tyrosine is also converteL to two

other important intermediate compounds, dihydroxyphenylalanine

(DOPA) (11) and its cyclic derivative, cycloDOPA (12). These com-pounds are especially common as intermediates in the synthesis of

alkaloids of the benzylisoquinoline and betalaine types as well as

alkaloids widely distributed in the Cactaceae ( 4 7 ,48) (see Section V, B).

In the Rutaceae many of these simple aromatic compounds are con-

verted to the corresponding amides, such as fagaramide (13) from

10 11

12 13

Fagara xanthoxyloides Lam. Although most gymnosperms do not

contain distinctive alkaloids (with the notable exception of the Taxa-

ceae and Cephalotaxaceae), the genus Ephedra (Ephedraceae), a group

only distantly related to more common gymnosperms, contains

methylated phenylethylamines such as 1-ephedrine (14) and d-pseudo-

ephedrine (15),which are also characteristic of this group of plants but

not restricted to it (49-52) .

CH3ICH3I

I IHC-NHCH,CNHCH,

HCOH HO-C-H

8 014 15



16 DAVID S. SEIGLER

The simple aliphatic compounds putrescine and cadaverine, derived

from ornithine and lysine, respectively, are intermediates in the syn-

thesis of many major groups of alkaloids and presumably occur in manyplant groups but are seldom isolated and studied. Ornithine (or its

successor N-methylputresine) gives rise to N-methylpyrrolidine via the

reactions below (53).

CHa-NH, CHaNHCH3 CHaNHCH3

I I ICHa CHa CHa

ICHa

I

CHNH,I

COaH

__f

-con- H,HS

CH,-NH,HNH,

COaH

CHaNHCH3

A similar reaction series can produce the corresponding piperidinehomolog from lysine. These compounds are easily alkylated by a

number of compounds, for example, p-ketobutyric acid, to produce

simple alkaloids such as hygrine (16) of the pyrrolidine type (43-55) .

In a similar manner attack on an N-methylpiperidium cation yields

16

N-methylisopelletierine, an intermediate in the formation of charac-

teristic alkaloids in the Punicaceae, Lythraceae, and Lycopodiaceae.

Simple pyrrolidine and piperidine alkaloids are widespread among

higher plants. Both groups may serve as substrates for additional

alkylation reactions either internally to yield alkaloids such as tropine

(17) and pseudopelletierine (18) or intermolecularly to yield more

complex alkaloids. Pyrrolidine alkaloids are widespread, no doubt areflection of the relatively small number of biosynthetic steps and

chemical probability of their synthesis, but they are characteristically

proliferated in a few families, such as the Solanaceae and Erythroxy-




laceae and less commonly in others such as the Euphorbiaceae and

Convolvulaceae and doubtfully in the Dioscoreaceae (49-52, 56, 5 7 ) .

Alkaloids of the piperidine type are more widely distributed. Manysimply derived ones are found in the Crassulaceae, Punicaceae, and the

Leguminosae, but they are also found in the Pinaceae, Euphorbiaceae,

Chenopodiaceae, Equisetaceae, Piperaceae, Caricaceae, and Palmae.

17 18

Alkylation by phenylpyruvic acid may occur to produce other

alkaloids characteristic of the Crassulaceae, such as sedamine (19) ( 5 3 )and lobeline (20), found in the genus Lobelia of the Campanulaceae.

Nicotinic acid may also alkylate the pyrrolidinium cation to produce

compounds such as nicotine (21), one of the most widely distributed of

all alkaloids ( 43 , 50, 58). Many related compounds are found in the

Solanaceae, especially in the genus Nicotiana. Anabasine (5) arises inNicotiana by alkylation of the lysine-derived piperidinium cation.

Coniine (22), the principal alkaloid of C o n i u m (Umbelliferae), closely

20

0

22



18 DAVID S . SEIGLER

resembles intermediates in the synthesis of the isopelletierine alkaloids

but has been demonstrated to be derived via a polyketide pathway

(5 3 ,59) from acetate precursors. This is a clear example of convergencein the types of compounds produced and it demonstrates why a knowl-

edge of biosynthetic pathways is valuable in studies of phylogeny.

Coniine has been reported from several other families ( 5 0 ) . t would be

especially interesting to determine the path of synthesis in each of these.

Simple derivatives of tryptophan are also widely distributed in

nature. Some, such as serotonin (23) and bufotenine (24), involve

subsequent oxygenation. N,N-Dimethyltryptamine (25) and psilocybin

(26) are widely known for their hallucinogenic properties. These com-

pounds are more restricted in distribution than 23 and 24; 25 is

7H3

23 24

0 -

IHO-P=O

25 26

found in several families (50-52) , but 26 appears to be limited to fungi.Tryptamine and its derivatives serve as intermediates for many groups

of alkaloids and by inference must occur in numerous plant taxa .

Another group derived from tryptamine is the /?-carboline alkaloids,

Q - + . L O Z H -Q- ,2--H

' NH

CH30O T J/ N

H H

27




which occur in many plant families such as the Passifloraceae, Sym-

plocaceae, Zygophyllaceae, Eleagnaceae, Malphigiaceae, Euphor-

biaceae, and Loganiaceae. Many families which contain alkaloids of the/3-carboline type are otherwise devoid of alkaloids.

Histamine (28)is widespread in higher plants, but only a few alkaloids

derived from the parent amino acid histidine, such as pilocarpine (29))

are known otherwise. Alkaloids of this type are mostly restricted to the

Rutaceae (Casimiroa and Pilocarpus) and certain groups of fungi.

28 29

Dimerization of intermediate compounds from ornithine and sub-

sequent cyclization can

alkaloids ( 5 3 ) . Further

lead to the basic skeleton of the pyrrolizidine

elaboration of basic pyrrolizidine structures

Ornithine + utrescino

HCO'

involves the type of oxidative process noted previously in relation to

the biosynthesis of pyrrolidine and piperidine alkaloids. Pyrrolizidine

alkaloids are usually esterified with mono or dibasic acids, many ofwhich are unique to this series, e.g., heliosupine (30) and senecionine

(31) 49-52, 60-64). Alkaloids of this type are found in several families

CH3

H3C'foHHO--CCHOH--CHB

I

I

H

c=o

30 31



20 DAVID S. SEIGLER

bu t are characteristic of t he Boraginaceae (several genera), the Com-

positae (tribe Senecioneae), and the Leguminosae (Crotalaria) 49-52,

Similar reactions with cadaverine, derived from lysine, produce lupin

alkaloids such as lupinine (3). In this instance the corresponding

aldehyde may condense with another molecule of piperidine to yield

more complex compounds such as lamprobine (32), parteine (Z), and

matrine (33).Alkaloids of this type are best known from certain genera

of the Leguminosae (28 , 49-52, 65 ).

60-64).

32 33

In this section several fundamental pathways of alkaloids biosyn-

thesis have been examined. We will make frequent reference to thesein the subsequent examination of a number of specific taxonomic

problems because all have been observed to occur in many higher

taxonomic groups.

IV. Alkaloids in Lower Vascular Plants and Gymnosperms

Alkaloids are rarely found in lower plant groups. Algae, bryophytes,

and ferns seldom contain compounds of this type. Among the lowervascular plants there are two notable exceptions; one is the genus

Lycopodium, which contains complex alkaloids such as lycopodine (34)

derived from lysine by means of precursors similar to those involved in

the formation of pelletierine alkaloids in the Punicaceae (49-52, 66-69).

The other exception is the genus Equisetum, which contains several

alkaloids, such as palustrine (35). Nicotine (21) is also reported from

Equisetum species. Although alkaloids are relatively uncommon among

gymnosperms, simple compounds such as pinidine (36)are found in the

Pinaceae and closely related families. The biosynthesis of compoundsof this type has been previously outlined (Section 111, B).

The Taxaceae (Taxales) ( 7 0 ) and Cephalotaxaceae (Cephalotaxales)

( 7 2 , 7 2 , 7 2 a ) contain alkaloids such as taxine (37), hich is possibly




34

of diterpine origin, and deoxyharringtonine (38),which are restricted to

their respective families (and orders). The homoerythrina alkaloids of

the Cephalotaxaceae are otherwise known only from the families

Aquifoliaceae and Liliaceae ( 7 3 , 7 4 ) . Both groups of alkaloids have

antitumor activity and are extremely toxic.

nu 0 16 H

3 1

OCH,

R = CH CH-CHa-CH2C(OH)4H2COpMe

Ico;

- ~

CH3

38

The presence of complex alkaloids in the Taxaceae and Cephalo-

taxaceae supports the separation of these orders from other gymno-sperms. This separation has been suggested by several workers on both

paleobotanical and morphological grounds (75-77) .

Although the fungi represent a distinct evolutionary line and are



2 2 DAVID S . SEIGLER

probably as distant from plants as they are from animals in evolutionary

terms I ) , hey do possess several interesting types of alkaloids. Many

ofthese compounds, such as psilocybin 26),which is found mostlyin the genera Psilocybe and Stropharia, are derived from simple amines

which are also widespread in higher plants. Muscarine 40) is a hallu-

cinogenic choline analog found in the fly mushroom, Amanita muscaria.

Others, such as gliotoxin 39) from Trichoderma viride, are more

CH,OH

39 40

complex in structure. Many nitrogen-containing compounds from

Fungi imperfect i , especially the genera Pen icill ium , Streptomyces, and

Aspergillus have pronounced antibiotic activity; these have been

reviewed elsewhere 49, 50, 78-80 . Indole alkaloids of the ergot type

are found in Claviceps and also in t'he angiospermous plant family

Convolvulaceae (Section V, B).

V. Alkaloids in the Angiosperms

A. INTRODUCTION

Among the Angiosperms (flowering plants), Cronquist recognizes six

subclasses of dicotyledonous and four subclasses of monocotyledonous

plants 6) .Alkaloids are scarcely known from some of these, whereas in

others they are common. Among the subclasses of Magnoliopsida

(dicots) he Hamamelidae and Dilleniidae have few alkaloids-primarily

simple bases and 8-carboline types t hat occur in many plant groups.

Benzylisoquinoline alkaloids are characteristic of many orders of the

subclasses Magnoliidae, although some tryptophan-derived bases are

found in a small number of families which do not contain alkaloids of

the benzylisoquinoline type. Diterpene alkaloids are found in several

genera of the Ranunculaceae.

The Caryophyllidae contain alkaloids derived from tyrosine and the

corresponding dihydroxyphenylalanine D O P A ) . Both simple types




and betalain pigments occur and their presence is characteristic

of many families of the order.

The situation is more complex in the subclass Rosidae, where families

of some orders synthesize alkaloids and others do not. Those that

produce significant numbers and types of alkaloids are the Rosales

(Leguminosae and Crassulaceae), Myrtales (Lythraceae, Punicaceae),

Proteales (Eleagnaceae), Cornales (Garryaceae, Alangiaceae), Euphor-

biales (Buxaceae, Euphorbiaceae, Daphniphyllaceae, and Pandaceae),

Celastrales (Celastraceae), Rhamnales (Rhamnaceae), Sapindales (Rut-

acae and Peganum of the Zygophyllaceae), Linales (Erythroxylaceae),

and Umbellales (Conium of the Umbelliferae). There is little unity

among the types of alkaloids produced by this group of plants.

The extremely large and diverse family Leguminosae produces many

types of alkaloids, among them are pyrrolizidine (Crotalaria) physo-

stigmine (Physostigma), quinolizidine (several genera), Erythrina

types (Erythrina),and Ormosia types (Ormosia).

The Lythraceae produce an interesting type of quinolizidine alkaloids

not known from other plants; the Punicaceae produce alkaloids similar

to the better known tropane types; and the Garryaceae produce

diterpene alkaloids, otherwise found principally in the Ranunculaceae.

The Buxaceae contain alkaloids derived from triterpene skeletons.

Euphorbiaceae is an extremely diverse family in terms of alkaloid

types; in this regard, it is only rivalled by the Leguminosae and Ruta-

ceae. Benzylisoquinoline, indole(?), emetine( ? ), securinine, nicotine,

polypeptide, Alchornea alkaloids, tropane, p-carboline, and simple

bases are all known to occur within the family. The Daphniphyllaceae

contain diterpene alkaloids of a unique type only known from this

small family. The Pandaceae, Rhamnaceae, and Celastraceae contain

alkaloids with attached polypeptide units.

In the subclass Asteridae, many orders produce alkaloids. Among

these are the Gentianales, Polemoniales (Solanaceae and Convolvula-

ceae) Lamiales (Boraginaceae), Campanulales (Campanulaceae), Rubi-

ales (Rubiaceae) and Asterales (Compositae). The Gentianales and

Rubiales are noted for prolific production of indole alkaloids and less for

others of the tylophorine, monoterpene, and quinine type. The

Solanaceae are known for the production of steroidal, tropane, and

nicotine types, whereas a related family, the Convolvulaceae, produces

both tropane and ergot alkaloids. The Boraginaceae and the tribe Sen-

ecioneae of the Compositae and Crotalaria, a genus of legumes, produce

highly toxic alkaloids of the pyrrolizidine type. The genus Lobelia of

the Campanulaceae synthesizes alkaloids of an unusual type restricted

to that genus.



24 DAVID S. SEIGLER

B. THEMAGNOLIOPSIDADICOTYLEDONOUSLANTS)

1 . IntroductionThe presence and phylogenetic significance of more advanced

alkaloid groups in the various subclasses and orders of dicotyledonous

plants (Magnoliopsida,sensu Cronquist) will now be examined. As the

simple alkaloids previously discussed (Section 111, B) are of lesser

significance from a systematic view, their presence will only be men-

tioned when appropriate, and numerous records of these compounds,

which may be useful a t the lower categorical levels, will be omitted.

The Caryophyllidae are probably the most primitive group and will

be examined first, followed by the Magnoliidae and Rutaceae. The

Hamamelidae, which do not contain alkaloids of complex structure, are

omitted, as are all families of the Rosidae except for the few that

contain alkaloids, i.e., the Leguminosae, Euphorbiaceae, Daphniphyl-

laceae, and Erythroxylaceae. Following this, a number of alkaloid

types based on terpenoid structures will be examined. Most of these

occur in families of the Asteridae, the most advanced subclass according

to Cronquist, although some orders, such as the Cornales (sensu

Cronquist), and a number of families of the Rosales possess the same

iridoid compounds and certain of their alkaloidal derivatives. Members

of the Nympheaceae (Magnoliidae,Sensu Cronquist) have sesquiterpene

type alkaloids. The Garryaceae (Cornales, subclass Rosidae) and the

genera Delphinum and Aconi tum (Ranunculales, subclass Magnoliidae)

as well as a few other isolated groups contain alkaloids based on a

diterpene structure. The Apocynaceae (Holarrhena), the Buxaceae

(Euphorbiales, subclass Rosidae), the Solanaceae, and many Liliaceous

plants (of the Liliopsida) contain alkaloids based on steroidal and

triterpenoid structures. Alkaloids based on tryptophan and mono-

terpene-iridoid structures and their distribution mostly in the families

Apocynaceae, Loganiaceae, and Rubiaceae (all subclass Asteridae)

will be reviewed.

The relationship of alkaloid chemistry and systematics in several

families of the Asteridae is then examined, e.g., the Solanaceae and the

Convolvulaceae. The distribution of ergot alkaloids in the latter family

and the fungal genus Claviceps is discussed.

2.The CaryophyllidaeThe subclass Caryophyllidae is recognized by Cronquist as having

4 orders, 14 families, and about 11,000 species. Of these orders, the

Polygonales, Plumbaginales, and Batales are largely without alkaloids




although harman, tetrahydroharman, and harmanine have been

reported from a species of Calligonum of the Polygonaceae (50).

In contrast, alkaloids are widespread in most families of the Caryo-phyllales. They have been reported from the Aizoaceae (2500 species),

Amaranthaceae (900 species), Basellaceae (20 species), Cactaceae

(2000 species), Chenopodiaceae (1500 species), Didieraceae (9 species),

Nyctaginaceae (300 species), Phytolaccaceae (150 species), and Portu-

laceae (500 species), but not from Caryophyllaceae (2000 species) and

Molluginaceae (100 species). Because of the considerable controversy

concerning the relationship of chemistry to the classification of this

order, it has been studied more extensively than many others.

Saponins are widely distributed through the order. They have been

reported from the Aizoaceae, Molluginaceae, Amaranthaceae, Basel-

laceae, Cactaceae, Caryophyllaceae, Nyctaginaceae, and Phytolac-

caceae. Many of these are based on triterpene aglycone skeletons

(78 , 81).

Some species of the Chenopodiaceae contain a number of simple

alkaloids derived from phenylalanine, tyrosine, tryptophane, ornithine,

and lysine. Alkaloids derived from tyrosine are of particular interest

because they are related to both benzylisoquinoline alkaloid precursors

and precursors of the betalain pigments which are widespread in the

order (37, 4 4 , 5 8 ) .Salsolin (41) is an example of an alkaloid of this type.

Several relatively simple piperidine derivatives are found, as well as the

41

alkaloid anabasine (5), which in this instance is structurally but notbiosyntheticalIy related to nicotine. Lupinine (3) and other quinolizidine

alkaloids are found in Anabasis aphylla.

Alkaloids with structures similar to those derived from tyrosine

above are widely distributed in Caetaceae ( 43 , 49-52, 78, 81). One of

these, mescaline (42), is widely known for its hallucinogenic properties.

Others such as anhalidine (43) and anhalonidine (44) show similarity to

OCH, OH

42 43 44



26 DAVID S. SEIGLER

certain precursors of benzylisoquinoline alkaloids. Other, more complex,

alkaloids involving mevalonate units such as lophocerine (45) and

dimerization of simple alkaloid units occur.

45

The genus Mesembryanthemum and related genera of the Aizoaceae

contain alkaloids such as mesembrine (46), which are also derived from

tyrosine ( 8 2 ) .

CH,46

The most widespread alkaloids of the order, however, are betalain

pigments derived from L-DOPA (83).These red or yellow compounds

have ultraviolet absorptions in the same ranges as anthocyanins and

probably serve much the same function in plants of the Caryophyllales.

The occurrence of the two classes of compounds is mutually exclusive;

no known plant in a betalain-containing family has ever been shown to

contain anthocyanins and vice versa (26 , 83-87) . The families Caryo-

phyllaceae and Molluginaceae contain anthocyanins, a fact that has

been used to suggest that they should be segregated into a closely-related but distinct order ( 8 7 ) . The red-violet pigment of beets is

betanin (47) whereas the related yellow pigment from the cactus

$ C0.HHO

47 48




SCHEME

Opuntia f icus- indica Mill. is indicaxanthin (48). The first of these

compounds arises via Scheme 1. Once formed, betanin may be converted

to other compounds via routes similar to those shown in Scheme 2.

Based on both chemical and morphological evidence, Mabry considers

that the Centrospermae families (the Caryophyllales without the

Caryophyllaceae and Molluginaceae) were derived from a common an-

cestral line from some precursor of the angiosperms and that this major

48

SCHEME




little can be said of the value of chemical characters for establishing

their taxonomic position. Among these are the Amborellaceae (1

species), Austrobaileyaceae (2 species), Canellaceae ( 16-20 species),Degneriaceae ( 1 species), Schisandraceae (47 species), Trimeniaceae

(7-1 5 species), and Winteraceae (95-120 species). When one compares

the numbers of species in the remaining families, it is evident that at

least several species of the larger families have been examined-

Annonaceae (2100 species), Calycanthaceae (9 species), Eupomatiaceae

(2 species), Hernandiaceae (50-65 species), Himantandraceae (2-3

species), Illiciaceae (42 species), Lauraceae (2000-2500 species),

Magnoliaceae (215-230 species), and Monimiaceae (450 species).

Members of the orders Piperales and Aristolochiales also havespecialized oil cells, but in contrast to the Magnoliales are mostly

herbaceous plants. The families of the small order Piperales, the

Saururaceae (5-7 species), Piperaceae (1490-3000 species) (Cronquist

accepts about 1500), and the Chloranthaceae (65-70 species) are

generally low in alkaloid content but rich in compounds derived from

phenylalanine or tyrosine metabolism via cinnamic acid and its

relatives.

The Aristolochiales, which consist of one family, the Aristolocbiaceae

(600 species), are rich in compounds derived from the metabolism of

cinnamic acid, p-coumaric acid, and their relatives but also contain

many alkaloids.

The Nympheales are aquatic plants that do not possess the oil

glands typical of the three previously described orders. Some workers

have considered the Nelumbonaceae to be sufficiently distinct so as to

comprise a separate order, usually called the Nelumbonales ( 6 ) .

Cronquist separates the Nelumbonaceae ( 2 species) from the Nym-

pheaceae (65-93 species) (but retains both in his order Nympheales),

largely on a basis of morphological characters, and the chemistry of

these two groups has not been investigated with the exception of their

alkaloids. The Ceratophyllaceae (4-1 0 species) has been little studied

chemically.

The Ranunculales also lack ethereal oil glands and most speciesof the

order belong to three large families-the Ranunculaceae, Berberidaceae,

and Menispermaceae. I n morphological features they are generally

more advanced than the Magnoliales and are probably derived from

them (6 ) .

Chemical constituents from the three large families Ranunculaceae

(800-2000 species), Berberidaceae (600-650 species), and Menisperm-

aceae (350-425 species) have been studied extensively, but the remain-

ing families of the order have been little examined. These are the




intermediate in the biosynthesis of several more highly modified series

of compounds is widely distributed and is known to occur in the

Anonaceae, Hernandiaceae, Lauraceae, Monimiaceae, and Papa-veraceae as well as the non-Magnoliidean family Rhamnaceae (49-52).

Aporphine alkaloids [e.g., glaucine (53) nd bulbocapnine (54)] have

essentially the same distribution as simple benzylisoquinoline types

(49-52) and arise by ortho-para coupling of compounds such as

laudanosoline ( 5 2 ) (5 3 , 9 4 , 99-101) or where ortho-para coupling is not

possible via the intermediacy of proaporphine compounds such as

orientalinone ( 5 5 ) in the biosynthesis of isothebaine (56) in Papaverorientale L. ( 5 3 , 9 3 , 1 0 2 ) .Aporphine alkaloids are known to occur in the

CH,O

CH,O CH3

CH,O HO

OCH, O H

53 5 1 54

cH30O

56



32 DAVID S. SEIGLER

Berberidaceae, Ranunculaceae, Fumariaceae, Aristolochiaceae, Magno-

liaceae, Lauraceae, Hernandiaceae, Monimiaceae, Menispermaceae,

Nelumbonaceae, Papaveraceae, Symplocaceae, Euphorbiaceae, Ruta -ceae, and the Rhamnaceae.

Morphine alkaloids, such as morphine (57), also arise by ortho-para

coupling of compounds such as 1-reticuline(58) in the family Papaver-

aeeae ( 5 3 , 9 3 , 9 4 , 1 0 3 - 1 0 8 ) .Certain intermediates in this pathway occur

in other families, for example, salutaridine (59) in Croton salutaris

Casar of the Euphorbiaceae.

OH

58

57

In Cryptocarya bowiei (Hook.) Druce, an Australian member of the

family Lauraceae, benzylisoquinoline precursors yield compounds with

closure to the isoquinoline nitrogen such as cryptaustoline (60) ( 5 3 , 1 0 9 ) .In the family Papaveraceae, various species of the genera Argemone

and Eschscholtzia synthesize alkaloids from benzylisoquinoline pre-

HO

60

0

59




cursors with another type of closure. Representatives of these are

Z-eschscholtzine (61)and Z-munitagine (62) (53 , 93 , 94 , 96 , 110 ) . In the

closely related Fumariaceae, closure occurs to include an oxygen atomring of cularine (63) (48 , 93 , 9 4 , 10 3 ) .

?H

61 62

,OCH,

63

The genus Cocculus of the Menispermaceae synthesizes alkaloids of

the Erythrina type. Alkaloids of this type are known to arise in the

genus Erythrina (Leguminosae) by complex rearrangements of benzyl-

isoquinoline alkaloids such as N-norprotosinomenine (53 , 93 , 94 , 111-

115) .

The N-methyl carbon atom of several benzylisoquinoline alkaloids is

known to participate in formation of a berberine bridge" n compounds

such as berberine (64) 1 1 6 , 1 1 7 ) .Although protoberberine alkaloids are

known to occur in several families (Anonaceae, Ranunculaceae?Aristolochiaceae, Magnoliaceae, and Menispermaceae), they are

characteristic of the genus Berberis (Berberidaceae) and of the genera

Corydalis and Dicentra of the Fumariaceae (49-52) . Stylopine (65) n the



34 DAVID S. SEIGLER

65 66

latter two genera is converted to protopine (66) 118).The benzophenan-

thridine skeleton encountered in a number of alkaloids of the Papaver-

aceae is also derived from benzylisoquinoline precursors ( 4 8 , 9 3 , 9 4 ) .

Chelidonine (67) s an example of this type of alkaloid.

Phthalideisoquinoline alkaloids, e.g., narcotine (68), are also found

in the Papaveraceae and Fumariaceae with occasional occurrences

in the Berberidaceae and Ranunculaceae (49 , 53 , 93 , 94 , 119) .Coupling of benzylisoquinoline units occurs in a n intermolecular as

well as in an intramolecular fashion ( 5 3 , 9 3 , 9 4 , 1 2 0 , 1 2 1 ) . he individual

components are usually linked by one or two diphenyl ether bridges.

< S O:%’ CH,o

H

0 OCH,

67 68

The distribution of compounds of this type is essentially the same as for

the simple benzylisoquinoline units and aporphine alkaloids; they are

found in the Menispermaceae, Lauraceae, Magnoliaceae, Monimiaceae,

Hernandiaceae, Nelumbonaceae, Aristolochiaceae, and Ranunculaceae,

with a questionable record from the Buxaceae (49-52) .

Aristolochic acid (69) occurs in the Aristolochiaceae and is often

accompanied by aporphine alkaloids. Feeding studies have demon-

strated that this naturally occurring nitro compound is probably

derived from orientalinol (70) ( 9 4 ) . Further, noradrenaline is incor-porated into aristolochic acid with good incorporation rates, suggesting

that 4-hydroxynorlaudanosoline is a precursor and tha t the 4-hydroxyl

group is required for oxidation of the heterocyclic ring.




70 69

Many botanists agree that the orders of the Magnoliidae according to

Cronquist are related and derived from common ancestors. This con-clusion is largely based on morphological evidence, and chemical

evidence is considered supplemental, although in the subclass only the

order Piperales and the order Nympheales (if one removes the Nelum-

bonaceae) lack either the simple benzylisoquinoline alkaloids or their

more highly evolved derivatives. The Piperales are closely linked to

other orders by the presence of many phenylpropanoid and terpenoid

compounds as well as morphological features. The Nelumbonaceae are

linked by the presence of benzylisoquinoline alkaloids to other orders of

the subclass, but the other families of this order, especially the Nym-pheaceae, do not possess compounds of this type but rather alkaloids

with a sesquiterpene skeleton. Because of the presence of ellagic acid

and the absence of benzylisoquinoline alkaloids, Bate-Smith believes

that the family Nymphaeaceae is completely out of place in this

subclass ( 1 2 2 ) ,a view shared by some other workers (89-91). Pathways

leading to benzylisoquinoline alkaloids are found in many (but not all)

families of the remaining orders. Within these orders the presence of

these types of alkaloids is observed because the plants that contain

them descended from common ancestors and not because the pathwayshave evolved numerous times.

The families Magnoliaceae, Annonaceae, Eupomatiaceae, Monimi-

aceae, Lauraceae, and Hernandiaceae of the Magnoliales contain

benzylisoquinoline alkaloids. The families Himantandraceae, Myristic-

aceae, and Calycanthaceae contain alkaloids of other types, 71,26, and

72, respectively, and do not contain benzylisoquinoline alkaloids. At

least one species of the Winteraceae contains alkaloids of an undeter-

termined type (1 2 3 ) ,whereas species of the Degeneraceae, Austrobailey-

aceae, and Trimeniaceae have been tested and found not to containalkaloids (78, 1234. The Lactoridaceae, Canellaceae, Illiciaceae,

Schisandraceae, Amborrelaceae, and Gomortegaceae have apparently

not been tested. The families Ranunculaceae, Berberidaceae, and



36 DAVID S. SEIQLER

Menispermaceae contain benzylisoquinoline alkaloids, while members of

the Lardizabalaceae (123u, 123b), Corynocarpaceae (123a), and the

Coriariaceae ( 1 2 3 ~ - 1 2 3 c ) ave been tested and found not to containalkaloids. The Sabiaceae and Circaeasteraceae have apparently not been

tested. The families Aristolochiaceae (Aristolochiales) and the Papaver-

aceae and Fumariaceae (Papaverales) all contain benzylisoquinoline

alkaloids as previously mentioned.

8HC

< N 4 &

71 72

Other lines of reasoning demand that certain families with othertypes of alkaloids [the Myristicaceae, Calycanthaceae (1 2 4 ) , and

Himantandraceae] must be accorded a place in the Magnoliales, but if

so, what is their status Have they lost the ability to synthesize

benzylisoquinoline alkaloids and taken on the ability to synthesize

others ? Or are they derived from non-benzylisoquinoline alkaloid

synthesizing ancestors ? Similar questions may be asked about those

families with no alkaloids, i.e., the Degeneriaceae and Trimeniaceae of

the Magnoliales; the Lardizabalaceae, Coriariaceae, and Coryno-

carpaceae of the Ranunculales; the entire order Piperales; and theNympheales exclu Nelumbonaceae.

The complexity of structures derived from simple benzylisoquinoline

skeleta is generally in accord with the origin of the orders as proposed

by Cronquist. The simpler types of alkaloids are found in families of the

Magnoliales and more highly derived compounds are found in the

Aristolochiales on one hand and in families of the Ranunculales and

Papaverales on the other (125) .Certain genera and species within each of the above groups lack

alkaloids. These should probably be interpreted as cases where muta-tions or metabolic changes have produced blocks to particular lines of

biosynthesis. It is also possible that, for some unknown reason, other

biosynthetic lines have been favored and the machinery needed to make




benzylisoquinoline alkaloids sits unused. Examples of this are the genus

Aniba of the Lauraceae, which appears to utilize the precursors that

most Lauraceous plants convert into alkaloids to make compounds suchas 6-styryl-2-pyrones, cinnamides, and neolignans; many species of the

Piperaceae; certain species of Asarum of the Aristolochiaceae; and

Podophyllum of the Berberidaceae (125) .The distribution and taxonomic significance of benzylisoquinoline

alkaloids within several families of the subclass have been reviewed.

The distribution of alkaloids in the Lauraceae has been studied by

Gottlieb (126) .The family was subdivided into two subfamilies by

Kostermans (127) . n the subfamily Lauroideae, the tribe Perseae seems

capable of synthesizing only the most primitive types-those withthe benzyltetrahydroisoquinoline skeleton. In contrast, the tribe

Cryptocaryeae can make numerous alkaloids, e.g., aporphines, 1-(w -

aminoethyl)phenanthrenes, benzylisoquinolines, bibenzpyrrocolin, and

pavine types, as well as pleurospermine (73) and compounds similar to

tylophorine (74). The other two tribes, the Cinnamomeae and Litseae,

are in an intermediate position. The other subfamily, the Cossythoideae,

OCH,

73

OCH,

74

consisting mainly of vines, is clearly different as it contains oxyapor-phines and a morphine type alkaloid. The chemistry and distributions

of phenylpropanoid derivatives, which seem to supplant the alkaloids

in certain taxa, is discussed in detail in that work (125, 126) . The

treatment of Kostermans is largely upheld by data of alkaloid, phenyl-

propanoid, terpene, flavonoid, and other chemical origin.

The distribution and systematic significance of alkaloids in the

Menispermaceae has been recently reviewed (128) .The alkaloids of this

family are closely related to those of the Berberidaceae, Papaveraceae,

Annonaceae, Rutaceae, and Ranunculaceae both in the type and range ofalkaloids in agreement with Cronquist’s placement of this family. The

family contains several unique types, such as the hasubanan skeleton

(75) (which have the opposite configuration to t hat found in morphine



38 DAVID S. SEIGLER

types) and others of the Erythrina type such as dihydroerysodine (76)

that are otherwise known only from the Leguminosae.

In contrast to the findings of Gottlieb in the Lauraceae, there is notsuch clear-cut correlation between the occurrence of specific alkaloid

types and the subfamilies of the Menispermaceae [as proposed by

Engler ( 1 2 9 ) ] , lthough the hasubanan, morphine, Erythrina, and novel

bases are only found in tribes of the subfamily Menispermeae.

CH30 / \CH3 -

0 CH30 ‘OH

75 76

There has been considerable debate in the past about the placement

of the Papaverales in this subclass. This argument has largely been

resolved by means of morphological characters, although the chemistryof this order closely resembles that of the Magnoliidae and especially

the Ranunculales from which Cronquist supposes them to be derived

(5 -7 ) . These alkaloids range from simple bases to some of the most

complex structures derived from the benzylisoquinoline skeleton. Some

of these (e.g., the protopines) are found in both the Papaveraceae and

Fumariaceae, whereas other types are found only in the Fumariaceae

(e.g., cularine, ochotensine, and sendaverine alkaloids) or only in the

Papaveraceae (e.g., the papaverrubrin, pavine, isopavine, and ben-

zophenanthridine types). Cronquist does not feel that the Papaver-aceae and Fumariaceae are clearly distinct on purely morphological

grounds, but the differences in chemistry strongly suggest that they are

distinct a t the familial level ( 6 6 , 8 1 ) .Probably no other genus has been examined for the presence of

alkaloids as extensively as Pupawer (Papaveraceae) (110) comprehen-

sive reviews (108 , 130, 131) have surveyed the results of alkaloid

determinations in many species. Morphologically distinct seetions of the

genus also have distinct alkaloid chemistry (110). In another genus,

Argemone, subgeneric groupings are less distinct and chemistry does notclearly resolve them ( 1 1 0 ) .This evidence does suggest that Argemone is

derived from ancestors that had pavine-type alkaloids.

The variation of alkaloids at the specific and subspecific or infra-




specific levels in plants of this group has been reviewed extensively

because of their medicinal importance (14 , 37 , 78 , 81 , 107 , 110) . The

effects of many environmental and genetic factors surveyed in SectionI11 are reviewed by TBt6nyi (110 ) .Within individual species quantities

of alkaloids may be modified drastically by environmental factors but

normally not the types produced. Many of these variations must be

accounted for if one wishes to utilize alkaloid chemical data to study

problems a t the specificor subspecific levels in the Papaveraceae.

4 . The Rutaceae

The Rutaceae is one of the more interesting and complex familieswith regard t o alkaloid chemistry as well as the formation of flavonoids;

mono-, sesqui-, and triterpenes; furocoumarins; and other secondary

compounds ( 7 8 , 8 1 ) . The family contains alkaloids based on several

major biosynthetic pathways, such as benzylisoquinoline (tyrosine),

quinoline ( 1 3 2 ) , furoquinoline ( 1 3 3 ) ,quinazoline (134 ) , acridine (135)

(anthranilic acid), imidazole (histidine), ndoloquinazoline (tryptophan),

and both simple aliphatic and aromatic amines (5 3 , 93 , 136-138) .

Quinoline and furoquinoline alkaloids are especially widespread within

the family, being found in four of the five subfamilies from whichalkaloids have been reported ( 1 3 6 ) .Neither the furoquinoline, acridine,

or indoloquinazoline alkaloids, which are derivatives of anthranilic

acid, have been reported from sources other than this family ( 7 8 , 8 1 ) .

Most reports of quinoline alkaloids are also from the Rutaceae. Benzyl-

isoquinoline alkaloids occur widely in the Magnoliidae (Section V , B)

and also in the Rhamnaceae, Euphorbiaceae, and Celastraceae.

Engler (129) divided the Rutaceae into seven subfamilies-the

Rutoidae, Dictyolomatoideae, Spathelioideae, Toddalioideae, Auran-

tioideae, Flindersioideae, and Rhabdodendroidae. Willis ( 1 3 9 )felt thatthe groups that make up the Rutaceae differ to the extent that some

could be regarded as independent families. Airy-Shaw ( 1 4 0 )and Prance

( 1 4 1 ) recognized the Rhabdodendroideae as a close relative of the

Phytolaccaceae; little, if any, chemical work has been done on this

group. The Flindersioideae and Spathelioideae have been elevated to

familial level and the former taxon placed in a position intermediate

between the Rutaceae and the Zygophyllaceae ( 1 4 2 ) , but recent

evidence ( 1 3 7 , 1 43 , l 4 4 ) , largely based on alkaloid structures, sug-

gests that both the Flindersioideae and the Spathelioideae should bemaintained in the Rutaceae. Moore in Hegnauer (145 ) contended that

the Rutoideae is a highly complex subfamily phylogenetically and that

the present classification of the Rutaceae is one which runs directly<



40 DAVID 5. SEIOLER

0 OCH, OCH,

qH,O JCH,

CH3 \

Acronycine Skimmianine

(an acridine alkaloid) (a furoquinoline alkaloid)

Casimiroine Arborine

(a quinoline alkaloid) (a quinazoline alkaloid)

CH,OQyq6 Or$N / /

OCH3\

(an indoloquinazoline alkaloid)

Hortiacine 5-Methoxyoanthin-6-one

(a canthinone alkaloid)

f

Pilocarpine

(an imidazole alkaloid)

across the lines of specialization in floral anatomy." Waterman, in

agreement with Moore's work, states that Engler's classification of both

major subfamilies Rutoideae and Toddalioideae is untenable and

proposes a new scheme of classification (1 3 7 ) .Support for the view that the Rutaceae isa distinct and homogeneous

group is provided by its essential oils and coumarins. Essential oils and

coumarins are found in at least four subfamilies. This view is also




confirmed by alkaloid chemical data: (a) furoquinoline alkaloids are

essentially ubiquitous in the family and acridones are also widespread;

(b) magnoflorine (77) and berberine (a),wo of the most commonalkaloids in the Ranunculales and the Magnoliales, occur in species of

Rutaceae along with the chelerythrine (78),which is characteristic of

the Papaveraceae.

CH,O

HO

OCH,CH,O

77 78

O Y O C H ,

OCH,

79 80

Alkaloids of the benzylisoquinoline type are mostly found in the

genera Zanthoxylum (including Fa ga ra ), Phellodendron, and Toddalia.

These three genera, which Engler placed in the Rutoideae-Zanthoxyleae,

Toddalioideae-Phellodendrinae, nd Toddalioideae-Toddaliinae, espec-

tively, are closely related with an apparent phylogenetic link betweenToddalia and Zanthoxylum (1 3 7 ) . In the Boronieae (Rutoideae), only

furoquinolines are produced, whereas in the Diosmeae (Rutoideae) none

are found. In the Ruteae (Rutoideae)no less than five types of alkaloids

are common to the three major genera.

Alkaloids of the 1-benzyltetrahydroisoquinolineype are assumed to

be primitive in the Rutaceae and thus the genera producing them are

the most primitive extant genera of the family ( 7 8 , 8 9 - 9 1 ) .As anthran-

ilate-derived alkaloids are found in the same genera, i t appears that the

evolutionary trend was for direct replacement of one type with another

( 1 3 7 ) . The genera of the Rutaceae that do not have l-benzyltetra-

hydroisoquinoline alkaloids, e.g., the Diosmeae, Boronieae (Rutoideae),

and Aurantioideae, must be relatively advanced.




possessed the necessary pathways t o synthesize alkaloids but failed to

express them and later in ancestral Rutaceous stock they became

turned on once more. As previously mentioned, Cronquist (6)and otherphylogenists (6, 6 9 , 142, 147) generally place the family in the Sapin-

dales or in similar groupings, such as the Rutales ( sensuTaktajan). Few

of the plants of these orders possess alkaloids of the appropriate type,

nor do most members of the Rosales, hypothetical ancestors of the

order. At this point we must either accept possibilities (b)or (c) above,

or look for other possible ancestors. Several other workers ( 7 8 , 89-91,

145) have postulated that the origins of the Rutaceae lie in the Mag-

noliidae, near the Ranunculales or Papaverales ( 1 4 5 ) . While this

appears unlikely to many i t should be noted th at this decision has beenreached by several investigators (88, 148) on strictly morphological

grounds.

5. The Leguminosae

The family Leguminosae,as defined by Cronquist, is a member of the

Rosidae and one of the largest plant families with about 13,000 species.

Takhtajan, Stebbins, and Hutchinson considered the group to be

sufficiently distinct to comprise a separate order ( 1 2 , 6 9 , 1 4 2 ) .The threesubfamilies that make up the family, the Mimosoideae, Caesalpinoideae,

and Lotoidae, have all been elevated to familial ranks by various

authors. Most investigators have seen a fairly close relationship between

the Leguminosae and Rosaceae.

The family has many interesting secondary plant compounds, but

none that characterize the family as a whole nor any that establish a

close relationship to the Rosaceae. The alkaloids of this large plant

family have recently been reviewed by Mears and Mabry ( 1 5 ) .These

compounds are widespread throughout the former but are largelymissing from the latter family.

Simple amines derived from phenyalanine, tyrosine, and tryptophan

are widespread throughout the Leguminosae but are most commonly

found in the subfamily Mimosoideae. Derivatives of the preceding

amino acids occur in the genus Acacia and are also found as oxygenated

and methylated derivatives, e.g., candicine (82), phenylethylamine,

tyramine, and tryptamine in the genera Desmodium and Lespedeza.

Physostigmine (83),a representative of an unusual type of alkaloid

with great pharmacognostic value, is isolated from Physostigmavenenosum Baifour, the Calabar Bean (15 , 149, 150) .

Quinolizidine alkaloids are widespread in certain tribes of the

subfamily Lotoideae, among which are the Genistae, Podalyrieae, and




a7

these alkaloids. The Boraginaceae and the tribe Senecioneae of the

Compositae also contain pyrrolizidine alkaloids.

The biogenesis of Erythrina alkaloids has been reviewed (111-115).These alkaloids are derived from benzylisoquinoline alkaloids by

complex rearrangements (53, 93, 94) and are known only to occur in

the genus Erythrina and in certain genera of the Menispermaceae.

The presence of sphaerocarpine (88) in Ammodendron has led Mears

and Mabry (15) o suggest that this genus should be relocated with the

CH,O O W N H

--CH,Oq

H O

H O

C H 3 09--H 3 0 O H

CH,OqOH




genera Genista and Adenocarpus, which have long been considered

related and both produce similar alkaloids.

Four of the 15-20 species of Erythrophleum have been reported tocontain alkaloids such as cassamine (89), representing one of the rare

reports of alkaloids from the Caesalpinoidae (151 , 152) .

88 89

The alkaloids of the three subfamilies are derived from distinct

biosynthetic pathways with the exception of certain simple amines

which are widely distributed but primarily found in the subfamily

Mimosoideae. Thus, alkaloid chemical data (and other chemical da ta

such as the distribution of canavanine and certain nonmetabolic amino

acids) support the separation of these three groups. Alkaloid datais less informative with respect to the identification of possible ancestors

of any of the three subfamilies but it is interesting in this regard th at

~ r ~ t h r i n alkaloids occur in the genus ~ r ~ ~ h r i n and also in certain

members of the Menispermaceae and that many of the quinolizidine

alkaloids found in the subfamily Lotoideae also occur in the Berberid-

aceae, Ranunculaceae, Papaveraceae, and Monimiaceae (all of the

Magnoliidae) and only rarely in other sources (145 , 153) . Many of these

records are in need of reexamination, as several of them are based on

unvouchered plant materials and older chemical work. Further, thepresence of numerous alkaloids derived from benzylisoquinoline path-

ways in the same plants suggests problems in identification of smaller

amounts of cooccurring quinolizidine alkaloids. A few previous in-

vestigators (89-91) have considered the possibility that the Legum-

inosae are derived from a ranunculalean-berberidalean line on a

basis of both chemical and morphological lines of evidence.

Recent work by Boulter has shown that the amino acid sequence in

cytochrome c from Phaseolus aureus Roxb. (Leguminosae, Lotoideae)

and Nigella damascena L. (Ranunculaceae) are closely related (88).Alkaloid chemistry has been useful within the Leguminosae for the

investigation of many problems a t the generic, specific, and infraspecific

levels. Several of these have been reviewed by Mears and Mabry ( 1 5 , 2 2 ) .




6. The Euphorbiales

Cronquist ( 6 ) considers the family Euphorbiaceae (with about 7500

species) to be a member of the Euphorbiales, subclass Rosidae. The

family is extraordinarily diverse in terms of both morphological and

chemical characters and is of considerable economic importance. Qther

workers have a t times placed the family in different orders. The Buxa-

ceae (60 species), Daphniphyllaceae (35 species), and Aextoxicaceae

(1 species), three other families of the order, were not considered closely

allied to the Euphorbiaceae by Webster ( 1 5 4 ) , while the Pandaceae

( 3 5 species) was thought to be related.

Although the Euphorbiaceae contains many types of secondary plant

compounds few of these are so widespread as to characterize the family.

The principal exceptions are esters of phorbol(90) and other diterpenes

which are found in genera belonging to several parts of the Euphorbi-

aceae as well as the Thymeliaceae [which Thorne places in his Euphorbi-

ales, see Thorne (1 4 6 ) l (155-158). These compounds are apparently

responsible for the irritating properties well known for members of this

family.

90

R, = long, R, = short chain fatty acid

The alkaloids of the Euphorbiaceae have been reviewed by Hegnauer

( 1 5 3 ) . Among these are compounds of the securinega type, such as

securinine (91), which are widely distributed in two related genera,

Securinega and Phyllanthus. It has recently been demonstrated that

91



48 DAVID 9. SEIQLER

these compounds are derived from L-tyrosine in a unique manner (159)in which tyrosine provides carbon atoms 6-13 of the securinine skeleton.

The genera Hymenocaridia and Julocroton contain alkaloids, 92 and 93,respectively, that are based on polypeptide structures (153, 160) . The

genus Croton contains several benzylisoquinoline alkaloids, mostly of

NHC-CH(CH3)aII0

93

HN-H--CH(CH,),

II I0 NH-G-CH-N(CH3)S

II I0 CH(CH3)(Ca&)

92

the proaporphine type such as crotonsine (94). The genera Ric inus and

Trewia contain two unusual alkaloids derived from nicotinic acid,

ricinine (95) and nudiflorine (W),espectively. Alchorneine (97),

alchorneinone (98),and other similar alkaloids have been isolated from

AlchorneaJloribunda (1 6 1 ) .These alkaloids appear to be of an imidazole

OCH,I

HO

CH3F NcrJoI ICH3

95

CH,

96

94

O Me

,OMe

97




type. d-(3R, 6R -3a-acetoxy-6/3-hydroxytropane,-2a-benzoyloxy-3/3-

hydroxynortropane, and tropacocaine have been isolated from Peripen-

tadenia mearsii (C. T. White) L. S. Smith (162) .M,-Methyltetrahydro-harman has recently been isolated from Spathiostemon javensis Blume

(=Homoroia riparia Lour.) and represents the first harman alkaloid

from this family ( 1 6 3 ) .A number of other alkaloid records in this family are questionable and

should be reexamined. Among these are the presence of phyllalbine (a

tropane type) in Phyllanthus discoideus Muell. Arg., 4-hydroxyhygrinic

acid in Croton gabouga S. Moore, an ester of vasicine in Croton draco

Schlecht., a bisbenzylisoquinoline alkaloid from Croton turumiquirensis

Steyerm., yohimbine from Alchornea jloribunda Muell. Arg., andphysostigmine from Hippomane mancinella L. [original references given

in Hegnauer ( 1 5 3 ) ] . Vouchering of plant materials is especially

important in this group of plants, many of which are notoriously

difficult to identify. Excluding these reports, the alkaloids of the

Euphorbiaceae coincide reasonably well with the various subfamilial

taxa although a large number of types are represented. Screening

studies suggest that the Euphorbiaceae is still a source of unstudied

alkaloids (123-123c, 1 6 3 ~ ) .

The small family Pandaceae has recently been found to containalkaloids such as 99, which closely resemble that of Hymenocaridia

(Euphorbiaceae) and those of the Rhamnaceae ( 1 6 4 )and Celastraceae

( 1 6 5 ) .

99

The Daphniphyllaceae is a rather small family with 35-40 species,

which most workers have considered to be related to the Euphorbiaceae

(5, 6 ) .Webster ( 5 4 ) , n accord with Hutchinson ( 1 4 2 ) ,would place the

family in the Hamamelidae (sensu Cronquist). The chemistry of the

family has been little studied with the exception of its unusual alkaloids.Some members of the family contain asperuloside, an iridoid monoter-

pene (Section V , B) ( 8 1 , 1 6 6 ) .Compounds of this type are not found in

other families of the Euphorbiales (sensu Cronquist), nor are they



50 DAVID S. SEIGLER

commonly found in the Hamamelidae. They are, however, found in

the Gentianales, Rubiales, Cornales, etc., which are discussed in

Section V , B. The complex and unique alkaloids of this family, such asdaphniphyllin (loo), have been shown to be of terpenoid origin. Six

mevalonate units are involved in the synthesis of one alkaloid molecule

(2 6 , 167, 168) .

100

Alkaloids which occur in the Buxaceae are derived from triterpenes

and are discussed in Section V , B.

In summary, the Euphorbiaceae are rich in alkaloids of several major

types. Two other families of the order that contain alkaloids, the

Buxaceae and Daphniphyllaceae, do not appear to be closely related,

while the third, the Pandaceae, produce alkaloids similar to a t least onegenus of the Euphorbiaceae. The Aextoxicaceae have apparently not

been investigated.

The ancestry of the Euphorbiaceae has long been in question. The

family has been transferred from place to place although it has generally

been considered close to the Geraniales or other orders of the Rosidae.

Cronquist considers the Euphorbiales to be descended from the Rosales

(6), whereas Stebbins ( 1 2 ) did not consider the Rosales as necessary

intermediates. The genus Croton contains benzylisoquinoline alkaloids.

We should again ask th e questions posed when we considered the originsof the Rutaceae: Did this family come from ancestors that synthesized

benzylisoquinoline alkaloids, i.e., is it linearly descended from the

Magnoliideae; did benzylisoquinoline alkaloids arise independently in

the family or did they come from a long line of intermediates in which

synthesis of benzylisoquinoline alkaloids was “turned off” and in some

proto-Euphorbiaceous ancestors was turned on again 2

7 . The Rhamnaceae and CelastraceaeThe Rhamnaceae (Rhamnales) contain alkaloids of the benzyliso-

quinoline type as well as those with polypeptide skeletons; both of

these types are found in the Euphorbiaceae. Cronquist ( 6 )and other



52 DAVID S. SEIGLER

that the alkaloids of this family represent a case of independent

evolution of tropane-type alkaloids.

9. Alkaloids with Monoterpene Sesquiterpene and Diterpene Skeletons

A number of monoterpenoid compounds, such as nepetalactone (104)

of the iridoid group ( 4 9 - 5 3 , 9 3 , 9 4 , 1 7 0 ) , ncorporate nitrogen to produce

alkaloids such as actinidine (105).These compounds are found in several

plant families; among them are the Gentianaceae, Apocynaceae,

Actinidiaceae, Bignoniaceae, Loganiaceae, Orobanchaceae, Menyan-

thaceae, Plantaginaceae, Oleaceae, Scrophulariaceae, Valerianaceae,

and Dipsacaceae (49 -52 , l r O a) .One of these compounds, gentianine, hasbeen shown to be an artifact of isolation under certain conditions.

104 105

The parent terpenoids have wide distribution. They occur in ants of

the genus Iridomyrmex and in many plants, primarily as the glycosides.

Several aspects of the biosynthesis, distribution, and chemotaxonomy

of this group of compounds have been reviewed ( 8 1 , 1 6 6 , 1 7 1 ) .Many of

the families in which they occur are in the Asteridae and Rosidae ( sensu

Cronquist) and the presence of iridoid monoterpenes and the monoter-

pene alkaloids (Table I) appears to demonstrate several relationships

within the group. For example, the presence of these compounds

suggests a close relationship between the Actinidiaceae (order Theales)and the Pyrolaceae and Ericaceae (order Ericales), all of the subclass

Dilleniidae. The presence of iridoid compounds in these three families is

anomalous in the subclass. Investigations of plant taxa for the presence

of both iridoids and the corresponding glycosides appears to be a

fertile area to provide additional information for the placement of

several families.

10. Alkaloids Derived from Tryptophan That Contain a Monoterpenoid

A large number of alkaloids that are important medicinally are

derived by union of simple amines derived from tryptophan and an

iridoid monoterpene unit. These are commonly known as the indole

Moiety




TABLE I

FAMILIESHAT CONTAIN IRIDOID COMPOUNDS

Rosidae

Escalloniaceae

Daphniphyllaceae ,

Fouquieriaceae

Cornaceae

Garryaceae

Hippuridaceae

Hydrangeaceae (Hydrangea )

Alangiaceae

Hamemelidae

Eucommiaceae

Hamamelidaceae (Liquidambar)

Dilleniidae

Ac tinidaceae

Ericaceae

Proteaceae

As teridae

Rubiaceae

Scrophulariaceae

Orobanchiaceae

Globulariaceae

Plantaginaceae

Buddlejaceae

Lentibulariaceae

Apocynaceae

VerbenaceaeMartyniaceae

Callitrichaceae

Acanthaceae

Dipsacaceae

Pedaliaceae

Labiatae

Myoporaceae

alkaloids. The biosynthesis of simple amines derived from tryptophan

and condensation of these units to produce Calycanthus alkaloids has

previously been mentioned and the distribution of both iridoid monoter-

penes and the corresponding monoterpene alkaloids has been summarized

(Section V, B).

Loganin (106), a precursor of most indole alkaloids, as well as of

emetine alkaloids, is found in several families; among them are the

HO

0-glucosyl

CH30.C CH3O.C

106 107

Apocynaceae, Loganiaceae, Meyanthaceae, and several Lonicera

species (Caprifoliaceae) ( 1 7 1 ) .The corresponding acid, loganic acid isfound in the Gentianaceae, Apocynaceae, Alangiaceae, and Loganiaceae

( 1 1 9 ) . Loganin is converted in certain plants to secologanin (107))

which is a more immediate precursor of indole and emetine alkaloids.



54 DAVID S. SEIOLER

Relatively unchanged addition products of tryptophan and secologanin

u n i t s such as cordifoline (108)are found in A d i n a cordifolia Hook. of the

Rubiaceae.

108

The corresponding decarboxylated compound strictosidine (109)has

been found in Rhazya and Catharanthus species of the Apocynaceae,

although the compound with opposite configuration a t C = 3 has not

been isolated from the higher plants.

109

The route(s) from intermediates of the above type to the various

types of indole alkaloids has been the subject of much speculation (171).Among the types observed are ajmalacine (110) and its relatives

(Corynanthe type), stemmadinine types ( l l l ) ,spidosperma

types,

such as tabersonine (112),Iboga types such as catharanthine (113),and

Xtrychnos types such as strychnine (114).Several other basic skeletons

are known, and the relation of many of these to the preceding types is

enigmatic.

111




112 113

114

Indole alkaloids are found in several families-the Nyssaceae,

(Camptotheca acuminata Decne.), Icacinaceae, (Nappia foetidu Miers

and Cassinopsis ilicifolia Kuntze), Alangiaceae, Loganiaceae, Apocy-

naceae, and Rubiaceae (49-52, 172-224). The families Nyssasaceae(8 species) and Alangiaceae(18species) are members of subclass Rosidae

order Cornales, whereas the families Icacinaceae (400 species) is a

member of the order Celastrales. Other workers (225 , 226) consider the

Icacinaceae to be more closely related to the former two families.

There is both chemical and morphological unity among the families

Gentianaceae (1100 species), Menyanthaceae (40 species) (which

Cronquist places in the order Polemoniales, subclass Asteridae),

Loganiaceae (500 species), Apocynaceae (2000 species), Asclepiadaceae

(2000 species), and Rubiaceae (6000-7000 species). All except theAsclepiadaceae contain precursors of the indole alkaloids if not the

alkaloids themselves (e.g., the Gentianaceae and Menyanthaceae). The

complex pathways leading to these compounds preclude independent

evolutionary origin of the indole alkaloids they contain.

The Apocynaceae has been divided into three subfamilies by Pinchon

[see complete series of references in Hegnauer (78j.l Of these, the

Plumerioideae contains indole alkaloids, the Cerberoideae monoterpene

alkaloids, and the Echitoideae steroidal alkaloids ( 7 8 ) .Problems a t the

genus and species level have been extensively investigated in this familybecause of the medicinal importance of the alkaloids; several of these

studies have been reviewed ( 1 8 , 25, 145, 153 , 186, 190-201, 204-212,227 , 228 ) .




,A&CH30,C

HN-

116

117

of indole alkaloid precursors. The former (emetine type) are restricted

to the Rubiaceae and occur in several genera, among them Cephaelis and

Psychotria. Quinine and closely related compounds are found in the

genera Cinchona, Rem ija , Contarea, and Ladenbergia of the Rubiaceae.

However, by far the most common alkaloids in the Rubiaceae are those

th at are identical with or derived from those found in the Apocynaceae

and Loganiaceae. There is little question that the Rubiaceae must have

been derived from common ancestors of the Gentianales or from

members of the Gentianales.Did the families of the Asteridae that contain iridoid compounds and

their derivatives come from families of the Rosidae that are iridoid

containing (i.e., the Rosales) as Cronquist suggests? Or have these been

derived from Saxifragalean and Cornalean ' ancestors as other authors

suggest (89-91) The same possibilities of independent origin, dormant

biosynthetic mechanisms, or linear descent rise again.

11 . Alkaloids with Sesquiterpene Structures

Alkaloids with sesquiterpene skeletons are unusual in nature (49-52,2 3 2 , 2 3 3 )but are known to occur in the Nympheaceae (see the discussion

of alkaloids in the Magnoliales). Both Nymphaea and Nuphar contain

compounds such as 118 (26,232 , 233) .



58 DAVID S. SEIQLER

118

The alkaloids of Nuphar and Xymphaea are not found in the Nelum-

bonaceae, nor are those of Nelumbo found in other families of the order.

A clear dichotomy exists between the groups from both morphological

and chemical grounds suggesting that the two groups are not closelyrelated.

12. Alkaloids with Diterpene Structures

Alkaloids with modified diterpene structures occur in the Garryaceae

(5 species)(order Cornales, subclass Rosidae), th e genera Aconitum and

Delphinum of the Ranunculaceae (order Ranunculales, subclass

Magnoliidae), in Inula royleana DC. (order Asterales, subclass

Asteridae), and Spiraea japonica L. (order Rosales, subclass Rosidae)(49-52, 78, 81) . Many of these compounds are intensely poisonous and

some are among the most toxic materials of plant origin known to man.

Several are used medicinally. These compounds may be divided into

two broad categories. The first of these includes a series of relatively

simple amino alcohols that are modeled on a C-20 skeleton, and the

second group is more highly substituted and frequently based on a C-19

skeleton (234-239). These alkaloids arise from tetra- or pentacyclic

diterpenes in which atoms 19 and 20 are linked with the nitrogen of a

molecule of /3-aminoethanol, methylamine, or ethylamine to form aheterocyclic ring ( 2 3 6 ) .Pour basic skeletons of diterpene alkaloids are

known. The veatchine skeleton, e.g., veatchine (119),which occurs in

the genera Garrya (Garryaceae) and Aconi tum (Ranunculaceae), is

based on a kaurane skeleton (120) and obeys the isoprene rule. The

other three skeletons, the atisine, lycoctonine, and heteratisine types,

€19



1 . PLANT S Y S T E M A l T C S 59

do not obey the isoprene rule and are found in both Ac o n i t u m and

Delph in ium species. Compounds such as atisine (121), yeoctinine (122),

and heteratisine (123) are respective representatives of these groups.The latter two types are based on a C-19 skeleton. Alkaloids from I n u l a

120 121

O H

122 123

royleana (Compositae) are identical with certain alkaloids of the

lycoctonine type which occur in the genus Ac o n i t u m ('78),whereas those

from Spiraea (Rosaceae) (e.g., 124) represent a unique type.

It is difficult to assess the taxonomic significance of these alkaloids.

The kaurane series of diterpenes also give rise t o gibberellins, which are

OH

124

found in most if not all higher plants. The number of changes necessary

to produce compounds such as veatchine from these intermediates may

be less than would appear on casual observation. No doubt many morechanges are required to produce more complex diterpene alkaloid

types. The Garryaceae are probably not closely related to the Ranun-

culaceae and neither are particularly close to the Compositae.



60 DAVID S. SEIGLER

13 . Alkaloids Containing Steroidal or Triterpenoid Nuclei

Several plant families produce alkaloids that are biosynthesized fromsteroids (240-249) . The genera Holarrhena, Funtinnia, and Malonetia

of the Apocynaceae and Sarcocca and Pachysandra of the Buxaceae

produce alkaloids based on the 5-a-pregnane skeleton. Cholesterol has

been suggested as an intermediate i n the synthesis of steroidal alkaloids

such as holophyllamine (125) and conessine (126) in species of Holar-

rhena (53).CH,

125 126

The family Solanaceae is widely known for its diverse and plentiful

alkaloid content. The genera So l anum and Lycopersicon (and others)

contain steroidal alkaloids t hat are similar in structure t o the steroidal

saponins they possess. Many of these compounds have complex.di-andtrisaccharide moieties. Alkaloids of this type, such as solanidine (127)

and solanocapsine (128), indicate a close relationship between these

alkaloids and cholesterol.

r

alkaloids and cholesterol.

HO

H

127 128

The structures of several C-nor-D-homosteroids from the genus

Veratrum of the Liliaceae will be discussed in Section V , C.Several members of the Buxaceae (Euphorbiales sensu Cronquist)

contain exceedingly complex mixtures of alkaloids ( 2 5 0 ) .Most of thesealkaloids have substitution patterns that resemble triterpenes but do

not possess the typical C- 17 side chain. Several possess cyclopropane

rings reminiscent of cycloartenol, such as cyclobuxine-D (129), whereas

others, such as buxenine-G (130),have a ring expanded system.




129 130

B u x u s alkaloids are not known from other plant groups, although

they are widespread in the family. Webster (154)does not feel that theBuxaceae is closely related t o the Euphorbiaceae; the two families have

few chemical characters in common (78). Hutchinson ( 1 4 2 ) suggested

the family was in the Hamamelidales, but there is little chemical

evidence to confirm or deny this placement.

14. The Solanaceae

The Solanaceae is one of the richest families with regard to the

absolute number of species that contain alkaloids. Cronquist places

the Solanaceae in the order Polemoniales of the Asteridae ( 6 ) . t is the

largest family in the order with about 2300 species (about 1700 of these

in the genus So lanum )followed by the Convolvulaceae with about 1400.

While the Solanaceae are extremely rich in alkaloids, few are found in

other families of the order. Pyrrolidine and tropine types have been re-

ported from the genus Convolvulus and ergot alkaloids (Section v, B)

are present in the Convolvulaceae (49 -52 , 5655 ) .A large number of genera of the Solanaceae contain alkaloids derived

from ornithine via pyrrolizidine intermediates (Table 11) (53, 93, 94 ) .The biosynthesis of these alkaloids has been previously discussed

TABLE I1

GENERAOF THE SOLANACEAEHAT CONTAIN ALKALOIDSERIVEDROM

ORNITHINEAND LYSINE

Atropa

Hyoscyamw

Physochlaina

DaturaDuboisia

Latura

Mandragora

Scopolia

Solanum Brugmansia

Solandra Salpiglossis

Physalis Salpichroa

Anisodus StreptosolenNieandra Dunalia

Methysticodendron Cyphomandra

Withania Anthoeereis

Nicotiana




132

clavine (132),arise by condensation of tryptophan and mevalonate units

and subsequent cyclization ( 2 7 , 5 3 , 9 3 , 9 4 , 2 1 6 , 2 2 0 , 2 2 1 , 2 5 2 ) .lkaloids

of the clavine series are found in both Claviceps and in the genera Riveaand Ipomoea of the Convolvulaceae. In certain alkaloid-producing

strains of ergot, agroclavine (132) is converted to elymocIavine (133),

which serves as a precursor for lysergic acid (134) and other related

132 133

compounds. Ergine (lysergic acid amide) (135)and erginine (isolysergic

acid amide (136)have been isolated from hydrolyzates of Rivea corym-

bosa (L . )Hall. f. and Ipomoea tricolor Cav., which were used by Mexican

indians as a drug under the name ololiuqui (221 , 253) .

The majority of alkaloids from ergot are peptides of lysergic acid.

The therapeutically most important ergot alkaloids are of this type.There is no question of close relationship between Claviceps (an Ascomy-

cete) and the Convolvulaceae (an angiosperm from an evolutionarily

134 135 136




isolated from this family, most of which are related to the glucosinolates

which are widespread in the family, although several (e.g.,138),mainly

those from the genus Lunaria appear to be of a unique type ( 7 8 , 8 1 , 2 5 6 ) .

138

C. THELILIOPSIDAMONOCOTYLEDONOUSLANTS)

Alkaloids among the monocotyledonous plants are, with the exception

of simple amines, mostly found in families of the Liliales and the

Orchidales, although a few are known to occur in other families.

Liriodenine, lysicanine (139), and nuciferine have been reported

CH,O

139

from Lysichitum camtschatcense Schott. var. japonicum Makino of theAraceae (order Arales, subclass Arecidae)(2 5 7 ) .Several simple alkaloids,

such a s arecoline (140), are found in the Palmae (order Arecales, sub-

class Arecidae). A number of simple amines, e.g., hordenine (12),

candicine, tyramine, and N-methyltyramine, are widely distributed in

the Gramineae ( 4 9 ) .More complex alkaloids such as festucine (142) and

loline (143), pyrrolizidine alkaloids that occur free in nature, have been

CH,

140 141



66 DAVID S. SEIGLER

HNCH,

142 143

found in the genera Festuca and Lolium, respectively. Perlolyrine (144)

has also been isolated from the genus Lolium (258).Most alkaloids of the monocotyledonous plants are concentrated in

the Liliidae, especially in the order Liliales, but also in the Orchidales.

CH,OH

144

Alkaloids commonly found in the Liliaceae (including the Amaryllida-

ceae) are derived from phenylalanine and/or tyrosine but differ in

structure from types found in dicotyledonous plants. Alkaloids in the

Orchidaceae are mostly restricted t o several genera of that family and

are of an unusual type.

1 . The Liliales

The Liliales, as defined by Cronquist, comprise 13 families and nearly

7700 species. He combines the Liliaceae and Amaryllidaceae to produce

the largest family of the order, the Liliaceae, which has about 4200

species. Other families in the order are the Iridaceae (1500 species),Dioscoreaceae (650 species), Agavaceae (550 species), Smilacaceae

(300 species), Velloziaceae (200 species), Haemodoraceae (120 species),

Xanthorrhoeaceae (50 species), Pontederiaceae (30 species), Stemona-

ceae (30 species), Taccaceae (30 species), Philydraceae ( 5 species), and

Cyanastraceae (5 species). Of these, alkaloids are known from the

Liliaceae (from members of both the former Liliaceae and Amaryllida-

ceae), Dioscoreaceae, and Stemonaceae (49-52) .

The Liliaceae and Amaryllidaceae were traditionally separated from

one another by the single character of position of the ovary-inferiorin Amaryllidaceae and superior in the Liliaceae ( 6 ) .This difference is

now not considered so significant with separation of the Agavaceae

from this group, and Cronquist says that it appears the traditional




COMMELINIDAE

FIG.2. Subclasses of Liliopsida according to Cronquist (6).

Amaryllidaceae were really several different groups that had indepen-

dently become epigynous. Steroidal glycosides are widespread among

species of the Liliaceae, Agavaceae, and Dioscoreaceae, but are not

found in the Amaryllidaceae (78 , 8 1 ) .

The Amaryllidaceae alkaloids comprise a unique group of bases that

have so far been found only in that family (49-52,259-261) . Conversely,

with the exception of hordenine, alkaloids of other plant families havenot been found in the Amaryllidaceae. Three major pathways of

alkaloid biosynthesis in this family arise from the compound norbella-

dine (145), which is derived from one molecule of tyrosine and one

molecule of phenylalanine. One of these pathways gives rise to lycorine

HO+&H,NHCH. dO145

(146)and its congeners via Scheme 3. A second gives rise to haemantha-

mine (147), pretazettine (148), and tazettine (149) via Scheme 4. The

third pathway gives rise to compounds such as narwedine (150) and

galanthamine (151) via Scheme 5. All three pathways are present in

many genera of the family (49-52, 7 4 , 7 8 , 81) and in most of the tribes

of the Amaryllidaceae according to Hutchinson ( 78 ) .Other subfamilies,

a number of which were raised to the rank of family by Hutchinson, do

not have these alkaloids ( 1 4 2 ) .In some members of the Liliaceae, one molecule of phenylalanine and

one molecule of tyrosine unite to form series of compounds such as

colchicine (152) and androcymbine (153).



68 DAVID 5. SEIGLER

Norbelladine --+

CH30 OH

CH.0

++

HO

146

SCHEME

147

HO

148

SCHEME

149

150

CH,O

.*-

151

SCHEME




\OCH,

‘ 0CH,O

Hutchinson ( 142 )divided the Liliaceae into 28 tribes and a t the same

time elevated a number of groups previously placed in the Liliaceae to

familial level (78) .Of these 28 tribes, the Uvularieae, Anguillarieae, andColchiceae contain colchicine and related alkaloids. These alkaloids are

present in the genera Androcymbium, Colchicum, Gloriosa, Littorica,

Merendera, Camptorrhiza, Kreysigia, Dipidax, and Iphigenia but

absent from many others from which related alkaloids have been

reported (262-265).The Veratreae, a related tribe, contain many alkaloids that are

derived from steroidal precursors such as cholestanol as well as those of

the C-nor-D-homo type (78,247-250). These extremely toxic compounds

are found throughout the genera Ve ratr um , Schoenocaulon, and Zyga-denus and are similar to those found in the Solanaceae, Buxaceae, and

Apocynaceae. An example of the former type is veralkamine (154).

H

154

The genus Fritillaria of the subfamily Lilioideae contains alkaloids

that are similar in structure to those of the Veratreae. The similarity in

alkaloids and in certain lactones leads Hegnauer ( 7 8 ) to suggest a

relationship between the two groups. Others have previously considered

the Lilioideae to be derived from members of the Melanthioideae ( 265 ) .

The Dioscoreaceae is best known for the steroid glycosides its species

contain. These are similar in structure to those found in the Liliaceae,Agavaceae, and certain allied groups. In contrast to the Liliaceae,

however, the Dioscoreaceae contain alkaloids based on a quinuclidine

structure such as 155 (49-52, 78) .It has now been demonstrated that

four acetate units are condensed with a lysine derived piperidine unit to



70 DAVID S. SEIGLER

yield Dioscorea alkaloids (2 6 6 ) .To date these have only been found in

African and Asian species of the genus, and interestingly, those with

alkaloids were found to be practically free of saponins (78). Earlierreports of tropane alkaloids in this family are probably erroneous.

155

The Stemonaceae, a small family of three genera (4, ave been shownto contain approximately fourteen alkaloids of a unique type such as

tuberostemonine (156).

156

Cronquist views the families of the Liliales as being derived from the

Liliaceae, with the exception of the Philydraceae and Pontederiaceae.

He further views the Amaryllidaceae as several groups of the Liliaceae

that had independently become epigynous. The Dioscoreaceae and

Stemonaceae are broadleaf climbers that are also derived from Lili-

aceous parents. The Iridaceae are much like the Liliaceae in th at theyfrequently exploit the bulbous and cormose habit, but they have not

been reported to contain alkaloids. In summary, alkaloid chemistry

suggests that the Liliaceae and several groups of the Amaryllidaceae are

distinct. The Dioscoreaceae and Stemonaceae contain alkaloids not

found in either and do not contain alkaloids of the type found in the

Liliaceae-Amaryllidaceae.

2. The Orchidaceae

This large family with approximately 20,000 species has been littleinvestigated chemically but is known to contain alkaloids derived from

ornithine. Appropriate alkylation of a pyrrolidine intermediate with an

acetate- and or propionate-derived precursor gives compounds such




as crepidine (157), which are known principally from the genus Dendro-

bium but also from other genera which have been summarized (78 , 81 ,

267-269). Simpler compounds such as hygrine (16) have also been

I

157

reported from several genera and add credence to the proposed bio-

synthesis of more complex alkaloids by the internal alkylation of a

pyrrolidine moiety. Pyrrolizidine types such as 158 from the genus

Lipuris and Mu&xis are also known.

R' various R and R' substituents

158

The differences between major groups of orchids have few absolute

distinctions and several taxonomic schemes have been proposed, for

example, those by Garay ( 2 7 0 ) , Dressler and Dodson ( 2 7 1 ) , and

Airy-Shaw ( 1 4 0 ) .Most alkaloid-containing species are concentrated in

the group Epidendreae and especially in the genus Dendrobium.

Cronquist views the Orchidaceae as being derived from the Liliales,

probably from Amaryllidaceous ancestors. The alkaloids of this giant

family do not resemble those of the Lilales, nor do the Orchidaceae

contain alkaloids of the types found in either the Amaryllidaceae, the

Liliaceae, or other extant families of the Liliales.

3. Alkaloid Chemical Data and the Origin of the Monocotyledonous

PlantsBessey (272) and several other systematists proposed that the

monocotyledonous plants arose from plants similar to the Ranunculales

and that primitive monocots resembled the Alismatales. Cronquist (6)



72 DAVID S. SEIGLER

discards this theory and derives them from the Nympheales of his

Magnoliidae, primarily on a basis of resemblance of extant members

of the Nympheales (especially Nymphuea and Nuphur), to a model heproposes for a primitive monocotyledonous plant. Stebbins ( 12 ) re-

jected this hypothesis as well as that of Bessey, as he felt many of the

characters used by both of the previous investigators were secondarily

derived rather than primitive. He further states that no modern orders

of either monocotyledonous or dicotyledonous plants are derived from

extant ancestors and suggests that monocots are derived from ancestors

similar to Drirnys (Winteraceae, subclass Magnoliidae).Chemical data do not clearly resolve problems related to the origin

of monocots. Alkaloids of the monocots are different from those of thedicots. I n only a few cases similar compounds are produced, e.g., some

amaryllidaceous alkaloids resemble those derived from benzylisoquino-

line precursors, certain orchidaceous alkaloids resemble those derived

from ornithine in dicots, and steroidal alkaloids of the Liliaceae resemble

those of the Solanaceae, Apocynaceae, and Buxaceae. Several simple

amines (tyramine, gramine, tryptamine, candicine, etc.) do occur in

monocots and dicots, but as previously discussed these are rarely

significant a t higher taxonomic ranks. If the proposals of either Bessey

or Cronquist are correct it is necessary to derive the monocots from

non-alkaloid-containing lines or to suppose that the ability to synthesize

either benzylisoquinoline alkaloids of advanced types (as occur in the

Ranunculales) or sesquiterpene alkaloids (as occur in the Nympheales)

has been lost. From extant data for the distribution of alkaloids in

monocots it is clear that most primitive monocots (as discerned by

either the system of Bessey or Cronquist) are devoid of alkaloids, and

alkaloid synthesis as seen in monocots, e.g., the Liliales, must be

independently derived. Cronquist suggests that the Winteraceae is one

of the families ancestral to other families of the order Magnoliales. It is

interesting that no benzylisoquinoline alkaloids have been isolated and

characterized from this family. On the other hand, benzylisoquinoline

alkaloids have been reported from at least one monocot, a member of

the Arales (257), although with apparently unvouchered plant mat-

erials. This record should be reexamined since it represents a most

important occurrence for studies of phylogeny and origin of this group.

Studies of the amino acid sequences of cytochrome c by Boulter (88)

indicate that monophyletic origin of the monocots from dicotyledonous

lines is probable. It also appears from this evidence that both the

monocotyledonous and magnolidean lines diverged after those of the

Caryophyllales and thus the flower and chemistry of truly primitive

angiospermous plant may resemble that proposed by Meeuse (89-91)

rather than the Ranalean type, which has become widely accepted.




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200. J. E. Saxton, in “Th e Alkaloids” (R. H. F. Manske, ed.) , p. 207. Academic Press,

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231. E. Gellert, A w t . J . Chem. 9, 489 (1956).

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~ H A P T E R-

THE TROPANE ALKALOIDS

ROBERT . CLARKE

Sterling Winthrop Research Institute

Remselaer. New York

I. Introduction ...................................................... 84

85

A. Proteaceae ..................................................... 85B. Rhizophoraceae ................................................ 89

C. Solanaceae .................................................... 89

D. Euphorbiaceae ................................................. 92

E . E ~t h r o x y l a c e a e............................................... 92

F. Natural Tropane N-oxides ....................................... 93

G. A Secotropane ................................................. 94

111. Syntheses ......................................................... 95

A. Oxallyl Additions to Pyrroles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

B. Robinson Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96

C. Dienone Amine Additions ........................................ 97

D. From Bridged Aziridines ......................................... 98

E. From Pyrrolidines .............................................. 100

F. Nitrone-Induced Cycloadditions .................................. 101

G. 1,3.Dipolar Additions .................... . . . . . . . . . . . . . . . . . . . 102

H. Nitrosation of Phenylalanine Tropanyl Ester . . . . . . . . . . . . . . . . . . . 104

I Phosphorous an d Sulfur Analogs .................................. 105

J . Radiolabeled Tropanes .......................................... 106

IV. Reactions ......................................................... 107

A. Quaternization ................................................. 107

B. N-Oxides . . . . . . . . .................................. 112

C

.Nitroxide Radicals

....................................... .114

D.Cocaine Analogs . . ....................... 116

E. Demethylation ................................................. 120

F. Reduction of Tropinone ............................... 123

G. Tropanyl Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

H . Miscellaneous Reactions ......................................... 125

V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136

A . Tropane Moiety ................................................ 136

B. Carboxylic Acid Moiety ......................................... 138

C. Transformations ................................................ 141

D. Tissue Culture Studies........................................... 144

E . Miscellaneous Biosyntheses ....................................... 146VI. Biological Activit ........................................ 147

V I I I Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

162

References .......................... ........................... 167

I1. New Tropane Alkaloids .............................................

VII. Plant Content . . . ........................................ 153

I X Analytical Methods ................................................



2. TROPANE ALKALOIDS 85

II. New Tropane Alkaloids

A . PROTEACEAE

In 1971 , the first report of isolation of a tropane alkaloid from the

family Proteaceae marked the beginning of a flurry of activity in this

area. Some drastically different types of substituents on the tropane

skeleton have been encountered and the first apparent racemic mixtures

of naturally occurring, unsymmetrical tropane skeletons have been

isolated.

1. Bellendena m ontana R . Br.

Bellendine, the first alkaloid to be isolated from the Proteaceae,

has been shown to be 2,3-(2,3-tropeno)-5-methyl-y-pyrone3) (7 ) .Racemic bellendine has now been synthesized (8 )starting with tropi-

none: Reflux of this ketone with sodium hydride in benzene for 20

(1) NaH

3

hours followed by treatment with 3-methoxymethacryloy1 chloride

gave diketone 2. Acid catalyzed cyclization of the ketone afforded

bellendine (3) n low overall yield ( 8 ) . The acylation process alsoproduced some O-acylated material 4.

Also isolated from this species were isobellendine ( 5 ) and cis-endo-dihydroisobellendine (6) (9 ) .The same group has indicated privately



86 ROBERT L. CLARKE

( 1 0 ) that this source also provided three esters of tropane-3a,6/3-diol,

namely the 3-acetate (7, R = H , R ’ = CH,CO-), the 3-acetate-6-

isobutyrate (7, R = (CH,),CHCO--, R’ = CH,CO-), and the 3-

isobutyrate-6-acetate (7,R = CH,CO-, R‘ = (CH,),CHCO-). Theabsolute configurations of these B . montana compounds have not been

established.

6Rf7

2 . Darlingia ferruginea J. F. Bailey

The major alkaloid of this species, darlingine, is a methylated form

of bellendine with the structure 8 ( 1 1 ) .Analyses and spectroscopic data

established its identity. It has also been isolated from D . darlingiana

(F.Muell) L. A . S . Johnson ( 1 1 ) .A minor constituent, called ferrugine,

c C P h

8 9

proved to be 2a-benzoyltropane (9) (11). t appears to have a close

biosynthetic relationship with the 2-benzyltropanes described below,

but ferrugine shows [a]1f9+55O,whereas the 2-benzyltropanes appearto be racemates. If there is indeed a relationship between the two series,

it will be interesting to find out whether ferrugine has the 1R or 1sconfiguration.




Another surprise lay in the isolation of ferruginine (2-acetyltrop-2-

ene, 10) from this same species (10).

0

c&kcH3 10

3 . Knightia deplanchei Vieill. ex Brogn. e t Gris

A total of six new tropanes have been isolated from K . deplanchei thatare unique in having a benzyl group on C-2. Four of these will be

considered first (11, 12, 13, and 14) because the benzyl group is unsub-

stituted ( 1 2 ) .

CHiPh

0II

O q P h

11

CHaPh

0

0-CCH,II

12

CH3

CH,N

PhCOI \ ) T C H 2 € ’ h r J ) TOH OX\; ; /H

C==C/ \

H Ph

13

14

The nature and location of the substituents in these four compounds

were established primarily by mass spectrometry with supportive

evidence from IR, MR, and hydrolytic data. All of these alkaloids

showed zero optical rotations and are apparently racemates. The

configurations of the various substituents were established later by 13C

NMR spectral studies ( 1 2 ~ ) .he latter studies also distinguished the

points of attachment of the hydroxyl groups on the ethylene bridges of

13 and 14.




B. RHIZOPHORACEAE

Bruguiera sexangular (Lour ) Poir ; Bruguiera exaristata Ding Hou

Several esters of tropine have been found in these two related species

( 1 5 , 1 6 ) . Esters identified were the acetate, propionate (a new natural

ester), isobutyrate, butyrate (new), a-methylbutyrate or isovalerate

(not differentiated), benzoate, and the 1,2-dithiolane-3-carboxylate

(the major component, a new alkaloid called brugine).

Studies on brugine showed that the skew sense of the C-S-S-Csystem is right handed in the 1,2-dithiolane-3-carboxyliccid portion

of the ester ( 1 5 ) .Optically active brugine has since been synthesizedfrom 1,2-dithiolane-3-carboxyliccid of known absolute configuration

( 1 7 )so that the natural d-alkaloid can be represented by 17.

I

0-

17

C. SOLANACEAE

1. Datura suaveolens H. and B. ex Willd.

Some new esters have been isolated from D. suaveolens, a species

indigenous to South America. From the aerial parts were isolated

3a,6/3-ditigloyloxytropane-7/3-ol18, R1 = R2 = tigloyl), hyoscine,

norhyoscine, meteloidine, atropine, noratropine, 1- and dl-3a-tigloyloxy-tropane-6/3-01 (not previously shown conclusively to be a normal

constituent of plant material), and a new alkaloid, 6p-tigloyloxy-

tropane-3a,7P-diol (18, R' = H, R2= tigloyl) ( 1 8 ) .

O R '

1s

0- C\ ,H

CH3\

c=cCH3

19




Biosynthesis of the acid moiety of this ester will be discussed in Section

V . No information has appeared yet on the other two bases.

4. Datura sanguinea R. and P

a-Hydroxyscopolamine (21A) has been isolated ( 1975) from the

leaves of Datura sanguinea from Ecuador (22) .The scopolamine from

this plant is quaternized with n-butyl bromide to form a commercial

antispasmodic drug. The reportedly new tropane alkaloid 21A was

OH

21A

first isolated in quaternized form as an impurity in the crude commercial

product. Hydrolysis of this quaternary salt afforded known 2-phenyl-

glyceric acid.

Pure 21A, isolated from scopolamine mother liquors by preferential

extraction a t pH 9 followed by chromatography, proved to be 400-fold

less soluble in chloroform containing 2% ethanol than is scopolamine.

No literature reference was recorded for this base (optically active).

The dl-form of a-hydroxyscopolamine was reported six years earlier,

its being prepared by hydroxylation of aposcopolamine (22a) . Here

again there was no reference to earlier preparations. On the other hand

there is a Chinese report (1973) (copy not available) (22b) hat describes

the distribution of a-hydroxyscopolamine (called anisodine) in 19

genera and 54 species of Chinese solanaceous plants. A rapid scan of

Chemical Abstracts formula and subject indexes revealed no further

references to this compound. Anisodamine is a name given to tropane-

3a,6fl-diol 3-tropate (22c),the synthesis of which is described in this

reference.

5.Physochlaina alaica

E.Korot.

Physochhina alaicu has been found to contain 3a-(pmethoxyphenyl-

acetoxy)-tropane-6fl-o1(22), called physochlaine, together with some

apoatropine (23) .



92 R OB E R T L. CLARKE

D. EUPRORBIACEAE

Peripentadenia mearsii (C. T. White) L . S. Smith

Two new alkaloids were isolated from this Queensland tree along with

tropacocaine (3~-benzoyloxytropane)2 4 ) .Although the identity of the

specimen was confirmed, further collections of P. mearsii in the same

area failed to yield any tropane alkaloids.

One of the new alkaloids was d-tropane-3ct,6/3-diol 3-acetate (23)[1R-(3-endo-6-exo)J, dentified by analysis, I R, NMR, and mass spectra

and by comparison of i ts diacetate with the enantiomeric 1-tropane-3a76/3-

diol diacetate prepared from valeroidine by hydrolysis and acetylation.

OCOCH,23 24

The absolute configuration of valeroidine was established earlier (25).This same ester was found in Bellendena montana (see above) ( 1 0 ) .

The other new alkaloid proved to be d-2~-benzoyloxynortropan-3fl-ol

(24) of unknown absolute configuration. Initial structural studies were

done on the natural alkaloid. It was then N-methylated (benzoate

cleaved) and acetylated to give tropane-2a,3fl-diol diacetate which was

used for the final structural studies ( 2 4 ) .

E. ERYTHROXYLACEAE

Erythroxylum monogynum Roxb.

An ether extract of the alkaline root bark of E. monogynum was

chromatographed to give five crystalline components of different




molecular weights ( 2 6 ) .One of these proved t o be 3a-( ,4,5-trimethoxy-

benzoy1oxy)-tropane (25),dentified by spectral and hydrolytic studies.

Also present was 3a-( ,4,5-trimethoxycinnamoyloxy)tropane(26),

C H s N

0A O A G O C H 3CH, 2% O - - C C H = C Hi

OCH, OCHa

a5 26

previously reported as a constituent of E . el l ipt icum leaves (27). The

most recently reported compounds from E. mo n o g y n u m are tropane-

3a,6p-diol 3-(3',4',5'-trimethoxycinnamate)-benzoate (26A),he first

heterodiester to be found in Ery throxy lum (27a )and tropane-3a,6p,7/3-

trio1 3-(3',4',5'-trimethoxybenzoate) 27b) .

26A wOCH,

F. NATURALROPANE-OXIDES

Until very recently there were no reports of isolation of tropane

N-oxides from natural sources although several other types of alkaloids

have been isolated in this form. In one search for such tropane oxides

authentic samples of the N-oxides of both hyoscyamine and hyoscine

were prepared. Each formed a mixture of axial and equatorial oxides,

the components of which were separated and characterized. With this

reference background, both isomers of hyoscyamine N-oxide wereisolated from the roots, stems, leaves, flowers, pericarps, and seeds of

dt ro pa belladonna L., Hyo scyam us niger L., and Datura s t ramonium L.The equatorial AT-oxideof hyoscine was isolated from all parts of the

latter two species and from the leaves of A . belladonna. The roots, stems,



94 ROBERT L. C W K E

and leaves of Scopolia lurida Dun. and S . carniolicaJacq. contained the

two N-oxides of hyoscyamine and the equatorial oxide of hyoscine.

Mandragora oficinarum L. roots, stems with leaves, and fruits containedboth oxides of hyoscyamine. These oxides were probably missed

heretofore because they are not soluble in the solvents customarily

used for alkaloid extraction. The proportions of N-oxide to tertiary base

varied among the organs examined and with different stages of plant

development ( 2 8 ) .

Another oxide, 3a-tigloyloxytropane N-oxide (27), was isolated from

the roots of Physalis alkekengi L. var. francheti Hort., formerly P.

I

04\ / H/C=c

\

-J)-yJ J>x/ H CH3 CH,

I0 4

> C d ,CH3 CH3

2’1 28

bunyardii Makino. Also isolated were tigloidine (28), tropine, pseudo-

tropine, an unidentified alkaloid, and the previously reported 3a-

tigloyloxytropane (29). An investigation of Physochlaina alaica has

revealed the presence of the N-oxide of 6-hydroxyhyoscyamine ( 3 0 ) .

G. A SECOTROPANE

Physoperuvine (28A), new alkaloid isolated from the roots of

Physalis peruviana Linn., appears to be a biogenetic variant of the

tropane alkaloids. The genus Physalis (Fam. Solanaceae) is well known

for its elaboration of a novel group of C,,-secosteroids called physalins

but its alkaloid content has not been determined. The structure of

physoperuvine was established by NMR and mass spectral studies of

QNHCH3 QNTZ

0 OH

Z8A Z8B



2 . TROPANE ALKALOIDS 95

the parent base, its N-benzoyl derivative, and of a methylated a,nd

reduced form 28B. Present knowledge of biogenetic pathways to

tropanes indicates that this alkaloid is a shunt product and not anintermediate in tropane biosynthesis ( 3 0 ~ ) .

III. Syntheses

A. OXALLYLADDITIONSO PYRROLES

A new route to tropanes involved oxyallyl intermediates of the type

29 (L = Br, CO, solvent, etc. and R = alkyl) generated from a,a'-

dibromoketones and iron carbonyls. Trapping these intermediates with

N-carbomethoxypyrrole or N-acetylpyrrole led to substituted tropanes

(30) 3 1 ) . The method suffered in that dibromoacetone could not be

used to give tropanes without substituents a t C-2 or C-4.

29 30

A modified synthesis by the same investigators (32) allowed more

generality. Thus, a,a,a',a'-tetrabromoacetone could be used to give a

2,4-dibromotropen-3-one(31). ebromination was accomplished essen-

tially quantitatively to give 32 n SOY0 yield based on N-carbomethoxy-

pyrrole.

31 32

A simultaneous investigation accomplished the synthesis usingN-methylpyrroles and dibromoketones in the presence of sodium iodide

and copper (33).The yields ranged from 50 to 89Yo. These reactions

have the advantage of being run under neutral conditions.



96 ROBERT L. CLARKE

Another oxallyl equivalent is produced by treatment of silylated

epoxide 32A with fluoride ion whereupon an allene oxide-cyclopropa-

none system 32B s presumed to form. Trapping of this intermediate

- h b ]

-H H

32B

f F A C H z

P h ? iPh, F-

H CH,CI

32A

with N-carbomethoxypyrrole afforded N-carbomethoxy-2-phenylnor-

trop-6-ene-3-one 32c)n 49y0 yield ( 3 3 a ) .An earlier example of this

type of reaction involved dimethylcyclopropanone (3%) .

12c

B. ROBINSONYNTHESIS

whereas earlier expansions of the classic Robinson synthesis ( 3 4 )involved variation of the nitrogen substituent, a recent study (35 , 35a)successfully (25y0yield) substituted acetonylacetone for succindialde-

hyde. The optimum pH for production of 33was 9.Use of heptane-2,B-

dione and diacetonylsulfide gave 1$-dimethylated granatanes and

thiagranatanes , respectively.

31

The same investigators ( 3 5 ) determined the effect of space require-

ments of the alkylamine on yield in the Robinson reaction:

Methylamine 100 180-butylamine 22%

Ethylamine 90% Go-propylamine 50j,

n-Propylamine 74y0 tert-butylamine 0%

n-Butylamine 35y0




A polarographic study of the synthesis of tropinone by the Robinson-

Schoepf method was used to obtain optimum reaction conditions.

Using a 15% excess of acetonedicarboxylic acid and 3% excess ofmethylamine a t 40°C for 30 minutes gave an 82y0 yield of tropinone

(35b) .The synthesis of the optical isomers of tropan-2a-01 and tropan-2/3-01

on a large scale was studied from an economic standpoint (36).The most

efficient route started with acetonedicarboxylic acid and 2,5-diethoxy-

tetrahydrofuran in a Robinson-type synthesis and ultimately produced

dl-anhydroecgonine amide (34). Rearrangement of this amide to

34 35

dl-tropan-2-one and reduction to dl-tropan-2a-ol by known procedures

( 3 7 )gave the material chosen for resolution. Tartaric acid served as the

resolving agent. The enantiomeric 2a-01s could then be epimerized to

2/I-ols (35) by strong alkali (37). One further slight modification of the

Robinson-type synthesis has been reported (37a).

C. DIENONE MINE ADDITIONS

The reaction of 2,6-cycloheptadienone (36) with amines has been

studied further ( 3 8 ) .See Fodor ( I ) or earlier work. Dienone 36 reacted

36 37 38

with p-RC,H,NH, (R = MeO, Me, H, C1, NO,) to give corresponding

N-arylnortropinones (37) n 45--93Yn yields. The lowest yield was

obtained with p-nitroaniline. However, when even one equivalent ofmorpholine was added to 36, a 2:1 adduct (38)was formed. With two

equivalents of morpholine, 38 was formed in 74y0yield.

Another study on addition of amines t o 36 was directed principally



98 ROBERT L. CLARKE

to the preparation of optically active compounds (39) 3 9 )suitable for

study of their circular dichroism (CD). Development of this mode of

tropane synthesis was particularly useful for the large number ofN-substituted derivatives desired (alkyl, aralkyl, cycloalkyl, carboal-

koxyalkyl, and aryl). NMR data were fully discussed. CD information

was published later ( 4 0 )and is discussed in Sections IV-A and VIII.

A further extension of this reaction involved addition of hydrazines and

hydroxylamines to dienone 36 ( 4 1 ) .Acetylhydrazine and 1) -dimethyl

hydrazine gave 40 (R = CH,CONH-) and 40 (R = (CH,),N-),respectively; hydroxylamine gave 40 ( R = OH). 1,2-Dimethyl-

89 40 41

hydrazine, however, produced a diazabicydo[3.2.2]nonane ( 4 1 ) andN-methylhydroxylamine formed both possible N-oxides, 42 and 43.The picrate of the axial oxide shows no carbonyl absorption in its IR

spectrum and presumably exists in the cyclic form 44 ( 4 1 ) .

0

t

picric

X -

4L 43 44

D. FROM RIDGEDZIRIDINES

5-Aminocycloheptene (45) was the starting material for another

tropane synthesis ( 4 2 ) . Lead tetraacetate converted this olefin to abridged aziridine (46) which corresponds to the hypothetical aziridin-

ium salt (47) proposed by Archer et al. ( 4 3 ) to interpret the ready

racemization of d-2-tropanol acetate (48).




46 46

( d ) - 4 8 47 (Z)-48

Reaction of the bridged aziridine 46 with diethyl pyrocarbonate

followed by reduction (LAH) produced dl-tropan-2a-01 49. Quaterniza-

tion of 46 produced 50 which reacted with sodium dimethyl malonate

to form the tropanylmalonic ester 51.

EtOCON CH,N

49

CH , N

CH(COOCH3),

&sC H ( C O 0 CH&

51

6 iFCH3-

50

In another transformation of aziridines into tropanes, ethyl 8

azabicyclo[5.1.O]oct-3-ene-8-carboxylate(51A) rearranged into N -

carbethoxynortropidine (51E)n the presence of dichlorobis-(benzoni-

tri1e)palladium as catalyst. On the basis of NMR and product isolation

studies the reaction appears to involve four steps. A palladium-7r olefin

complex (51B) robably first forms which then undergoes attack by

chlorine on the aziridine ring with cleavage of one C-N bond (giving

51C). Regioselective intramolecular attack on the olefinic bond by-NCOOEt furnishes tropane 51D, nd loss of PdC1, gives the observed

product. This postulated reaction course is supported by diversion of

some of the intermediates with added reagents (43a).



100 ROBERT L. CLARKE

51E51D

E. FROMYRROLIDINES

An earlier study (1961) (44) of the reaction of cis-N-tosyl-2,5-bis-

(chloromethy1)pyrrolidine (52 , R = tosyl) with phenylacetonitrile

(NaNH,, PhCH,) reported isolation of only one (53) f the two possibleisomeric products (28y0). Condensation of the corresponding N-benzyl-

Ph

CH&l

N-R + PhCH,CN +

r:H&I

CN

52 53 64

pyrrolidine (52,R = PhCH,) with phenylacetonitrile in the presence of

NaH and DMF allowed isolation of both isomers (53and 54, R =

PhCH,) (4107, combined yield) ( 4 5 ) .The endo-nitrile 54 predominated

threefold. Separation of the mixture of isomers could be accomplishedby selective hydrolysis, the endo-nitrile being considerably shielded and

difficult to cleave (1 hour at 150°C in 80% H,SO, for the p-nitrile; 48

hours under these conditions for the a-nitrile).




The degree of shielding of the 3a-position is such th at the 3a-acid

chloride can be recovered essentially unchanged following a 3-hour

reflux period in EtOH ( 4 5 ) .Esterification of the pair of acids formed from hydrolysis of 53 and 54

afforded two rigid analogs of meperidine ( 4 5 )which are discussed in the

section on Biological Activity (VI).The 13Cand proton magnetic spectra

of these esters are discussed in Section VI I I .

F. NITRONE-INDUCEDYCLOADDITIONS

In the process of a Cope rearrangement on 5-allyl-3,3,5-trimethyl-l-

pyrroline-1 oxide (55) n boiling toluene the expected product (56)cyclized partially during the reaction to form isoxazolidine 57. The

isolated nitrone 56 was slowly converted to cycloadduct 57 in boiling

0 -

55

__f

CH,

CH;

56 57

xylene. Reduction of 57 with LAH or Pt/H, afforded 1,6,6-trimethyl-

nortropan-3/3-01(58, = H). Catalytic reduction of the methiodide of

57 gave 58 R= CH,) ( 4 6 ) .

RN

58

A similar cyclization was reported shortly thereafter. 4-Nitrobutene,

upon reaction with acrolein in methanol containing sodium methoxide

followed by acidification with dry HC1, afforded nitroacetal 59.Thisnitroacetal was converted to nitrone 60 by zinc (NH,Cl) and the latter

was cyclized by heat to form isoxazolidine 61. Quaternization with

CHJ and reduction with LAH then afforded tropan-3/3-01(62) 47 ) .




62

G. DIPOLAR ADDITIONS

A communication and a follow-up paper (48) describe the synthesis

of some tropanes (64, 65) that are considerably different from those

found in nature. However, structural modification of natural tropane

alkaloids is leading to compounds of such interesting biological activity

(see Section VI) that it appears desirable to record all routes to this

system.

Anhydro-3-hydroxy-1-methylpyridinium ydroxide (63) reacts with

N-phenylmaleimide, acrylonitrile, and methyl acrylate in the first

examples of the C-6-N-C-2 unit of a simple pyridine ring acting as the

1,3-dipole in a dipolar addition.

Compound 63 reacted with phenylmaleimide in refluxing THF to

form 64 n 60% yield, the ex0 configuration being demonstrated by

NMR. In a similar manner (but with hydroquinone present) acrylo-

nitrile added to form 65 with R = CN in an ex0 configuration. Withmethyl acrylate a 1 : 1 isomer mixture (R = COOMe) was reported.

Dimethyl acetylenedicarboxylate gave only resinous products. Maleic

anhydride formed a salt.




Further studies on this reaction (49 ) involved the N-phenyl analog

66 which failed to react with maleic anhydride (see above) and merely

formed a saIt. However, with N-phenylmaleimide, acrylonitrile, andmethyl acrylate this betaine (66) gave the expected cycloadducts as

mixtures of endo and exo isomers in good yields. Unlike the methyl

Ph

66

series, the isomers were easily separable and the structures could be

confirmed by IR, mass, and NMR spectra. Attempted quaternization

with CH,I failed, probably because of the large steric requirements of

the N-phenyl group. In some related work on the N-phenyl analog 66,

it was found that diethyl maleate and diethyl fumarate would react

with 66 to form the expected 3-tropen-2-ones as mixtures of isomers

In a similar reaction N-carbomethoxy-2,3-homopyrrole7 (R = H)

reacted with N-phenylmaleimide (100°C) to form a mixture of exo and

(49u).

COOCH,

I

COOCH:,

I

0 68

p67

endo isomers 68. This same pyrrole reacted with dimethyl acetylene-

dicarboxylate to form 69 (R = H ) . If the pyrrole 67 has R = COOCH,,

this group assumes an ezo configuration in the product 69 (R =

COOCH,). An intermediate dipole (70) is postulated for the reaction

( 5 0 ) .FOOCH,I

COOCH,I

OOCH,I

CH30C H 3 0 aI /

H - H

R -R

69 70




The work on 1,3-dipolar additions to form tropenones has been done

principally by A . R. Katritzky's group, quite a few other papers by

them having appeared. A review on the subject is now available (50u)which contains references to all pertinent publications so only one

other will be described. Treatment of tropenone 70A with a very strong

acid (CF,SO,H) caused cyclization with formation of 70B. Several

analogs were prepared (50b) .

( -N

NCF.SOaH

70A 70B

H. NITROSATIONF PHENYLALANINEROPANYLSTER

A synthesis of atropine (73), ittorine (76), apoatropine (74), and

related alkaloids has been accomplished ( 5 1 )by a one-step deamination

reaction of dl-phenylalanine 3a-tropanyl ester (72). This amino acid

ester was obtained by coupling tropine with N-phthalyl-dl-phenylalanyl

chloride 71 followed by hydrazinolysis with an equimolar amount of

hydrazine hydrate.

PhCHa-CH-COCI PhCHa-CH-COORI I

71

O \

U0PhCH CH-COOR

INHa

N2H4A




Nitrosation of amino ester 72 using NaNO, and 2N H,S04 a t room

temperature gave a mixture of six tropine esters, 7%78, two of which

(73 nd 74) involved phenyl migration.

Ph4H-COOR Ph---CHz-CH-COOR

IO H

ICHzOH

73 76

E O N 072 ___f

P h - G - C O O R P h 4 H d H - C O O R

c i s 77

74 tram8 78

IICHZ

Ph-CH-CH&OOR

IOH

75

A related synthesis of natural littorine and hyoscyamine also started

with phenylalanine, in this case with the D-isomer. I n this sequence the

amino acid was deaminated and the resulting phenyllactic acid was

esterified with tropine, giving littorine. The tosylate derivative (78A) of

this ester was solvolyzed with trifluoroacetic acid in the presence ofsodium trifluoroacetate, phenyl group migration occurring in the process

and producing the trifluoroacetate ester (78B)of hyoscyamine. Hydroly-

sis with aqueous HC1 then give hyoscyamine (51a).

ooc 0

II00s

H +-O T~ H++CH,OCCF,- -

phazCH,Ph

78A 78B

I. PHOSPHOROUSND SULFURNALOGS

Although the phosphorous analogs of natural tropanes are quite

different f rom the natural alkaloids, it appears worthwhile to acknowl-

edge their existence. Structures of types 79-82 have been prepared (52).




0

IIR-P

79 80

81 82

Formulas 82A and 82B llustrate two of eight sulfuranalogs of tropanes

which have been synthesized (5%).

82A 82B

J. RADIOLABELEDROPANES

Acid catalyzed exchange tritium labeling of cocaine gave randomlylabeled [3H]cocaine of 98y0 sotopic purity and specific activity of 630

pCi/mg. Similar tritiation of ecgonine followed by esterification,

benzoylation, and exhaustive purification provided ring-labeled [3H]-cocaine of 99% isotopic purity and specific activity of 48 pCi/mg (53 ) .

Z-(p-Butoxybenzyl-a-t hyoscyaminium bromide (83)was prepared by

condensation of p-butoxybenzyl-a-t bromide with I-hyoscyamine in

40 yield. The tritiated benzyl bromide was prepared by reducing

p-n-butoxybenzaldehyde with tritium-enriched hydrogen and treating

the resulting benzyl alcohol with 48y0 HBr ( 5 4 ) . Esterification ofbenzoylecgonine and benzoylnorecgonine with tritiated methanol

afforded cocaine and norcocaine bearing a label on the methyl ester

group ( 5 3 4 .




The reaction of neonorpsicaine (84,R = H, R’ = C3H7)with CTH,I

yielded [N-3H,-methyl] neopsicaine (84, R = CTH,, R’ = C3H7).In

order to obtain a randomly labeled sample of psicaine (84, R = R’ =CH,) this compound was adsorbed on silica gel and exposed to tritium

8 ,CHT-CeH,OBu

COOR‘~3I Br- J>xOCOPhCHpOH

0--CCH-Ph

83 84

gas at room temperature for 11 weeks (modified Wilzbach method).

Chromatography of the material eluted from the silica gel gave a 32y0

yield of single tlc spot psicaine with a specific activity of 90.7 mCi/gm

corresponding to 30.8 mCi/mmole. The distribution of tritium in this

[3H]psicaine in the benzoic acid, in the pseudoecgonine, and in the

CH30 group was 84.5:11.5:4 (55).

IV. Reactions

A. QUARTERNIZATION

The stereochemistry of quaternization of tropanes has been the

subject of controversy for quite a few years. Fodor’s 1971 review of

tropanes in this treatise concluded that equatorial attack (with respect

to the piperidine moiety) predominated, although in many cases asubstantial product was formed from simultaneous axial attack. The

observed facts seem to indicate that diaxial interaction of the 28- and

4p-hydrogens with the approaching reagent is greater than that caused

by the 68- and 78-hydrogens. Angular deformation of the five-mem-

bered ring helps to diminish this latter compression. Furthermore, the

group already bound to nitrogen can accommodate more easily to

2,4-diaxial compression than the incoming group, which, in the tran-

sition state, is a charge-separated and solvated species ( 1 ) .

In a review on quaternization of piperidines in which tropanequaternization was discussed at about this same stage of development

(1970) (56 ) , McKenna still had some reservations about the steric

course of these reactions. He concluded that, with a nitrogen atom




positioned commonly to two different rings, qualitative predictions of

stereospecificity are difficult.

Another review appeared in 1970 by Bottini (5 7 )who reported thatthe discrepancies in the controversy had been pretty well resolved and

that equatorial attack seemed to be the predominant mode in tropane

quaternization. He published a summary table showing reported

quaternizations, reaction conditions, and product ratios.

The possibility tha t it is the pyrrolidine ring of the tropane system

that is the directing influence was considered by Otzenberger et al. (58).With tropane viewed as a piperidine, N-alkylation has t o be considered

as primarily equatorial, in contrast to the wealth of data demonstrating

that piperidines undergo preferential axial alkylation. This anomalycan be eliminated, however, by considering tropane as a substituted

pyrrolidine. Therefore, in this series we can expect axial alkylation.

Bottini et al. (5 9 ) substantiated the configurational assignment of

N-ethylpseudotropinium bromide by means of X-ray analysis. They

also made the interesting observation that in the process of quaternizing

tropinone there was an 88:12 equatorial: axial attack ratio a t 70y0

reaction ( 3 0 minutes) and a 7 7 : 2 3 ratio at the end of 2 4 hours. With

added tropinone or pyridine, this ratio fell to 50:50. In this instance, an

equilibration may be occurring through reverse Michael addition withtransient formation of cycloheptadienone followed by readdition. Such

addition of secondary amine salts to cycloheptadienone has been

observed (38 , 39, 4 1 ) .

Another example of this equilibration &furnished by Kashman and

Cherkez who found that aqueous solutiens of N-[(AS)-a-phenethyll-

nortropinone methiodide underwent equilibration a t room temperature

in 48 hours to give a 40:60 mixture of 85 and 86, respectively. The

equilibrium could be attained from either-ure isomer ( 4 0 ) . This same

work possibly provides a means for establishing the structures of certainisomeric quaternary salt pairs, namely through measurement of circular

dichroism induced by a chiral center awched t o the nitrogen. A

85 86




carbonyl group at C-3 enhances this effect for that isomer with the

chiral group in an axial configuration (85). Some further discussion of

this work is given in Section VIII.Supple and Eklum (60)quaternized some tropidines (87) where the

pathway for axial approach of the alkylating agent would be less

CHaPhe/

H3iR, phcHhR e l Br- c

I -

87 88 89

hindered by axial hydrogens, whereas equatorial approach would

suffer essentially the same interactions as in the tropanes. Larger

proportions of products from axial attack might be expected. Treatment

of tropidine (87, R = CH,, R‘ = H) and 3-phenyltropidine (87, R =

CH,, R’ = Ph) with benzyl bromide gave 92 and 91% yields, respec-

tively, of the products resulting from equatorial attack (88,R = H and

88, R = Ph). The same predominance of equatorial attack was observed

upon inverse addition of the substituents on the nitrogen. Thus,N-benzylnortropidine (87, R = PhCH,, R’ = H) reacted with methyl

iodide to give 8 4 7 , of 89.

It should be kept in mind that the configurational assignments in the

Supple-Eklum work are based primarily on the generally assumed

principle that a reference compound, “3-phenyltropine, should quater-

nize principally by equatorial attack.” In this series, the axial methyls

were upfield of the equatorial methyls, a finding in accord with earlier

reports from established series ( I ) .There were some NMR data on non-

equivalence of ,certain benzylic methylene protons that stronglysupported the assigned structures.

Thut (61)studied the stereochemistry of quaternization of tropane,

tropine, pseudotropine, and tropinone with ethyl haloacetates, benzyl

halides, and benzyl benzenesulfonates but the results were incon-

clusive.

A sophisticated I3C NMR study has just appeared that shows the

practicality of determining configurations about the nitrogen of

tropane quaternaries using this tool. The systems studied bore only

alkyl groups on the nitrogen (61a).For further details see Section VII I .At this time, there seemed to be a rather consistent picture of

predominantly equatorial attack with respect to the piperidine moiety

in tropanes. But in 1974, a report by Szendey and Mutschler (62)




appeared that stated that benzylic bromides reacted with tropine

principally by axial attack.

The “direct” reaction (Eq. 2) gave the isomers shown with a selec-tivity of 98,96, and SOY o , respectively forR1,2,nd R3.The previously

reported patterns of quaternization ( I )and observed downfield locations

R(1.2.3)

e /

d H d H

R’ = PhCHi-

R2 = PhCeH4CHz-

R3 = -CH~CBH,CBH*CH~

(NMR) of methyl groups (1) versus the reverse isomers) would lead

ordinarily to assignment of configurations opposite t o those shown here.

However, the authors made their structural assignments on the basis

of mass spectral fragmentation patterns. Their basic assumption was

that equatorially bound ligands would have a higher energetic stability

than the axial ligands, and thus a greater amount of RBr (or fragments

thereof) than CH,Br would appear from the above isomers. In like

manner, the isomeric forms (90) would produce a preponderance of

CH,Br.

CH3e/

R(1.2.W-N

IOH

90

The mass spectral data (reported for R2 nd R3)showed consistent

patterns that were considered valid enough to use as a basis for assign-

ment of the structures shown. Unfortunately, there are no data available

on mass spectral fragmentation patterns of quaternary salts of provenconfiguration. Even so, i t would be hazardous to extrapolate those data

to these benzylic systems. Hopefully it will be possible to settle this

question eventually by X-ray analysis.



2. "ROPANE ALKALOIDS 111

Referring again to the work described above by Supple and Eklum

( 6 0 ) , those authors found that direct benzylation of tropidine with

benzyl bromide gave a 92:8 isomer mixture and that methylation(CH,I) of N-benzylnortropidine gave a 16:84 mixture, i.e., a consider-

able predominance of specific attack in each case. Szendey and Mutschler

( 6 2 )found that benzylation of tropine gave a 98:2 ratio of products but

that methylation (CH,Br) of N-benzylnortropine gave a 5 5 :45 ratio

(rather nonstereospecific).

Reaction rate measurements were used by Weisz et al. ( 6 3 ) o deter-

mine the effect of various substituents in the tropane skeleton upon the

reactivity of the tropane tertiary nitrogen. Cocaine (91) and ecgoninol

(92), with axial substituents on C-2, react slowly with CH,I a t room

CH,N J

2)OHCPh OH

91 92

temperature and not a t all with ethyl iodoacetate. [This reaction

selectivity was used elsewhere to separate a mixture of tropanes that

were epimeric at C-2 ( 6 4 ) . ]Likewise, the two p-hydroxyl groups of

teloidine (93, R = a-OH) and teloidinone (93, R = 0) greatly hinder

quaternization. But surprisingly, the single 6j3-hydroxyl function of

HOHR HoJ?T

R93 94

3a,6p-dihydroxytropane (94, R = a-OH) and 6p-hydroxytropinone

(94, R = 0) does not affect the rate of methylation as compared with

the corresponding derivatives containing no 6p-hydroxyl group.

Under more vigorous conditions ( S O T ) , ecgoninol diacetate reacts

with ethyl iodoacetate (65), but in boiling toluene this addition is

reversed (66).

The preparation of quaternary salts is often complicated by accom-panying dehydrohalogenation of the alkyl halide used. A hydrohalidesalt of the tertiary amine then precipitates together with the quaternary.

It has been found that addition of ethylene oxide to such reaction




mixtures acts as a scavenger of the acid, regenerating the amine which

is again free to quaternize. 1-Scopolamine was quaternized with 3,3-

dimethylallyl bromide, (2-methylcyclopropyl)methyl bromide, cyclo-butylmethyl bromide, and 2-cyclopropylethyl bromide to give the

corresponding quaternary salts in 66,48,51, and 61% yields, respectively

(67)..

Tropine, atropine, and hyoscyamine were treated with propane-

sultone(1,3) and butanesultone-(1,4) to give inner salts of type 95 where

n = 3 or 4. These crystalline salts were quite soluble in most common

organic solvents and had high melting points ( 6 8 ) .

CH3(-)O&I--(CH~)~-N, Ll

OR

95

B. N-OXIDES

A reaction related to quaternization and one that raises the same

questions about stereochemical course is the formation of tropane

N-oxides. The major product from the N-oxidation of scopolamine has

been fully characterized by X-ray crystallographic analysis in the form

of 1-scopolamine N-oxide hydrobromide monohydrate. I t s N-methyl

group is axial and the oxide function is equatorial (96).

0

t

o ~ o ~

0 CHaOHOR

97OR II I

96 R = -G-CH-Ph

Huber et al. went on to examine by 100 MHz NMR spectroscopy the

crude reaction mixtures from oxidation of scopolamine, atropine, and

tropine (H 20 2 n EtOH at 30°C). Both atropine and tropine gave

product ratios of 3:l of the N-oxides, the major N-methyl resonances




being a t lower field in each ( A S = 0.1 and 0.03 ppm, respectively). In

contrast, the methyl resonance of the major oxide from scopolamine

appears at higher field (AS = 0.21 ppm). Assuming that the majorproduct from atropine and tropine has an equatorial oxide configuration,

it must be concluded that the epoxide oxygen of the scopolamine

deshields the equatorial methyl of (97)and causes the observed reversal

of methyl signals in th at substance relative to tropine and atropine (69).

Isomeric pairs were not isolated in pure form.

About the same time Werner and Schickfluss ( 7 0 ) described the

oxidation of tropine with H 202 n EtOH (reflux) with actual isolation

of the two possible N-oxides. On the basis of their NMR spectra (100

MHz but not very well defined), the major product (65y0)was tenta-tively assigned the configuration with oxygen axial; the minor product

(2.8y0)was drawn with the oxygen equatorial. No interpretation was

given to the N-methyl peak positions. The configurational assignments

[the reverse of the assignments for tropine in the study just described

(69)l were made on the basis of the positions of what were assumed to

be the C-2 and C-4 axial hydrogen peaks.

A 220 MHz study by Bachmann and Philipsborn ( 7 1 ) of this same

pair of isomeric N-oxides (one pure; one a 2 : l mixture) gave very clear

spectra that allowed assignment of each hydrogen resonance. Thefallacy in assignment of the C-2 and C-4 axial hydrogen peaks in the

100 MHz work just described was demonstrated and the major product

was shown to have the oxygen actually in the equatorial configuration.

This equatorial oxygen deshields the 6/3 and 7 8 hydrogens quite

significantly. The N-methyl peaks are reported with a difference of only

0.01 ppm, the major product (axial methyl) being a t lower field.

The final chapter of this particular story was written by Werner’s

group recently (71a) when dipole moments were determined on both

pure isomers, X-ray structure analysis was performed on one of these

and 200 MHz NMR spectral studies were made of both isomeric

[2,2,4,4-D4]tropine-N-oxides.he assignments of the Huber, the

Bachmann and the Werner groups are now in agreement. Yet another

study of tropine N-oxides was not very satisfactory since the isomers

were not separated ( 7 2 ) .An analytical procedure for the determination

of N-oxides such as t,hose from atropine and scopolamine involves

controlled potential coulometry ( 7 3 ) .

The isolation of some N-oxides from plant sources was described

in Section 11, F (28-30) .Although an earlier report expressed preference for H,02 over

m-chloroperbenzoic acid for N-oxide formation (69), the most recent

paper on the subject recommended the peracid ( 2 8 ) .




C. NITROXIDE ADICALS

Stable dialkyl nitroxide radicals other than sterically hindereddi-tert-alkyl nitroxides were unknown until 1966. Those nitroxide

radicals that were unstable (98) appeared to decompose by dismutation

to a nitrone (99) and a hydroxylamine (100) or, a t least, to involve a

nitrone as an important intermediate. A clever solution to the stability

98 99 100

problem was achieved through the synthesis of norpseudopelletierine-

N-oxyl (101),a ring system that does not allow formation of a double

bond between the nitrogen and an adjacent carbon (Bredt's rule). This

radical, although stable in the solid state and in benzene or water

solution, is very reactive (much more so than the related 2,2,6,6-

tetramethylpiperidine-N-oxyl), and the ESR absorption disappears

rapidly in acidic or in basic solution ( 7 4 ) .

The same group went on to study 1,5-dimethylnortropinone-N-oxyl(102) and determined all proton hyperfine splitting constants with

0 .I

0 .

IN N

101 102

magnitude and sign and with complete specific assignments ( 7 5 ) .X-ray

analysis of this N-oxyl ( 7 6 ) has shown that the N-0 bond (103) is

inclined a t an angle of 24.9" to the plane of C-1-N-C-5. This angle

is comparable with those shown by other nitroxyls and is less large than

th at of 30.5"shown by granatane-N-oxyl. As in the granatane case and

contrary to the finding with pseudotropine, the N-0 bond is inclined

toward the ring containing the carbonyl group. This inclination has

been predicted by calculation of conformational effects ( 7 5 ) .Nortropine-N-oxyl was reported in 1970 from oxidation of nortropine

with 307' H202 in the presence of NaWO,. I ts EPR spectrum was

shown ( 7 7 ) .




101 104

The first of a series of papers by a Canadian group (78) reported that

nortropane-N-oxyl (104) is stable a t room temperature in neutral

solution. Since the electron paramagnetic resonance signal due to this

radical in solution could be reversibIy decreased and increased by cooling

and warming, it was assumed th at 104 could form a diamagnetic dimer

at low temperatures. The free nitroxide radical is relatively more

abundant below room temperature in CF,Cl, than in isopentane.

During the course of studies on this reversible dimerization of

nortropane-N-oxyl(79), it was discovered t hat an irreversible dimeriza-

tion was occurring. This change was accelerated by heat but transpired

fairly readily at room temperature in CC1, ( 8 0 y 0 in 12 days). The

principal dimeric product was 105.However, when dimerization took

place in the presence of silver oxide, a second dimeric product (106)was

isolated (dark red crystals, 2%). It was also noted in this report that

0

?--@ fjqh05 106

nortropane-N-oxyl oxidized aqueous hydrogen peroxide rapidly a t room

temperature with copious gas evolution, whereas 2,2,6,6-tetramethyl-

piperidine-N-oxyl was inert to these conditions.

The material in the communication just discussed (79) is reported in

more detail in two follow-up papers ( 8 0 ) .Here, the N-oxyls of nortro-

pine and norpseudotropine were also described. Labeling studies showedthat the bridgehead hydrogens were not involved in the irreversible

dimerization to form 105. The most recent paper in this Canadian

series (81) overs some calorimetric and equilibrium studies on nitroxide




and iminoxy radicals. Equilibrium constants are given for some radical-

oxime reactions in benzene where nortropane-N-oxyl is one of the

radicals utilized.Excellent yields of nitroxides in nonaqueous medium have been

obtained with m-chlorobenzoic acid and with CH,CN-CH,OH-WO,

(very little water) (81~).

Electrochemical oxidation of seven different nitroxyl radicals (two

tropanes) has been investigated in CH,CN with a platinum electrode.

The oxidation is a reversible, one-electron process leading to an

oxammonium ion (Eq. 3) 8 2 ) .

D. COCAINEANALOGS

Some cocaine analogs have been prepared for biological purposes;

the testing results are described in Section VI. However, the chemical

reactions are appropriately detailed here.

Benzoylation of tropane-ZP,3p-diol with one equivalent of benzoic

anhydride with a routine work-up gave the 3-benzoate (107) as the

major product together with a small amount of 2-benzoate (108)and a

very small amount of dibenzoate. It was shown that the %benzoate is

107 108

intermediate in the formation of the 3-benzoate. Acetylation of these

benzoates then gave some reverse-ester analogs of cocaine ( 8 3 ) .

8-Ethoxycarbonylnortropane-2/3,3/3-diol,n intermediate used in thesynthesis just described, reacted with variously substituted benzalde-

hydes to form isomeric acetals 109 and 110 (R = EtOCO-). Configura-

tions were assigned to these isomers on the basis of NMR data. Lithium



2. TROPANE ALKALOIDS 1 1 7

109 110

aluminum hydride converted them to the corresponding N-methyl

acetals 109 and 110 (R = CH,).Acetals 109 and 110 (R = EtOCO-) were converted by N-bromo-

succinimide (BaCO,) into a single bromoester, 111, which was trans-

formed by aqueous alcoholic potassium carbonate into the 2/3,3,%epoxide

Br

111 112

112. Hydrolysis of this epoxide produced a diaxial diol, 113, which

failed to form acetal 114 (Eq. 4). Such acetal formation would have

required a boat conformation for the piperidine moiety ( 8 4 ) .

nIE t O C N E t O C N

I \ OH I

O H113 114

A series of central nervous system stimulants was prepared in which

the elements of COz were (formally) removed from cocaine, i.e., the

aromatic ring was attached directly to carbon-3. Phenylmagnesium

bromide reacted with anhydroecgonine methyl ester (115) in ether at

- 0°C in the absence of copper salts to form a 1:3 mixture of 28-carboxylate 116 and 2a-carboxyIate 1I?. Structural assignment was

based upon NMR data and reduction to the corresponding alcohols

(118 and 119), one of which showed intramolecular hydrogen bonding.




CH,N

\\ ,COOCH3

115

CH,N

115 COOCHj

Ph

PhMgBr4 16

CH,N

I\

117

The axial ester 116 quaternizes more slowly than the equatorial ester

117, fact that can be used to separate isomer mixtures when it is

desired to recover only the axial (stimulative) isomer. Attempts to

influence the ratio of isomers formed in the Grignard reaction failed

( 6 4 ) .

-**‘H-o\

z)<phX Y H

118 119

Treatment of either the axial ester 116 or the equatorial ester 117

with polyphosphoric acid at 150°C produced a single product, a 1,3-

ethanoindeno[2,1-c]pyridine, 120. A series of such compounds was

studied for analgesic activity (85).

120

In 1896 tropan-3-one was found to react with HCN to form a single

crystalline cyanohydrin (86).Only one crystalline isomer was obtainedby addition of HCN to nortropan-3-one many years later (1957) (87),and both compounds were shown to belong to the same series, i.e.,

a-cyano-p-ols (121). These cyanohydrins were then converted by




CN

1 2 1

COOCHB

122

conventional means to a position isomer of cocaine called a-cocaine

(122). Recently, N-benzylnortropan-3-one was treated with HCN and,

when the adduct could not be induced to crystallize, the crude oil was

hydrolyzed with concentrated hydrochloric acid and the resulting

carboxylic acid was esterified (see Eq. 5 ) . Both of the possible epimers

were isolated (123 and 124). Presumably both cyanohydrins ordinarily

CN

COOCH,123

I

OH

P h C H a N

O H124



120 R O B E R T L. C L A R K E

form, but if one crystallizes (as was the case with tropan-3-one and

nortropan-3-one), the equilibrium is shifted and little of the other

epimer remains. Hydrolysis of the oily N-benzyl cyanohydrin was thusable to provide both forms. The new ester (124) afforded an opportunity

to make the unknown /?-cocaine. Benzoylation of the axial hydroxyl

group proved difficult, but treatment with potassium hydride followed

by benzoyl chloride was effective (see Eq. 6 ) . Debenzylation and

methylation then afforded /3-cocaine (125) (88).

PhCH&,

(1) K H ( 1 ) HdPd

( 2 ) PhCOCl (2) H C H O

-H C O O HCOOCH,

IOCOPh

OCOPh

125

E. DEMETHYLATION

For many years the primary route to nortropanes lay in demethyla-

tion of tropanes by KMnO,, K,Fe(CN),, or cyanogen bromide. Another

method, which has found little use (89), as first reported in 1927 (90).

The N-oxides of several tropanes were treated with acetic anhydride

and the resulting N-acetylnortropanes were hydrolyzed (see Eq. 7)

(89).Trifluoroacetic anhydride has also been used in this transformation

(29).The usefulness of these early methods should not be discounted.

Proper control of pH in the oxidation of cocaine by permanganate has

furnished a yield of norcocaine based on recovered starting

material ( 9 0 ~ ) .




Recently, the use of chloroformic esters has become the method of

choice (83,91-93).Although ethyl chIoroformate reacts with tropan-3a-

01 acetate t o give urethane 126 in high yield, the same reagent reactswith tropan-3a-01 (the free alcohol) to produce a large amount of

0 0

EOJ) I t ~ EJ) II ~ 3)OAc OH OH

126 127 128

resinous material and only a little of the desired urethane 127. Both

products, however, are easily hydrolyzed with strong hydrochloric acid

to nortropan-3a-01 (128). With tropinone, the ethyl chloroformate

reaction goes well, but the hydrolytic step fails to produce any of the

desired nortropinone (93).

This problem in demethylation of tropan-3-one has been solved by

formation of an ethylene ketal (129),which reacted cleanly with ethyl

0II

129 130 131

chloroformate. The resulting urethane (130)was then hydrolyzed with

potassium hydroxide to generate the nor product (131).Acid hydrolysis

removed the protecting group (94).

Another variation of the N-demethylation procedure utilizing alkyl

chloroformates involved phosgene. Thus, treatment of tropan-3-one in

toluene at 10°C with phosgene in toluene and heating the product inwater until CO, evolution ceased gave nortropan-3-one. The hydroxyl

group of scopolamine was protected by acetylation prior to phosgenetreatment (95).

It should be noted that benzyl chloroformate gave very poor yields

of urethanes in the demethylation procedure under discussion (96).




Phenyl chloroformate gave good yields a t room temperature ( 9 2 ) ,and

vinyl chloroformate was quite effective, reacting exothermically a t

room temperature ( 9 6 ) .2-Chloroethyl chloroformate was used to demethylate a 3-phenyl-

tropane-2-carboxylic ester with the expectation that the resulting

urethane (132) ould be cleaved with zinc and alcohol, thus avoiding

hydrolysis with strong acid which would attack the ester. When zinc

0

132‘0

133

and alcohol (or acetic acid) failed to effect reaction the function on the

nitrogen was cleaved with chromous perchlorate ( 6 4 ) .

It turns out tha t 2,2,2-trichloroethyl chloroformate is the reagent of

choice for tropane demethylation. It produced from tropinone a good

yield (95y0) f trichloroethyl carbamate (133) hich was easily cleaved

by zinc in methanol or acetic acid ( 6 2 % ) ( 9 7 ) .

In addition to their usefulness as intermediates in the preparation of

nortropanes, the urethanes under discussion can be reduced with

lithium aluminum deuteride to form labeled tropanes. Thus, N-

ethoxycarbonyltropine is converted (6 6 y 0 ) to 133A (97a ) .

OH

133A

In the von Braun demethylation procedure, an intermediate N-

cyanoammonium salt structure has been considered probable. Such

intermediates have been isolated as crystalline solids by combining

tropine, pseudotropine, and tropinone with cyanogen bromide a t - 0°Cto - 0°C. These salts ordinarily decompose near 0°C to give N-cyano-

amines and CH,Br. However, conversion to fluoroborates (AgBF,)

effected considerably greater stability ( 9 8 ) .




Photooxidation of tropinone (98a) , tropan-3a-01, tropan-3/3-01, and

deoxyscopoline (98b) has caused N-demethylation. The presence of a

benzoate chromophore as found in cocaine, benzoyltropine, andbenzoylpseudotropine aids in the removal of the N-methyl group.

Cocaine yielded 20y0norcocaine together with 70y0 recovered cocaine.

It is not necessary that the benzoyl group be in close proximity to the

N-methyl reaction center but the specificity of the reaction for bicyclic

compounds with N-methyl bridges compared to monocyclic ones isapparently due to the operation of Bredt’s rule on a proposed imine

intermediate (98c).

F. REDUCTIONF TROPINONE

Until recently, reduction of tropinone to tropine with high stereo-

selectivity has been achieved only by catalytic reduction (see 99).Thisselectivity depends upon the presence of the basic nitrogen as evidenced

by the fact that 8-ethoxycarbonylnortropan-3-one s reduced by

Pt/EtOH (or HOAc) to give a 3:l mixture of the 3a- and 3p-01~espec-

tively ( 8 3 ) .A stereoselective chemical reduction has now been described.

Diisobutylaluminum hydride in tetrahydrofuran at - 78°C reducestropinone to form of the 3a-01 accompanied by only 3y0 of the

3p-01 ( 100) .Another example of this is described by Noyori et al. ( 3 2 ) .In a comparison of various methods of reduction of tropinone the

results tabulated below were obtained ( 2 9 ) .~~

3a/58-01Reagent Ratio

Na/EtOH 1/24Na/i-BuOH 1/27

Hz, PtOa, EtOH 99.410.6

NaBH, 54/46

Hz, PtOa, EtONa 1211

A somewhat surprising catalytic hydrogenolysis of ketone to methyl-

ene has been reported (101). ropinone, tropan-6-one, and 6p-hydroxy-

tropinone are reduced to ropane, tropane, and tropan-6p-01,respectively,

by hydrogen in the presence of PtO, in weight equal to that of the

ketone and a molar excess of acid. The obvious alcohol intermediatesin the reaction are untouched by the reaction conditions. Earlier

examples of this type of reduction are to be found in some work on

cyclitols ( 102) .




In a reaction conducted on a thin-layer chromatographic plate,

tropinone was reduced with a NaBH, spray reagent a t 50°C. The

products were then separated by normal plate development ( 1 0 3 ) .Photochemical studies indicate that /?-aminoketones (especially

tropinone) are subject to photochemical reduction, probably yielding a

highly fluorescent p-amino alcohol among the reaction products (1 0 3 a ) .

G. TROPANYLTHERS

Until fairly recently there was no good general method for preparing

tropanyl ethers. In 1968 a report appeared (1 0 4 ) of the conversion of3a-chloro-, 3a-bromo-, and 3a-mesyloxytropanes in to 3a- and 3/?-phenyl,

n-butyl, methyl, and thiophenyl ethers in moderate (21-48y0) yields

with concomitant elimination and fragmentation. More recently, this

same group published four papers (105-105c) that described many more

ethers and showed that (a ) for strong nucleophiles (PhO-, PhS-), S,2

reactions predominated over SN1and gave /?-substituted tropanes; (b)weaker nucleophiles (CN- , N3-) involved both mechanisms; (c) with

compounds containing basic nitrogen (PhCH,NH,, PhCH,CHMeNH,)

the SN1 mechanism predominated, giving a-derivatives; (d) the

character of the displaced group played a role, i.e., PhO- reacted with

the 3a-mesylate with inversion but with the 3a-chloride with retention

of configuration. I n configurational studies it was shown by dipole

moments that a C-3 phenoxyl group in the a-orientation causes con-

siderable distortion of the tropane skeleton.

The mechanism for formation of benzhydryl ethers from /?-di-

alkylaminoalcohols has been postulated ( 1 0 5 4 as involving initial

formation of a quaternary ammonium salt followed by a nucleophillic

attack by oxygen on the tertiary carbon atom and extrusion of the

nitrogen (see I33B). Since such a mechanism would be impossible in the

formation of 3a-tropinyl o-methyl-0’-methoxybenzhydrylther (133C),only a direct attack on oxygen can be considered (105e) .

l33B 133C




Another approach to ether formation at C-3 featured treating the

anion from 8-benzylnortropane-3a-01 or ,9-01) (134) with m- or p -

fluorobenzotrifluoride (135) in dimethylformamide a t 60-70°C (seeEq. 8). The ethers produced (136) have the same C-3 configuration as

that of the tropanol used. The benzyl group was then cleaved and other

substituents placed on the nitrogen for biological studies ( 106) .

(8)hCH,NApq q c F 3 - p h ~ k i o d

0 - / \-134 135 136

H. MISCELLANEOUS EACTIONS

A study of asymmetric induction involving an optically active

Wittig reagent [(R)-benzylidenemethylphenylpropylphosphorane137)]

included its reaction with tropan-3-one to produce optically active

3-benzylidine-8-methyl-8-azabicyclo[3.2.loctane (138)of unknown con-figuration and optical yield (107) .

CH3N,

HPh\+ - /

C3H,-P-C

CH,/ ‘Ph

137“H

138

Willstgtter et al. (108) obtained an unknown crystalline product by

benzoylation of methyl 3-oxotropane-2-carboxylate139). PMR and IR

spectrometry have shown (109) his product to be methyl 3-benzoyloxy-

trop-2-ene-2-carboxylate140). Attempted hydrogenation of 140 to a

cocaine epimer failed.

CH3N

COOCH,

0

4>---qXOCH3

‘&C-Ph

139 140




The preparation and characterization of the tropic acid esters of

tropan-3j3-01 and granatan-3a and 3p-01 are described (110).

Earlier efforts to prepare tropane-3j3-aceticacid (141) had given verypoor yields (111). urther studies have developed a satisfactory route

to the corresponding 3a-acetic acid 142 (llZ),ut none of the 3j3 epimer.

141

CH,COOH

142

N-Acetylnortropanone (143) reacted with malononitrile in the presence

of piperidine and acetic acid to form a dicyanomethylene derivative

(144). Catalytic hydrogenation followed by acid hydrolysis led exclu-

sively to the 3a-acid 142 (Eq. 9).

CH,CON

- 42 (9)

*oH* 143 144 ‘\CNCN

Addition of HCN to the dicyanomethylene intermediate 144 gave

trinitrile 145,which hydrolyzed and decarboxylated to form dicarboxylic

acid 146 (Eq. 10). Attempts to esterify this dicarboxylic acid failed.

CHaCON

144- H< +H CH,COOH (10)

CN COOH

145 146

Approaches to the 3j3-acetic acid 141through halomethyl or tosyloxy-

methyl intermediates (147, R = C1 or OTs) failed owing to ready

quaternization forming 148 (Eq. 11).




R - ( 1 1 )

148147

This problem of intramolecular alliylation in the synthesis of 3/3-

substituted tropanes was avoided by protecting the nitrogen with atosyl group. Tosylated nortropane carboxylic ester 148A was reduced

to tropanemethanol148B which was then sequenced through R’ = OTs,

TsN R N

1 4 8 A 148B , R = Ts, R’ = O H148C, R = H, ’ = C O O H

R’ = CN and R’ = COOEt to 148C, the acid desired earlier. The

tosylate group was removed in the process of nitrile hydrolysis.The /?-configurationof the acetic acid group was demonstrated by

converting the 3/3-acetic ester substituent above to hydroxyethyl, to

chloroethyl (148D), and finally (cyclizing) to tropaquinuclidine 148E

(112a) .

HN

148D 148E

Several dl-tropic acid esters of tropan-3-01s were prepared by a

transesterification procedure. Thus, tropine reacted with the aldehydo-

ester 148F to form tropine ester 1486 (R = CH,). Reduction of the

aldehyde function then gave atropine. The method was applied to

ICHO

IPh-CH-COOCH,

1 4 8 F




nortropan-3a-01s carrying a broad variety of groups on the nitrogen.

N-isopropylnortropan-3~-01 nderwent the same transformations

(112b) .Tropane-3,6-diol esters were used to demonstrate the selective

hydrolysis of dihydrocinnamate esters (DHC)by a-chymotrypsin. The

mixed ester 149 was hydrolyzed only a t position 3 by a-chymotrypsin,

ODHC

149

Y--chymotrypsin

J

O H

150

ODHC

151

forming 150. Carefully controlled basic hydrolysis gave selective

cleavage a t position 6 with formation of 151 (113) .

Solvolysis of unsaturated tosylate 151A in 70ojb aqueous dioxane

occurred 2.1 x lo5 faster than did solvolysis of its saturated analog

151B. The reaction involving the saturated tosylate 151B produced only

O T s

l 5 l A

C H z \ O T a

151B

a trace of the parent alcohol together with 37% of 3-methylenetropane,

20y0 of 3-methyltrop-2-ene, 9% of 3,8-methyltropan-3a-01,and 10% of3a-rnethyltropan-3/3-01.Synthesis of the required tosylates was accom-

plished via hydroboration of appropriate 3-methylene intermediates

(113~).




Grignard reactions on tropinone have not been very satisfactory,

presumably owing to formation of insoluble complexes with the amine

moiety prior t o reaction. Conversion of tropinone to urethane 152 bymeans of ethyl chloroformate gave a neutral ketone th at reacted with

aliphatic Grignard reagents to form 153 n moderate yields (R = benzyl,

0 0

II IIE t O C N

h52 E t o a R53 OH

5 0 % ; R = methyl, 32%; R = ethyl, 33%; R = propyl, 23%). Although

the urethane moiety was claimed not t o be attacked, some 4070of the

reactants were not accounted for in the highest yield reported. The

single isomers isolated were presumed to have axially oriented hydroxyl

groups; with 153 (R = benzyl), the orientation was proved ( 1 1 4 ) .

A spiro tropane (154) was prepared by the following sequence of

reactions (Eq. 12) ( 115) .The authors were not aware of the Heusner

CH,NH2 CH2-NH

I54

work on HCN addition to tropinone ( 8 7 )and agree (private correspon-

dence) th at the configurations shown here a t C-3 are correct. In a

second phase of this work, butyronitrile was condensed with tropinone.




CHsN CH3N CH3N

& h + , A l H A + , H O HH,CH&HCONHp ~ ~ / o \ c N opHs-CH H

CH&H&HCN

155 156 157

The resulting cyanoalcohol (155) was hydrolyzed (156) and converted

to oxazolidone 157. On the basis of present information, the con-

figuration at C-3 in this series remains unproved.

e PH3CH3N

~ 1 1 ~~ H . - Q - ; ~ N H ~__tNso3-

0

158

Tropinone reacts with O-(mesitylenesu1fonyl)hydroxylamine inCH,CI, to form (80y0)a hydrazinium mesitylenesulfonate (158).

N-Amination appears to proceed faster than oxime formation. The

configuration about the nitrogen was not determined (116) .Pyrolysis of the hydrochloride of ethyl 3a-phenyltropane-3j3-

carboxylate (159) caused ring cleavage and chlorine insertion with

formation of pyrrolidone 160 (117).

.HC1

COOCaH,

4159 160

The racemization of hyoscyamine has been studied in refluxing

methanol, isobutyl alcohol, toluene, and dioxane ( 1 1 8 ) .Racemizationin water was studied earlier (119).

In some microchemical investigations of medicinal plants (1 2 0 ) ,scopolamine was hydrolyzed in microgram amounts with Ba(OH), at




25°C n I hour to give scopine. At 100°C the main product was scopo-

line. Atropine and homatropine were similarly hydrolyzed at 25°C

while apoatropine remained unchanged.Some enamines (161and 162) of tropinone were prepared by treating

this ketone with cyclic secondary amines such as piperidine and

morpholine in the presence of an organic solvent, p-toluenesulfonic acid,

and a water-absorbing agent such as zeolite (121) .

CH,N CH3N

161 162

A tropanyl Grignard reagent was prepared (122) by heating 3a-

chlorotropane with magnesium turnings in refluxing THF for 24 hours

(the p-isomer failed to react with magnesium under similar conditions).

This reagent reacted with 2-(trifluoromethyl)thioxanthen-9-oneo form

2-trifluoromethyl-9-(3-tropanyl)thioxanthen-9-01163). This alcohol

was dehydrated and then reduced to form the 9-tropanyl derivative 164.

HO R CFS qR CF,

164163 R =

In accord with earlier work on tropinone (98a) ,photooxidation oftropan-3a-01, tropan-38-01, and deoxyscopoline (165) produced N -

demethylated and N-formylated products. Scopoline (166), however,

formed tetrahydrooxazine (167)along with the N-formylated derivative.

165 166 167




0 0

I1 II

NH3 \IH NKO’29 0

I70C 170D,R = CH,

170E,R = COCH,170F,R = C H O

Hydroboration of tropidine (171) ith oxidative work-up gave a 68%

yield of tropanols with a ratio of 43: 3:50:3 2a: 2/3: 3a: 3p. Principal

attack of the double bond from the a-face presumably resulted from

blockage of the p-face by an amine-borane complex. With a phenyl group

on carbon-3, only a-01s were isolated, 3/3-phenyltropan-2a-01(172)eing

171

L Z d

172

produced in threefold greater amount than the 3a-01. Substituents on the

aromatic ring modified this ratio ( 125) .

Oxidation of the 2a-01 (172) o 3p-phenyltropan-%one could not be

accomplished with the usual oxidizing agents, so it was treated with

ethyl chloroformate, and the resulting urethane was oxidized with Jones’

reagent to produce 173.Reduction of 173 with LAH then gave 3/3-

E t O C O N

4Jkb73 2qQ74

phenyltropan-2p-o1(174), hich was wanted for biological testing ( 126) .Some 2a-01 was also formed in this reduction.

Variation of the substituent on the nitrogen of norscopolamine and

noraposcopolamine has been accomplished through reaction of these




transferred to form deuterated benzaldehyde, two molecules of which

then attack a single tropinone. The structure of the deuterated product

was confkmed by NMR and mass spectroscopy.Tropinone reacted with the lithium salt of o-lithium-benzoic acid

(178A) t -78°C o form a spiro tropane (178B)n 58 yield. Reduction

II0

178A 178B

of this lactone (178B) ith LAH-BF, afforded spiro ether 178C n 81%

yield. Reaction of tropinone with o-lithium-phenol gave the phenolic

alcohol 178D n 20% yield ( 1 3 1 ~ ) .

178C 178D

The radiation yield from the 6oCo irradiation of dilute aqueous

atropine sulfate and scopolamine hydrobromide was independent of

alkaloid concentration but decreased with increasing radiation dose.

The biological activity of irradiated solutions correlated with radiolytic

decomposition. Atropine yielded tropine and tropic acid, indicating

radiation-induced ester cleavage (1 2).

Cocaines labeled with deuterium on the aromatic ring a t position 4

and (separately) a t positions 3 and 5 (179) ere prepared by reductivedehalogenation (NaBD,-PdC1,) of the corresponding chlorobenzoates.

Hydrolysis of the methyl ester functions then provided the correspond-

ingly labeled benzoylecgonines (180) 1 3 3 ) .




D

D

V. Biosynthesis

A. TROPANEOIETY

Substantial evidence has accumulated to support Scheme 2 as the

route for bioconversion of ornithine to hyoscyamine. A detailed review

of this evidence appeared in “The Alkaloids” (London) in 1971 ( 134) .Only a few key experiments will be reported here. Incorporation of

[Z-14C, 6-15N]ornithine 181),[1,4-14C,]putrescine, and [4-3H]N-methyl-

putrescine (182) nto hyoscyamine has been observed. Evidence indicated

that these precursors were confined almost entirely to the pyrrolidine

ring ( 1 3 5 ) .

N-Methylputrescine ( 1 8 2 ) was a much better precursor for hyoscya-mine in Scopolia lurida Dun. than either putrescine or ornithine ( 135) .Whereas 6-N[3H]-methylornithine served as a good precursor for

hyoscyamine with a major portion of the radioactivity confined to the

N-methyl group, ~t-N-[~H]-methylornithinehowed only minute non-

specific incorporation ( 1 3 6 ) . When this experiment was done with

6-N-[14C]-methyl-[2-14C]-ornithine,egradation experiments indicated

that all of the activity was located in the tropine base a t the bridgehead

carbon C-1 [having the (R)-configuration]and on the N-methyl group

(137‘).dZ-N-[14C]Methyl[2’-14C]hygrine as incorporated into hyoscyamine

by D . stramonium L. ( 1 3 8 ) .

A slightly different sequence has been proposed wherein ornithine is




181 Ornithine 182

ICHB

ICH,

0 183 Hygrine

Tropinone

SCHEME

said to be converted to aminobutyraldehyde, which then gives y -(N-methylamino)-butyraldehyde (139).A further different sequence

postulates that hygrine-a-carboxylic acid is the key intermediate in

tropane synthesis. Radioactive hygrine showed a lower incorporation into

tropane alkaloids than did [2-14C]-ornithine.The same study showed

that [1-l4C]-acetate gave rise to labeling of the carboxyl group of

ecgonine (140 ) .

Another proposal for tropine biosynthesis is an outgrowth of studies

with tissue cultures. A cell suspension culture of Datura ferrox L.,when

supplied with dl-[2-l4C]ornithine, yielded radioactive a-keto-Bamino-valeric acid (184), among other products. However, none of the tropane

alkaloids produced was radioactive. It was proposed that this in vitro

cell culture lacks the enzyme that catalyzed the reaction between

A1-pyrroline-2-carboxyliccid (185) and acetoacetylcoenzyme A. This

condensation product can ultimately yield hygrine and then tropine, as

illustrated in Scheme 3 (141 ) .

Finally, there is the observation that [1,4-14C,]succinic acid is incor-

porated in Datura species, the molecule becoming carbons 1, 5 , 6, and 7

of the tropane structure. [1 3-14C,]acetone and [14C]methylaminewerealso utilized ( 1 4 2 ) .

An enzyme (atropinase) is believed to play an important role in the

biosynthesis of tropane alkaloids (142a).




0

ItCOOH C S - C O AOOH

0

COOH CS-COAI I

184 185

tropinone

- L O -ck-oHygrine

SCHEME

B. CARBOXYLICCIDMOIETY

A critical review of the biosynthesis of tropic acid appeared in Biosyn-thesis ( 1 4 3 ) in 1973. Feeding experiments using variously labeled

phenylalanine have shown that all of its carbon atoms are incorporated

into tropic acid but that the carboxyl group migrates fiom C-2 to C-3 in

the process (Eq. 13) (143 ) .The intramolecular character of thisrearrange-

ment was demonstrated by feeding phenylalanine containing 13C a t

Phenylalanine Tropic acid

positions 1 and 3 to Dutura innoxiu. Movement of the two labeled

carbons to contiguous locations resulted in the appearance of satellite

peaks (NMR) due to spin-spin coupling, symmetrically located about

the corresponding singlet peaks. If the rearrangement had been inter-

molecular, endogenous unlabeled phenylalanine would have diluted this

effect beyond visibility ( 1 4 4 ) .

Although it had been shown earlier that cinnamic acid, a metabolite ofphenylalanine, failed to serve as a precursor of tropic acid ( l 4 5 ) , here was

the possibility that rearrangement might occur after esterification of

tropine with an acid derived from phenylalanine. Therefore, [2-14C]-




cinnamoyl N[14C]methyltropine was fed to D . stramonium. Although

activity was found in both hyoscyamine and scopolamine, all of i t was

located in the N-methyl groups, indicating that hydrolysis of the esterhad occurred with no use of the cinnamic acid in biosynthesis of tropic

acid (1 4 6 ) .Similarly, [2-14C]cinnamicacid was not incorporated into the

alkaloids of D . innoxia plants when fed via the roots. I n this same study,

(dZ)-[2-14C]phenyllactic cid served as a better precursor than [2-14C]-

phenylalanine for tropic acid in hyoscine and hyoscyamine and for

atropic acid in apohyoscine. Phenylalanine served as an effective

precursor for the phenyllactic acid moiety of littorine ( 1 4 6 ~ ) .I n contrast with the above observations, a feeding of [2-14C]cinnamic

acid to D. innoxia through the stem via the wick method has recentlyshown specific incorporation into the tropic acid moiety of atropine. The

tropic acid was labeled at C-3. This 0.0S70 incorporation of [2-14C]-

cinnamic acid into atropine compares favorably with that reported by

others for the incorporation of radioactive phenylalanine into this

alkaloid (147 ) .

Biosynthetic studies of hyoscyamine in callus tissue and intact plants

of A . belladonna showed that addition of phenylpyruvate produced a

significant increase in alkaloid production. Phenylalanine had little

effect and cinnamic acid inhibited both growth and alkaloid production.

I n a tagged precursor study using leaf discs, tyrosine showed less

incorporation than did phenylalanine ( 1 4 7 ~ ) .Whereas considerable attention has been given to the formation of

tropic acid from phenylalanine, little attention has been devoted to its

biosynthesis from phenylacetic acid (148) and from tryptophan (149)

following these early studies. A criticism leveled at the proposed route

from tryptophan (149) (see Scheme 4) was that the [3-14C]tryptophan

I I1R--CH,-CH-COOH ---- - E H ~ - - C - C O O H + - ~ H ~ C O O H-+ REHO

NHz 0

R = (J--3-"C] Tryptophan

H

COOH - COOH

Tropic acid

SCHEME




used for the study did not show that tryptophan was able to furnish the

entire carbon skeleton of tropic acid. Recently (154 , [benzene ring

U-14C]tryptophan and [2-ind01yl-~~C]tryptophanere converted totropic acid by D . innoxia roots. The bulk (My0)of the benzene labeling

appeared in the phenyl ring of the tropic acid and 61% of the 2-indolyl-

14C label appeared at C-3 in the tropic acid, thus substantiating the

earlier hypothesis (149). 1-14C]Phenylalanine, -14C]phenylaceticacid,

[3J4C]serine, and [14C]formicacid were also utilized.

Dually labeled littorine, 3a-([l-14C]-2-hydroxy-3-phenylpropionyl-

0xy)[3-~H]tropane,was fed to D . stramonium which then yielded

radioactive hyoscyamine. Both the tropine and the phenyllactic acid

halves of the molecule were incorporated into the hyoscyamine moiety,but the ratio of labeled atoms was so drastically changed that there

was indication that the ester was hydrolyzed to tropine and phenyl-

lactic acid, the latter undergoing rearrangement to tropic acid before

being reesterified by tropine (146).

The origin of the phenyllactic acid moiety of littorine in D . sanguinea

is phenylalanine. A specific incorporation of [1J4C]- and [3-14C]phenyl-

alanine was observed into carbons 1and 3, respectively, of the side chain

of the phenyllactic acid portion of littorine. The fact th at phenylalanine

appears to be a better precursor for littorine than for hyoscyamine andscopolamine suggests that phenylalanine is more readily converted to

phenyllactic acid than to tropic acid (151).

Whereas tropic acid and 3-phenyllactic acid are formed from phenyl-

alanine, the tiglic acid of tigloidine and related esters and the 2-methyl-

butanoic acid of 6/3-(2-methylbutanoyloxy)tropan-3cr-olhave their

origin in (8)-isoleucine. (8)-Isoleucine was first shown to be a precursor

for the tigloyl moiety of tropine tiglate (186), tropane-3a,6/3-diol

ditiglate (187), meteloidine (188), and tropane-3a,6/3,7/3-triol 3,6-

ditiglate (189) in D . innoxia and in D . meteloides D. C. ex Dunal in 1966

(152). The next year these findings were substantiated when the

0

-0-c HII

\ /

Tig = ,c=c \

CH3 CHa

Tig

186

187

188

189

R' = H, Ra = H

R' = Tig, R1 = H

R' = OH, Ra = OH

R1 = Tig, Ra = OH




radioactivity of [2-14C](S -isoleucine was specifically incorporated into

the ester carbonyl of meteloidine (188)in D. meteloides ( 1 5 3 ) .The tiglic

acid moiety of tigloidine (pseudotropine tiglate) and tropine tiglatefrom Physalis peruviana L. is also derived from (S -isoleucine (154) .

The intermediacy of 2-methylbutanoic acid in this conversion was

indicated when d l - [ -14C]-2-methylbutanoicacid was fed t o D . innoxiaand the root alkaloids tropane-3a,6/3-diol ditiglate (187) and tropane

3a76/3,7/3-triol ,6-ditiglate (189) were isolated. In each case, the radio-

activity was located in the ester carbonyl group (155) .The same sort of

incorporation was observed when dl-[l-14C]2-methylbutanoic cid was

fed to D . meteloides, radioactive meteloidine being isolated. It was

predicted that i t is the (S)-2-methylbutanoic acid which is the actualprecursor of the tiglic acid since it is the ( S ) orm of isoleucine that

starts the sequence (1 5 6 ) .The tiglic acid observed in these alkaloids apparently is formed by a

direct dehydrogenation of 2-methylbutanoic acid, although nothing is

known of the stereochemistry of elimination. In order to discount the

possibility that the dehydrogenation first gave angelic acid which then

isomerized, [l-14C]angelicacid was fed to D. innolcia plants. There was

no incorporation, thus clearly indicating that angelic acid is not a

precursor to tiglic acid. Tiglic acid was incorporated under these same

conditions (1 5 7 ) .2-Methylbutanoic acid, which was an intermediate in the conversions

j u s t described, appears as an end product in tropane-3a76/3-&o1 -(2-

methylbutanoate) from D. ceratocaula. The origin of this acid was

demonstrated by feeding [U-l*C](S -isoleucine(22).

Leucine and valine appear able to act as precursors of the isovaleryl

and senecioyl moieties of the tropane alkaloids, although such a

conversion may not occur in a normal plant. Radioactivity from

[U-14C](S)-leucine nd [U-l*C](S)-valinewas incorporated into the acid

portions of tropine senecioate and isovalerate, tropane-3,6-diol diseneci-

oate, and diisovalerate, and into tropane-3,6,7-triol 3-senecioate,

3-isovalerate, 3,6-disenecioate, and 3,6-diisovalerate. The species fed

were D. sanguinea and D . stramonium (158) .

C. TRANSFORMATIONS

The principal pathways for the biotransformation of cocaine in menand in animals are N-demethylation and deesterification. Monkeys

injected intraperitoneally with cocaine were shown to develop identifi-

able levels of norcocaine in brain tissue (extraction, gas chromatography



142 ROBERT L.CLARKE

and mass spectrum). This metabolite is about as active as cocaine in

inhibiting 3H-norepinephrine uptake by synaptosomes prepared from

rat brain (159) .It has been observed that ditiglate esters of tropane-3a,6f15-diolnd

tropane-3a,6fl,7/3-triol xist in the roots of Datura species, bu t th at only

monotiglate esters are found in the leaves. The isolation of some

ditiglate esters in transpiration streams led t o the hypothesis that such

diesters are metabolized to monoesters in the leaves. The idea was

substantiated when tropane-3a,6/3-diol ditiglate was fed to D . innoxiaand D. cornigera Hook. leaves where it underwent hydrolysis to yield

the 3-tiglate, the 6-tiglate, and tropane-3a,6/3-diol (160) .

A subsequent substantiation of the process was effected usingsolanaceous species that normally do not contain tiglate esters. Experi-

ments with tropane-%a,6/3-diol itiglate in Atropa belladonna L. and

Lywpersicum esculentum (L.) Mill. and with tropane-3a,6/3-dioldisene-

cioate in L. esculentum and Datura ferox indicated their conversion to

monoesters (161) .[3/3-3H,N-14C-methyl]tropinewas fed to D . meteloides, giving rise to

radioactive meteloidine, scopolamine, hyoscyamine, and tropane-

30,6/3,7/3-triol 3,6-ditiglate. These products had essentially the same

3Hj'4C ratio as in the administered tropine. Degradation of the metel-

oidine established that all of its 3H was located at C-3 and all of the 14Cwas on the N-methyl group, indicating that tropine is a direct precursor

of teloidine (162) . Feeding of [N-14C-methyl-6,8,7/3-3H,ltropineo D .

inmoxia and D. meteloides produced hyoscyamine with a 3H/14Cratio

essentially t h e same as that of the administered tropine. However, the

meteloidine and scopolamine formed retained only small amounts of

tritium. Thus, the dihydroxylation of the tropine moiety proceeds with

retention of configuration. If previous work on the biosynthesis of

scopolamine is accepted, the present results indicate that a cis-dehydra-

t i on is involved in the formation of 6,7-dehydrohyoscyamine from

6bhydroxyhyoscyamine(16%).A mutual interconversion between scopolamine and hyoscyamine has

been ascertained during incubation of shoots and roots of D . innoxia.

When [N-14C-methyl]scopolamine as added, radioactive hyoscyamine

could be isolated. When [N-14C-methyl]hyoscyamine as added,

labeled scopolamine was formed. 6-Hydroxyhyoscyamine was an

iutermediary (163).

In studies concerning the biosynthesis of tropane-$a,6/3-diol, ropane-

3a,6/3,7jS-triol, and their tigIate esters it has been shown by feeding

experiments with [14CO][N-14Me]3a-tigloyloxytropane nd [ l4C0][P4Me]valtropine that neither precursor is incorporated intact togipe diesters. Extensive reversible hydrolysis occurs ( 1 6 3 ~ ) .




A different approach to this problem involved the determination of

whether the entering tigloyl groups labeled equally the 3a and 6p

positions in ditigloyl esters. Two different mechanisms appeared to beinvolved when [1-14C]tiglicacid was fed toD. eteloides. 3a,6p-Ditigloyl-

oxytropane contained roughly equal radioactivity a t positions 3 and 6.

This suggested hydroxylation of tropine followed by simultaneous

esterification. In contrast, 3a,6/3-ditigloyloxytropan-7~-01ad only 9%

of the label a t position 3.It may well have been formed by hydroxylation

of 3a-tigloyloxytropane (163b) .A third study by the same group resorted to feeding [N-14Me]tropine,

a known precursor that does not lose its label, alongside postulated

intermediates in each of the biosynthetic schemes to act as competitiveinhibitors. The results favored two separate routes for the biosynthesis

of the tigloyl esters of tropane-3a,6/3-diol and tropane-3a,6p,7/3-triol

(1 3c):

a) ither

or more probably,tropine+ ropane-3a,6fi-diol 3a,6fi-ditigloyloxytropane

tropine+ a-tigloyloxytropane+ fi-hydroxy-3a-tigloxytropane.+

3a,6fi-ditigloyloxytropane

(b)tropine+ 3a-tigloyloxytropane -f 7fi-hydroxy-3a-tigloyloxytropane

6fi,7fi-dihydroxy3a-ditigloyloxytropane-f 3a,6fi-ditigloyloxytropane-7~-ol

An independent study of this same question involved feeding a 1 :1

mixture of 3a[l-14C]tigloyloxytropane nd 3a-tigloylo~y[3/3-~H]tropane

to D . innoxia. The 7/3-hydroxy-3a,6/3-ditigloyloxytropaneo formed

contained the same 3H/14C atio as that fed. From this result it seems

probable that hydroxylation at C-6 and C-7 occurs on the preformed

%a-tigloyl ster ( 1 6 3 d ) .

In another study of hyoscyamine and scopolamine, the latter was

infiltrated into shoots of intact Solandra gra nd if lra Sw. In addition to

the normal alkaloidsto be found there, dl-scopolamine, aposcopolamine,

dl-norscopolamine, and oscine were isolated. It was inferred that the

new metabolites arose from scopolamine and that racemization of the

optically active bases is in keeping with the normal occurrence of

atropine and noratropine in the plant. In another experiment [GJ4C]-

hyoscyamine and unlabeled hyoscyamine were infiltered into alkaloid-

free scions of s. grandi f l ra grafted onto tomato stocks. Atropine,

noratropine, and tropine were isolated ( 164) .[2-14C]Acetate, [3H]atropine, and [N-14C-methyl]tigloidine were

applied to seedlings and cut off young stem ends of D. innoxia and the

disposition points were determined by autoradiograms. The tigloidine

was not transformed into scopolamine in 3 days. However, within 1 day




radioactivity appeared in 6-hydroxyhyoscyamine and tropane-3a,6/lB,7/l-

trio1 3,6-ditiglate. On the second day i t was detected in meteloidine (165).

Two other metabolic studies in animals have been reported. Themetabolism in rats of methylscopolammonium methylsulfate, a

quaternary developed as an anticholinergic agent, was investigated.

The major pathway apparently involved introduction of a hydroxy or

methoxy group in the para position of the benzene ring. There was also

indication of glucuronide formation (166). njection of [N-14C-methyl]-

scopolammonium methylsulfate and two related salts into rats (intra-

venously) resulted in localization of the radioactivity in the lysosomes

of the light mitochondria1 fraction of the liver (167).

D. TISSUECULTURESTUDIES

It was hoped tha t tissue cultures of alkaloid-producing plants would

be an ideal system for studying biosynthetic routes since these systems

could be so well controlled. Unfortunately, these systems produce

much poorer yields of alkaloids than the intact plants and work of this

type has proved disappointing.

Cell cultures of Datura innoxia have developed shoots that in a

different medium have developed into complete plants. During root

differentiation and plant development, scopolamine synthesis begins

and there is progressive increase in alkaloid content. The majority of

plants develop a normal pattern of alkaloid content (168).

The alkaloid spectrum of tissue cultures of D. metel, D. stra-

monium var. stramonium, and D. stramonium var. tatula was

found to differ considerably from that of intact plants. Neither

hyoscyamine nor scopolamine was detected in these tissue cultures.

Hyoscyamine, added to the cultures, was steadily consumed over a

14-day period but no scopolamine developed, a transformation that

occurs in intact plants (169). n contrast to the results of that study,

calius tissue cultures of D . myoporoides leaves contained at least five

alkaloids which corresponded by tlc to those found in leaves and roots

of intact plants. The main alkaloids identified were scopolamine,

valtropine and atropine ( 1 6 9 ~ ) .allus cultures from leaves of anther

regenerates of D. f e r ox , D. inermis, D . meteloides and D. tatula were

analyzed for their ability to produce tropane alkaloids and t o excrete

these into the culture fluid (169b).Optimum release of alkaloids into the

broth of cultures of D. innoxia and S. stramonijolia occurred a t 25 and

15 atmospheres of sucrose osmotic pressure (169~) . yoscyamine

production by anther cell suspensions of D. metel was highest when the

Murashige-Skoog medium was used (169d).




In excised root cultures of D. innoxia, the addition of tritium-

labeled atropine did not affect the normal synthesis of atropine and

scopolamine. Part of the exogenous atropine was converted to scopola-mine. The relation between unchanged and converted substrate

indicated a regulation of the enzyme required for this conversion (170) .Formation of tropoyl esters in cultures of D . innoxia stem callus was

stimulated by dl-tropic acid, phenylpyruvate, or tropine but was little

affected by (S -phenylalanine or (8-ornithine. Acetyltropine was

formed in large quantity by cultured cells when tropine was supplied to

cultures of D . innoxia and D . tatula L. (171) .Another study also observed

evidence for the presence of enzymes for tropine acetylation in Datura

cultures (172) .A . belladonna, S. lurida,and H . niger cultures did notesterify tropine ( 1 7 3 ~ ) .

A three- to sixfold increase in atropine production resulted from

addition of (,Y)-phenylalanine or (S -tyrosine to tissue cultures of

D. metel (173) . Addition of dl-[l-14C]tyrosine to this same kind of

culture yielded radioactive atropine (174) .The shapes of cells in tissue cultures of D. i nnoz ia depended on

growth conditions, while their size depended upon origin. Biomass

formation was faster in calluses from leaves and petioles than in those

from stem, root, or seed. Amino acids, such as ornithine, phenylalanine,serine, aspartic acid, methionine, and glycine, caused an increase in

alkaloid synthesis by the medium (175) . In contrast, another report

states that addition of (S -ornithine, (#)-proline, or (S)-hydroxyproline

caused no appreciable synthesis of tropane derivatives in D . metel stem

and root cultures and in D . stramonium var. tatula root cultures. These

cultures do not produce tropane alkaloids without addition of some sort

of precursor, however. Addition of tropine caused production of a large

quantity of hyoscyamine ( 1 6 ) .In order to maximize the alkaloid formation in tissue cultures of

D . innoxia seeds and Scopolia stramonifolia roots, a two-factor dispersion

analysis was applied. Studied were the method of sterilization of the

medium, the number of transplantations, the revolution speed of the

cultures, and the volume of the nutrient medium (177) . In tissue

cultures of callus cells of S. stramonifolia, the total alkaloid content was

highest after 3-month cultivation (0.1157J. Additives such as trypto-

phan and ATP caused higher proportions of scopolamine and hyo-

scyamine to form ( 1 7 7 ~ ) .Suspension and static cultures of tissues of D . innoxia and S. stramoni-

fo l ia exhibited similar annual rhythms, manifested in uneven growth

and production of alkaloids. Greatest productivity of alkaloids occurred

in spring; least occurred in winter. There appeared to be a reciprocal




relationship between growth and alkaloid formation. Diurnal rhythms

were expressed in the mitotic activity and annual rhythms in the

metabolism of nitrogen, principally in proteins and amino acids (1?7b).A relationship has been demonstrated between protein synthesis and

alkaloid synthesis in root cultures of D . stramonium var. tatula (178).Studies in several nutrient media were conducted on root explants of

D . stramoniurn var. tatula, D . stramonium var. stramonium, D . stra-monium var. chalybea, D. nnoxia and D . ferox. D . stramonium var.

stramonium grew best in Torrey’s medium without vitamins. Production

of atropine and scopolamine was confirmed by chromatography (178a).The possibility of replacing the production of hyoscyamine and

scopolamine from Scopolia himalaiensis root callus tissues on agaror from whole plants by production from liquid suspension cultures

was explored. The process has the advantage of ease of nutrient

addition and simplified product isolation. The results were promising

(179) .Aeration of a suspension culture of D . innoxia stimulated tissue

growth and alkaloid productivity. While the content of alkaloids in

callus tissue increased under these conditions of intensified oxygen

supply, excretion into the medium decreased (179a).In tissue cultures

of Scopolia species leaves the presence of tropane alkaloid precur-

sors is said to lower the total yield of alkaloids (180) . The effect ofsome aminoacid precursors on the growth and alkaloid-production of

callus tissue cultures of severalScopolia species was studied. Tryptophan,

phenylalanine, glutamic acid, proline, ATP, and various combinations

of these were added. Tryptophan, followed by glutamic acid and ATP,

showed strong induction of hyoscyamine and scopolamine formation

(181). Addition of atropine sulfate to D. innoxia cultures stimulated

growth and biosynthesis of hyoscyamine and scopolamine (181a).

E. MISCELLANEOUSIOSYNTHESES

Exposure of D . stramonium plants to l4CO; resulted in incorporation

of radioactivity into all the alkaloids present. The ratio of radioactivity

of hyoscyamine to that of scopolamine was much higher in the roots

than in the foliage. This activity was present in both the acidic and

basic moieties of these alkaloids (182) .Atropa belladonna that had been grown to maturity in aqueous

nutrient solution died within a week when transplanted into 1 0 0 ~ oD,O. Plants lived only about three weeks in 7 5 7 , D,O but survived in

50 and 60% D,O. Alkaloid production was drastically reduced in these

survivors (183) .




Autoradiographic studies of histological structures of various

freeze-dried animal organs permitted the location of atropine and its

metabolites in the animal. Atropine and atropine 9’-glucuronide were

found in largest amounts followed by 4’-hydroxyatropine and itsglucuronide. Tropine and tropic acid were found in small amount. There

was a direct relationship between these concentrations and the pharma-

cological activity (1 4).

M. Biologid Activity

Only a selected few biological activities will be reported here, those

being of unusual degree or involving tropanes with other than stereo-

typical structures. The vast literature on biological properties of cocaine

and the various tropan-3-01 esters will be omitted.

One of the first properties observed about cocaine was its ability t o

produce numbness of the tongue. When Willstltter prepared a position

isomer of cocaine in 1896 called a-cocaine (190), he observed bhat it

produced no local anesthetic action on the tongue ( 8 6 ) .I n 1955 it was

demonstrated that a-cocaine was actually one-third to one-eighth as

strong a local anesthetic as cocaine in an intradermal infusion test (185) .

J q 0 l P hOOCHB Jk$COPhOOCH,

190 191

Two years later it was proved that the isomer prepared by Willstltter

had the carbomethoxy group in the endo configuration as drawn (190)

Recently (1975) , ?-cocaine(191) was prepared (see Section IV, D).

It proved also to have no local anesthetic action on the tongue but was

one-third as active as cocaine in the intradermal wheal test (88).Thus,

the two isomers have similar local anesthetic activities. , ?-Cocainedoes

not have the stimulative action shown by cocaine ( 186) .a-Cocaine has

not been studied in this respect.Several further modifications of cocaine have been studied pharma-

cologically. The preparation of these compounds is described in Section

IV, D. A L‘reverse ster” of cocaine (192) was found to be devoid of

(87).




stimulative action (83).However, some benzaldehyde acetal derivatives

(193) of the intermediate diol used in the preparation of this “reverse

ester” proved to be stimulants ( 8 4 ) .Those isomers in the group which

0

CH,N

i\ O---CCHBCH,N

I\ H

192 193

had the aromatic ring in the a configuration showed activity in thereserpine-induced eyelid ptosis test. Included in this same study were

the benzaldehyde acetals of ecgoninol and pseudoecgoninol (194), only

the former of which was active. The latter was the most lethal of all the

compounds tested.

dl-3/?-Phenyltropan-2/?-01195) has about the same activity as does

cocaine in the reserpine-induced ptosis test but is more active as a

locomotor stimulant. The activity appears to reside in only the 1-

enantiomer. Curiously, the racemate appears to be more active than the

active enantiomer alone. The ethylene bridge of the tropane system isrequired for activity. Acetylation of 195 produces a decreasein activity

(1 2 6 ) .

In contrast to the above observations, i t is the acetate of the 2a-01

(196) that is a strong stimulant. The alcohol produces questionable

depression (1 2 6 ) .

195 196




The most dramatic change in the cocaine activity profile resulted

from elimination of the elements of CO, from cocaine, i.e., attachment

of the benzene ring directly to carbon-3. The compound of structure197 (R = p-F) is about 65 times as active as cocaine as a locomotor

197

CH3?,

198

COOCH,&199

stimulant, about 20 times more active in inhibition of tritiated nor-

epinephrine (NE-3H)uptake in mouse heart, 25 times more active ininhibition of NE-3Huptake in r at brain, 5 times as active in preventing

reserpine-induced eyelid ptosis and 20 times more active in reversing

this ptosis, one-tenth as strong a local anesthetic, and about one-fourth

as toxic as cocaine intravenously. The oral therapeutic ratio as a

locomotor stimulant is about 300 ( 8 5 ) .

This compound (subcutaneously) was able to cause a 5970 inhibition

of NE-3H uptake in rat brain at a 5.3 mg/kg dose as compared to a

6-87, inhibition (subcutaneously)by desmethylimipramine a t 20 and 40

mg/kg. The latter compound, one of the most active NE-3H uptakeinhibitors known, apparently is not very effective in penetrating the

blood-brain barrier ( 187) .

The sensitivity of 197 (R = p - F ) o structural change is demonstrated

by the fact that removal of the ethylene bridge (198) or epimerization

a t carbon-2 (199) destroys the central nervous system stimulation. It is

the levorotatory enantiomer (with the cocaine absolute configuration)

that is active. The dextro enantiomer actually produces a slight

depression ( 8 5 ) .

One of the metabolites of cocaine is norcocaine. It has been found tobe about as active as cocaine in inhibiting uptake of NE-3Hby synap-

tosomes prepared from rat brain. Other metabolites were found to be

relatively inactive (159).




Central nervous system stimulant activity has been reported for

another type of tropane ester, namely ethyl A3*a-tropeneacetate200),

prepared by a Wittig reaction on tropinone (188).A somewhat similarstimulant (201)was prepared from tropinone via treatment with a

reagent prepared from P$P, t-BuOK, and trichloromethane ( 1 8 9 ) .

200 201

The fact that a synthetic homolog of batrachotoxin containing a

2,4,5-trimethylpyrrole-3-carboxylate as twice as active as batra-

chotoxin prompted the esterification of some hydroxylated alkaloids

with this acid. Scopoline 2,4,5-trimethylpyrrole-3-carboxylate202)

was 20y0more active than codeine as an analgesic in the hot plate assay.

202

It had no effect on release of tritiated norepinephrine from heart tissue

Earlier, the troprtneanalog(203)f meperidine (204)was found to haveabout the same activity as meperidine as a narcotic analgesic (1 9 1 ) .Recently, the epimeric form (205) of this tropane analog was prepared

(190).

kO O E t cH3N% C O O E t

C H 3 N

A k hO O E t

203 204 205




(45) and found to be about one-third to one-fourth as active as the

earlier epimer. The difference in activity is not great and could be due

to differences in rate of passage into the brain. It suggests that theanalgesic activity in meperidine-like compounds is not very sensitive

to the conformation of the phenyl group. These results tend to support

the findings of other workers with regard to phenyl group configuration

(192, 193). Since 203, 204, and 205 all have equal local anesthetic

activity, the study also shows that there is little conformational

requirement for local anesthetic activity.

Of nine tropane esters studied only tigloidine (206) and 3/?-senecioyl-

oxytropane (207) significantly reduced the hypothermia induced by

tremorine. None of the esters reduced the tremors caused by this agent.Only dZ-3,6-bis(2-methylbutyryloxy)tropane educed the salivation.

Tigloidine has been shown to be beneficial in the treatment of parkin-

sonism like atropine, but without many of the undesirable side effects

of the latter drug. The antihypothermic effects of ester 207 suggest

No-C / H

\206 R = \C-c

C H / C H 3

No-c\ /CH3

H/ CH,\

207 R = c=c

a possible use of this agent in the symptomatic treatment of parkin-

sonism (194) .A patent claims that some N-(ethoxycarbony1)nortropi-

none derivatives are also useful in the treatment of Parkinson's disease

(195) .Some 3-phenoxynortropanes of structure 208 where R = NH,,

CH,NH, (CH,),N, or C,H,NH and R' = m-CF, or p-CF, have shown

anticonvulsant activity. While none of these compounds is quite as

active as diphenylhydantoin in suppressing electroshock-induced

convulsions, several had protective ED,, values against pentylene-tetrazole lower than that of ethosuximide. Both 3a- and 3fi-isomers

were included in the study (106) .The preparation of these compounds is

described in Section IV, G .




208 209

3-Phenoxytropane (209) and six derivatives carrying substituents in

the aromatic ring are reported to induce hypermotility, potentiate

the action of norepinephrine and inhibit that of tyramine on bloodpressure, and to antagonize some effects of tranquilizers. The unsub-

stituted phenyl derivative was the most active (196) . Another broad

study of tropanyl ethers showed indications of antidepressant and

anticholinergic activities. fl-Phenoxytropane and /?-(p-chlorophenoxy)-

tropane seemed to be active enough antidepressants and antiparkinson

agents to warrant clinical trials (105).3a-Hydroxy-8-isopropyltropaniumbromide (dZ)-tropate (Ipratro-

piumbromide) (209A) as pronounced anticholinergic properties. As

O-C-CH-CH~OH

209A

an inhibitor of the secretion of free hydrochloric acid in the stomach, it

is five times more effective than atropine. A whole issue of ArzneimittelForschung is devoted to the synthesis, pharmacology, toxicology, and

clinical trials of this compound ( 1 9 6 ~ ) .

S

210




Duboisia myoporoides is used by New Caledonian natives as an

N-(Allylthiothiocarbony1)tropane 210) is reported to have herbicidal

antidote against ciguatera poisoning (196b).

activity (192').

W. lant Content

Since the thrust of this review is primarily chemical and biochemical

and not botanical, a detailed discussion of new or repeat isolations of

known tropane alkaloids from new or old sources will not be given.

However, the literature search for this review has provided what ishoped are essentially all references to work of this nature in the period

reviewed. It appeared useful a t least to catalog these references here as

resource material. They are organized alphabetically according to

family, genus, and species.

Family Erythroxylaceae

Erythroxylum momgynum Roxb. ( 2 6 ) .

E. Ellipticum R. Br. ex Benth. ( 2 7 ) .

E. coca vm. nOv0granaterwi.q ( 1 9 8 ) .

Peripentadenia m r 8 i i ( C . T. White) L.S. Smith (24) .

Agastachys dw a ta R. Br. ( 9 ) .

Belkndena mntana R. Br. (7 -9) .

Darlingkaferruginea J. F. Bailey ( 1 1 ) .

Darling&&rlingiana (F. Muell) L.A. S. Johnson ( 1 1 ) .

Knight& de-phnchei Vieill. ex Brogn. et Gria (12-14) .

Brugukra 8exanghr (Lour.) oir ( 1 5 , 1 6 ) .

B. ezarktata Ding Hou ( 1 5 , 1 6 ) .

Family Euphorbiaceae

Family Proteaceae

Family Rhizophoraceae

Family Solanaceae (1 9 8 a ) -A broad study of some 19 genera and 54 species of Chinese

solanaceous plants focused on the distribution of four tropane alkaloids, hyoscyamine,

scopolamine, anisodamine (6-hydroxyatropine), and anisodine (a-hydroxyscopolamine)

(211), and a nontropane alkaloid, cuscohygrine. These alkaloids were distributed in

Ph

311




Solmeae, Hyoscyaminae, Mandragorinae, and Datureae but not in Nicandreae, Lyeiinae,

Solaninae, and Cestreae. Przewalskk ahebbearei and P. tangutica were the best sources

of these alkaloids (22b).

AnthocerA litto7ea. Labill (199).

A. tasmanica Hook. F . (200).

A. ViacosaR.Br. (199).

Atropa belladonnu L. 28, 147a, 201-205, 205a, 205b).

Cyphnzandra betacea Sendtn. (206).

Datura dba Nees (206a).

D. arborea L. (207).

D. bernhardii Lundstrom (208).

D. candida (Persoon) Safford (209).

D. ceratocaula Jacq. (20 , 21).

D. Cornigera Hook. (209).D. discolor B e d . (210, 211).

D. fastuosa L. (212).

D. ferox L. (169b, 209, 209a).

D. godronii (212a).

D. inno& Miller (16, 19, 20, 169c, 207, 209, 212a, 213-218, 218-218e).

D. leichardtii Muell ex Benth. (206a, 208, 209).

D. Metel L. (207, 218-220, 218f, 218g).

D. Metel var. fastuosa ( B e d . ) Dannert (209, 221, 221a).

D. meteloides DC. ex Dun. (169b, 207, 209, 222).

D. pruimsa Greenm. (223).

D. sanguima R. and P. (22, 209, 224).D. stramni um L. (28, 201, 207-209, 213, 225-230, 230a).

D. s tramnium var. inermis (207).

D. stramnium var. tatula (230b).

D. stramni um x D. discolor (231).

D . suaveolens H. and B. ex Willd. (18, 232).

D. tatula L. (169b, 207).

D. tatula var. immzis (169b, 207).

Duboisia hopwodii F . (233).

D. myoporoides R.Br. (169a, 196b, 234, 235, 235a).

Hyoscyamw d b w L. (236).

H. aurew L. (233).

H. n@er L. (28, 201, 233).

H. orientdis Bieb (236a).

H. pu8illw L. (233).

Mandragora autumnalis Bertol. (237).

M . oficinarum L. ( v e d i s ) 28, 237).

Nicotiana tabacum L. (238).

Physali.9 alkekengi L. var. Franchetti Hort. (formerly bunyardii Makino) (29, 239).

P. peruViana Mill. (30a, 154).

Physochlaina a l a k E. Korot. (23, 30, 240, 241).

P r m a k k i u shebbeurei (22b).

P . tangutica Maxim. (22b).

Salpichroa or-iginifolia (Lam.)Baillon [S. rhomboidea (Hook) Miers] (242).

ScopolBa carnblica Jacq. (28, 206a, 225, 243-246).

S. himalaiensis (179).




S. a p o n ic a Maxim. (2 4 7 , 2 4 7 a ) .

S. Zurida Dun. (2 8 , 2 2 5 ) .

S. a&&ra (Dun.)Nakai (2 2 2 , 2 4 7 , 2 4 7 a , 2 4 8 ) .S . 8inesisHemsl. (2 4 9 , 2 5 0 ) .

S. tranzonifolia (1 69c , 251-254).

S. tangut& Maxim. (2 2 5 , 250, 251 , 255-261 , 261a) .

S o la n d r a g r a n d i f i r a Sw. ( 2 6 2 ) .

S . guttata D. Don ex Lindley ( 2 6 2 ) .

S. hartwegii N. Br. ( 2 6 2 ) .

S. hirauta Dun. (262).

S. muwantha Dun. ( 2 6 2 ) .

VIII. Stereochemistry

The determination of molecular configuration using NMR, IR, and

mass spectra has become so routine and such an incidental part of so

many publications on tropane alkaloids that no attempt will be made

to give overall references. In a few cases where spectral studies are the

principal thrust of the paper, a description will be given in this section.

A novel approach to establishing configurations of molecules has

involved attaching a chiral group to the nitrogen of some piperidones,

tropan-3-ones, and pseudopelletierine systems ( 4 0 ) .Where the chiral

Ph CH3‘3 @ /

212 cH 213 0

group was in closer proximity to the carbonyl (as in 212) the amplitude

of the circular dichroism was enhanced over that of the isomer with the

more distant chiral center (213).Both quaternary and tertiary chiral

bases were studied. The conformer populations and their Cotton effect

signs and amplitudes as predicted by the octant rule and theoretical

considerations were confirmed by circular dichroic measurements.

I3C NMR data are beginning to accumulate on tropanes. Shiftassignments have been made for the carbons of tropane ( 2 6 3 ) ;nortro-

pane ( 2 6 3 ) tropinone ( 2 6 3 ) tropinone ethylene ketal ( 2 6 3 ) tropine

(263 , 264) and its benzoate ( 2 6 3 ) ; tropine (61a ,263), t? methobromide




(61a ,263, 264 ) ,and other alkyl quaternaries ( 6 1 a ) ;pseudotropine (263 )

and its benzoate ( 2 6 3 ) ; tropidine ( 2 6 3 ) ; scopolamine (263 , 264 ) ;

scopolamine N-oxide (263 ) ; ropic acid (264 ) ethyl 3-phenyltropane-3-carboxylate (both isomers) ( 4 5 ) ;and 3-benzoyl-3-phenyltropaneboth

isomers) (45).It is worthy of note that Wenkert’s group (263 ) has assigned the

6 2 5 .7 peak to carbons 6 and 7 of tropine and the 39 .1 peak to carbons

2 and 4, whereas Maciel’s group ( 2 6 4 )has made the reverse assignment.

The latter group observed that atropine methobromide (214) showed

methyl peaks at 6 4 4 . 8 5 and 51.54. The N-methyl of atropine (known to

/

OTr

214

be equatorial) appeared at 39.57, in fair accord with the lower of thetwo values seen for the quaternary. X-ray work (265 )has indicated an

axial configuration for the N-methyl of scopolamine. The observed

NMR shift for this carbon in scopolamine was S 53 .42 , in agreement

with the other methyl peak location ( 6 5 1 .5 4 ) found in atropine

methobromide. With proper control studies, it might be possible to

use 13C NMR effectively for structural assignments of tropane quater-

naries. (The work following disagrees with these quaternary peak

assignments.)

This possibility of using 13C NMR has now been carefully exploredfor quaternaries carrying methyl, ethyl, n-propyl, isopropyl, n-butyl,

and n-octyl groups on the nitrogen. The shift differences between peaks

for the two nonring carbons attached to the nitrogen and the peaks for

the ring carbons at C-6/C-7, C -l /C-5, and C-2/C-4 have been correlated

to show definite and distinct trends relatable to the orientation of the

R groups on the nitrogen. This study allows configurational assignments

for alkyl groups where one group is methyl but has not yet been exten-

ded to pairs of higher alkyl groups or to aralkyl substituents ( 6 1 ~ ) .

The normal 13C population in molecules is so low that a specificallylabeled 13C position stands out prominently in proton noise decoupled

13C NMR spectra. Likewise, adjacent 13C atoms give rise to satellite

peaks (due to 13C-13C spin-spin coupling) that are symmetrically




located about the singlet peaks. This phenomenon was utilized in

establishing that phenylalanine (215) is a precursor of tropic acid (216)

biosynthetically by intramolecular migration of the carboxyl group. No

215 Phenylelenine 216 Tropic acid

satellite peaks were visible in the dl-[l ,3-13C,]-phenylalanine fed t o

Datura innoxia, but they were plainly visible in the hyoscyamine and

scopolamine isolated from the plant tissues (Eq. 14) (144).

While on the subject of tropic acid, NMR studies (100 and 220 MHz)

of it, its methyl ester, and the methyl ester acetate indicated a prefer-

ence for the conformation where the phenyl and hydroxyl (or acetoxyl)

groups were in anti positions to each other. Solvent and concentration

effects upon the coupling were weak (266) .Dipole moment, NMR and temperature-dependent NMR studies and

qualitative considerations of van der Waals interactions provided data

on the conformation of atropine (267) .Since the primary focus was on

the conformation of the ester function, acetyltropine, trimethyl-

acetyltropine, benzoyltropine, hexahydrobenzoyltropine, and diphenyl-

acetyltropine served as models. The structure wherein the C=O is

cis to the tropane skeleton (218)appears to be the preferred conformation

rather than the trans form (217). This brings the N to C=O distance to

4.5-5.0 A, which is close to that found for acetylcholine.An earlier study

II

0,,CHPhCH,OH O\,@

II0

217

ICHPhCHaOH

218

(268) on tropine benzoate and pseudotropine benzoate had concluded

that the former prefers the conformation 219 while the latter is anequilibrium mixture of 220 and 221. All of this work was directed

toward gaining information on the characteristics of cholinergic

receptors.




I

O\,//O

IPh

219 220 121

The question of whether the lone electron pair or hydrogen assumes

the equatorial position on nitrogen in piperidines and nortropanes hasbeen the focal point of much controversy. A low temperature 13C-NMR

study, directed toward a solution in the latter case, has revealed an

almost equal population of axial and equatorial hydrogens (268,).The conformations of both phenyl tropan-3a-yl ether and p-chloro-

phenyl tropan-3a-yl ether as well as their 3b-epimers were determined by

analysis of IR , NMR, dipole moment, and Ken constant data. The

piperidine ring of the tropane was found to be in a chair form and the

N-methyl occupied an equatorial position. Where the 3-substituent was

oriented a , steric repulsion with the ethylene bridge caused flatteningof the piperidine chair at the C-3 end (105b) .

In order to determine the effect of esterification on the conformational

preference of tropine and pseudotropine, PMR studies were made on

their acetates and benzilates as well as on atropine. On the basis of half

bandwidths of the C-3 hydrogen, it was concluded that the conformation

of the piperidine moiety was unaffected by esterification of the alcohol

function (2 6 9 ) .A tropane analog222 (191)of meperidine (223) was at one time (270 ,

271) considered to have a large skew-boat population (as shown) on thebasis of analogy with a distorting interaction between the a-phenyl group

and the ethylene bridge of the 3b-benzoyl-3a-phenyl analog 224 (2 7 2 ) .With the advent of NMR spectroscopy a detailed analysis of these com-

pounds led to the conclusion that the meperidine analog actually exists

COOEt

PPh

C O O E t

dH.-N

223 224222




interactions of the kind that would be expected to occur in a boat form

such as 224 are known to introduce large up-field shifts in the 13C-

carbonyl signal (274) .There is a negligible difference in the 13C-carbonylsignals of epimers 228 ( =224) and 230. The proximity of a carbonyl to

the nitrogen of such a boat form (224) should cause a difference in N -methyl shift. There is no difference in N-methyl resonance position

between ester 227 (flattened chair) and the ketone in question (224

versus 228).

It should be noted t hat there are reversals in the assignments of the

proton resonances for the equatorial hydrogens a t C-2(4) and a pair of

those at C-6(7) n these two NMR tructural studies. In the latter work,

the models for assignment of the C-6(7) protons were two 2,4-tetra-deuterated tropanes.

N-Oxides were discussed in Section IV, B, but attention is called

here to the very clear 220 MHz NMR pectra of the two isomeric oxides

of tropine in CD30D. These data were used in assigning configurations

to the two N-oxide isomers ( 7 1 ) .The mass spectra of these two oxides

have been recorded ( 7 0 ) .Correlations between NMR shifts and struc-

ture have also been investigated for the isomeric N-oxides of hyoscya-

mine and hyoscine. In addition, the mass spectral fragmentation

patterns of these oxides were given ( 2 8 ) .The advantage of chemical ionization (CI) mass spectrometry over

conventional electron impact (EI)mass spectrometry was demonstrated

with homatropine among other alkaloids ( 2 7 5 ) .In C I mass spectrom-

etry, the quasimolecular ion M + 1 is invariably more abundant than is

the molecular ion in EI spectrometry. In the case of homatropine (231)

the C I method gave a moderately strong M + 1 peak and showed an

ion at m/e 258 (M + 1 - H,O). In the EI spectrum this substance gave

bCO-CH-Ph

231

only a weak molecular ion and no ion at m/e 258. The same research

group has reported the mass spectra of cocaine and scopolamine ( 2 7 6 ) .

Application of isobutane chemical ionization mass spectroscopy to




the forensic identification of drugs has been reported in considerable

detail. Data on 303 drugs and common diluents have been tabulated.

Most of these compounds show an MH+ peak with four or fewerfragmentation ions in abundances greater than 10%. Described are

atropine, cocaine, homatropine (molecular weight should be 275),

hyoscyamine [shows a 237 peak (20y0) ot listed for atropine], scopola-

mine, and tropine ( 2 7 7 ) .An earlier report by this group reported the

spectra of 62 commonly abused drugs (278) .Fragmentation patterns produced by eleven tropane derivatives

under the conditions of electron impact mass spectrometry were related

to the nature of the substituents. Unsaturation in the six-membered

ring caused preferential fragmentation of the two-carbon bridge. Asaturated six-membered ring containing poor leaving groups (OH and

CN) underwent preferential fragmentation of that ring (279) .Data on defocused metastable ions were obtained for a series of

structurally significant fragment ions in the mass spectrum of tropine.

These data, in conjunction with parallel information on 6,7-d2-tropine,

provide important insights into the details of fragmentation processes

(280) .A paramagnetic shift reagent, tris(dipivalomethanato)europium(III),

has been used to obtain simplified NMR spectra of tropine, pseudo-

tropine, nortropine, tropinone, and nortropinone. Evidence was

presented for a distorted chair conformation in the a- and /3-tropines

and tropinones. This work demonstrates the applicability of shift

reagents where two centers for coordination are present. The order of

coordination was secondary amine > secondary alcohol > tertiary

amine 2 ketone (281) .Further evidence for this flattening (semiplanar

form) in tropanes was gathered using Ni(I1) acetylacetonate and

Co(I1)acetylacetonate as shift reagents. Tropine benzoate, homatropine,

and tropinone were studied (282) .An attempt was made by X-ray diffraction analysis to show the

conformation of the N-methyl group in 3a-chlorotropane. The crystal

proved to be a monohydrate with the water apparently bonded to the

nitrogen, so the primary purpose of the investigation was not realized.

It was determined, however, that interaction between the chlorine and

the ethylene bridge causes a flattening of the C-2, C-3, C-4 portion of

the molecule toward the plane established by C-1, C-2, C-4, and C-5

(283) .Another approach to this conformational problem also involved

3a-chlorotropane along with 3a-bromotropane. NMR spectroscopy and

dipole moment measurement indicated that perhaps up t o lOyoof the




N-methyl groups occupied an axial position and that a flattening of the

piperidine chair occurred as described in the X-ray work immediately

above (284).

M.AnalyticalMethods

Microchemical identification of methylatropine, methyl homa-

tropine, hyoscine, and hyoscyamine has been accomplished through

formation of salts, including reineckates, chloroplatinates, hexacyano-

ferrates, and chloromercurates (285) . Salts of atropine, homatropine,

scopolamine, cocaine, and tropacocaine with arenesulfonic acids aresparingly soluble and have sharp melting points (286) . Complexes of

alkaloids, including tropanes, with potassium tetraiodomercurate (287),

radiolabeled (l3II) otassium tetraiodomercurate (288),and antimony-

containing acids (289) have also been studied. Microcrystalloscopic

reactions have been used to identify apoatropine and tropic acid in the

presence of atropine ( 290) .A rapid and sensitive gas-liquid chromatographic method (GLC) is

described for detecting small amounts of ecgonine and benzoylecgonine

in cocaine. It is necessary to silylate these polar substances in order t o

achieve adequate volatility (291) .A similar procedure was used for the

detection of cocaine and its principal metabolite, benzoylecgonine (BE),

in urine. Separate simultaneous determinations of cocaine and BE were

accomplished by analyzing both a methylated (combined cocaine and

BE) and an unmethylated (cocaine only) aliquot of the specimen

extract. Detection limits were < 0.1 and 0.2 pg/ml for cocaine and BE

respectively (291a) . A broad study of GLC of tropane alkaloids in-

vestigated column materials and packings. Extracts from Datura ferox,

D . innoxia, D . stramonium, and Atropa belladonna were used in the

study ( 292) .Hyoscyamine and scopolamine (293)and these plus tropine,

pseudotropine, nortropine, scopoline, pseudoecgonine, cochlearine, and

meteloidine (294)have been separated and identified by GLC. Cocaine

has been detected at 20-30 ng/ml by the same technique (295) .GLC has

also been used for identification of unknown drugs in forensic chemistry

(295a) .See refs. 277 and 278 for other forensic studies. Simultaneous

determination of the major alkaloids of D . innoxia and any fungicide

Vitavax present in the sample was also accomplished by this technique

(295b) .GLC was effective for assay of belladonna but marked differences

in results were related to different isolation schemes in sample prepara-

tion (295c) .Approximately 1000 tons of Duboisia plants are grown yearly to




obtain the mydriatic alkloid scopolamine. Control analyses by GLC are

most satisfactory when phenylacetyltropine is used as an internal

standard. Silanization of the samples prevents dehydration to apoforms. The alkaloid content from a commercial bale of Duboisiamyoporoides varied with sample position in the bale (2 3 5 ) .

A GLC-mass spectrometric method for scopolamine sensitive to

50 pg/ml for a 4-ml plasma or urine sample has been reported (296) .The

method used a deuterated internal standard and involved hydrolysis

to scopoline followed by heptafluorobutyrate formation.

High-speed, high pressure liquid chromatography has been used (297)for separation of similar tropane alkaloids. It offers the advantages that

it is not necessary to liberate free bases prior to analysis as with gaschromatography, the analysis can be performed a t room temperature,

and the procedure can be scaled up easily if preparative samples are

required. A separate study applied this technique to tropine, scopola-

mine, and cocaine, among other alkaloids, using six solvent systems and

UV monitoring (298).Flow rates and retention times were recorded. Asecond study by this latter group dealt with atropine, scopolamine and

apoatropine ( 2 9 8 ~ ) .

Paper and thin-layer chromatography have been used extensively

for separation and identification of tropane alkaloids. The followingnotations are from papers dealing primariIy with these problems. Paper

and thin-layer plates (299)and paper alone (3 0 0 )were used to separate

atropine and scopolamine. Gel chromatography has been used for the

study of scopolamine in forensic chemical analysis (300a). odine is a

good reagent for developing spots sinde i t is nondestructive (300, 301) .

Dipping paper chromatographs in 1,-KI produces a blue color for

atropine and a red-orange color for hyoscyamine (3 0 2 ) .Alkaloid spots

have also been located with potassium iodoplatinate and cerium

sulfate-H,SO, (303) and with Dragendorff’s reagent followed by

NaNO, (3 0 4 ) . Experiments designed for transferring alkaloids from

drug samples directly to chromatoplates a t elevated temperatures

using water-charged molecular sieve as a propellant showed that

alkaloid decomposition limited the applicability of the process ( 3 0 4 ~ ) .

A combination of extractive prOcedures and chromatographic

separation allowed the determination of hyoscyamine and scopolamine

in Solanaceae within 2% error (3 0 5 ) . For the determination of hyo-

scyamine and scopolamine in the total alkaloids of belladonna, MeOH-

benzene was used for plate development, and UV absorption was used

for quantitation (3 0 6 ) . A similar study was done on atropine and

scopolamine (3 0 7 ) . For alkaloids in Caucasian scopolia roots and

belladonna leaves, 95:5 acetone-lO~oNH,OH was used to separate




hyoscyamine, apoatropine, and scopolamine ( 308) . A 97: 3 acetone

NH,OH solvent system separated atropine, apoatropine, Cropine, tropic

acid, tropinone, scopolamine, scopoline, scopine, and aposcopolamine(309). In this case, the colors obtained using fourteen chromogenic

reagents were reported. A 6:3:1 CH3COC2H5-CH30H-7.5yo NH,OH

system effectively separated essentially this same group of bases ( 310) .A partial paper chromatographic separation of hyoscyamine and

atropine (dZ-hyoscyamine) is reported that allows estimation of the

compositions of mixtures of these substances. A periodate of the

alkaloid hydriodide is formed which subsequently liberates iodine ( 311) .

No asymmetric reagent was used to impregnate the paper or to develop

the system.Five solvent systems were studied in the separation of metabolites

of atropine by thin-layer chromatography ( 2 9 0 ) .

Partition chromatography on chromatoplates using cellulose coatings

allowed the detection of microgram quantities of tropane alkaloids;

0.7 M H,S04 + 0.7 M NaCl was used as the stationary phase and

BuOH served as the mobile phase ( 3 1 2 ) .A related study used cellulose-

coated plates, a borate/phosphate buffer at pH 6.6, and n-butanol

saturated with water. Assay involved a colorimetric method ( 313) .

Thin-layer electrophoresis of atropine, homatropine, and cocaine has

been accomplished on glass plates coated with cellulose powder using

both acidic and alkaline electrolytes ( 314) .Electrophoretic identification

of these same substances plus scopolamine and tropacine (3a-tropanyl

diphenylacetate) was studied at a variety of pH values from 1.8 to 8.0

with spot detection by iodine ( 3 1 5 ) .A group of local anesthetics studied

by this same technique included cocaine ( 3 1 6 ) .Paper electrophoresis

followed by ultraviolet spectrophotometry for assay of atropine,

dicaine, cocaine, novacaine and scopolamine was found suitable for

forensic purposes (316a) .Electrophoretic separation of some Datura and Atropa samples

afforded atropine, hyoscyamine, apoatropine, 6-hydroxyhyoscyarnine7

scopolamine,3,6-ditigloyloxy-7-hydroxytropane,nd meteloidine. Their

relative migratory rates were recorded a t pH 8 ( 3 1 7 ) .The same method

with pH 9.5 borate buffer showed that hyoscyamine is the pharmaco-

logically active principal of the hybrid Atropa martiana (belladonna)

( 3 1 8 ) . Electrophoretic separation has also been used with Duturu

bernhardii (319)and D. stramonium ( 2 2 9 ) .

The polarographic properties of several amine oxides have been

determined including those of 3-tropanol N-oxide ( 3 2 0 ) .Thermal analysis of d and Z-hyoscyamine mixtures containing from

0 o 50y0 d-hyoscyamine indicated an unbroken series of isomorphic




mixed crystals. Two polymorphs of 1-hyoscyamine were observed, a

stable one melting at 107-109°C and a metastable one melting at

104"C, but no polymorphism of atropine was observed (321) .Tropic acid ester hydrolase and tropic acid dehydrogenase, enzymes

obtained from P s e u d o m o m putidu, were used for enzymatic assay

of atropine sulfate, hyoscyamine sulfate, and tropic acid in the

10-7-10-4 M range (322) . Atropinesterases from nine Pseudomonasstrains were compared with respect to activity and composition (323) .

Photometry was used to assay atropine, homatropine, cocaine,

scopolamine, and tropazine. Reaction with barbituric acid or thio-

barbituric acid in dimethyl or diethyl oxalate was used to develop the

chromophore (324) .The highest sensitivity was obtained with diethyloxalate and thiobarbituric acid. Another colorimetric method was used

to determine the alkaloids in Solanaceae extracts (325) .The alkaloids

were nitrated by a mixture of HNO, and H,SO,, extracted by CH,Cl,,

and assayed by the Vitali reaction in dimethyl sulfoxide (326) .A third colorimetric method, used on atropine, homatropine,

scopolamine, and the methobromides of the last two named, has been

based on the hydroxylaminolysis of the ester function to produce

hydroxamic acids followed by addition of ferric ion to produce the

colored complex (327) .Quantitative methods for determination of microamounts of solan-

aceous alkaloids are few, none involving direct UV measurement. It has

been found that about a 50-fold increase in the UV molar absorptivities

of the tropane alkaloids can be achieved via charge-transfer complex

formation with iodine in chlorinated hydrocarbon solvents. This

allows adequate assay of single drug tablets ( 3 2 7 ~ ) .ltraviolet measure-

ment can also be used for determination of scopolamine in the 0.16-1 .OO

mg/cm3 range when this alkaloid is complexed as Scopolamine H[Cr-

(NCS),-(p-toluidine),] (327b).Immunoassay offers the most sensitive measurement available for

specific alkaIoidal substances. Benzoylnorecgonine and norcocaine have

been derivatized on nitrogen with groups susceptible to diazotization.

Coupling of these derivatives to antigenic substances has allowed the

preparation of antibodies to cocaine and benzoylecgonine. Other

derivatives are also described ( 3 2 7 ~ ) .n a similar approach, atropine

was coupled via its hemisuccinate ester to bovine and serum albumin to

produce antibodies (327d) .Several variations on and evaluations of pharmacopeia methods of

various countries for tropane alkaloid assay have appeared. Four

studies related specifically to belladonna (328-331), variations being

made in extractive techniques and ultimate titration methods. Drying




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29, 357-360 (1976).

401-402 (1970); CA 74, 505360 (1971).

BangladeshJ.Sci. Ind.Rea. 9, 79-81 (1974); CA 82, 28529w (1975).

55194f (1976).

64-68 (1973);C A 83, 126883~1975).

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(1973); C A 80, 130509k (1974).

5, 1-15 (1973);C A 81, 101848% 1974).

(1972).

55756v (1975).

Acta Pharm. Hung. 45, 167-174 (1975); CA 83, 142865~1975).

132796h (1976).

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224. J. D. Leary, Lloydia 33, 264-266 (1970).

225. L. V. Selenine, V. I. Gladkov, an d G. L. Glinskaya, Tr. Leningr. Khim.-Farm. Inat.

226. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270, 19-27 (1971); CA 76, 33171d

227. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270,3-18 (1971);CA 76,33212t (1972).

228. I. Tammaru, Tartu Riikliku Ulik. Toim. No. 270, 28-40 (1971); C A 76, 33177k

229. V. Koppel, Tartu Riikliku Ulik. Td m . No. 270, 63-70 (1971);C A 76,23078q (1972).

230. N. G. Bozhko, Khim.-Farm. Zh. 4, 42-44 (1970); C A 74, 34568j (1971).

230a. M. Dorer and R. Malnersic, Farm. Veatn. (Ljubljana) 25, 169-195 (1974); C A 83,

230b. L. Stecka, A. Mruk-Luczkiewicz, and S. Wilk, Herba Pol. 21, 17-23 (1975); C A

231. M. Al-Yakya an d W. C. Evans, J . Pharm. Ph am co l. 27 Suppl., 87P (1975).232. S. I. Balbaa, A. H. Saber, M. S. Karawya, an d G. A. E l Hossary, J . Pharm. Sci.

233. G. S. Kennedy, Phytochemistry 10, 1335-1337 (1971).

234. K. J. Sipply, PZanta Med. Suppl. 186-188 (1975).

235. W. J. Griffin, H. P. Brand, and J. G. Dare, J . Pharm. Sci. 64, 1821-1825 (1975).

235e. L. Cosson, J. C. Vaillant, and E. Dequeent, Phytochemwtry 15, 818-820 (1976).

236. A. Ghani, W. C. Evans, and V. A. Woolley, Bangladwh Pharm. J . 1, 12-14 (1972);

236a. N. I. Telezhko, Aktual. Vopr . Farm. 2 , 45-48 (1974); CA 84, 102349~1976).

237. B. P. Jackson and M. I. Berry, Phytochemistry 12, 1165-1166 (1973).

238. D. E. Koeppe, L. M. Rohrbaugh, E. L. Rice, and S. H. Wender, Phyeiol. Plant. 23,

239. K. Basey and J. G. Woolley, Phytochemistry 12, 2557-2559 (1973).

240. R. T. Mirzamatov, V. M. Malikov, K. L. Lutfullin, 0. Khakimov, and S. Y .Yunusov, Khim. Pr ir. Soedin. 9, 566 (1973); C A 80 45709f (1974).

241. R. T. Minamatov, K. L. Lutfullin, V. M. Malikov, and S. Y. Yunusov, Khim. P&.

Soedin. No. 3, 416-417 (1974); C A 81, 16 63 59 ~1974).

242. W. C. Evans, A. Ghani, en d V. A. Woolley, Phytochemistry 11, 469 (1972).

243. L. N. Bereznegovskaya and G. M. Fedoseeva, Rastit. Resur. 5, 512-519 (1969);CA

244. I. L. Krylova, L. N. Shakhnovskii, S. V. Rusakova, end E. F. Mikhailova, Rastit.

245. B. Srepel, Acta Pharm. Jugosl. 21, 8 6 9 0 (1971); CA 75, 1439 44~1971).

246. I. L. Krylova, L. N. Shakhnovskii, and S. V. Rusakova, Rastit. Resur. 8, 54-59

(1974).

105-110 (1970); C A 75, 67420d (1971).

26, 40-55 (1968); CA 73, 63233f (1970).

(1972).

(1972).

142837r (1975).

83, 1305252 (1975)..

U.A.R. 10, 125-134 (1969); C A 73,127727e (1970).

GA 79, 758712 (1973).

258-266 (1970).

72, 75609v (1970).

Rwur. 7, 9-18 (1971); C A 74, 108128q (1971).

(1972);CA 76, 124146r (1972).




247. M. Tabata, H. Yamamoto, N. Hiraoka, A. Oka, K. Kawashima, an d M. Konoshha ,

247s. Y. Watanabe, I. Yasuda, T. Seto, K. Nakajima, and Y. Nishikawa, Tokyo ToritsU

248. M. Tab ata , H. Yamamoto, N. Hiraoka, an d M. Konoshima, Phytochemistry 11,

249. M. Szymanska, Pol. J . Pharmacol. Pharm. 25, 201-206 (1973); CA 79, 102854e

250. S. A. Minina and E. A. Marchenko, Rmtit. Reaur. 9, 203-205 (1973); CA 79,

251. S. A. Minina, L. P. Mashkova, an dL. A. Kulikova, Rmtit. Reaur. 5 , 385-390 (1969);

252. M. Gorunovic, N. Prum , and J. Raynaud, Plant. Med. Phytother. 4, 286-291 (1970);

253. M. Yankulova and I. Yankulova, Dokl. Akad. Nauk Bolg. 4, 299-307 (1971); C A

254. M. Gorunovic and P. Lukic, Acta P h r m . Jugosl. 22, 69-71 (1972); C A 77,79580k

255. G. M. Ulicheva, Rmtit Resur. 6, 528-534 (1970); C A 74, 95405a (1971).

256. I. Barene and S. A. Minina, Rasti t. Resur. 7 , 124-128 (1971);CA 74,108131k (1971).

257. B. A. Samoryadov and S. A. Minina, Khim. Pri r. Soedin. No. 7, 209 (1971); CA 75,

258. I. Barene and S. A. Minina, Khim. Prir. Soedin. No. 7 , 379-380 (1971); CA 75,

259. G. M. Ulicheva, Rastit. Resur. 7 , 18-24 (1971); CA 74, 108126n (1971).260. S. A. Minina and I. Barene, Bwl. Akt. Veshcheatva F l q Fauny Dal'n. Vost.

261. N. I. Ryabova, Rastit. R w r . 9, 548-550 (1973); CA 80, 105856~1974).

261a. S. A. Minina, T. V. Astakhova, and N. V. Nazarova, Rastit. Resur. 11, 493-496

262. W. C. Evans, A. Ghani, and V. A. Woolley, Phytochemistry 11, 470-472 (1972).

263. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochran, and F. M. Shell, Ace. Chem.

264. L. Simeral and G. E. Maciel, Org. Magn. Reson. 6, 226-232 (1974).

265. P. Pauling and T. J. Petcher, Chem. Commun. 1001-1002 (1969).

266. V. S. Dimitrov, S. L. Spasov, and T. Radeva, J. Mol. Struct. 27, 167-176 (1975).

267. P. Scheiber and K. NBdor, Arzneim.-Forsch. 25, 375-378 (1975).

268. K. NBdor and P. Scheiber, Arzneirn.-Forsch. 22, 459-462 (1972).

268a. H.-J. Schneider an d L. Sturm, Angew. Chem. Int. Ed. Eng. 15, 545-546 (1976).

269. A. F. Casy and W. K. Jeffery, Can. J . Chem. 50, 803-809 (1972).

270. A. F. Casy, Prog. Med. Chem. 7 , 265-276 (1971).

271. P. S. Portoghese, A. A. Mikhail, and H. J. Kupferberg, J . Med. Chem. 11, 219-225

272. M. R. Bell an d S. Archer, J . Am. Chem. SOC. 2, 151-155 (1960).

273. A. F. Casy and J. E. Coates, Org. Magn. Reson. 6, 441-444 (1974).

274. T. T. Nakashima and G. E. Maciel, Org. M q n . Reson. 4, 321-326 (1972).275. H. M. Fales, H. A. Lloyd, and G. W. A. Milne, J . Am. Chem. SOC. 2, 1590-1597

276. H. M. Fales, G. W. A. Milne, and N. C. Law, Arch. Mass Spectral Data 2, 654-657

Shoyakugaku Zasshi 23, 83-88 (1969); CA 73, 73844v (1970).

Ebei Kenkyuaho Kenkyu Nempo 26, 90-92 (1975); CA 85, 10345k (1976).

949-955 (1972).

(1973).

15907f (1973).

C A 72, 3978% (1970).

C A 74, 108125rn (1971).

77, 45657a (1972).

(1972).

31332n (1971).

115920r (1971).

Tikhogo Okeana 22-23 (1971); C A 77, 111461k (1972).

(1975); C A 84, 56481j (1976).

Res. 7 , 46-51 (1974).

(1968).

(1970).

(1971).




328. M. Dorer and M. Lubej, Arch. Pharm. Ber. B@ch. €’harm. Urn. 305,273-276 (1972);

329. A. Puech, M. Jacob, J. Dupy, and J. Grevoul, J . Pharm. BeZg. 24, 389-396 (1969);

330. A. Puech, M. Jacob,J. Dupy, and J. Grevoul, J . Pharm.BeZg. 26, 520-524 (1971);

331. W. Wisniewski and H. Piasecka, Acta: Pol. Pharm. 28,55-58 (1971);C A 75,25456q

332. W. Wisniewski and S. Gwiazdzinska,Acta Pol. Pharm. 29, 347-348 (1972);CA 77,

333. I. S. Simon, T. A. Pletneva, T. N. Gubina, and Y. V. Shostenko,Khim.-Farm.Zh. 4,

333a. S . A. H. W alil and S. El-Masry, J . Pharm. Sci. 65, 614-615 (1976).

334. M. J. Solomon and F. A. Crane, J. Pharm. Sci. 59, 1680-1682 (1970).335. Y. V. Shostenko,I. S. Simon, and T. N. Gubina. Otkqtinya, Izobret., Prom. Obraztsy,

336. S . Bukowski and A. Bartosiak, Farm. Pol. 28,125-127 (1972);C A 77,9559m (1972).

336a. A. L. H. DeDujovne and J. Helman, Rev. Farm. (BW?%08ires) 117,66-72 (1975);

337. L. P. Khudyakova, Aktual. V o w . Farm. 1, 127-129 (1970);C A 76,63129~1972).

338. V. Kamedulski, B. Bozhanov, I. Tonev, and M. Dzherova, B’armatsiya (So$a) 25,

CA 77, 39316x (1972).

CA 72, 82995b (1970).

CA 77, 393268. (1972).

(1971).

137031~1972).

58-60 (1970);C A 74, 34639h (1971).

Tovarnye Z m k i 51, 68 (1974);CA 80, 146395f (1974).

CA 85, 2154g (1976).

11-15 (1975);C A 85, 831526 (1976).



-CHAPTER 3-

NUPHAR ALKALOIDS*

JERZY. W R ~ B E L

University of Warsaw

Warsaw, P o l a d

I. Introduction

........................................................181

11. C,, Alkaloids ....................................................... 181

A. Chemistry....................................................... 181

B. Absolute Configuration............................................ 185

C. New Compounds ................................................. 186

111. Sulphur-ContainingC,, Alkaloids ..................................... 195

197

B. C,, Alkaloids of Carbinolamine Structure.. .......................... 198

IV. Mass Speotromet y .................................................. 204

V. Total Synthesis of CI5 Nuphar Alkaloids ............................... 211

VI. Biosynthesis ........................................................ 213

References ......................................................... 213

A. C,, Alkaloids of Sulfoxide Structure ................................

I. Introduction

Nuphar alkaloids were extensively studied in the last decade mainly

in Poland and Canada, as well as in Japan, the United States, and the

Soviet Union. Several new C15 and thio-C,, alkaloids were isolated.

Special attention was paid to conformational and configurational

problems studied by various chemical and spectral methods. The

fragmentation of both C,, and thio-C,, systems was studied by massspectrometry, and general conclusions were formulated concerning the

mechanism of fragmentation and its structural implications. Preliminary

biosynthetic studies were carried out using I4C-labeledmevalonic acid.

II. C,, Alkaloids

A. CHEMISTRY

Nupharidine and deoxynupharidine were the most extensively

studied C,, alkaloids. Arata et al. ( 1 ) oxidized nupharidine (1) ntodehydrodeoxynupharidine (2) using ferric nitrate. The reaction was

* For the first review on Nuphar alkaloidsby J. T. Wrbbel, see Vol. IX of “The Alka-

loids.” Chapter 10, p. 441.



182 JERZY T.W R ~ B E L

1 2

shown to have a more general preparative value, as exemplified by

oxidation of 4-phenyl-quinolizidine N-oxide. Several derivatives of

deoxynupharidine (3), substituted in the furan ring, were prepared

b///,,/ e3

3a R = NO13b R = COCH,

3e R = -c> O2

using certain electrophilic reagents (2).5-Acetyl-deoxynupharidinewas

transformed to the 3-hydroxy-2-methylpyidyl erivative (4) on

heating with aqueous ammonia and ammonium chloride (2).

M eI

M e

4

Polonovski transformation of ( + )-nupharidine carried out in a large

excess of acetic anhydride resulted in A6-enamine 5 )(3).Hydrogenation

of 5 resulted in (- deoxynupharidine and ( - -7-epideoxynupharidine



184 JERZY T. W R ~ B E L

demonstrated that the hydrogen atom eliminated in the Polonovski

transformation was the 6a-hydrogen.

The oxidation of deoxynupharidine to nupharidine was found to bealmost three times faster than the oxidation of 7-epideoxynupharidine.

This was explained in terms of oxidation of deoxynupharidine with

inversion on nitrogen to give a cis-fused quinolizidine N-oxide (10)

(Eq. 3). The cis-fused conformation of nupharidine was confirmed by

H? I

X-ray studies. In view of the cis ring fusion in 1, the Polonovski

transformation was considered to be a t rans8 elimination; the mecha-

nism would then involve the steps shown in Eq. 4.

Me Me

Me Me

(+ )-Nupharidine was transformed to A3-dehydrodeoxynupharidine

11)using a modified Meisenheimer rearrangement ( 4 ) (Eq. 5 ) .

M e

l -

( 5 )

11




h

e

14 15

M eI Me

16

18

C. NEWCOMPOUNDS

1 . 7-Epideoxynupharidine (19)

This alkaloid was isolated by LaLonde et al. ( 9 , 10) from Nupharluteum Sibth. et Sm. subsp. variegatum. The structure was confirmed

by IR and NMR spectra and hydrogenation of As-dehydrodeoxynu-

pharidine ( 5 ) ,which produced deoxynupharidine (3) nd the 7-epiisomer

(19).

Me

19

The NMR spectrum of 19 displayed methyl resonance doublets a t

9.08 and 9.26 T (J = 3 and 5.4 Hz, respectively). In comparison withNMR data for deoxynupharidine (3), he axial methyl groups with

lower field signals and larger splittings and the equatorial methyl groups

with higher field signals and smaller splittings can be correlated-a



3. N U P HAR ALKALOIDS 187

phenomenon well-known in quinolizidine chemistry ( IO U ) .The absolute

configuration of 7-epideoxynupharidine represented by structure 19

follows correlation through 5 with deoxynupharidine (3).

2. Nuphenine (20) and Anhydronupharamine (24)

20

Nuphenine (20) was isolated first by Forrest et al. (11, l l a ) . Itsmolecular formula was determined as C,,H,,NO (mw = 233). The I R

spectrum shows N-H (3310 cm-l), Bohlmann bands (2800 and 2730

cm-l), furan (1505, 880 cm-l) ; the NMR spectrum indicates the

presence of a substituted double bond (multiplet at 4.88 7 -

Nuphenine can be hydrogenated either to a dihydro compound (21)or

to hexahydro derivative (22) (Eq. 7 ) . The 4.88 signal is absent in the

20

22 21

NMR spectrum of 21, and the peak at 8.3 r (6H,S) in nuphenine is

shifted to 8.75 T (6H,d); his, together with the peaks at mle 164 (M-69)

in the mass spectrum of 20 and at mle 168 in the spectrum of 22,

confirms the presence of the (CH3)2C=CH-CHz- (m/e 69) group in

20. Easy loss of this group suggests that it is located in the position

alpha to nitrogen in the piperidine ring. SinceH, is split by only one ring

proton, the methyl group is assumed to be located on the adjacent

carbon; the protons H, and H, with a coupling constant of 2.5 Hz must

be in an axial-equatorial or equatorial-equatorial relation to one another( 1 2 ) .The presence of bands at 2800 and 2730 cm-l in the IR spec-

trum of nuphenine was taken as evidence for t.wo hydrogens axial to the

nitrogen atom. The proposed configuration ofnuphenine is shown in 23.




~ b - k - ~ e\ /Me

He /C=C\Me

23

Isomeric with nuphenine is anhydronupharamine (24) isolated by

Arata et al. ( 13 , 1 4 ) from Nuphar japonicum DC. It proved to beidentical with the dehydratation product of (- -nupharamine (15) and

therefore it s configuration should be as in 24.

24

3. Nuphamine (17)

17

The chemistry of this alkaloid was further studied and its configura-

tion was related to deoxynupharidine (3) and nupharamine (15). The

transformations in Eq. 8 have been effected. On the basis of Eq. 8,

nuphamine is thought to have configuration 17. A study of the con-

figuration around the double bond in nuphamine led to the conclusion

th at in the side chain the methyl group and hydrogen were in the transposition ( 1 5 ) .This deduction is based on a general observation that inthe X-CH,-C(CH,)=CH,-Y system a trans relationship between

the methyl group and the vinyl proton results in a higher r value



3. N U PHAR ALKALOIDS 189

Na2C03, C H d17 24

( A T = 0.06-0.07) for the methyl protons than that observed for the

cis isomer. Thus, the absolute configuration 27 of nuphamine (17) was

established:

4. 3-Epinuphamine (28) (C,,H2,N02)

The alkaloid was isolated by LaLonde et al. ( 1 6 ) from Nupharluteum subsp. variegatum and was shown to have configuration 28. I ts

molecular formula was confirmed by mass spectroscopy. The IR and

NMR spectra indicate the presence of a %fury1 group. Attachment of




this group to the carbon a to nitrogen (C-6) was concluded from the

presence of the proton (3 . 58 6) deshielded by the fury1 group and the

nitrogen. The presence of OH and NH groups was established inthe conversion of 28 to an N,O-dibenzoyl derivative. The presence of a

28

trisubstituted double bond was indicated by the I R and NMR spectra;

the latter showed a hydroxymethyl group (3 . 93 6, 2H, broad singlet), a

vinyl methyl group (1.65 6, 3 H , broad singlet), and a methylene group.

The trans stereochemistry of the double bond was based on the charac-

ter of the vinyl proton signal in the NMR, as it was shown in nuphamine

( 1 5 ) .Oxidation of 28 with MnOz resulted in an aldehyde (29), giving

additional support to the proposed double bond stereochemistry. The

F YM eM e

29

UV spectrum of this aldehyde was in accord with known trans-2-methyl-

2-pentanal. a-Attachment of the side chain to nitrogen was consistent

with the appearance of an ion at m/e 164 ( l O O ~ o ) n the mass spectrum.

The NMR spectrum showed the C-2 proton as a triplet of doublets,

which could be explained as a coupling to the side chain methylene

group and to a single proton. This implied substitution a t C-3 of a

methyl group whose presence is indicated by a doublet at 0 . 99 6.The substitution pattern in piperidine was determined by converting

both the N,O-dibenzoyl derivative (30) and nuphenine benzamide to

the aldehyde (32):

0

30

31

R = CH,OCOCeH,, R’ = C e H 5 C 0

R = Me, R’= CeH,CO

32




The presence of an axial methyl group at C-3 is implied by a doublet

a t 0.99 6, which is at a lower field than the resonance (0.91 6) displayed

by the equatorial methyl of nuphamine. Other characteristics of NMRspectra are consistent with this assignment.

5 . Nupharolidine (33) C,,H2,N02)

33

This alkaloid isolated from the rhizome of Nuphar luteum by Wr6bel

and Iwanow ( I Y ) ,was the first among the C,, alkaloids to be shown to

have its hydroxyl group situated in the quinolizidine ring.

The suggested structure of this alkaloid was based on spectroscopic

correlation (IR , NMR, and mass spectra) with three other C,, bases-deoxynupharidine (3),castoramine (34), and nuphamine (17). The

M e

34 R1 CHaOH, Ra = H

crucial observations pertaining to the structure beside the trans-

quinolizidine and a B-substituted furan ring indicated the presence of

two CH-CH, groups ( T = 9.12 and 8.80; doublets), CH,-O&

( 7 = 6.35, and 4.75,; IR, 3342 cm-l).

The presence of two methyl groups, which appear as two doublets,ruled out the presence of a hydroxymethyl group and eliminated the

possibility of C-1 and C-7 being the points of O H substitution. Since a

strong signal at mle 178 (fragment 35) was observed in the mass

spectrum the presence of an OH group at C-6 position was also ruled out.

\ \

/ /




M e

35

The presence of the fragment 35 and of two others at mle 7 1 and 206

to which structure 36 and 37were ascribed, respectively, point to C-9 as

the location of the hydroxyl group. Thus, nupharolidine is thought to

have structure 33.

36

m/e 7 1

37m/e 206

6. Nupharolutine (38) (C,,H,,NO,)

Nupharolutine is another C,, alkaloid with a hydroxyl group. It was

isolated and its structure was established by the Polish-Canadian

group of workers (18).It is isomeric with nupharidine (1) and castor-

amine. Structure 38 for nupharolutine was based on spectroscopic and

chemical data.

M e

38



3. NUPHAR ALKALOIDS 193

The IR spectrum shows the presence of an intermolecularly bonded

hydroxyl group and a trans-quinolizidine system. Unsuccessful at-

tempts at acetylation indicate the tertiary character of the hydroxyl.The NMR spectrum of the new alkaloid shows a doublet centered a t

0.92 and a singlet (3H) at 1.21 6. The singlet peak and its chemical shift

are compatible with a -C --C(CH3)OH-C-- grouping in the molecule.

Other signals in the NMR spectrum were in accord with those observed

for deoxynupharidine and indicated the presence of a p-substituted

furan ring in the equatorial position (C-4-Haxial uartet 3.03 8 , J = 8.3

and 6.0 Hz). The final data for structure 38 were obtained from themass spectrum. High resolution studies gave the composition of the ions

observed, thereby giving further insight into the fragmentation process.

The fragmentation is discussed later with that of other Nupharalkaloids.

Nupharolutine was correlated wiih deoxynupharidine (3)as in Eq. 9.

I I I

I I I

This sequence offers the final proof for the proposed structure and for

the absolute configuration of nupharolutine. A dimeric compound

related to nupharolutine was isolated by LaLonde et al. (19).Spectro-

scopic data indicate structure 39. This structure was confirmed by a

synthesis beginning with dehydrodeoxynupharidine (14) (Eq. 10).

Osmium tetroxide oxidation of 14 yielded diol 40, which wa,s trans-

formed upon dehydration into 39, borohydride reduction of which

generated a mixture of 41 and 42.

Me

M e

39




14

40

b R 2i

Q4 1 Rl = O H , R, H

42 Rl = H RZ = OH

NaBH 9

7. Epinupharamine (Epi-15) (C,,H,,NO,)

3-Epinupharamine (epi-15) was isolated by Forrest and Ray who

established its structure. Its structure was proved on the basis of its

spectra and by its synthesis from nuphenine (20). Mass spectrometry

confirmed the molecular formula and the presence of the 3-methyl-3-

hydroxybutyl side chain (peak at mle 164). The IR and NMR spectra

Epi - 15

showed the presence of the hydroxyl group (3575, 3150 em-, and

T = 7.35) and the furan ring (IR, 1500, 1170, and 875 cm-l; NMR,

2.63 (2H), 3.57 (1H) T ; CH-CH, (ring) 9 .03~d nd a gem-CH, 8.83 T,

8.75 T). This assignment of the structure and stereochemistry was

verified by the conversion of nuphenine (20) into a compound identical

with the naturally occurring epi-15.




111. Sulfur-ContainingC,, Alkaloids

Thiobinupharidine (43) (C3,H,,N,02S)

" A s

43

It was shown earlier (20 , 21) that 43 is isomeric with neothiobi-

nupharidine (44) and both 43 and 44have almost the same characteristic

structural pattern (quinolizidine, furan, -S-CH,-, two methyl

groups, and similar pK, values). Extensive spectroscopic studies led todeduction of the structure and of the relative configuration of 43. The

structure has been firmly established and the absolute configuration

has been determined by a study of the crystal structure of thiobinu-

pharidine dihydrobromide dihydrate ( 2 2 ) .

The structure of thiobinupharidine was established by Wr6bel and

MacLean ( 2 2 )by comparing the IR , NMR, and mass spectra with those

previously obtained for neothiobinupharidine (44) ( 2 0 ,2 1 ) . The I R and

NMR studies ( 2 3 )of the alkaloid in question, of some model compounds,

and of reduction products of biscarbinolamines led LaLonde to thesame conclusion. Equimolecular solutions of 43 and 44 examined under

the same conditions showed Bohlmann bands of nearly equal intensities.

This indicates the presence of two trans-quinolizidine rings in 43.

High-resolution mass measurements showed identical compositions of

the major ions in the spectra of 43 and 44. The NMR spectra of the two

alkaloids have been examined at 220 MHz, and the anomalies of the

earlier studies (20 , 21 ) have been clarified. There is a signal of area 6

centered at 6 0.91 ( J = 5 Hz) assignable to two CH-m groups

(compare 6 0.85, J = 5.5 Hz for 44 and 6 0.92, J = 5.6 Hz, for 3 assignals for the equatorial methyl groups). Observations concerning the

furan proton are in accord with those made earlier ( 2 0 , 2 1 ) . In the

region 6 2.7-3.08, complex signals of area 4 appear that are attributed



196 JERZY T. WROBEL

to two protons in the furan ring (a t C-4 and C-4') and to the two equa-

torial protons at C-6 and C-6'. These assignments are made by analogy

with the chemical shifts of the corresponding protons in 3.The spectrum of 43 also contains a well-defined AB pair of doublets

centered at 6 2 . 3 2 (J = 1 1 . 5 Hz) and attributed to the CH2-S group

(compare with a singlet at 6 2 . 6 7 , W + = 3 Hz, in the spectrum of 44).

By analogy to the studies on model compounds ( 2 4 ) the absorption of

the thiomethylene group suggests an equatorial conformation of the

CH2-S with respect to the quinolizidine ring.

0-

44

The equatorial linkage of the sulfur atom to the second ring was basedon evidence presented by LaLonde (25) for the equatorial character of

the C-7-S linkage in thionuphlutine A , which in turn was shown to be

identical with thiobinupharidine.

All the evidence indicates structure 43 or thiobinupharidine. It has

been confirmed by an X-ray crystal structure determination of thiobinu-

pharidine dihydrobromide dihydrate. The observed bond lengths are in

good agreement with the accepted values. The only bond that exceeds

the average value is that between C-17' and C-7'. The alkaloid has a

pseudo-twofold axis. The nonpolar character of the S-containing ringand the inequivalence of S and C-17' destroy this element of symmetry.

LaLonde et al. (23)provided further evidence consistent with structure

43.

The 1 0 0 MHz NMR spectrum of thiobinupharidine determined in

benzene shows the two C-4 protons as two overlapping quartets both

with splittings of 1 . 5 and 1 0 Hz. Such a splitting pattern may be

ascribed to an axial (3-4 proton rather than to an equatorial one.

Evidence for the stereochemistry of the C-1 and C-1' methyl group

comes from the direction of the solvent-induced shift of the C-1 methylgroup observed in the NMR spectrum. The C-7 axial methyl group in

deoxynupharidine is shifted downfield by 4 . 2 Hz and the C-1 equatorial

methyl is shifted upfield by 5.0 Hz when deuterochloroform is replaced



198 JERZY T. WROBEL

B. C,, ALKALOIDSP CARBINOLAMINE TRUCTURE

A number of C,, sulfur-containing alkaloids have hydroxyl or alkoxylgroups in the 6 position to the nitrogen atom (27-30) . Compounds of

that type of structure are listed in Table I1 (23 , 26-34) (Compounds

2-1 0). Spectroscopic chemical and mass spectrometric studies (see

Table I) led to the structures of a number of carbinolamines.

Nuphleine (46) (C,,H,,N,O,S) was shown to have two hydroxyl

groups. Sodium borohydride as well as catalytic reduction yielded

thiobinupharidine (43). Thus, nuphleine was shown to be a dihydroxy

derivative of 43.

Thionupharoline (47) (C,,H,,N203S) recognized first as a mono-hydroxy derivative of the C,,H,,N202S alkaloids ( 2 8 ) was recently

proved by MacLean, Wrbbel, et al. ( 3 1 ) o be 6-hydroxythiobinuphari-

dine, a compound identical with 6-hydroxythionuphlutine A isolated by

LaLonde ( 2 3 ) ,who independently elucidated its structure.

The alkaloid was isolated as its immonium ammonium diperchlorate,

which revealed in the I R spectrum the presence of the C = N band

a t 6 . 0 2 ~nd R,N+H absorption at 4 . 3 5 ~ . he immonium monoper-chlorate showed Bohlmann bands a t 3 . 6 0 ~ . hese observations sugges-

ted the dual amine-hemiaminal character of the free base. The latter

recovered from the perchlorate showed in its mass spectrum the highest

mass fragment at m/e 492 (M+-H,O). The I R spectrum revealed

Bohlmann bands and absorption characteristics of the 3-fury1 group,

whereas the NMR spectrum showed the presence of one proton ex-

changeable with D20.Reduction of 51 with sodium borohydride results

in thiobinupharidine (43), and reduction with sodium borodeuteride

gives thiobinupharidine-6-d,. Since the NMR spectrum displays a

singlet a t 6 3.98 attributed t o the proton HO-C€J-N , a o nitrogen

and t o the hydroxyl group, the lat ter can only be located a t C-6or C-6'.

The location of the hydroxyl group a t the C-6 position was supported

by NMR and MS studies of the thiobinupharidine-d, obtained by

reduction of 51 with sodium borodeuteride. NMR spin decoupling

experiments on the deuterated sample showed C-6' axial and C-6'

equatorial protons at 6 1.41 and 3.16, resp and a C-6 axial proton at6 1.91. These findings demonstrate that the C-6 position was reduced

stereospecifically with the introduction of an equatorial deuterium.

Incorporation of the equatorial deuterium indicated that the hydroxyl

\ + /

/ \

/

\



TABLE IC1, Nuphar ALKALOIDSND THEIR ROPERTIES

Compound

Melting point

oormula ("C)

7-Epideoxynupharidine (19) C15H23NO - - 9

Nuphenine (20) (anhydronupharamine) CI5Hz3NO - -23 (Hg)

-Epinuphamine (28) Ci,Hzi"zNupharolidine (34) C15H2,N02 110 -

Nupharolutine (38) C15H23N02 9&98 - 105

7 -Epinupharamine (epi-15) c1a sNO2 -

- -41.5

6,7-Oxidodeoxynupharidine 39) C3,H*2N20, 165-170 - 9 3-

a Cf. Table I in Wr6bel (5).



TABLE I1

NATURALLYOCURRINQc30SULFUR-CONTAININQALKALOIDSND THEI

Compound

Melting point

Formula ("C) an Melting p

Neothiobinupharidine sulfoxide (45)

Thionupharoline (47)

(6-hydroxythiobinupharidine)

6-Hydroxythionuphlutine B (54)

6'-Hydroxythiobinupharidine (55)

6,W-Dih ydroxythiobinupharidine

6,6'-DihydroxythionuphlutineB (53)

Nuphleine (46)

Thionupharodioline (48)

Ethoxythiobinupharidine (49)Diethoxythiobinupharidine (50)

(6,6'-dihydroxythionuphlutineA) (52)

240-242

Amorphous

Amorphous

156-158

Amorphous-

-

- 2HC104,

C104

+34 2HC104,

+44.5 2HC104,

- 2HC104,

- ~ H C ~- 2HC104,

- 9

-

a Cf. Table I1 in Wr6bel ( 5 ) .



3. N U P H A R ALKALOIDS 201

group is located a t C-6, since th e reduction a t C-6' results in incorpora-

tion of an axial deuterium atom. The stereochemistry of the reduction

was established through studies on 6,6'-dihydroxythiobinupharidineand on model compounds (23).In addition, it was pointed out ( 2 3 , 30)th at the fragments of m/e 228 (37-3970) and 176 (37-10070) observed

in the spectra of 6,6'-dihydroxy Nuphar C, , alkaloids, although present

in the spectra of thio- and neothiobinupharidine, are of very low

intensity. The appearance in th e mass spectrum of 6-hydroxythiobinu-

pharidine of these fragments with intermediate intensities (62 and goy0)seems to confirm the presence of one hydroxyl group a t the 6- or 6'-

position in 51.

MeIp'-'\

mle 228 m/e 178

MacLean, Wr6be1, et al. (31) presented further experimental data,

which led to structure 51 for thionupharoline (47). Of special value

were extensive NMR studies a t 220 MHz, which very clearly recognized

the following protons (in CDC1,); 6 2.26 ( O H exchangeable with D,O),

2.89 ( lH , C-4'), 2.92 ( l H , C-6 H eq), 3.70 ( l H , C-4), and 3.97 ( lH, C-6

sharpens on addition of D,O).

The 220 MHz NMR spectrum of thiobinupharidine-6d (obtained

from the reduction of 47 with sodium borodeuteride) allowed the

protons a t C-4 (4') and C-6) (6') to be more precisely recognized.The following data were obtained in CDC1,: 6 1.45 (C-6' H,,), 1.70

(broad singlet superimposed on envelope C-6 H,,), 2.79 (0.55, C-6 H,,),

M e

51




2.93 (C-4 H, C-4’ H), 2.93 (C-6’ Heq); nd in CsD,: 1.40 (C-6’ H,,),1.93 (0.32 H, C-6 H,,), 2.80 (2H, C-4’ Ha, and C-4 H,,), 3.10 (0.62 H,

6,6’-Dihydroxythiobinupharidine 6,6’-dihydroxythionuphlutine )

(52) (C3,H4,N2O4S)was first isolated by LaLonde et al. (89) from

C-6 Heq),3.18 (1.04 H, C-6’ Heq).

1 7 ’7 s

52

Nuphar luteum subsp. macrophyllum ( 2 3 , 31, 33). The NMR spectrum

a t 220 M Hz ( 3 1 ) showed signals at 6 3 . 9 8 ( l H , C-6 Heq)and at 4.24

( l H , C-6’ Heq) in CDCl,. I n C6D6+ D,O solution, these protons

appeared at 6 4.23 (1H, C-6 Heq)and 4.35 ( lH , C-6’ Heq).An axialconfiguration was assigned to the hydroxyl groups a t C-6 and C-6‘.

Thionupharodioline (48) C,,H,,N,O,S is isomeric with 52. Wr6bel

et al. ( 3 0 )suggested that the two alkaloids differ in the configuration a t

C-6 and C-6’. It was isolated from Nuphar luteum (Polish origin) and is a

crystalline solid of mp 156-158°C. Both potassium borohydride and

catalytic reductions resulted in thiobinupharidine. The strong hydrogen

bonding observed in the IR spectrum and the very low intensities of the

Bohlmann bands indicate equatorial configurations for O H groups at

C-6 and C-6’. The proposed structure (48) is shown below.

M e

48




Ethoxythiobinupharidine (49) and diethoxythiobinupharidine (50)

were isolated from Nuphar luteum ( 3 0 ) .Their structures were based on

on IR , NMR, and mass spectrometry studies as well as on the productof reduction with potassium borohydride, which in both cases gave

thiobinupharidine (43).The configuration of the ethoxyl groups has not

yet been established. Since no ethylating agents were used during the

49 R1 = O E t , R, = H or R, = H , R, = OEt

50 R, = R, = OEt

isolation procedure of 49 and 50, the ethoxy group could not have been

introduced during the process ( 3 0 ) .The structure of 6,6'-dihydroxythionuphlutine (53) (C,,H,,N,O,S)

isolated by LaLonde (29)was recognized as isomeric with those of both

thio- and neothiobinupharidine ( 2 3 , 3 2 )dihydroxy- derivatives. On the

53

54

R,,R, = H,OH; R,,R4 = H, OH

R1, R, = H, H; R, = R, = H

basis of extensive NMR studies of 53 and of its deuterated reductionproducts, it was possible to show that this alkaloid contains an axial

sulfur atom attached to t he A B quinolizidine system and an equatorial

-CH2-S- group attached to the A'B' quinolizidine system.




6-Hydroxythionuphlutine B (54) is another monohemiaminal

isolated and investigated by LaLonde ( 3 4 ) .The evidence for the position

of O H group was based on NMR, mass, and CD data. The significantdifference in the chemical shifts of the carbinyl hemiaminal protons

were observed (for C-6 and C-S’, 4.08 and 3.94 6, respectively).

The mass spectrometry of thiaspiran singly labeled by deuterium

showed a mle 1 7 8 to m/e 179 shift. It was found th at the singly deuter-

ated thiaspirans th at were labeled at C-6 resulted in m/e 178 shifting to

1 7 9 by g o y o , and those labeled a t C-6’ resulted in a 10% shift only. The

CD of C-6’ hemiaminals in acid solution showed positive bands but

those with C-6 hydroxy substitution showed both positive and negative

bands. These results allowed LaLonde ( 3 4 ) to establish the structureof 6’-hydroxythiobinupharidine 55) (C,,H,,N,03S).

IV. Mass Spectrometry

Considerable progress has been made in the mass spectrometry of

Nuphar alkaloids C,, and C3,,. MacLean and Wr6bel gave the basic

mechanism of the fragmentation of several types of Nuphar alkaloids

using high-resolution mass spectrometry. The mass spectra of followingC,, alkaloids were recorded: deoxynupharidine (3), upharidine ( l ) ,

castoramine (34), nd nupharolutine (38) see Scheme 1 ) . The mass

Me M e

C

SCHEME

D




spectrum of deoxynupharidine was first reported in 1964 ( 3 5 ) . High

resolution studies confirmed the composition assigned to the intense

ions in the previous work ( 3 5 ) and allowed the composition of lessintense ions to be determined.

The fragmentation involves the four bonds in position /3 to nitrogen,

to yield molecular ions A, B, C, D. The ion C either splits further into

homologous ions a, b, c or undergoes the retro Diels-Alder reaction to

yield ions d and e. Ions D and C can also result in ions f and g. Another

pa th of decomposition of 3 consists in a loss of the furan ring and forma-

tion of the h ion (Scheme 2).

The formation of the major ions in the spectrum of 3 is shown in

Scheme 3. All the major ions at m/e = 136 ( j ) , 98 (k), 97 (l),94 (m), and55 (n ) originate in the ion C.

When fragmentation proceeds with hydrogen transfer, as shown in

route 3d (there is no evidence that the hydrogen actually originates

from site C-2, as schematically shown), the resulting ion is k a t m/e 98.

The recent labeling studies (29) are in accord with the structure

proposed for these ions. Further fragmentation of the ion j , a t m/e 136,

has also been observed (cf. Scheme 3 routes 3e and 3f).

Fragmentation of castoramine (34)is similar to th at of deoxynuphari-

dine, as shown by parallel Schemes 1-3. The spectrum of 34 shows ionsabsent in the spectrum of 3, owing to the presence of the hydroxyl

group, as also shown in Schemes 1-3.

Recent work ( 2 6 ) on the spectra of neothiobinupharidine (44) nd

related systems showed that the dimeric compounds have many ions

in their spectra whose formation may be interpreted in terms of the

schemes suggested above. The fact that the fragmentation of 3 and 34

and many of the fragmentations of 44 may be interpreted through

Schemes 2 and 3 lends credibility to them.

The hydroxyl group present in 34 leads to new ions in its spectrum,

which are absent in the spectrum of 3.Thus, a strong ion a t m/e 96

can be ascribed to 34K-H20;an ion a t m/e 164 to 34K-H20and the ions

a t m/e 218 and 219 to the loss of C H 2 0 and C H 2 0 H from the molecule

as shown in Scheme 4. The spectrum of nupharolutine (38) has many

features in common with that of castoramine, but it is distinctly

different from that of nupharidine.

The differences between the spectra of 38 and 34 are compatible with

the structural differences. Thus, the loss of Me and OH is favored more

in 38 than in 34 as would the formation of ion f. The spectra bear this

out. It should be noted that the loss of H20 from m/e 114 to form m/e

96 is more pronounced in 38, the tertiary alcohol, than i t is in 34, he

primary alcohol.




a b C

3 m/e 204 (Cl3H1,NO) m/e 190 (ClzH16NO) m/e 178 (CllHl,NO)

38 and 34 m/e 220 (Cl,Hl,NOa) m/e 204 (C12H16NOz) mle 192 (C1iHiiN"a)

y cJ? P M e

d e h

3, 38, nd 34 3, 38,and 34 3 mje 166 (C11HaoN)

m/e 162 (Cl,H12NO) m/e 148 (C,H,,,NO) 38 and 34 m/e 182 (ClIHa0NO)

C'I D f

M e

( J Q R z H transfer I ';z3, 38, and 34 n / e 178 (C,,H,,NO)

g C

SCHEME



3. N U P HAR ALKALOIDS

Route 3b

d’2‘NQR, K . 1

0 0

j

3. 38. and 34 m/e 136 (CsH,,O)

V

207

3 m/e 97 (C,H,,N)

38 and 34 m/e 113 (C&,,NO)

3, 38, and 34

mle 55 C,H,N)

0

m/e 136 (C,H,,O)

k

3 m/e 98 (C,H,,N)

38.34 m/e 114 (C.H,,NO)

\ * 3,38,and 1 4

3, 38, and 34

m /e 94 (C,H,O)

rn

SCEEME




mle 219 mle 218

SCHEME

The spectrum of nupharidine ( l ) ,ike those of other N-oxides, showsthe loss of oxygen and OH [peaks a t r n /e 232 and 231 ( 3 6 ) ] .The peak

at m/e 220 does not result from loss of an ethyl fragment but from loss of

CHO, a fragmentation characteristic of furans.

In Scheme 5 , suggestions are made for the derivation of the major

ion at m/e 114 and related fragments based upon a determination of

their compositions by high resolution studies (18).MacLean and Wr6bel

( 2 6 )have also suggested a mechanism of fragmentation of C,, alkaloids,

such as neothiobinupharidine (44),hiobinupharidine (43), and neo-

thiobinupharidine sulfoxide (45). pectra of these compounds show anumber of ions identical with those shown in Schemes 1-3.

Fragmentation of neothiobinupharidine (44) and of related systems

M e M e Me



3 . N U P HAR ALKALOIDS 209

( 2 6 ) ,as well as of 54, can also be interpreted in terms of Schemes 2-3.This lends credibility to the suggested reaction paths.

Ions at m/e 461 and 4 4 7 have no counterpart in the spectrum of 3,and they owe their origin to the loss of SH and CH,SH, respectively,

from the molecular ion. An ion at mfe 359 formed by loss of C,H,,O

Me

44

from the molecular ion may be represented as in Scheme 6. The anal-

ogous ion in 3 appears at m/e 9 8 . If hydrogen transfer does not occur

and the charge remains with the furan moiety an ion at mle 136 results

with the same mass and composition as in the spectrum of 3.

The spectrum shows ions at mle 230, 178, 107, and 9 4 besides that at

mle 1 3 6 . The ions at mfe 94 and 107 , which also appear in 3 can be

M e

H transfer/J

Me

m/e 359, C,,H,,N,OS

+

SCHEME



2 1 0 JERZY T. W R ~ B E L

formed from 44 in a similar way. The structure of the ion a t m/e 230(C,,H,,NO) is formulated and derived as shown in Scheme 7 . If a

hydrogen is transferred to the sulfur-containing fragment and chargeis retained on this fragment, the ion at m/e 264 is observed (C15H22-

NOS). The most intense ion of the spectrum a t m/e 178 corresponds in

Me

44 M + = 494

mle 231

Me M e

m/e 264, C1,H,,NOS m/e 230, C,,H,,NO

SCHEME

composition t o C,,H,,NO. Its derivation is shown in Scheme 8. Charge

is also carried by the residual fragment, for a peak of low intensity isalso present a t m/e 316 (CISH,,NOS). An ion of m/e 178 is present in 3,

but i ts intensity is relatively weak.

I n their study of the reduction products of the thionuphlutines,

LaLonde et al. (29)came to t he same conclusion regarding the derivation

of the ions a t m/e 178 and 230 . New fragments due to the oxygen

function on sulfur appear in th e spectrum of 45, which has a sulfoxide

structure bu t the general pathway of fragmentation remains unchanged.

The mass spectrum of 45 shows losses of SOH and CH,SO from the

molecular ion at m/e 461 and 447 paralleling the losses of SH andCH,SH from neothiobinupharidine. An intense peak a t m/e 4 9 3

corresponds to the loss of OH. The rest of t he spectrum of 45 is similar

to tha t of neothiobinupharidine. Thus, the peaks a t m/e 230, 178, 136,




44 M + = 494

* I+Me

Me1

+\CH,

107, and 94 are all present and have composition identical with those

found in the spectrum of 44. ons of low intensity are also present at

m/e 280 (C,,H,,NO,S), 262 (280-HZO), 375 (C,,H,,N,O,S), and

(357-H20). The mle 280 ion is cognate to mle 230, while m/e 375 is

cognate to mle 136-H.

V. Total Synthesis of C,, Nuphar Alkaloids

Racemic forms of nupharamine (15) and 3-epinupharamine (epi-15)

were synthesized by Szychowski et al. (37) from @-acetylfuran(56)

(Eq. 12). The Claisen type condensation of 56 with ethyl formate

resulted in ketoenolate 57, which with /I-aminocrotonate yielded the

furylpyridine derivative (58 ) (Eq. 13).

C-CHSHONe

(12)W E t l 0

56 57




NH2I CO,Et

Me-C-CH-COzEt

benzene/AcOH57

M e

58

The O H group in compound 59, obtained by LAH reduction of 58,

was replaced with hydrogen resulting in 60. This compound in the

presence of NaNH,/liquid NH, reacted with ,t?-methallyI chloride.

Compound 61 had the required carbon skeleton; the NMR proton

characteristics are given in 61. Nupharamine and 3-epinupharamine

7.3803)

HI 2.31

1.84M e

(2M.92H~ r ~ N ^ . H 2 - c H 2 - c ~ ~ 2

2.92 2.5 4.78

(2)7.5H 10; ) (10: 5)

8.05

61

were prepared from 61 in two steps. The first consisted in the selective

and stereospecific hydrogenation of 61 with sodium/ethanol in xylene

resulting in a mixture of epimers 62 on carbon C-3 with both equatorial:fury1 group and the side chain. Compound 62 was hydrated with formic

acid (catalytic amount of HCIO,) ; subsequent chromatography on

alumina resulted in two racemates of ( )-nupharamine and ( & )-3-

epinupharamine.M eb:.*

NH /

-

6




VI. Biosynthesis

The sesquiterpenoid structure of Nuphar alkaloids suggests thattheir carbon skeleton may be derived from mevalonic acid, but the

biosynthesis of the furan and spirotetrahydrothiophene rings can not

be clearly predicted. Preliminary evidence indicates that label from

[3,4-14C]mevalonateenters thiobinupharidine (38).Partial degradation

was carried out, but the results remain inconclusive, since their inter-

pretation was based on a structure of thiobinupharidine that was

incorrect. Incorporation of [1 ,5-14C]cadaverine ( 3 8 ) was presumably

indirect.

REFERENCES

1. Y. Arata, S. Yasuda, and K. Yamanouchi, Chem. Pharm. Bull. 16,2074 (1968).

2. Y. Arata and K. Yamanouchi, Yakugaku Zasshi 91, 76 (1971) .

3. R. T. LaLonde, E. Auer, C. F. Wong, and V. P. Muralidharan, J. Am . Chem. SOC.

4. R. T. LaLonde, J. T. Wooleveler, E. Auer, and C . F. Wong, Tet . Lett. 1503 (1972) .

5. J. T. Wr6be1, i n “The Alkaloids” (R. H. F. Manske, ed.), Vol. IX, p. 450, 1967.

6. D. C. Aldridge, J. J. Armstrong, R. N. Speake, and W. B. Turner, J . Chem. SOC.

7. C. F. Wong, E. Auer, and R. T. LaLonde, J . Org. Chem. 35, 17 (1970) .

8. K. Oda and H. Koyama, J . Chem. SOC. 450 (1970) .

9 . C. F. Wong and R. T. LaLonde, Phytochemistry 9, 417 (1970) .

93, 2501 (1971) .

Academic Press, New York.

1667 (1967).

10. C. F. Wong and R. T. LaLonde, Phytochemistry 9, 59 (1970) .

10a. T. M. Moynehan, K. Schofield, R. A. Y. Jones, and A. R. Katritzky,J. ChemSoc.

11. R. Barchet and T. P. Forrest, Tet . Lett. 4229 (1965).

l l a . T. P. Forrest and S. Ray, Can. J . Chem. 49, 1774 (1971) .

12. C. Y. Chen and R. J. W. LeFevre, J . Chem.SOC. 467 (1965) .13. Y. Arata, T. Ohashi, M. Yonemitsu, and S. Yasuda, Yakugaku Zmshi 87, 1094

14. Y. Arata end T. Ohashi, Chem. Pharm.Bull. 13, 1247 (1965).

15. Y. Arata and T. Ohashi, Chem. Pharm. Bull. 13, 1365 (1965) .

16. C. F. Wong and R. T.LaLonde, Phytochemktry 9, 851 (1970) .

17. J. T. Wr6bel and A. Iwanow, Rocz. Chem. 43, 997 (1969) .

18. J. T. Wrbbel, A. Iwanow, C. Braeckman-Danheux, T. I. Martin, and D. B. MacLean,

19. R. T. LaLonde, C. F. Wong, and K. C . Das, J.Am . Chem. SOC.4, 522 (1972).

20. 0. Achmatowicz and J. T. Wr6be1, Tet. Lett. 129 (1964).

21. G. I. Birnbaum, Acta Crystabgr. 23,526 (1967) .22. J. T. Wrbbel, B. Bobeszko, T. I. Martin, D. B. MacLeen, N. Krishnamachari, and

23. R. T. LaLonde, C. F. Wong, and K. C . Das, J . Am . Chem.SOC.5, 342 (1973) .

24. R. T. LaLonde, C. F. Wong, and H. G . Howell, J . Org. Chem. 36, 3703 (1971) .

2637 (1962).

(1967) .

Can. J . Chem. 50, 1831 (1972).

C. Calvo, Can. J . Chem. 51,2810 (1973).



-CHAPTER4

THE CELASTRACEAE ALKALOIDS

ROGERM. S ~ H

School of Natural Resources

The University of the South Pacijk

Suva, Fiji

I. Introduction ....................................................... 215

11. Occurrence and Isolation ............................................ 216

111. Structures of Esters of Nicotinic Acid ................................. 219

219

B. Esters of C 1 5 Hz 6 0 6Polyols ....................................... 224

C. Esters of Cl5HZ6O7Polyols ....................................... 224

D. Esters of Cl5HZ6Os Polyols ....................................... 226

IV. Structures of Diesters of Subs tituted Nicotinic Aci ds .. .................. 227

A. Structures of the Diacids ......................................... 227

229

231239

241

VI. Biosynthesis ....................................................... 245

VII. Biological Properties ................................................ 246

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

A. Esters of Cl5HZ6O5Polyols .......................................

B. Esters of Cl5HZ4O9Ketopolyol ....................................

C. Esters of Cl5HZ4Ol0 Ketopolyol.. ..................................D. Esters of C15H260, , Polyols.. .....................................V. Structures of Related Sesquiterpene Esters an d Polyols.. . . . . . . . . . . . . . . . .

I. Introduction

In 1970 the structures of the nicotinoyl alkaloids maytoline (I)*andmaytine (2) from Maytenus ovatus Loes. (Celastraceae) were reported as

prototypes of a new family of alkaloids ( I ) . Subsequently, the closely

related structures or partial structure for twenty-two further alkaloids

from a number of different species in the family Celastraceae have been

elucidated. They all contain either a nicotinate or substituted n k o -

tinate group and are polyesters of hydroxy derivatives of dihydro-

agarofuran (3).7The other ester groups can include benzoate, acetate,

and 3-furoate. Many of these alkaloids had been isolated previously,

* All the sesquiterpene polyols have been aasumed to have the same absolute stereo-

chemistry as bromoacetylneoevonine (SO), the only member of the series to have been

fully elucidated.

t The sesquiterpene nucleus is numbered in accordance with Chemical Abetracts.



216 ROGER M. SMITH

but their structures had not been fully elucidated, although in most

cases the presence of a C,, nucleus and a nicotinic acid group had been

recognized.A number of closelyrelatednonbasic sesquiterpene polyestersand free polyols have also been reported.

This review covers the isolation and chemistry of the nicotinoyl

polyester alkaloids reported up to late-1975. Previous reviews of the

pyridine alkaloids ( 2 , 3 ) have included the substituted nicotinic acids,

but the full structures of the alkaloids were not then known. More general

reviews of members of this family have considered the constituents

including alkaloids of Khat (Catha edulis Forskal) ( 4 , 5 ) and the

pharmacology of alkaloids and terpenes from the Celastraceae and

Hippocrateaceae ( 6 ) .

CH3

1 Maytoline R = OH

2 Meytine R = H

11. Occurrence and Isolation

The first report of the presence of highly oxygenated C,, ompoundsin the Celastraceae was during a study in 1938 of the seed oil ofCelastrus

paniculatus Willd. (7) . Hydrolysis of a methanol-soluble fraction

yielded formic, acetic, and benzoic acids, and a tetraol (c15&,@5).

Nicotinic acid would, however, not have been detected.

The first Celastraceae alkaloids, base A (C,,H,,NO,,), base B

(C27H35N012),nd base C (C,,H,,NO,,), were isolated in 1947 from

the spindle tree E u o n y m u s (or Ev ony mu s) europaeus L . , which is used in

folk medicine. They were thought to be tetra-, tri- , and pentaacetates,

respectively, and on acetylation both A and B were converted to base C(8). Because of a n interest in their pharmaceutical activity, the ripe

seeds were later reexamined by Pailer and Libiseller in 1961 ( 9 ) ,who

isolated evonine (base C), the principal alkaloid. They showed that the

basic function of evonine was evoninic acid (4), a substituted nicotinic



4. CELASTRACEAE ALKALOIDS 217

acid, present as its diester of an unidentified polyhydroxy nucleus

(C15Hz6010)1 0 ) .TLC examination showed the presence of other basic

components, but these were not isolated.Similarities were recognized between the partial structure of evonine

and five partially characterized alkaloids that had been isolated between

1950 and 1 9 5 3 from the thunder god vine (Trip teryg ium wilfordii Hook.)

by Acree and Haller ( 1 1 )and by Beroza (12-15) using a combination of

partition chromatography and countercurrent distribution (16, 7 ) .

These alkaloids contained a common polyol nucleus (C15H26010),

which was esterified with a substituted nicotinic acid, either wilfordic

(6) or hydroxywilfordic acid (7 ) 1 8 ) ,acetic acid, and either 3-furoic or

benzoic acid ( 1 4 , 1 5 ) .

N CHz-CHZ4(CH3)-CO2HIR

m;&&RH 3 cICozHA A

H3C H

4 Evoninic acid R = CO,H 6 Wilfordic acid R = H

5 R = OH 7 Hydroxywilfordic acid R = OH

The stimulating effect of Khat, Catha edulis another member of theCelastraceae, had been widely studied, and the major alkaloidal

constituents have been found to be norpseudoephedrine and related

compounds ( 4 , 5 ) . During a search in 1 9 6 4 for further alkaloids, a

weakly basic compound, cathidine D (C,,H,,NO,,) was isolated ( 1 9 ) .Analysis showed it to be a polyester of acetic, benzoic, and nicotinic

acids and an undefined polyol (C,,H,,06), and it was suggested that i t

could be related to the other Celastraceae nicotinoyl alkaloids.

For some years, no further work in this area was reported, until, in

1970, Kupchan, Smith, and Bryan, investigating Maytenus ovatus fortumor inhibitory compounds, isolated the weakly basic but inactive

alkaloids maytoline (1) and maytine (2) and determined their full

structure and relative stereochemistry by NMR spectroscopy and X-ray

crystallography (1 ,ZO) .These compounds were based on a hydroxylated

tricyclic dihydroagarofuran nucleus, and i t was suggested that this was

structurally related to the C,, polyols of the Euonymus and Tripterygiuma1kaloids.

Following this report, a series of papers appeared on the alkaloids of

Eu on ym us Sieboldianus Blume by Yamada and his co-workers, whoreported the isolation and structures of a series of related alkaloids

including evonine (21-24) and by X-ray crystallography determined

their absolute stereochemistry ( 2 5 )and confirmed their relationship to

maytoline.



218 ROGER M. SMITH

TABLE IOCCURRENCEND ISOLATIONF CELASTRACEAELKALOIDS

Alkaloid (synonyms) Plant Part Reference

Alatamine

Cathidine D

Celapagine

Celapanigine

Celapanine

2-Deacetylevonine

2,6-Dideacetylevonine

Euonine

Euonymine

Evonine (alkaloid C)

Evonoline (4-deoxyevonine)

Evozine (alkaloid B)

Isoevonine (evonimine)

Isoevorine (alkaloid D)

Maytine

Maytolidine

Maytoline

Neoeuonymine

Neoevonine (evorine, alkaloid A)

Wilfordine

Wilforgine

Wilforine

Wilforgine

Wilforzine

Euonymua alatusa -

Leavesatha edulis

Celastrus paniculatus Seeds

paniculatus Leaves

paniculatus Seeds

Euonymus europaeus Seeds

europaeus Seeds

Sieboldianus Seeds

alatus Seeds

Sieboldianus Seeds

alatus Seeds

europaeus Seeds

Sieboldianus Seeds

europaeus Seeds

europaeus Seeds

europaeus Seeds

SieboldianusSeeds

europaeus Seeds

Maytenus ovatus Seeds

ovatus Seeds

w a t m Seeds

Euonyrnua Sieboldianus Seeds

europaeus Seeds

Sieboldianus Seeds

alatus Seeds

Tripterygium wilfordii Roots

wil ford i i Roots

Maytenus senegalensis' Stems and

Tripterygium wil fordi i Roots

wilfordii Roots

wilfordii Roots

roots

26

19, 27

28

28, 29

28, 29

30

30

31

26

23

26

8 , 9 , 3 2 - 3 5

21

32, 34 , 36

8 , 33

36, 37

3133

1, 38

38

1 , 38

23

8 , 3 3 , 34

23

26

1 1 , 1 2

13

39

12

1 3

15

E. alatus forma striatus (Thunb.) Makino.

Known subsequently as M . arbutifolfolia(Hochst. ex A. Rich.) R. Wilczek ( 4 1 )andnow

as M . sewata (Hochst. ex A. Rich.) R. Wilczek (persona1 communication from Professor

S. M. Kupchan).

M . senegalem's (Lam.) Exell.




Subsequent investigations of these and other members of the family

Celastraceae have yielded further alkaloids (see Table I) ( 1 , 8 , 9 , 11-13,

15 , 19 , 21 , 23 , 26-41) . The nature of the sesquiterpene nucleus andester functions is known in each case, but for some of the alkaloids, the

position of the acyl groups have not yet been determined. The alkaloids

can be grouped into those containing an unsubstituted nicotinate group

and into the generally larger and more complex compounds in which the

basic function is a substituted nicotinate group.

Many studies have reported the presence of alkaloids in these and

other members of the Celastraceae by TLC spot tests or as crude basic

extracts. However, as well as the nicotinoyl alkaloids, a wide range of

other alkaloids have been isolated, more than one type frequentlyoccurring in the same plant. M ayten us ovatus, in addition to maytine

and maytoline, has yielded the antitumor ansa macrolide maytansine

( 4 0 ) from the seeds and the spermidine alkaloid celacinnine from the

twigs ( 4 1 ) . Maytenus Chuchuhuashu Raymond-Hamet and Colas has

given an open chain spermidine alkaloid maytenine ( 4 2 )and Maytenus

buchanii has yielded a further ansa macrolide ( 4 3 ) .A series of peptide

alkaloids was found in Eu ony mu s europaeus following TLC analysis ( 4 4 )

and Catha edulis has been reported to contain a number of alkaloids

related to norpseudoephedrine ( 4 5 ) .In addition, a number of nonbasic polyesters and polyalcohols have

been isolated with sesquiterpene nucleii similar or identical with those

found in the alkaloids (see Section V).

III. Structures of Esters of Nicotinic Acid

Seven alkaloids have been isolated in which the basic function is a

nicotinate group (Table 11). Similarities in the NMR spectra havesuggested that in each case the nicotinate group is at C-9.

A . ESTERSF C,,H,,O, Polyols

1. Celapanine

Celapanine (8) was isolated together with a neutral diester malkan-

gunin (see Section V), and much of its structure was derived by their

interrelation ( 2 8 , 2 9 , 4 6 ) .The mass spectrum of celapanine (C,oH,,NO,o)

(mle 569) confirmed the molecular formula and suggested the presenceof nicotinate (m/e 106 and 78) and 3-furoate (m/e 95) groups. These

conclusions were in agreement with bands in the NMR and UV spectra.

The NMR spectrum (Table 111) also contained signals for two acetyl




groups (6 1.68,2.12), four tertiary and one secondary methyl groups, and

coupled signals at 6 2.60, 5.73, and 5.4, which were assigned to the

grouping -CH,-CHOAcyl-CHOAcyl-. The alkaloid is therefore, atetraester of a C,,H,,O, nucleus, celapanol. As the infrared spectrum,

vmaX1740,1730,1590,1560cm-l , contained no bands for a free hydroxyl

or ketonic carbonyl groups, the remaining oxygen must be an ether

8

9

10

11

Celapanine Ac Fur Ac Nic Bz = benzoyl

Celapanigine Ac Bz Ac Nic

Celapagine Ac Bz H Nic

Celapano1 H H Nic = nicotinoyl

Fur = 3-furoyl

group. Dehydrogenation of 8 yielded eudalene (12),which was also

obtained from the diester malkangunin (13) 28, 4 6 ) . Comparisonof theNMR spectrum of 8 with that of malkagunin suggested that the sesqui-

terpene nucleus in both cases contained similar tricyclic dihydroagaro-

furan skeletons, 9 and 14, respectively.

One acetate group was positioned a t C-1 in 8 as the high-field position

(6 1.68) was considered to be due to interaction with a nicotinate group

at C-9. A similar relationship had been previously reported in maytoline

(1) (I).The 3-furoyl group was placed a t C-6 as in the related alkaloid,

celapanigine (lo), it is the position of a benzoyl group. The second

acetate group was assigned to C-8 from the NMR spectrum.The stereochemistry of the ring system and substituents was based

by Wagner and his co-workers on the structural assignments in mal-

kangunin (13) 4 6 ) .A spin-spin coupling between the protons at C-8




I11

C O N T ~ ~ I N GNICOTINATEROUP"

C-8 c - 9 c-12 C-13 C-14 (3-15 OAc Reference

5.73 ddc 5.4 d o 1.59 s 1.42 s 1.01 d

5.70 ddc 5.36 d o 1.61 s 1.45 8 1.04 d

4.66 ddc 5.30 dc 1.60 s 1.44 s 1.01 d

(397) (7 ) (7 )

(3, 7 ) (7) (7)

(39 7 ) (7 ) (7)C-Methyl

1.42 s 1.68 46

1.49 s 1.67 46

1.38 s 1.64 46

2.12

1.92

- 5.75 m 1.40(3H), 1.54(6H), 1.66(3H)

- 5.47 m 1.51 6H), 1.56(3H)

- 5.49 bd 1.54(6H) 1.61 3H)

(7.5)

- 5.52 bd 1.55(3H), 1.59(3H), 1.61(3H)

(7.5)

5.01 s 1.66 27

4.39, 4.93d 1.60 1, 38

2.12

(13) 2.09

2.10

2.26

(13) 2.15

2.18

2.30

(13) 2.142.30

2.34

4.40, 4.96d 1.66 1, 38

4.43, 4.90d 1.64 38

Unresolved multiplet 1.4-2.2 ppm.

Position determined by spin-spin decoupling.

AB quartet.

coupling of 7 Hz seems more appropriate. Examples elsewhere in this

series of alkaloids have found J 8 , gax,eq = 6 Hz; ax,ax = 10 Hz (50) .This group also isolated polyalcohol B to which they assigned

structure 67 identical with celapanol (9). However, in this compound

J 8 , g= 10 Hz and J , , 8 = 3 Hz, in contrast with the values for the

alkaloids.

2. Celapanigine and Celapagine

The spectra of celapanigine (10) (C32H3,N09)and celapagine (11)

(C30H,,N08) were very similar to those of celapanine, except thatinstead of the bands assigned to the 3-furoyl group, there were signals

characteristic of benzoate ( m le 105 and 77) (28, 29, 4 6 ) ; 10 contained

two acetyl groups ( 6 1.92, 1.67, NMR spectroscopy) but 11 only one,



224 ROGER M. SMI TH

? H : 9R' O H OR'

W O R 2R2

13 R' = Bz, 2 = AC 15 R' = Bz,R2 AC

14 R'= R2 = H 16 R' = R2 H

H3C CH3 HSC 0 CH3

CH3 CH3

which from it s chemical shift (8 1.64) was assigned to C-1 due to the

influence of a C-9 nicotinate group. The free hydroxyl group in 11 was

secondary (-CHOH 6 4.66 dd, J = 7, 3 Hz) and from decoupling

studies was assigned to C-8 ( J 8 , 9= 7 Hz, J , , 8 = 3 Hz). The remaining

ester function, the benzoate group, must be a t C-6. Compound 10 was

thus based on the same polyol (9) as celapanine but contained a 6-

benzoate group instead of a furoate group, 11 being the corresponding

8-deacetyl compound. The stereochemical assignments were based on

the same arguments as those for celapanine.

B. ESTERSF C,,H,,06 POLYOLS

Although a number of pentaols have been isolated from hydrolyzates

of Celmtrus paniculatus (Section V), so far no corresponding alkaloids

have been reported.

C. ESTERSF Cl5HZ6O7 OLYOLS

1. Cathidine D

Analysis and mass spectroscopy of cathidine D (17) confirmed the

molecular weight of this weakly basic alkaloid from Catha edulis.

Hydrolysis yielded nicotinic acid, benzoic acid, and 2 mole equivalents

of acetic acid. Two of the remaining oxygen functions were assigned to a

vicinal diol from the IR spectrum (v,,, 3565, 3480 cm-l unchanged ondilution). The formation of a monoacetate and NMR spectra suggested

that one hydroxyl was secondary and the other tertiary. This assign-

ment was confirmed on treatment with lead tetraacetate, which cleaved




the diol quantitatively to give a ketoaldehyde. Cathidine was thus a

tetraester of the C,,H,,O, hexaol, cathol ( 1 9 ) .

Subsequent reexamination of the structural studies and comparisonof the NMR spectrum with that of maytoline and maytine (Table111)suggested that cathidine D contained the same C-1 to C-3 system as

maytoline but lacked an ester function at C-6. As in maytine, the C-1

acetate group (6 . 66 ) apparently interacted with a C-9 nicotinate group.

However, it was not possible to distinguish between the possible posi-

tions for the benzoate and the second acetate groups. Cathidine was

thus assigned the partial structure 17 (27), the stereochemistry of the

nucleus cathol (18) being based on the similarities of the coupling con-

stants t o those of maytoline (1).

CH3

17 Cathidine D R' = Ac, Ra = Nic, R3 = Bz, R* = AC

or R3 = Ac, R4 = Bz

18 R' = RS = R3 = R4 = H

OAc

I

VH*

A C O , ~ : ,c? ; VAc OAc

AcO

H3C' O H OAc

, CH3

CHa-OAc

19

A recent note reported that cathidine (as a crude alkaloid fraction) on

hydrolysis and then acetylation yielded octaacetyl euonyminol (19)

(51 ) . This result conflicts with the formula and structure of purifiedcathidine D, and this derivative is presumably derived from further

alkaloids in C. edulis th at have yet to be isolated.

2. Maytine

Maytine (2) (CZ9H,,NO,,) and maytoline (1) were isolated togetherfrom Maytenus ovatus, and a comparison of their NMR and IR spectra

suggested th at they were very similar ( 1 ) .Both contained a nicotinate

and four acetate groups. However, the NMR spectrum of maytine

lacked the signal at 6 3.60 (d, J = 3.5 Hz) assigned to the C-3 protonin maytoline, and the signal for the adjacent C-2 proton (6 5.47) was a

multiplet instead of a triplet. Maytine contained a free hydroxyl group

(v,,, 3550 cm-l ), which was unreactive on attempted acetylation and




on acidification. The formula was determined by high resolution mass

spectroscopy (HRMS) and elemental analysis, and IR spectroscopy

showed the presence of hydroxyl, vmax 3500 cm-l, and ester groups,vmax 1735 cm-l. The nicotinate group gave characteristic mass ( m / e

124 and 106),UV, and NMR spectra. The NMR spectrum also contained

signals for the partial structure -CHOAcyl-CHOAcyl-CHOH-

6 5.91 (d, J = 3.5 Hz), 5.60 (t, = 3.5 Hz), and 3.60 (d,J = 3.5 Hz) ,a

primary C&OAcyl 6 4.96 and 4.40 (ABq J = 13 Hz), and two secon-

dary esters (CHOAcyl) 6 6.16 s, 5.49 (d, J = 7 . 5 Hz), and a D,Oexchangeable proton. Acetylation converted the partial structure to

-(CHOAcyl)3- and the signal a t 6 3.60 shifted t o 6 4.87 (d, J = 3.5

Hz). On hydrolysis, maytoline gave maytol(22), C15H2608, hose NMRspectrum contained signals for three quaternary methyl groups and no

olefinic protons. Maytoline was readily converted to a methiodide,

which was examined by X-ray crystallographic analysis ( 2 0 ) . The

structure and relative configuration were determined but the absolute

configuration could not be defined. The results agreed well with the

NMR spin-spin couplings.

2. Maytolidine

Maytolidine (23) (C36H41N014) ave UV, NMR, and mass spectros-

copy signals assignable to a benzoyl, four acetyl, and a nicotinoyl

groups ( 3 8 ) . Hydrolysis yielded maytol (22) and acetic and benzoic

acids. Benzoylation of 1 gave 3-benzoylmaytoline, which was isomeric

with maytolidine but showed a different NMR spectrum, principally in

the chemical shifts of the acetyl methyl groups. Detailed examination

of the spectrum suggested that the benzoyl group in 23 was at C-6;

C-6H 6 6.23 compared with 6 6.08 in 3-benzoylmaytoline.

IV. Structures of Diesters of Substituted Nicotinic Acids

On hydrolysis, seventeen of the Celastraceae alkaloids (Table IV)yield a pyridine dicarboxylic acid, which in the intact alkaloid is present

as a diester at C-3 and (2-12 on the sesquiterpene nucleus. This nucleus

is more highly oxygenated than in the alkaloids containing an unsub-

stituted nicotinate group, and in some cases a (2-8 keto group is present.

A . STRUCTURESF THE DIACIDS

Three pyridine diacids have been found, each containing a five-carbon

side chain at the 2 position of nicotinic acid.



TABLE I VPROPERTIESF CELASTRACEAELKALOIDSONTAININQ DIESTER

Alkaloid Formula Mol, wt. (m/e) mp ("C) [alOa Sesquiterpene nucleus Formula

~~ ~~ ~~

Evonoline (24) C3eH43NOie 745 150-158 + 6.0' Evonolinol C,,H,,Og

(4-deoxyevoninol)

Evonine (25) C3eH&Oi, 761 184-190 +8.4 Evoninol C,,H,4010

Isoevorine C34H4iNOie 719 185-188 +2 2. l0 Evoninol Cl~H 2401

Evoninol C,,H,,O,, ,B-Didmetylevonine (29) C,,H,,NO,, 677 141 -Evozine (27) C32H39N016 677 288-290 + 13' Evoninol C,,H,,O,,

2-Deacetylevonine (28) C.34H41N018 7l9 135 - Evoninol C,,H,40,,

Neoevonine (28) C34H41N018 719 264-265 +24.9' Evoninol C,,H,40,,

Isoevonine (47) C38H43NOl, 761 Amorphous + 30.50b Evoninol C,,H,40,,

210

Alatemine (48) C41H46N018 839 185-193 +44' Evoninol C,,H,40,,

Euonymine (50) C,eH4,NOi, 805 - - 0' Euonyminol C,,H,eOl,

Neoeuonymine ( 5 1 ) C3eH4sNOi7 763 259-262 - 1' Euonyminol C,,H,,O,o

Euonine (52) C 3dbNOie 805 149-153 - .5" Euonyminol C,,H,,Olo

Wilforzine C41H47N017 - 177-178 + 6 O C Euonyminol C,,H,,O,,

Wilforgine (55) C41H47N019 857 21 1 + 25OC Euonyminol C,,H,,O,,

Wilfordine (53) C43H49N019 883 175-176 + 1ZoC Euonyminol Cl,H,,O,,

Wilfortrine (58) C4,H4,N0,, 873 237.6-238 + ooc Euonyminol C,,H,,O,,

Wilforine (54) C43H48N018 867 169-170 + 3OoC Euonyminol C,,H,,O,,

Solvent CHCl, unless noted.

ECOH.

Acetone.



230 ROGER M . SMITH

and analysis of evonoline showed that it contains one less oxygen than

evonine, and the IR spectrum lacked a band for a hydroxyl group. In

the NMR spectrum, the C-4 methyl signal was a doublet 6 1.29 ppm(J = 8 Hz) and thus secondary, unlike the tertiary C-4 (Me)OH group

in evonine; the rest of the spectra were very similar (see Table V ) .From the long range coupling of C-2H and C-4H (J = 1.1 Hz) these

protons were assigned to a W diequatorial configuration, and thus the

C-4 methyl group was axial, in the same orientation as in evonine. The

C-1H and C-9H must both be axial as a strong nuclear Overhauser

effect (NOE) (20y0)was demonstrated between them. Evonoline was

therefore assigned the structure 24 (32).

OAc

IFHZ

AcQ 9R4

24 Evonoline Ac H Ac Ac

25 Evonine Ac OH Ac Ac

26 Neovonine Ac OH H AC

27 Evozine Ac OH K H

28 2-Deacetylevonine H OH Ac Ac

29 2,6-Dideacetylevonine H OH H AC

80 Bromoacetylneoevonine Ac OH BrAc Ac

A n independent report by Budzikiewicz and co-workers ( 3 4 ) eached

the same conclusion for the structure of a compound they named

4-deoxyevonine. Their paper illustrated the hWR and mass spectra of

24. Analysis of the mass spectrum suggested that a Maclafferty re-arrangement of the C-3 ester group involving a coplanar and hence

equatorial C-4H led to a ready loss of COz not found in the mass

spectrum of evonine.




C. ESTERSF C,5H,,010 KETOPOLYOL

1. EvonineEvonine (25) (C3,H4,NO13)was initially isolated as “base C ” by

Doebel and Reichstein and reported to be a pentaacetate with the

tentative formula C31H39N0148). It was reisolated by Pailer and

Libiseller as the major component from E. europaeus and named

evonine (C36H43-45Nol,)9). Hydrolysis of evonine yielded formalde-

hyde, 5 moles of acetic acid, and a diacid Cl1H,,NO4, subsequently

elucidated as evoninic acid (4) ( 1 0 ) .X-ray analysis of evonine suggested

the mol. wt. 7 6 4 .6 and thus the formula C36H45N017mol. w t . 763 .73)

( 5 4 ) .The formula of polyol nucleus would therefore be C,,H2,010.Studies in Budapest found that if the crude alkaloid mixture from

E. europaeus was acetylated, the yield of evonine (semisynthetic) was

70y0 compared to a usual 2 3 y 0 ( 3 5 ) . On hydrolysis of 25, 7 moles of

alkali were consumed to give a polyol that reacted with periodate. The

polyol could be converted into a perbenzoate whose IR spectrum still

contained a band at 3500 cm-I from an unacylated tertiary hydroxyl

group. A NMR spectrum suggested two C-methyl groups were present

in the polyol nucleus, which was thus probably a terpene rather than a

sugar ( 5 5 ) .Following the report of the structure of maytoline, two groups,

Yamada and his co-workers in Japan (21 , 22 , 24) and Pailer and his

co-workers in Austria ( 3 2 ) ,almost simultaneously but independently

published reports of the structure determination of evonine (C36H43-

NO,,; mass spectrum, m / e 761) based on a polyol nucleus evoninol (31)

(C15H24010).

HoqcH3 VHaOH

HO..

H d O H

~ H ~ O H

51 Evoninol R = =O

H

OH32 Euonyminol R = <.

OH33 IsoeuonyminoI R = <

‘H



232 ROGER M . SMITH

TABLE

lH NMR SPECTRAF CELESTRACEAE

Alkaloid c-1 c-2 c- 3 c-4 C-6

Evonoline (24)

Evonine (25)

2-Deacetylevonine (28)

Neoevonine (26)

2,6-Dideacetylevonine (29)

Evozine (27)

Isoevonine (47)

Alatamine (48)

Euonymine (50)

Euonine (52)c

Wilfordine (53)

5.79 d

(3.4)5.71 d

(3.2)5.73 d

(3)5.72 d

(3.2)

5.67 d

(3)5.87 d

(3.4)5.70 d

(3.5)5.90 d

(3.5)5.55 d

(4.0)5.64 d

(3.2)5.77 d

(3.0)

5.33 ddd

(3.4, 2.6, 1.1)

5.29 t

4.00 t

(3)5.34 t

(3.2)

3.95 t

(3)5.22 dd

(3.4, 3.0)

5.15 t

5.46 dd

(3.5, 3.0)

5.23 dd

(4.0, 2.5)

5.15 dd

(3.2, 3.0)

(3.2)

(3.5)

-

4.84 dd

(2.6, 1.2)

4.78 d

5.14 d

4.82 d

5.24 t

4.80 d

4.97 d

5.18 d

4.72 d

4.93 d

5.08 d

(3.2)

(3)

(3.2)

(3)

(3.0)

(3.0)

(3.0)

(2.5)

(3.0)

(2.8)

7.13 qdd 6.45 d

(8.0, 1.2, 1.1) (0.9)- 6.72 d

- 6.78 bs(1.0)

- 5.41 d

(1.5)

- 5.36 d(1)

- 5.20 s

- 6.72 d

(1.0)- 6.82 d

(1.0)- 7.02 d

(1.0)6.90 s

~ ~~ ~ ~ ~ ~~~~

a Spectra run on solutions in CDCl, unless noted. Chemical shifts are in parts per million

relative to TMS. Figures in parentheses are couplings in Hertz. Bands were present as appro-

priate for ester groups.

Subsequent full papers by Yamada and his co-workers have discussed

the details of the structure determination (50) and the chemicalreactivity (56)of evonine. They found that the NMR spectrum showed

the presence of five acetate methyls, two tertiary methyl groups, an

aceotoxymethylene (-CH,-OAc), and a hydroxyl group adjacent

to a tertiary methyl group (Table V). Decoupling experiments showed

the presence of a 1,2,3-triester (-CHOAcyl-),. Reduction of 25 with

LAH gave two isomeric C,,H,,O,, polyols, euonyminol (32)and

isoeuonyminol (33), implying a keto group was originally present.

Analysis of the NMR spectra of their peracetates confirmed this view

and led to the partial structure -CHOH-CO-CH- in evonine.Chemical degradation of 25 with NaOMe-NaON gave a pentadeacetyl

evonine (mp 257'C), which reacted with 2,2-dimethoxypropane to give

an acetonide. Comparison of the spectra of this compound and 25




V

ALEALOIDS ONTAINING DIESTER~

c-7 C-8 c-9 c-126 C-13 C-14 C-15 Reference

3.09 d

3.04 d(0.9)

(1.0)-

3.02 d

(1.5)

-

3.22 d

3.02 d

3.10 d

2.33 dd

(3.8, 1.0)

2.62 d

2.40 dd

(1.2)

(1.0)

(1.0)

(3.0)

(1.0, 4.5)

-

-

-

-

--

-

-

5.51 dd

(3.8, 6.2)

5.48 dd

(3.0,6.7)-

5.50 s

5.57 8

5.63 s

5.59 8

5.69 s

4.49 8

5.53 s

5.65 s

5.34 d

(6.2)5.20 d

(6.7)-

4.90, 5.34

(11.3)

3.76, 6.04

(11.7)

3.87, 5.82

3.78, 6.10

3.76, 6.04

3.74, 6.09

(11.5)

3.79, 5.81

3.80, 5.94

5.94 d(1H)

4.10, 5.77

3.77, 5.82

(13.0)

(12)

(12.0)

(13)

(12.0)

(12.0)

(12)

(12.0)

1.47 s

1.61 s

1.54 s

1.64 s

1.61 s

1.51 s

1.55 s

-

-

-

-

1.29 d

1.61 s

1.24 s

1.90 s

1.28 s

1.84 s

1.61 s

(8.0)

-

-

-

-

4.46, 4.80

(12.8)

4.58, 4.82

(13.0)

5.03, 4.60

(11.0)

4.47, 4.92

(13.0)

4.50, 5.18

(13)4.62 s

4.47, 4.85

4.85 s

4.50, 5.13

(13.5)

4.43, 5.42

(13.0)

4.21, 4.50

(13.0)

(13)

32

50

30

50

30

57

36

26

23

31

26

b AB quartet.

C Solvent (CD&CO.

showed that evonine contained one primary and four secondary acetate

groups and that the triester could be assigned the partial structure-CHOAcyl(CHOAc),-. Acetylation of the acetonide afforded an

acetonide triacetate 34, which with aqueous acetic acid was converted

to a triacetate. The NMR spectra showed that the primary hydroxyl

and the hydroxyl of the a-ketol had been involved in the acetonide

formation and must thus be in a 1,3 relationship.

Cleavage of the triacetate with Pb(OAc), gave an aldehyde ester

triacetate (35). he changes in the coupling constants enabled a second

of the secondary alcohols to be related to the ketone in evonine as

-CHOH. CO .CH .CHOH-. Potassium tert-butoxide reacted with thealdehyde ester to yield an a$-unsaturated aldehyde ester (36) nd

formaldehyde. This retroaldol reaction enabled the correlation of most

of the partial structures in evonine as 37.The remaining alcohol group,



234 ROGER M . SMITH

YH,OH

Ac? j

C02CH3

H3C OH OAc

34 35

C(OH)Me, was related to the triester by the conversion of evonine to a

pentamethyl ether by the replacement of acetate by methyl, reduction

of the remaining ester functions with LAH to give 38, cleavage of the

3,4-diol o an aldehyde methyl ketone (39), and thus the partial

structure 40 could be derived.

A n important degradation led to the l,%napthoquinone 41, as this

related the side chain to the carbon skeleton. Only one oxygen was

uncharacterized at this point, and it was deduced to be ethereal and

must be attached to the ring junction and give the tertiary hydroxyl

in 41.

The structure was then complete except for the orientation of the

diacid. Partial methanolysis of evonine gave 42 and complete hydrolysis

CHzOAcI

AcO&o

AcylO 'HH

OAc

37

36




~ H , O H

38

~ H ~ O H

39

CHaOAc

A c O h H

Hcyl-0

OH OAcH3C

40

then yielded monomethyl evoninate with the free carboxyl group onthe side chain, which therefore must have been attached to C-3.

The stereochemistry of the substituents was derived from NMRspectra and by NOE enhancement studies ( 2 4 ) . These confirmed that

the ring junction was trans and that the C-4 methyl and C-6 protons

were diaxial. These conclusions were disputed by KlBsek et al. (57),

OHI9 2

0 OH ?H

CH,OOH

AcO

41

42



236 ROGER M. SMITH

although they agreed with the structure from their own unpublished

studies, but were reemphasized in the full paper ( 5 0 )by Yamada. The

stereochemistry was conclusively established by the relationship ofevonine to neoevonine (6-deacetylevonine) (26) ( 2 3 ) and the X-ray

crystallographic analysis of bromoacetylneoevonine (30) ( 2 5 ) .During

the structural determination, a number of unusual reactions involving

the oxygen functions of evonine and neoevonine were noted (56 ) .The independent study by Pailer and his co-workers followed a

similar argument t o th at of the Japanese workers and reached the same

conclusion ( 3 2 ) .The key compound in their analysis was the unexpected

acetal (43) formed by the action of periodic acid on evoninol, which on

acetylation gave 44 (c23 13).This compound contained a ketaland hemiketal (NMR spectra) and led to the elucidation of the tetraol

ring system. Further analysis gave the complete structure, the orienta-

tion of the diester being derived from the anisotropic effect of the

pyridine ring on the C-12 methylene group.

Reichstein’s group, who were first to work in this area, have sub-

sequently reported the full details of their studies on the isolation and

properties of evonine and a number of related alkaloids (33).In a recent study, a selective recombination of evoninic acid as the

43 R = H44 R = AC

CH,? : OCH,

CO,CO,Et

CH3

45

J.

25

46




trityl ether 45 and the acetonide 46 yielded a monoester, which after

conversion of the trityl group to a methyl ester and then removal of the

acetonide, yielded evonine on treatment with sodium hydride ( 5 8 ) .

2. Neoevonine, Evozine, Isoevorine, 2-Deacetylevonine, and 2,6-Dide-

acet ylevonine

These five deacetylevonine alkaloids have all been found as con-

stituents of Euonymus species. The positions of substitution were

principally derived by analysis of the NMR spectra (Table V).Originally “alkaloid A ” (8),neoevonine (26) (C,,H,,NO,,) was

isolated and the structure reported by the Japanese group ( 2 3 ) , andalmost simultaneously the full details of its isolation as “evorine” were

reported by Reichstein ( 3 3 ) .Acetylation of neoevonine yielded evonine,

and the NMR spectrum showed th at 26 was 6-deacetylevonine. It was

used during the structural and chemical studies on evonine ( 5 0 , 5 6 ) nd

could be prepared from evonine by controlled mild hydrolysis (2 3 , 5 0 ) .It also could be obtained in high yield by the treatment of evonine with

an enzyme preparation from the fruit of E. europaeus ( 3 3 ) .On bromo-

acetylation, 26 yielded a crystalline derivative (30))which was exam-

ined by X-ray crystallography ( 2 5 ) to give its relative and absoluteconfiguration. “Alkaloid B ) ) ( 8 )was reisolated a s evozine (27) (C32H3s-

NO,,) ( 3 3 ) ,and its structure was determined by NMR spectroscopy as

6,9-dideacetylevonine ( 5 7 ) .Hydrolysis of evonine, followed by the acetylation of the pentade-

acetyl product, as well as yielding evonine and neoevonine, also gave a

second monodeacetylevonine, isoevorine (C,,H,,NO,,), identical with

a previously isolated but unpublished “alkaloid D” ( 3 3 ) .However, its

NMR spectrum was not reported nor a structure proposed, except that

it differed from both 2- and 6-deacetylevonines.

2-Deacetyl (28) (C,,H,,NO,,) and 2,6-dideacetylevonine (29)

(C,,H,,NO,,) were isolated from E. europaeus as minor alkaloids and

their structures elucidated by NMR spectroscopic comparison with

evonine ( 3 0 ) .

3. Isoevonine

Isoevonine (47) (C,,H,,NO,,) was reported almost simultaneously by

groups in Czechoslovakia (3 6 , 3 7 ) and in Japan (3 1 ,named evonimine).It is isomeric with evonine, but on methanolysis yielded the dimethyl

ester of wilfordic acid (6).Similarities between the NMR spectra of the

two alkaloids suggested that the rest of the molecules were probably



238 ROGER M . SMITH

identical (Table V ) . Both contained five acetoxyl groups and could be

converted into the hexaacetate of evoninol (31) or by reduction and

acetylation into euonyminol octaacetate (19) ( 3 1 ) .Selective hydrolysisof the aromatic ester group enabled the orientation of the wilfordic

diester to be established ( 3 1 ) .

4. Alatamine

Alatamine (48) (C,1H,5N0,,) on mild reduction and acetylation was

readily converted to a mixture of the previously isolated alkaloid

wilfordine (53) and its C-7 epimer (26). Thus, alatamine was derived

from a C,,H,,O,, keto-polyhydroxy compound, which from itsrelationship t o wilfordine, was linked to benzoic acid, hydroxywilfordic

acid, and 4 moles of acetic acid. Acetylation of alatamine and methanol-

ysis yielded a methyl ester, which on comparison with the spectra of

the acetate, showed th at one of the diacid ester linkages was to C-12.

Further acetylation to a hexaacetate, reduction, and cleavage gave 49.

This compound could also be prepared from the evonine derivative 42

on acetylation and benzoylation followed by reduction. Thus, both the

position of the benzoate and acetate groups, of the second diester

linkage, and the presence of evoninol (31) as the nucleus of alatamine

were confirmed. The benzoate position also agreed with an NMR study

of model C-1, C-2, and C-3 benzoates prepared from evonine.

R ' O . . M

47 Isoevonine R' = Ac, RZ= H

48 Alatamine R1 Bz, Ra = OH




' D. ESTERSF C15H,,010 POLYOLS

I . Euonymine and Neoeuonymine

Reduction of euonymine (50) (C38H47N018) ith LAH yielded the

diol5 (from evoninic acid) and euonyminol (32) ( 2 3 ) , dentical with one

of the reduction products of evonine ( 2 1 ) .A comparison of the spin

couplings of C-9H in euonyminol (32) ( J 8 , g= 6 Hz) and isoeuonyminol

(33)( J E S g 10 Hz) showed th at in 50 the C-8 hydroxyl was axial. This

assignment was confirmed by an NOE interaction between the diaxial

C-6H and C-8H in the octaacetate of isoeuonyminol(33)( 2 4 ) .Methanol-

ysis confirmed the number and position of the acetyl groups in euony-mine and that the evoninic acid aromatic carboxyl was attached to

Neoeuonymine (51) (C,,H4,NO1,), isolated with 50, was converted

to euonymine on acetylation and, from its NMR spectrum, which lacked

the C-6H signal in the 6-7 region (euonymine 6 7 .02) , was deduced to be

6-deacetyleuonymine (23).

The stereochemistry of both compounds was derived from the

relationship of euonyminol to evonine ( 2 4 ) .

C-12 (23).

OAcIFHz

AcO i OAc

AcO- &, OAc

50 Euonymine R = Ac

51 Neoeuonyrnine R = H

2. Euonine

Euonine (52) (C38H47N018)s isomeric with euonymine and on

exhaustive methanolysis and acetylation afforded also euonyminol

octaacetate, but dimethyl wilfordate rather than dimethyl evoninate



240 ROGER M . SMITH

( 3 1 ) . Partial methanolysis gave hexadeacetyleuonine methyl ester.Comparison of the NMR spectra enabled the position of the acetyl

groups and the orient*ationof the wilfordic acid group to be determined.

AcO OAc

R’ Ra

52 Euonine Ac H53 Wilfordine Bz O H54 Wilforine Bz H (postulated)

55 Wilforgine Fur H (postulated)

56 Wilfortrine Fur OH (postulated)

3. Wilfordine

Initial studies on Tripterygium wilfwdii yielded the crude alkaloid

triptergine (C,,H,,NO1 (59),reisolation by Acree and Haller yielded

“wilfordine,” but it was still a mixture ( 1 1 ) .Wilfordine (C43H4gN0,g)was finally obtained pure by Beroza ( 1 2 ) ,who assigned the formula.

He showed that i t contained 1 mole of benzoic acid, 5 moles of acetic

acid, and 2 moles of a non-steam-volatile acid. Further studies ( 1 4 )

identified the nucleus as “C15K16(OH)10” nd the acid as hydroxywil-

fordic (7) 1 4 , 1 8 ) , but no structure was proposed.

Subsequently, Yamada et al. isolated wilfordine from E uonym us

alatus and related it to the product of the reduction and acetylation of

alatamine (48) ( 2 6 ) .The stereochemistry of the introduced acetate was

determined by LAH reduction of wilfordine to euonyminol (32), hosestereochemistry had already been established ( 2 4 ) .Thus, wilfordine (53)

must have the same ester substitution pattern as alatamine and an

additional axial C-8 acetate instead of a keto group.




4. Wilforine and Wilforzine

Wilforine (C,3H,gNOl,) was first isolated by Beroza ( 2 2 )who showedit to contain one fewer oxygen than wilfordine. Degradation yielded 5

moles of acetic acid, 1mole of benzoic acid, 1 mole of wilfordic acid, and

a "Cl5H1,(OH),, " nucleus ( 1 4 ) . Further isolation studies yielded

wilforzine (C,,H,,NO,,), whose formula and hydrolysis suggested it was

deacetylwilforine ( 1 5 ) .It could be converted to wilforine on acetylation

(25) and was shown not t o be artifact. The C15 nucleus in both wilforzine

and wilforine was found to be identical with that from wilfordine by

X-ray analysis (14).

Despite the recent isolations of wilforine from Maytenus senegalensis( 3 9 )and T . wilfordii ( 5 3 ) , he full structure has not yet been reported.

The biogenetic relationship to wilfordine and the presence of the same

nucleus (32) uggest that wilforine differs only in the diacid group and

is probably 54. Wilforzine is probably the 6- or 2-deacetyl derivative of

54, by analogy with the derivatives of evonine and euonymine.

The name wilforine is noted to be also in use to describe a pregnane

from Cynadum wilfordii ( 3 9 ) .

5 . Wilforgine and Wilfortrine

Wilforgine (C,,H,,NOlg) and wilfortrine (C,,H,,NO,,) were also

isolated from T . wilfordii by Beroza ( 1 3 ) and were found to yield

3-furoic acid, 5 moles of acetic acid, and wilfordic or hydroxywilfordic

acid, respectively, on hydrolysis. They both contained the same C15

nucleus as wilfordine ( 1 4 ) .Although these alkaloids have recently been

reisolated ( 5 3 ) , their structures have not yet been reported. They

probably correspond to those of wilfordine and wilforine in which the

benzoate group is replaced by a 3-furoate group (i.e., 55 and 56).

V. Structures of Related Sesquiterpene Esters and Polyols

As well as the sesquiterpene alkaloids that have been found in the

Celastraceae, a number of neutral polyester sesquiterpenes have been

isolated (Table VI). These compounds are clearly related to the alka-

loids and are also based on hydroxylated dihydroagarofurans, in some

cases identical with those found in the alkaloids.

The ester malkangunin (13) (C24H3207)rom Celastrus pan iculatuswas shown by Wagner and his co-workers to be the acetate benzoate of

malkanguniol (14) (CI5H,,O5) ( 4 6 ) .Doubt has been cast on the stereo-

chemical assignments by the work of den Hertog and his co-workers,



TABLE VI

NATURALLYCCURRINGPOLYESTERESQUITERPENES ROM CELAS

Ester

Ahtolin (61)

Euolalin (65)

Mctlkangunin (13)

Ester A-1 (57)

A-2 (58)

Ester B-1 (62)

B-4 (63)

A-3 (59)

Source a Formula. Mol. wt. (m/e)

EA

EA

C P

EE

E E

EE

EE

EE

756

694

432

756

694

652

674

684

Amorphous

240-245

219-221

95-100

188-192

85-90

112-120

106-110

CP = Celaatrms paniculatwr, EA = Euonymua alatua, E E = E . europaeua.Alternative structure 15 based on polyol 16 (47 ) .




who established the different stereochemical structure 16 for malkan-

guniol obtained by the hydrolysis of C. paniculatus seed oil ( 47 ) (see

Section 111, Al) . The position of the benzoate group in 13was based onthe chemical shift of the C-9 proton, 6 6.22, compared with the value

of 6 5.3-5.4 in the related Celastrus alkaloids (Table 111).

A series of five polyesters has been reported from E m y m u s europaeusbut their full structures have not yet been determined ( 6 0 ) .Three-

A-1 (57), A-2 ( 5 8 ) , and A-3 (59)-are based on the hexaol (60), the

remainder-B-1 (62) and B-4 (63)-are based on the isomeric hexaol

(64).The substituents and the structures of the hexaols were determined

by mass, IH, and 13C NMR spectroscopy, but it was not possible to

assign the positions of the ester functions.

OR

CH3

57 Ester A-1 R = 3 x Ac, 3 x Bz58 Ester A-2 R = 4 x Ac, 2 x Bz

59 Ester A-3 R = 3 x Ac, 2 x Bz

60 R = H

61 Alatolin R = 3 x Ac, 3 x Bz

CH,

62 Ester B-1

63 Ester B-2

64 R = H

R = 2 x Fur, 2 x Ac, 2-methylbutanoyl

R = 2 x Ac, 3 x Fur



244 ROGER M . SMITH

A closely related compound, alatolin (61), also based on the hexaol

60 has been isolated from Euonymus alatus ( 61 ) . Hydrolysis of 61

yielded 60 (named alatol), whose structure was determined by NMRstudies, including the NOE and by its synthesis from evoninol (32).The

NMR spectra of 61 and 57 were measured in different solvents, and

insufficient data have been reported to enable a comparison to be made

to determine if these two compounds are identical or positional isomers.

Euon ymu s alatus has also yielded euolalin (65) (C,,H4,Ol2), which

on hydrolysis gave deoxymaytol (21), 2 moles of benzoic acid, and 2

moles of acetic acid ( 6 2 ) .From the mass and NMR spectra, a fifth ester

group, a-methylbutyrate, was identified. The substitution pattern was

determined by partial hydrolysis and synthetic studies.

Studies on further components in Celastrus oils have continued in

three laboratories. Work on the hydrolysis products of nonglyceride

OAcI

CH3

65 Euolelin

-CHaCH,

CH3

R' R2 R3 R4 R5 RE66 PolyalcoholA OH H OH ---OH -OH OH

67 Polyalcohol B OH H OH -OH ---OH H

68 Polyalcohol C OH H OH -OH -OH OH

69 Polyelcohol D OH OH H ---OH -OH H



4 . CELASTRACEAE ALKALOIDS 245

esters in C . paniculatus oils, as well as yielding malkanguniol 16),ave

four related polyols, polyalcohol A 66) C15H2,0,; mp 185-186.5"c),

polyalcohol B 67) C15H2605; mp 236-239"C), polyalcohol C 68)(C,,H,,O,; mp 205-207"C), and polyalcohol D 69) C15Hzs05; mp

243-245°C) ( 4 7 ) .Their structures have been determined and related to

malkanguniol by IH and 13C NMR spectroscopy. The hydrolysis also

yielded acetic, benzoic, 3-furoic, and nicotinic acids, and thus, these

nuclei may represent further Celastrus alkaloids. Polyalcohol B 67)

has the same structure and stereochemistry as that reported by Wagner

for celapanol 9) 4 6 ) ;however, the coupling in 67 (J8,9 10Hz) ( 4 7 )

differs markedly from the value in the alkaloids 8,10, nd 11 (Js ,9=

7 Hz). Clearly, further studies in this area are needed to clear up theconfused stereochemistry.

A further group is studying the seed oil of C . orbiculatus and has

isolated three esters based on a trio1 (C15H2,04)containing acetic,

benzoic, and/or trans-cinnamic acids ( 6 3 ) .Detailed structures are under

study ( 6 4 ) .

VI. Biosynthesis

A systematic 14C-labeling study of t4he Tripterygium wilfordiialkaloids ( 5 3 ) has shown that the pyridine rings of wilfordic acid and

hydroxywilfordic acid are derived from nicotinic acid or nicotinamide

adenosine dinucleotide (NAD). However, no work has been reported

on the origin of the C, side chains of the substituted nicotinic acids.

A similar C5 unit is present in the polyesters 62 6 0 )and 65 (62) s

a-methylbutyrate, as the carbon skeleton of 3-furoate in the esters 62

and 63 go), and in the alkaloids celapanine S), ilforgine (55),and

wilfortrine 56). -Furoic acid has been found naturally with a limited

distribution, principally in the Celastraceae ( 6 5 ) .It was isolated as thefree acid from Euonymus autropurpureus ( 6 6 )and E . europaeus ( 6 7 )and

as an ester in t,he cinnamoyl spermidine alkaloid celafurine from

T. wilfordii ( 4 1 ) .

The high degree of hydroxylation of the dihydroagarofuran nucleus

is unusual in a sesquiterpene and is a characteristic feature of this

family. The stereochemistries of the poiyols have some common

features. The C-4 methyl group is axial irrespective of a C-4 hydroxyl

group. With the exception of polyalcoholD 69) 4 7 ) , he C-1, C-2, C-3,

and C-6 hydroxyl groups are, respectively, equatorial, axial, axial, andequatorial. Substitution at C-S and C-9 is highly variable in the nico-

tinoyl alkaloids (including the polyalcohols) but constant equatorial-

equatorial in the 0, and Ol0 alcohols.



246 ROGER M . SMITH

W. iological Properties

Much of the work on this group of alkaloids was prompted by theirinsecticidal properties. The thunder god vines, Tripterygium wilfordii

and l‘ Forrestii, were both widely used as contact insecticides in rural

Chins (68,69).Plants were introduced for testing into the United States

(70, 71) nd England (72). The American studies led t o the isolation of

the alkaloids from T. ilfordii, which were all active against selected

larvae (11, 3) but nontoxic to mammals (73).During these studies, insecticidal activity was also found to be

present in an unidentified Celastrus species (71), elastrus angu latus (69),

and Euonymus europaeus (72), but so far, the isolated Celastrusalkaloids have not been tested. The isolated alkaloids of Euonymusshowed no activity in rats ( 7 4 )but possessed insecticidal properties (33).

The alkaloids of M ayten us owatus were found to be inactive as antitumor

agents (38),the activity of the seeds being due to maytansine (40). I n

the recent isolation of wilforine from M . senegalesis, it was found to be

inactive in antitumor assays (39).E . europaeus (75) and C . paniculatus (2 8 ) are both used in folk

medicine as cardiototic agents, emetics, and purgatives or as sedatives,

but these activities have been related to the presence of cardenolide

glycosides rather than to the alkaloids.

Note added in proof. Wagner et al. ( 7 6 ) have recently reported the

isolation and structural elucidation of cassinine from Cassine matabelicaLoes. (Celastraceae.) The alkaloid is based on a new sesquiterpene

nucleus, 4-deoxyeuonyminol, and contains a unique pyridine diacid

cassinic acid (3-carboxy -ethyl-2-pyridinebutanoic cid).

Further alkaloids have been reported from Catha edulis (77) and the

full details of the structural determination of the polyesters from

Eumymus europaeus (78) and Celastrus orbiculatus (79) have been

reported.

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Abraham, G. J. Persinos, and 0. B. Dokosi, Lluydia 34,79 (1971);N. R. Farnsworth,

J. Phurm. Sci.62, 1028 (1973).

40. S. M. Kupchan, Y. Komoda, W. A. Court, G. J. Thomas, R. M. Smith, A. Karim,

C. J. Gilmore, R. C. Haltiwanger, and R. F. Bryan, J. Am. Chem.SOC.4,1354 (1972).

41. S. M. Kupchan, H. P. J. Hintz, R. M. Smith, A. Karim, M. W. Cass, W. A. Court,

and M. Yatagai, J. Chem. SOC., hem. Cornmun. 329 (1974).

42. G. Englert, K. Klinga, Raymond-Hamet, E. Schlittler, and W. Vetter, Helv. Chim.

Acta 56, 474 (1973).

43. S. M. Kupchan, Y. Komoda, G. J. Thomas, and H. P. J. Hintz, J. Chem.SOC., hem.

Commun. 1065 (1972).

44. D. W. Bishay and Z. Kowalewski, Herbu Pol. 17, 97 (1973); 17; 233 (1973); D. W.Bishay, Z. Kowalewski, and J. D. Phillipson,J. P h r m . Pharmcol . 23, 2445 (1971);

24, 169P (1972); Phytochemktry 12, 693 (1973).

45. M. S. Karawya, M. A. Elkiey, and M. G. Ghourab, J. Pharm. Sci. U.A.R. 9, 147

(1968); M. A. Elkiey, M. S. Karawya, and M. G. Ghourab, &id. 159; G. Rucker, H.

Kroger, M. Schikarski, and S. &6dan,Plan& Med. 24, 61 (1973).

1964 Abstracts, p. 95 (1964).

(1971).

103666 (1970).

(1973).



248 ROGER M . SMITH

46. H. Wagner, E. Heckel, and J. Sonnenbichler, Tetrahedron31, 949 (1975).

47. H. J. den Hertog, Jr., C. Kruk, D. D. Nanavati, and S. Dev, Tet. Lett. 2219 (1974) ;

48. H. J. den Hertog, Jr., J. T. Hackmann, D. D. Nanavati, and S. Dev, Tet. Lett. 845

49. A. B. van Egmond, S. Harkema, and T. C. Van Soest, in preparation.

50. Y. Shizuri, H. Wada, K. Sugiura, K. Yamada, and Y. Hira ta, Tetrahedron29,1773

51. H. Luftmann and G. Spiteller, Tetrahedron30, 2577 (1974).

52. M. Beroza, Anal. Chem.25,177 (1953).

53 . H. J. Lee and G. R. Waller, PhytochemGtry 11, 2233 (1972) ; H. J. Lee, Ph.D.

Thesis, Oklahoma State University, Stillwater, 1971; Dw8. Abstr. B 564 (1972).

54. R. Libiseller and A. Preisinger, Momztsh.93, 17 (1962) .

55. 0. Clauder, I. Huths, and K. Bojthe-Horvhth, Symp. Biochem. Physwl. Alkaloide

56. Y. Shizuri, H. Wada, K. Yamada, and Y. Hirata, Tetrahedron29, 1795 (1973).

57. A. Klhsek, Z. Samek, and F. santavf, Tet. Lett. 941 (1972) .

58. K. Sugiura, K. Yamada, and Y. Hirata, Chem. Lett. 579 (1975) .

59 . M. Chou, S. Hwang, and Y. Hsu, Chdah Agric. Quart. 1, 3 (1937); S. Hwang,

60. H. Budzikiewicz and A. Romer, Tetrahedron31, 1761, 2638 (1975).

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62. K. Sugiura, Y. Shizuri, K. Yamada, and Y. Hirata , Chem. Lett. 471 (1975).

63. R. W. Miller, C. R. Smith, Jr., D. Weisleder, R. Kleiman, and W. K. Rohwedder,

64. C. R. Smith, personal communication.

65. W. Karrer, “Konstitution und Verkommen der organischen Pflanzenstoffe.”

66. H. Rogenson, J . Chem.Soc. 101, 1040 (1912).

67. E. Ramstad, J . Am. Pharm. A880C. 42, 19 (1953) .

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71. C. S. Lee and R. Hansberry, J . Econ. Entoml . 36, 915 (1943).

72. F. Tattersfield, C. Po tter, K. A. Lord, E. M. Gillham, M. J. Way, and R. I. Stoker,

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(1973) .

(1973) .

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THE BISBENZYLISOQUINOLINE ALKALODS-OCCURRENCE. STRUCTURE. AND PHARMACOLOGY

M. P. CAVA. K. T BUCK.

University of Penmylvania

Philadelphia. Penmylvania

and K . L STUARTUniversity of the West Indies

Kingston. Jamaica

I. Introduction ...................................................... 250

I1. Structure Revisions ................................................ 251

A. Chondrocurine ................................................. 251

B.Chondrofoline.................................................. 252

C. Fetidine ....................................................... 252

D. Micranthine.................................................... 253

E. Thalfoetidine .................................................. 255

F. Tubocurarine Chloride .......................................... 255

. New Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

A. Belarine ....................................................... 257

B. Bisjatrorrhizine Chloride ........................................ 258

C. N,N-Bisnoraromoline ........................................... 258

D. Cancentrine.................................................... 260

F. Chelidimerine .................................................. 261

G

.Cocsuline ( = Effirine, Trigilletine) ................................ 262

H. Cycle~ur ine.................................................. 263

I. Cycleadrine.................................................... 264

J . Cycleahomine Chloride .......................................... 265

K. Cycleanorine................................................... 266

L. Cycleapeltine .................................................. 267

M . Dauricinoline .................................................. 267

N. Dauricoline .................................................... 268

0 . 0-Desmethyladiantifoline ....................................... 269

P. N'-Desmethyldauricine.......................................... 270

Q. 12'.O.Desmethyltrilobine ........................................ 270

R. 0, .Dimethy1micranthine ....................................... 271S. (-))-Epistephanine .............................................. 272

T. Espinidine..................................................... 272

U. Espinine ...................................................... 273

V. Funiferine ..................................................... 274

E. Cepharanoline.................................................. 261



250 M . P. CAVA. K. T. BUCK. AND K . L. STUART

W.Isotenuipine ...................................................X . 0-Methyldauricine ..............................................

Y. 0-Methylmicranthine ...........................................Z . Nemuarine ....................................................A A. 2.N.Norberbamine ............................................BB 2-N-Norobamegine ............................................CC. Nortiliacorine.A, Nortiliacorinine.A, and Nortiliacorinine-B ........DD. Oxoepistephanine .............................................EE. Pakistanamine ...............................................FF. Pakistanine ..................................................GG. Penduline ....................................................HH. Stepinonine ..................................................I1 Telobine .....................................................

JJ. Thalfhe .....................................................K K. Thalfinine ....................................................LL. Thalictrogamine ..............................................MM. Thalictropine .................................................NN. Thalidoxine ..................................................00. Thalisopidine .................................................PP. Thalmelatidine ...............................................QQ. Thalmineline .................................................RR . Thalrugosamine ..............................................

TT. Thalrugosine (E haligine) ....................................UU. Toxicoferine ..................................................W . Tricordatine..................................................

IV. Known Alkaloids from New Sources..................................V. Methodsand Techniques ...........................................

A. Spectrometry ..................................................B. Chemical Methods ..............................................

VI Pharmacology .....................................................VII. Bisbenzylisoquinoline Alkaloids Tabulated by Molecular Weight .........

VIII. Appendix .........................................................References ........................................................

SS. Thalrugosidine ...............................................

275

275

276276

277

278

278

279

280

281

282

283

285

286287

287

288

289

289

290

291

292

293

294

295

296

297

297

297

298

300

301

304

312

I. ntroduction

It is the purpose of this chapter to review the recent chemistry of the

bisbenzylisoquinoline alkaloids. The previous review in this treatise

covered the literature up to the beginning of 1970. With the exception

of a few 1969 references. which were inadvertently omitted from

the previous review (Volume XI11 of this treatise). we have covered the

period 1970-1973. the 1973 coverage being defined as inclusive of thelast issue of Chemical Abstracts for th at year. and an appendix similarly

covers the 1 9 7 4 period. All aspects of bisbenzylisoquinoline research

have been included. with the exception of synthesis. which is the subject

of Chapter 6 in this volume.



5. BISBENZYLISOQUINOLINE ALKALOIDS 251

We have defined a bisbenzylisoquinoline alkaloid in the broadest

sense, so as to cover compounds in which one (e.g., fetidine) or even both

(e.g., cancentrine) of the monomeric benzylisoquinoline units may bebiogenetically modified. We have included a table (seeSection VII)of all

bisbenzylisoquinoline alkaloids arranged in increasing order of molecu-

lar weight. We feel that this table should be of considerable practical

utility to workers in this area who wish to determine rapidly if a com-

pound they have isolated and examined only mass spectrometrically

may be identical with one of these alkaloids.

The authors have also introduced a brief section describing new and

useful techniques, both chemical and spectroscopic, dealing with

methods of structure elucidation of bisbenzylisoquinoline alkaloids.The section on pharmacology is not intended to be an exhaustive

coverage but should serve as a guide to current general aspects of this

area for these alkaloids during the period under review.

II. Structure Revisions

A. CHONDROCIJRINE

The sodium thiophenoxide N-demethylation of ( R , R ) - ( )-tubo-

curarine chloride (new structure 1) has been reported as giving the

presumably new base (+)-tubocurine ( 1 ) .Direct comparison of the

latter with ( + )-chondrocurine has now shown these t o be identical (2).

The former structure 2 for chondrocurine must therefore be discarded

in favor of structure 3. The bismethochloride of 3 is (+)-chondro-

curarine chloride, ( 4 ) ; he latter structure has recently been confirmed

by an X-ray crystallographic analysis (3).

1 R = H

4 R = M e

2

3

R1 = H , R , = Me

R, = Me,R, = H



252 M . P. CAVA, K. T. BUCK, AND K. L. STUART

B. CHONDROFOLINE

Chondrofoline was originally shown by King to have the sameskeleton as curine, and the alternative structures 5 and 6 were proposed

for it ( 4 ) .The new structure 7 has recently been assigned to chondro-

foline on the basis of a comparative NMR and mass spectral study of

chondrofoline, its 0-trideuteriomethyl derivative, and related known

alkaloid derivatives of established stereochemistry ( 5 ) .

M e o w

5

6

R, = Me,R, = H

R, = H , R , = Me

M e 0

OH

7

C. FETIDINE

On the basis of earlier reported chemical degradation, fetidine was

assigned structure 8 ( 6 ) . Subsequently, mass spectral data in general

support of this structure have been reported (7) . More recently, a220 MHz NMR study of fetidine revealed the presence of an AB quartet

(J = 8 . 5 Hz) centered at 6 6 . 7 5 (1H) and 6 6 . 8 1 (lH), indicating the

M e N K3'.=

\/ OMe M e 0

O Me0

8



5 . BISBENZYLISOQUINOLTNE ALKALOIDS 253

M e N P I

0

M e 0

presence of an adjacent pair of aromatic hydrogens. This fact, inconjunction with earlier evidence, requires a revision of the structure

of fetidine from 8 to 9 (8).

D. MICRANTHINE

In 1953, structure 10 was proposed for micranthine (9).Reinvestiga-

tion of this alkaloid [mp 193-195°C; C34H32N205M+ 548)] by NMR

IOH

10

R, = H, Ra = Me or vice verm

R, = H, R, = M e or vice versa

OH10

R, = H, Ra = Me or vice verm

R, = H, R, = M e or vice versa

indicated the presence of one methoxyl and one AT-methylgroup, and

of key significance, ten aromatic protons, thus invalidating structure

10. The trilobine-type structure (11) has now been proposed for micran-thine (10, 1).

The mass and IR spectra of 0,N-dimethylmicranthine (12) (mp

210-214°C) and isotrilobine were very similar, and the NMR spectra




0

11 R1 = R, = H

12 R1 Ra = M e

13 R1 = CD,, R, = M e

were superimposable, but the specific rotations of these compounds

were opposite in sign. Both 12 and isotrilobine yielded the same

Hofmann degradation product. Since the structure of isotrilobine has

been confirmed by synthesis ( 1 2 )and its stereochemistry is known from

degradation to be S,S ( 1 3 ) , t follows that micranthine must be R,R, s

shown in structure 11. The position of the phenolic hydroxyl, previously

established by ethylation and degradation, was confirmed by mass

spectrometry.

The location of the secondary and tertiary amine functions was

determined by the following experiments. Oxidative photolysis of 12yielded the dialdehyde 14 and a lactam carbinolamine, which was

reduced with NBH to the aminolactam 15. When O-methyl-N-tri-

C HO OMe

I I

14

M e

15 R = M e16 R = CD,

deuteriomethylmicranthine (13,50%deuterium incorporation, preparedby alkylating 0-methylmicranthine with formaldehyde-d, and NBD)

was similarly degraded, the product was shown by NMR to be 16, thus

establishing the secondary nitrogen at position 2' of 11.



5 . BISBENZYLISOQUINOLINE ALKALOIDS 255

E. THALFOETIDINE

Thalfoetidine was previously assigned structure 17 (14).Its earlierchemistry supports the structural features of 17apart from the location

of the ether termini of the isoquinoline units. Direct comparison has

now shown that 0-methylthalfoetidine is identical with thalidasine (18).

Thalfoetidine must therefore be assigned structure 19 (15, 1 6 ) . In

further support of structure 19, the racemic form of the thalfoetidine

degradahion product 20 has been synthesized and the spectral identity

of its diethyl ether with naturally derived material has been established

( 1 7 ) .

?HMe

I

"H "H

OH

17 20

18 R = M e19 R = H

F. TUBOCURARINEHLORIDE

The long-accepted bisquaternary structure 4 for ( + )-tubocurarine

chloride has been shown to be incorrect; the alkaloid is actually the

related monoquaternary salt 1 (2).The NMR of 1 shows only threeN-methyls, one of which shifts upfield on basification, showing it to be

a tertiary N-methyl. Benzylation of tubocurarine did not give an 0-

dibenzyl derivative as required by the old structure 4, but rather an




A variable temperature NMR study of 1 has revealed interesting

aspects of its solution conformation ( 2 0 ) . The very highly shielded C,.

proton at 6 4.80 moves slightly downfield to 6 5.08 a t 125OC as thedisubstituted central benzene ring begins to rotate. Indeed, the protons

of the latter ring (at Cl0,, Cllr, C1,,, and C,,,) are nonequivalent a t room

temperature but begin to coalesce to an AA'BB' pattern as rotation

increases at elevated temperatures. The trisubstituted central ring is

frozen even a t 125OC, and the protons a t Cl0, C13, and C,, are unaffected

by temperature changes.

III. New Alkaloids

A. BELAXIXE

Belarine (25) [C,,H,,N,O,; mp 158-160°C; [aID- 22" (CHCI,)] has

been isolated from the root bark of Berberis laurina Billb. ( 2 1 ) .Methyla-

tion of belarine yielded the previously isolated alkaloid O-methyl-

H'

25 R = H26 R = M e

isothalicberine (26). Structural proof of belarine therefore also firmlyestablishes the structure of isothalicberine. 0-Ethylation of belarine

followed by sodium-ammonia cleavage yielded the tetrahydroiso-

quinolines27 and 28, the latter being identified as the diethyl derivative

29.

When belarine was treated with D,O under basic conditions no proton

exchange was noted; this fact provides evidence in support of an ether

bridge at C, rather than a t C,, since a hydrogen ortho to a phenolic

group (C,) should have exchanged. Further support for the absence of a

C,-linked ether bridge was obtained by an acid-catalyzed exchangeexperiment on 25 in D,O; when the product was ethylated and subjected

to sodium-ammonia cleavage, compound 27 was obtained in which

deuterium was shown to be located at C, by NMR and mass spectrometry.




HO

MeO% ' M0M0

32

I 2c1-

OMe

31

33

34

Rl = R, = H

R, = H, R, = M e

Rl = Ra = M e

MeO'N '

36

37

38

Rl = Ra = H

Rl = Me, Ra = H

Rl = Ra = Me



260 M . P. CAVA, K . T. BUCK, AND K. L. STUART

gave obaberine (38). Since the absolute configuration of aromoline is

known from sodium-ammonia cleavage studies (25, 26), N,N-bis-

noraromoline is therefore unambiguously established as 36. It isapparently the first reported bisbenzylisoquinoline alkaloid containing

two secondary nitrogens, perhaps because of the low solubility in

common organic solvents observed for 36 and expected for similar

alkaloids.

D. CANCENTRINE

Cancentrine (39) (C,,H,,N,O,, mp 238°C) occurs in Dicentracanadensis Walp (27). It was, in fact, first isolated and characterized

over forty years ago as FZ2,n alkaloid of unknown structure (28, 9).

The IR spectrum of cancentrine reveals the presence of both hydroxyl

and carbonyl bands. Its NMR shows t,he presence of three aromatic

methoxyls and one N-methyl group. The second nitrogen of 39 is

essentially nonbasic. The phenolic group of 39 can be methylated, af-

fording 0-methylcancentrine (40), and acetylated to give O-acetyl-

cancentrine (41). Conversion of 39 to its methiodide, followed by a

Hofmann degradation, gave the methine base 42. Hydrogenation of 42followed by treatment with diazomethane afforded the 0-methyl

dihydromethine base 43. The structure of 43 was revealed by an X-ray

crystallographic determination of its hydrobromide. Spectral studies

(UV and NMR) showed that only the expected single chemical changes

\ I-42

OM0 OM0

439 R = H

40 R = M e

41 R = Ac



262 M. . CAVA, K . T. BUCK, AND K. L. STUART

'i\ / o

OH -

4 1

46 RlR2 OCH,O

48 R1 = R, = OMe

G. COCSULINE33)[=EFFIRINE3 4 ) ,TRIGILLETINE3 5 ) ]

Cocsuline (49) (C35H34N205;mp 272-2'74°C; [aID+ 280 ) was first

isolated from the leaves and stems of Cocculus pendulus Diels ( 3 3 ) .Cocsuline yielded a picrate (mp 194-196"C), O-methylcocsuline (mp 212-

214"C, [D + 289"), and O-ethylcocsuline. Recently, cocsuline has also

been reported from Triclisia gillettii (DeWild) Staner ( 3 4 ,35) and

T . ubcordata Oliv. ( 3 5 )under the names effirine ( 3 4 )and trigilletine ( 3 5 )[mp 272-274°C; [a]g2+348.2' (pyridine); acet,ate, mp 166-168"C] ( 3 5 ) .

O-MethyIcocsuIine was shown to be identical with the known alkaloid

isotrilobine (50). The location of the free hydroxyl group of 49 a t

position 12' rather than at 6 was established by mass spectral comparison

OMe

0 12'

OR

49 R = H50 R = M e



5. BISBENZYLISOQUINOLINE ALKALIODS 263

of the alkaloid, its ethyl ether and acetate. In all cases, intense peaks

were observed at mle 350 and m/2e 175 (loss of the top portion of the

molecule at a).

H. CYCLEACTJRINE

Cycleacurine (51) [C35H3,N20S.H,O; - 02’ (MeOH)] was

isolated from Cyclea pe2tatu Hook. f. et Thorns. ( 3 6 ) ;purification was

effected by way of the bishydrobromide (mp 293-296°C). Its batho-

chromic UV shift in base revealed its phenolic nature. Diazomethane

+

OR



264 M . P. CAVA, K. T. BUCK, AND X. L. STUART

alkylation of cycleacurine afforded the 0-trimethyl derivative (52),

which was identical with 0-dimethyl-(S)-curine 53) (37),except for the

opposite sign of i ts rotation; 52 is consequently the optical antipode of53. The positions of the phenolic functions of cycleacurine were de-

ducible from a study of the sodium-ammonia cleavage of O-triethyl-

cycleacurine (54). The structure of the diphenolic cleavage product ( 5 5 )was apparent, since it contained an ethoxyl group. The nonphenolic

product was assigned structure 56 from spectral considerations. Its

mass spectrum gave an isoquinoline fragment at m /e 220 showing that

one of the two ethoxyls must be an isoquinoline substituent. The meth-

oxyl of 56 appears in its NMR a t 6 3.84, indicative of a C, methoxyl

rather than a more shielded C, methoxyl.

I. CYCLEADRINE

Cycleadrine (57) (C,,H,,N,OG; mp 160-162"C) is an optically inactive

base found in the roots of Cyclea peltata (3 6 ).Alkali caused a batho-

chromic shift in its UV spectrum, indicating its phenolic nature.

Reaction of cycleadrine with diazomethane afforded an 0-methyl

derivative 58 , which was identical with isotetrandrine (59), except for

it s lack of optical activity. The mass spectrum of cycleadrine showed a

strong peak at m/e 381 for the linked isoquinoline units revealing that

fM e O m

57 R = H

58 R = Me ( R S + 5R acemate)

MeN O q N M O

H' - * H

5.9




one of these must contain the phenolic hydroxyl group. It is known that

only the right hand isoquinoline unit of a C,-C,, head-to-head base is

lost singly ( 3 8 ) ; he peak at mle 417 (M-191) indicates th at this unit incycleadrine must bear a methoxyl at C6, nd tha t the hydroxyl must be

born on the left-hand head unit. Finally, the hydroxyl must be at C,rather than a t C,, since a C, methoxyl in related compounds is highly

shielded ( 8 3.20), whereas the highest field methoxyl of cycleadrine

appears a t 6 3.73.

J. CYCLEAHOMME HLORIDE

Cycleahornine chloride (60) [C,,H,,N,O,C1; mp 190-194"C, [ID+ 103" (CHCl,)] was isolated from Cyclea peltata roots ( 3 6 ) . I t s NMRshowed one tertiary N-methyl a t 6 2.37 and two quaternary N-methyls

at 6 3.54 and 6 3.30. Cycleahomine was shown to be a monoquaternized

tetrandrine, since reaction of 60 with methyl iodide gave tetrandrine

bismethiodide (61). On the other hand, reaction of tetrandrine with one

equivalent of methyl iodide affords not cycleahomine iodide, but the

C1- Me,N+

H

\,-Me

60

61

isomer 62. Since the demethylative carbamylation of tetrandrine isknown to occur selectively at the right-hand isoquinoline unit (see

cycleanorine), the selective N-methylation giving 62 must occur a t the

same site. Cycleahomine is therefore the isomer of 62, namely 60.



266 M. P . CAVA, K . T.BUCK, AND K. L. STUART

62

K. CYCLEANORINE

Cycleanorine (63) [C,,H,,N,O,; mp 171-172°C; [aID+ 308" (CHCl,)]was isolated from CycZeapeZtataroots ( 3 6 ) . ts NMR showed the presence

of only one N-methyl (at 6 2.33). N-Methylation of cycleanorine by

formaldehyde and sodium borohydride (39)gave tetrandrine (64).The

position of the secondary nitrogen of cycleanorine was revealed by its

mass spectrum, which showed a peak at m/e 431 (M-177),characteristic

of the loss of the right-hand isoquinoline unit of a C,-C7, dimeric alka-

loid. Finally, cycleanorine was prepared from tetrandrine (64) by

selective N-demethylation using the carbamate method ( 4 0 ) . Thus,reaction of 64with methylchloroformate gave the monocarbamate 65,

alkaline hydrolysis of which afforded 63.

63

64 R = M e

65 R = COOMe



5. BISB ENZY LISOQUINOLINE ALKALOIDS 267

L.CYCLEAPELTINE

Cycleapeltine (66) [C3&40X206; mp 232-234OC;[aID- 106 CHCI,)]was isolated from the roots of Cyclea peltata ( 3 6 ) .The NMR and mass

spectral data for cycleapeltine were in accord with those reported for

limacusine (67),except that the optical rotation w-as of opposite sign.

Cycleapeltine should therefore be the optical antipode (66)of limacusine.

In accord wit,h this proposal, reaction of (66) with diazomethane gave

an O-methyl derivative that was identical with the known O-methyl-

repandine (68).

M e N

wo: q N M e

H "H

66 R = H68 R = M e

M. DAURICINOLINE

Dauricinoline (69) [C,,H4,N206;pale yellow powder; [a] 1-94.6(MeOH)] was isolated from Menispermum dauricum DC. (41). MR

evidence was given to support the presence of two N-methyl, three

methoxyl, and two hydroxyl groups. Treatment with diazomethane

yielded O-methyldauricine, thus establishing dauricinoline as the

O-methyl derivative (70) of the alkaloid dauricoline (71), also isolated

from Menispermum dauricum ( 4 2 ) . n further confirmation of structure69, sodium-ammonia cleavage of the 0,O-diethyl derivative 72 afforded

(R)-() - 1 -(p-ethoxybenzyl)-6-ethoxy-7-methoxy-2-methyl-1,2,3,4-

tetrahydroisoquinoline (29) and (R)-( -armepavine (73).



268 M. P. CAVA, K. T. BUCK, AND K. L. STUART

O M 0 M e 0

69

7 0

71

7 2

R, = H, Ra = M e

R, = R, = M e

R, = R, = H

R, = Et, R, = M e

MeO'q N & f eH

73

29

R, = Me, R, = H

R, = R, = Et

N. DAURICOLINE

Menispermum dauricum yielded dauricoline (71) [C,,H,,N,O,;yellow powder; - 150" MeOH)] 42).The NMR showed the presence

of three hydroxyl groups at 6 5.53 (exchangeable with D,O). Treatment

with diazomethane gave t,he 0-methyl derivative (70) of dauricine (74).

Final proof was provided by sodium-ammonia cleavage of O,O,O-

triethyldauricoline, which yielded the two tetrahydroisoquinolines 29

and 75.

71

74

70 R, = R, = M e

R, = R, = H

R1 = M e , R, = H



5. BISBENZYLISOQ UINOLINE ALKALOIDS 269

29 R = Et

75 R = OH

0. -DESMETHYLADIANTIFOLINE

0-Desmethyladiantifoline (76) (C41H,,N20,; mp 125-126°C; [a],,

+ 18") was isolated from the roots of Thalietrum minus f. datum (43) .

I t s 0-methyl derivative, formed by reaction with diazomethane, was

identical with adiantifoline (77).The position of the phenolic hydroxyl

of 76 was revealed by permanganate oxidation of its 0-ethyl ether (from

76 and diazoethane), which afforded the known isoquinoline 78 and

aldehyde 79, a known adiantifoline degradation product.

76 R = H77 R = Me

OMe

MeNp:0

79 78



5. BISBENZYLISOQUINOLINE ALKALOIDS 2 7 1

H,‘

R1 / /

12 ’\

0\

82 R, = R, = H

83 R, = H, R, = Me

49 R, = Me, R, = H

R . O,N-DIMETHYLMICRANTHINE

0,N-Dimethylmicranthine (12) (C,,H,,N,O,; mp 210-214°C; [.ID- 241°),was isolated from the bark of a Daphnandra sp. and Daphnandramicrantha Benth. ( l 0 , I I ) .

This alkaloid gave IR and mass spectra matching those of isotrilobine

(50)but of opposite specific rot,ation, and 12was identical with material

prepared by N-methylating 0-methylmicranthine (84).

Me0

I

OMe

12

50

84

R = Me, chiral centers 1 and 1’ = R (as shown)

R = Me, chiral centers 1 and 1’ = S

R = H. chiral centers 1 and 1’ = R



272 M. P. CAVA, K . T. BUCK, AND X.L. STUART

S. ( - )-EPISTEPHANINE

(- -Epistephanine (85) [C,,H,,N,O,; mp 198-206°C (MeOH); [.ID- 216" (CHCl,)] was isolated from the stems of Anisocycla grandidieri

(45). It was identical by NMR, UV, and I R with authentic (R)-() -

epistephanine (86), but its optical rotation was the opposite. It was

therefore assigned structure 85.

M e 0

85

86 Chirel center = S

C h i r d center = R (as shown)

T . ESPINIDINE

Espinidine 87) C,,H42N206; amorphous; [ID +31" (CHCI,)] was

isolated from Berberis laurina ( 4 6 ) .Espinidine is a diphenolic base and is

converted by diazoethane to an 0-ciiethyl derivative (88) and by diazo-

methane to an 0-dimethyl derivative; the latter was found to be

identical with 0-trimethylespinine (89). Espinidine must therefore be

an 0-methylespinine. Except for a very weak molecular ion a t m/e 610,

the mass spectrum of 87 was practically identical with that of espinine,

showing that the additional methyl group must be in the lower diphenyl

ether portion of the molecule. Confirmation of structure 87for espinidine

was obtained by sodium-ammonia cleavage of its diethyl ether 88,

which gave the two known benzylisoquinoline fragments 90 and 27.

MeNFoMeRM e 0 " q N M e.H

H"

87 R = H88 R = Et

89 R = M e




H*' I I"'H

27 90

U. ESPININE

Espinine (91) [C,,H,,N,O,; mp 123-125°C; [a]=+ 25 (CHCl,)] was

isolated from Berberis laurina ( 4 6 ) .It is a triphenolic base, giving an

0-trimethyl derivative (89) with diazomethane and an 0-triethyl

derivative (92) with diazoethane. Espinine gives a very weak (< 1%)

molecular ion, characteristic of a dimeric benzylisoquinoline joined only

in a tail-to-tail manner; the base peak a t m/e 192 reveals an N-methyl-

isoquinoline unit bearing m e hydroxyl and one methoxyl. The structure

91 for espinine was assigned on the basis of the identification of the

known monomeric benzylisoquinolines 90 and 56 as the sodium-ammonia cleavage products of 0-triethylespinine (92).

91 R = H

92 R = Et

89 R = Me

56 90



274 M . P. CAVA, K. T. BUCK, AND K . L. STUART

V. FUNIFERINE

Funiferine (93) [C,,H,,N,06; mp 232-234°C (EtOH) or 168-169°C(MeOH); [elD + 171.4’ (MeOH) or + 184.3” (CHCl,)] was isolated in

1965 from Tiliacora funif era Oliver ( T .warneckei ), although its struc-

ture could not be assigned a t that time ( 4 7 ) .I ts NMR spectrum shows

the presence of two N-methyls and four methoxyls. As a monophenolic

base, funiferine is converted by diazomethane to 0-methylfuniferine

(94)) which was shown by direct comparison to be identical with the

known 0-methylrodiasine. Conversion of funiferine to 0-ethylfuniferine

dimethochloride, followed by permanganate oxidation, afforded 2-

ethoxy-2’-methoxy-5,5’-dicarboxybiphenyl95); the correspondingdimethoxydiacid (96)was obtained by oxidation of 0-methylfuniferine

(94).Funiferine is therefore the positional isomer of rodiasine (97))fromwhich it differs only in the placement of the phenolic hydroxyl group

in the biphenyl system. The structure was confirmed by a comparative

mass spectral study of funiferine (93), rodiasine (97))and their common

methyl ether (94). In all cases, weak but significant ions were apparent

that correspond t o the loss of the lower left-hand benzyl unit (cleavage

a-b); ions corresponding to the loss of the other half of the biphenyl

unit (cleavage b-c) are not observed. The stereo-chemistry of funiferine

cannot be assigned a t this time, although it must be the same as th at of

rodiasine ( 48 ) .

93

94

97

R, = H, R, = Me

R, = R, = M e

R, = Me, Rz H

OR O M e

95 R = Et96 R = M e



5. BISBENZYLISOQUINOLINE ALKALIODS 275

W. ISOTENWINE

Bark material from a Daphnandra sp. collected over thirty years agoin Australia yielded isotenuipine (98) [C,,H&&; mp 240°C; [a];,

+ 129" (CHCI,); dimethiodide mp 278°C (decornp.);[ - 50" (as)].

0 - J

98

Placement of substituents was based on the fact that the mass

spectrum shows an ion a t m/e 485 (M-151) , indicating that the methylene-

dioxy is attached to ring E and also on NMR comparison with the

structurally similar known bases (R)- r (8 -tenuipine, tetrandrine,

isotetrandrine, and phaeanthine. Evidence for the stereochemistryassigned was also based on a comparison of the specific rotation ofisotenuipine with those of the above-mentioned bases.

X. 0-METHYLDAURICIXE

0-Methyldauricine (70) (C39H46N206;morphous; [aID - 28") was

isolated from Popowia cf. cyanocarpa Laut. and K. Schum. It s crystal-

line dimethiodide (mp 179-181°C) was identical with material preparedfrom dauricine (74) by methylation ( 5 0 ) .The bark of Colubrina asiatica

Brongn. has also been found to contain 70 as the major alkaloid ( 51 ) .

M e 0

74 R = H70 R = M e




Y. O-METHYLMICRANTHINE

O-Methylmicranthine (84) [C,,H,,N,O,; mp 163-165°C (dec.); [cz]i0

-208"] from a Daphnandra sp. and D . micranthu was assigned its

structure by direct correlation with micranthine, for which the correct

structure 11was reported a t the same time ( 1 1 ) .The N-acetyl derivative

has mp 1 7 P 1 7 9 C (dec.); - 03" (CHCI,).

M e 0

OR

84 R = M e11 R = H

Z. NEMUARINE

Nemuarine (99) [C37H40N206; p 222-223°C; [.ID - 42.7" (CHCl,)]

was isolated from the leaves of Nemuaron wieillardii Baill. (52,53). ts

mass spectrum shows intense ions a t M-213 and (M-212)/2, ndicative

of the loss of a diphenyl ether fragment from a head-to-head dimer

molecule. Nemuarine is monophenolic and reacts with diazomethane togive O-methylnemuarine (loo), the mass spectrum of which indicates

clearly that the phenolic function of 99 must reside in the diphenyl

ether moiety. Sodium-ammonia cleavage of ether 100 gave (R)-N-

methylisococlaurine (28) and (R)-O-methylarmepavine(30). Prolonged

heating of ether 100 with 3% DC1 in DzO a t 120°C resulted in the

introduction of one deuterium ; sodium-ammonia cleavage of the

deuterated 100 gave undeuterated 28 along with the deuterated

armepavine derivative 101, in which the shielded C, proton signal at

8 5.98 had virtually vanished. Nemuarine was therefore established asstructure 99 and represents the first example of a C,-C6. linked bis-

benzylisoquinoline alkaloid. It appears to be derived biogenetically

from two isococlaurine units.




O M e M e 0

99 R = H100 R = M e

M e 0

HOLy30 R = H

101 R = D

28

Pyenarrhena australiana F. Muell. afforded 2-N-norberbamine (102)

[C36H38N206;p 166-188°C; [a]=+ 117" (CHCl,)] (54 ) .Formaldehyde-

NBH methylation of it gave berbamine (103).Comparison of the NMRresonance of the N-methyl of 102 (6 2.62) with those of 103 "'-Me

6 2.65, N-Me 6 2.25 (55)] enabled the unambiguous assignment of

102 R = H103 R = Me




structure 102 o 2-N-norberbamine. Further support for this structure

was provided by the mass spectrum which shows ions a t mle 192

(cleavage a-c) and 174 (cleavage b-c).

BB. 2-N-NOROBAMEGINE

The two Australian menispermaceous vines Pycnarrhena australiana( 5 4 )and Pycnarrhena ozantha ( 2 4 )have been independently reported as

sources of 2-N-norobamegine (104) [C35H3&&6; mp 188-190°C (dec.)

(CHC1, or acetone); [aID +290" (CHCI,) ( 5 4 ) and [a]i5 - 146" (0.1 N

HCl)] ( 2 4 ) .N-Methylation of 104 gave obamegine (105)and subsequenttreatment of this product with diazomethane afforded isotetrandrine

(59). The structure and absolute stereochemistry of obamegine are

known from cleavage experiments (56).The relative location of the

secondary and tertiary nitrogens of 104 was revealed by the NMRspectrum, which showsa signal at 6 2.52, as expected for a 2'-N-methyl

not subject to the shielding effect normally observed for the 2-N-methyl

group in similar alkaloids ( 55 ) [S 2.27 for 2-N-methyl in 105 (54)].

104 R , = R2 H

105 R, = Me, R, = H

59 R, = R2 M e

CC. NORTZIACORINE-A,ORTILIACORININE-A,

AND NORTILLWORTNINE-B

Tiliacora racemosa Colebr. [synonymous with T. cuminata (Lam.)

Miers] yielded the alkaloids nortiliacorinine-A [originally called pseudo-

tiliarine (57) l [mp 262-268°C (dec.) (acetone); [a]D +268.8" (pyridine)]

and nortiliacorinine-B [mp 218-220°C (dec.) (acetone-MeOH); [ID

+ 356.2" (pyridine)] ( 5 8 ) . Tiliacora funifera (T. arneckei Engl. exDiels) also afforded nortiliacorinine-A and, in addition, nortiliacorine-A

[originally isotiliarine (57)l [mp 258-260°C; [ID + 194.5"(CHCI,)] ( 59 ) .All three alkaloids were shown to possess the same molecular formula




(C,SH3,N,0,). On N-methylation, nortiliacorine-A gave tiliacorine,while nortiliacorinine-A and nortiliacorinine-B afforded tiliacorinine.

Tiliacorine and tiliacorinine are isomeric bases (C,,H,,N,O,) to whichthe partial structure 106has been assigned from degradative and spectral

studies (58 ) . Thus, although more work is required to establish the

substitution pattern and stereochemistry of nortiliacorinine-A, norti-

liacorinine-B, and nortiliacorine-A, they may be assigned the pre-

liminary structures 107 or 108.

OMe

OR3 0

106

107

108

R, = Rz Me, R, and R 4 e , H or v i c e versaR , = H, R , = Me, R, and R, = Me, H or v ice versa

R, = Me, R, = H, R1 and R, = Me, H or v i c e v e r s a

DD. OXOEPISTEPHANINE

Stephnia hernandifolia Walp. afforded oxoepistephanine

[C3,H,,N,0,; mp 22P226"C (dec.) (MeOH-ether);[a]:' +272" (CHCl,)]

( 6 0 ) .The NMR spectrum was very similar to that of epistephanine (86),isolated from the same plant, except for a downfield shift of one of the

aromatic resonances. The IR band at 5.97 p indicated a conjugated

carbonyl and the mass spectral peak at mle 380 suggested that this was

380

109




86

located in the lower portion of the molecule. Structure 109 was proposed

as most reasonable for oxoepistephanine; however, several attempts to

interrelate chemically his alkaloid with epistephanine were unsuccessful.

EE.P A K I S T A N ~ N E

The first proaporphine-benzylisoquinoline dimer, pakistanamine

(110) (C,,H,,N,O,), has been isolated from Berberis baluchistanicu as

its picrate [mp 158-162°C (dec.)]. The free base darkens readily to a

deep purple color, but the hydrochloride [mp 215OC; [.II, + 20 (MeOH)]

is fairly stable (6 1 ,62).

H

a

1 O

UV, IR, and NMR da ta are in accord with structure 110, and mass

spectrometry shows the major cleavagesa, , and c .When pakistanamine

was reduced with NBH, a mixture of diastereomeric dienols was

produced. Acid treatment of this product with 3 N H2S04 afforded

1-0-methyl-10-deoxypakistanine111)via a dienol-benzene rearrange-

ment, while direct treatment of pakistanamine with 3 N H z S 0 4 esulted

in a dienone-phenol rearrangement to 1 0-methylpakistanine (112) .

Acetylation of the latter gave the corresponding acetate, and methyl-ation yielded 1,lO-di-0-methylpakistanine113).Catalytic reduction of

pakistanamine hydrochloride with Pd/C afforded 11 ,lZ-dihydro-

pakistanamine. ORD data are reported for most of these products.




OMe

111 R = H

112 R = OH

113 R = OMe

The occurrence of the alkaloids pakistanine and pakistanamine in t,hesame plant lends substantial support t o the earlier suggested biogenetic

sequence (63) benzylisoquinoline--f bisbenzylisoquinoline --f proapor-

phine-benzylisoquinoline dimer+ porphine-benzylisoquinoline.

FF. PAEISTANINE

Pakistanine (114) [C3,H4,,N206;mp 15P-156OC; [a]g5 + 106' (MeOH)]

was also isolated from Berberis baluchistanica (6 1 , 6 2 ) .The UV spectrumis similar to that of 9-phenylboldine, and the other spectral data are in

accord with a linked aporphine-benzylisoquinoline structure. Sodium-

b

114

113

C

R = H

R = Me

ammonia cleavage of the 0,O-dimethyl derivative 113 yielded (8)-()-

armepavine (115) and (R)-()-2,lO-dimethoxyaporphine116).

The presence of two phenolic hydroxyl groups in 114 was confirmed

by the formation of an amorphous diacetate and by a bathochromicshift in the UV spectrum on the addition of base. The fact that paki-

stanine gave a negative test with phloroglucinol, a reagent that has been

used to detect o-diphenols, was cited as evidence in partial support of




penduline shows a characteristic head-to-head fragment at rnle 198(doubly charged ion), showing that the free hydroxyl must reside in the

diphenyl ether portion of the molecule. Sodium-ammonia cleavage ofethyl ether 118 gave (8)-0-ethylarmepavine (119) nd (8)-N-methyl-

coclaurine (24). The structure 117 was therefore established for

penduline.

119 24

Penduline is apparently the enantiomer of the known alkaloid

pycnamine (65 ) .Also, 0-methylpenduline (mp 150-152°C; [.ID + 218";

hydrochloride, mp 272-275"C) picrate, mp 251-253OC) should be

identical with tetrandrine (Sa). However, direct comparisons of these

compounds were not reported.

HH. STEPINONINE

Stepinonine (120) [C36H34N20,; p 24&245"C, 2 8OOC (dimorphism);

[a];'' - 8 (pyridine)] was recently isolated from Stephania japonica

Miers ( 6 6 ) .The IR YE^ 3500 (OH), 166 3 (C=O) cm-l] and NMR [ 6 5.60-7.37

(10 H-aromatic), 3 .37 , 3 .85 , 3 .96 (3 OMe), 2.54 (N-Me)] revealed thefunctional groups present. Acetylation yielded a monoacetate and

OH

n o




OEt

124

lowed by reductive fission to armepavine (115) nd 125, euterated at

C, and C6,, respectively. The identity of 125 was established by com-

parison with racemic synthetic material ( 67 ) .This new dimeric benzyl-

isoquinoline-Z-phenyl-sec-homotetrahydroisoquinolineype could be

biogenetically closely related to the rhoeadine-type alkaloids.

11. TELOBINE

Another new alkaloid which was reported from a Daphnandra sp. was

named telobine (126) C,,H,,N,O,; mp 185-195°C (dec.); [a];' + 188"

(CHCl,)] ( 1 1 ) . Telobine yielded the derivatives N-acetyltelobine

[mp 180-185°C (dec.);[a];, + 111" (CHCl,)] and N-methyltelobine (127)

H

M e

OMe

126 R = H

127 R = M e

[C,,H,,N,O,, (M + 576.2624); mp 175-180°C (dec.); [a]h8 +248"

(CHCI,)]. NMR evidence indicated a diastereomeric relationship

between N-methyltelobine (127) nd 0,N-dimethylmicranthine (12);also, the properties of N-methyltelobine (mp and specific rotation) were

in good agreement with those of a base structure 127prepared by partial

synthesis from oxyacanthine (68).




JJ. THALFINE

The novel structure 128 has been proposed for thalfine, [C38H,SN,08;mp 141-142°C (dec.); [a]b5 +69" (EtOH)] isolated from Thalictrum

foetidurn L . (69) .

OMeI 4 '

128

Two Hofmann degradations on thalfine dimethiodide produced

trimethylamine, but in addition, a product that still contained nitrogen,

suggesting the presence of an isoquinoline moiety in the structure.

Reduction of thalfine dimethiodide with zinc in 20y0 H,SO, yielded

N-methyltetrahydrothalfbe methiodide, which on treatment withethanolamine gave N-methyltetrahydrothalfine. This product has an

IR spectrum identical with that of another new alkaloid from the same

plant, thalfinine (132), which is discussed in the next section.

The substitution pattern of the lower portion of 128 was established

by oxidation with KMnO, in acetone. The acid product afforded with

diazomethane the dimethyl ester 129. Cleavage of thalfine with sodium-

CO,Me

OMe

129

ammonia afforded the main products laudanidine (130) and 0-methylarmepavine (131) of unspecified stereochemistry. The formation

of 130 seems to be the result of an unexpected cleavage, perhaps

resulting from the influence of the isoquinoline system.The placement of the other methoxyl and of the methylenedioxy

group seems to be based mainly on NMR data. It is of interest to note

that no mention was made of a quartet in the NMR spectrum expected




130 R = OH

131 R = H

for the protons at C3, and C4, in ring D. Since no evidence is presented

for the chirality of 130and 131, o definitive assignment of configuration

can be made for 128.

KK. THALFINDTE

Thalfinine (132) [C39H42N208; amorphous, mp 117-1 18°C; [a]h6

+ 115 (EtOH); perchlorate, mp 23P235"C (dec.); hydrochloride,

mp 223-226°C (dec.)] wits isolated from Thulictrum foetidurn (69) . I ts

NMR showed two N-methyl groups (6 2.54, 2.30), four methoxyls

(6 3.36, 3.43, 3.66 and 3.80), a methylenedioxy ( 6 5.80) , and a C8H a t

6 5.92. As mentioned in the previous section, thalfinine was obtained

from thalfine by N-methylation and reduction. The structure 132 has

been proposed for thalfinine; however, no stereochemistry was assigned

to either chiral center.

OMe8

132

LL. THALICTROQAMINE

The alkaloid thalictrogamine (133), tructurally related to thali-

carpine (134),was isolated from Thulictrum polygamum Muhl. ( 7 0 ) .Thalictrogamine (C3,H44N20,) an amorphous base [ [a ]g5 + 3 5 O



288 M . P. CAVA, K. T.BUCK, AND K. L. STUART

133 R, = Rz = H

134

135

R, = R, = M e

R1 Me, R2 H

(MeOH)] on treatment with diazomethane gave a mixture of thalictro-

pine (135) nd thalicarpine (134). he mass spectrum [M+ 668 , m/e 4 7 6(M-a), 326 (M-b), 309 (M-c-1) , 192 (a, base)] provides evidence for the

placement of one hydroxyl group on the tetrahydroisoquinoline ring Band the other on the aporphine moiety. From a study of space-filling

models it was suggested that a C8. aromatic proton near 6 6 .4 , rather

than near 6 6 .2 in the NMR spectrum is diagnostic of the presence of a

C7, phenolic substituent.

MM. THALICTROPINE

Thalictropine (135) C40H4,N,08; mp 167°C (MeOH); + 120'

(MeOH)] was recently isolated from Thalictrumpolygumum (7'0).The

presence of the phenolic group was evidenced by a bathochromic shift

of the UV spectrum on the addition of base and by the preparation ofthalictropine acetate (mp 182-183°C).

The NMR spectrum of thalictropine was superimposable upon that

of 1-0-demethylthalicarpine synthesized in advance of its isolation

c

135




from nature ( 8 ) .The mass spectrum [M+ 682, m/e 476 (M-a), 326 (M-b),

310 (M-c), and 206 (a, base peak)] clearly indicated that the phenolic

hydroxyl was located on the aporphine residue.

Thalidoxine (136) [C,,H,,N,O,; amorphous; + 113" (MeOH)]

from Thalictrum dioicum L. (7 1 ) s a substitutional isomer of thalictro-

pine (135); accordingly, treatment with diazomethane yielded

thalicarpine (134).

C

136

134

137

R, = H, R, = M e

R, = R, = M e

R, = Ac, R, = Me

135 R, = Me, R, = H

Thalidoxine acetate (137) produced NMR evidence for the location

of the hydroxyl at Clz,. Although the Cll, proton was only slightly

shifted (0.10 ppm) to lower field in 137 than in 136, there was observed

a relative upfield shift of either 0.10 or 0.17 ppm in one of the aromatic

resonances of 137, stated from inspection of molecular models to bepossible for a C12, but not a Cll, acetoxylated system.

NMR values are tabulated ( 7 1 ) or 136 and several other thalicarpine-

type alkaloids. The mass spectrum of 136 shows the major fragmenta-

tions a, b, and c.

00. THALISOPIDINE

Thalisopidine (138) [C,,H,,NzO,; mp 215-216°C; - 9" (EtOH)]was isolated from Thulictrum isopyroides C. A . Mey. (72). The NMR

spectrum showed two N-methyl groups (6 2.44, 2.49), three methoxyls

(6 2.96, 3.30, 3.70), and a C8, proton a t 6 6.30.




OH

M e N

\ /

\0 RO

138 R = H139 R = M e

The structural assignment for thalisopidine is based solely on acomparison of its NMR with that of thalisopine (139); egradative,

mass spectral, and NMR evidence exists in support of the structure

suggested for this lat ter alkaloid ( 7 3 ) .It is noteworthy, however, that

no direct comparison was reported for 0,O-dimethylthalisopidine

(mp 238-239°C) and 0-methylthalisopine (amorphous; mp 163-166"C),

which should be identical if the assigned structures 138 and 139 are

correct.

PP. THALMELATIDINE

Thalmelatidine (140) [C42H48N2010;p 120-122OC; [a]= +47

(CHCl,)] was isolated from the roots of Th l i c t ru mminus f. elatum ( 7 4 ) .

Structure 140was assigned t o thalmelatidine on the basis of its NMRspectrum, as well as the formation of isoquinolone 141 and aldehyde 79

by permanganate oxidation. Aldehyde 79was identical with the known

aldehyde formed from adiantifoline 77) y a similar oxidation ( 4 3 ) .

Isoquinolone141was synthesized from the known base142 y an unusualreaction sequence involving (a) bromination, (b) treatment with meth-

v140




MeN@)0

Me

0

1 4 1 142

OM eIMee 0

1

7-NMe

U-

79

anolic sodium methoxide, (c) treatment with diazomethane, and (d)

permanganate oxidation. The S,S configuration for 140 (shown below)was suggested as likely from its positive rotation and analogy with

related alkaloids.

QQ. THALMINELINE

Thalmineline (143) [C,,H,,N,O,, ; mp 96-98°C (ether-hexane) or

mp 108-110°C (EtOH);[aID +22" (MeOH)]was isolated from the roots

of Thalictrurn minus var. elaturn (75).Thalmineline is a phenol that hasan unsubstituted position ortho or para to the hydroxyl function, since

it not only gives a positive ferric chloride test but also couples with

diazotized p-nitroaniline. Structure 143 has been assigned to thalminel-

ine on the basis of NMR and mass spectral analogy with the related

known bases thalicarpine (234) and adiantifoline (77).A salient feature

of the NMR spectrum of 143 is the high field aromatic singlet at 6 5.71 ,

attributed to the C, aromatic proton. Also, the mass spectrum of 143

shows a base peak at r n / e 222, characteristic of an N-methyltetrahydro-

isoquinoline unit bearing two methoxyls and a hydroxyl. The possibilityth at the hydroxyl may be at C7, ather than a t C5, cannot be discounted,

and the stereochemistry of 143 is apparently assigned by analogy withrelated bases.




143

R

134 R = H77 R = OMe

RR. TRALRUUOSAMINE

Thalrugosamine (144) [C,7H,,N20,; mp 122-125°C; + 280"

(MeOH)]was isolated from Thalictrum rugosum Ait. (T.laucum Desf.)

(2'6).It was converted by diazomethane into O-methyloxyacanthine

(145). The mass spectrum of thalrugosamine reveals a head-to-head

fragment ion, mle 382, showing that the phenolic hydroxyl must be

attached to an isoquinoline unit. Methyl ether 145, but not the parent

alkaloid 144, shows a high field methoxyl signal at 6 3.20 characteristic

of a C,-methoxyl; the hydroxyl of 144 must therefore be a t C,. Chemical

confirmation of structure 144 was obtained by diazoethane alkylationof thalrugosamine to give ethyl ether 146. Sodium-ammonia cleavage

of 146 afforded the known monomeric bases 147 and 148, which were

identical with reference samples (after methylation of 147).




144 R = H

145 R = M E

146 R = Et

M ~ N ;mlI o m N M e

mle 382

M e N

H*' "H

H M e 0

147 148

SS. THALRUBOSIDINE

Thalrugosidine (149) [C,,H,,N,O,, ( M+ 638); mp 172-174°C;

- 185" (MeOH)] was isolated from Thalictrumrugosum (77). Treatment

with CH,N, yielded the known alkaloid thalidasine (18) previouslyisolated from this plant. The location of the phenolic group was

established by sodium-ammonia cleavage of thalrugosidine ethyl ether,

OR M e 0

149 R = H

18 R = M e



294 M. P.CAVA, K. T. BUCK, AND K.L. STUART

which gave compounds 150 and 20. Compound 150 was shown to be the

optical antipode of a cleavage product derived from thalrugosine (151),

while 20 was identical with the phenolic cleavage product of 18. Thal-rugosidine is the substitutional isomer of thalfoetidine (19).

OH

150 20

TT. TRALRUGOSINE77) [=THALIGINE78)l

Thalrugosine (151)[C3,H40N20S,M+ 608-2848); mp 212-214°C; [a] 0

+128" (MeOH)] was isolated from Thalictrum rugosum

(77).Treatment

of thalrugosine with CH2N, gave the monomethyl ether (mp 180-

182"C), which proved to be identical with isotetrandrine (59).

151 R = H

5 9 R = M e

The mass spectrum showed linked isoquinoline units a t m/e 382- 1877

and m/2e 191.0938 (cleavage at a), requiring the free OH to be in the

top portion of the molecule. NMR data supported a C, located hydroxyl

in that the spectrum of thalrugosine shows no methoxyl signal higherthan 6 3.77, while compound 59 shows one at 6 3.15.

Sodium-ammonia cleavage of thalrugosine ethyl ether yielded 27,

identified as its methiodide, and 24, identified by conversion to 0-




Me

27 24 R = H

15 R = Me

methylarmepavine (152) (IR, UV, thin-layer chromatography, and CDevidence).

Thalrugosine has also been reported independently from T h l i c t r u m

polygamum under the name thaligine [mp 153OC; + 87" (MeOH)]

(78). Structural assignment was based on NMR, UV, ORD, and mass

spectral data and conversion with CH2N2 o 59. The identity of thal-

rugosine and thaligine has recently been established by direct com-

parison (79). The racemic form of 151 is the alkaloid cycleadrine (57).

UU. TOXICOFERINE

Toxicoferine (153) [C3,H3,N206;mp 286OC; [.ID - 63" ( 1 N HCI in

EtOH)] was isolated from the stems of Chondodendron toxicoferum

(Wedd.) Kruk. et Mold. (80).O-Ethylation of 153 with phenyltriethyl-

156 157\ J

Y

153




ammonium ethoxide gave the amorphous 0-diethyl derivative, which

was cleaved by sodium-ammonia to give (R)-N-methylcoclaurine(154)

and racemic0-diethyl-N-methylcoclaurine (155). The cleavage products

H

MeN /

'E t

OH

154 155

indicate that toxicoferine (153) must be a molecular complex of

(- -curine [= chondodendrine (156)] and (- -tubocurine [= ( - -

chondrocurine (1571,he enantiomer of 31.

VV. TRICORDATINE

Tricordatine (158) [C,,H,,N,O,; mp 280°C (dec.); + 247.9'

(pyridine)]was found in TricZisia subcordata Oliv. (35).The 0,O-dimethyl

PH

IOH

158

dimethiohde derivative was shown to be identical with isotrilobinedimethiodide. Further support for the assigned structure 158 was

provided by mass spectral data for 0,O-diethyltricordatine ( M + 604)

and the 0,O-diacetate ( M + 632).




IV. Known Alkaloids from New Sources

Reference Plant

45 Anisocycla grandidieri

81 Berberis lycium Royle

82 Berberis petwlaris Nall.

84 Ephwtrum willosum (Exell) Troupin

83 cyczea sp 9 )

85

44

8654

60

87

88

8 9 , 9 0

Mahonia aquifolium Nutt.

Menispermum mnadense

Pachygone pubeacens Benth.Pycharrhna australiana F. Muell.

Stephania hernandifoliaWalp.

Stephania sasakii Hayata

Thalictrum lawum L.

Thalictrum minus L.

4 3 Thalictrum minus f. elatum

91 Thalictrum minus, race B

7 1 Thalictrum polygamum

90 Thalictrum rugosum

Alkaloids

Stebisimine, trilobine

Berbamine (= berbenine)

Berbamine

Tetrandrine

Cycleanine, isochondoden-

Berbamine

Daurinoline

IsotrilobineBerbamine, isotetrandriine

Epistephanine

Berbamine

Thalicarpine

0-Methylthalicberine,

drine, norcycleanine

thalicberine, O-methyl-

thalicberine, thalidazine

Adiantifoline

Adiantifoline, thalline

Thalicarpine

Thalidazine, thalsimine

V. Methods and Techniques

A. SPECTROMETRY

1. Mass Spectrometry

Mass spectrometry has now been established as one of the most

important tools in the structure determination of bisbenzylisoquinoline

alkaloids. The general aspects of its use have already been reviewed in

Volume XI11 of this treatise. Three important papers have now ap-

peared that extend and elaborate previous studies. In the first of these

papers, detailed mass spectral data are presented for some simple

alkaloid dimers derived from two coclaurine units joined tail to tail.

Examples include molecules containing one, two, and three ether links;

the head units (isoquinolines), when linked, all contain a C,-C,, etherbridge. Deuterated derivatives were used in a number of cases to support

the proposed cleavage patterns ( 3 8 ) . In the second paper, a similar

analysis is made of alkaloids containing two ether bridges (head-to-head




and tail-to-tail linked) and containing head units linked by the more

unusual C5-C,,, C,-c,#, and C,-C5, ether bridges (92).Finally, the last

paper discusses the mass spectra of those alkaloids containing two etherbridges in which the monomer units are joined in a head-to-tail manner

(93).

2. Optical Rotatory Dispersion (ORD)

ORD curves have been recorded for a number of bisbenzylisoquinoline

alkaloids. These include thalsimidine, thalsimine, hernandezine, thal-

isopine, thalmine, O-methylthalicberine, thalfoetidine, and fetidine ( 9 4 ) )

as well as berbamunine and magnoline (95 ) .

B. CHEMICALMETHODS

1. New Deuteration Procedures

A simple method for the preparation of O-trideuteriomethyl deriva-

tives of phenolic alkaloids has been reported. The procedure involves use

of a solution of diazomethane in dimethyl sulfoxide containingD,O ( 1 1 ) .

The selective introduction of deuterium into bisbenzylisoquinolineshas been accomplished by heating with 3 7 , DC1 in D,O a t 120°C for

144 hours. Under these conditions, O-methyloxyacanthine (145) ex-

changed all protons ortho to methoxyl groups (bu t none ortho to the

diphenyl ether bridges), as shown by subsequent cleavage of the deu-

terated derivative (159) o 160 and 161; the location of deuterium in the

cleavage products was readily established by NMR spectroscopy (96).

However, extension of this deuteration procedure to the newly isolated

alkaloid nemuarine (99) resulted in the introduction of only one

deuterium, a t position C, (52 ,5 3 ) . It thus appears that ' the location ofthe ether bridging, the stereochemistry, and the substitution pattern

of the system govern the extent to which deuterium is incorporated.

Further work is clearly needed to evaluate these factors, as well as to

extend the utility of this method of deuteration in structural elucidation.

The utility of the sodium-ammonia cleavage of bisbenzylisoquinoline

alkaloids as a tool for structure proof has been extended by utilization

of ND, rather than NH,. Since deuterium is introduced at the points of

cleavage of the diphenyl ether linkages, this variation provides addi-

tional information of particular advantage for alkaloids containing twoether bridges, as in the case of belarine (25) ( 2 1 ) . ND, may be con-

veniently prepared from D,O and Mg,N, (28).

In the case of alkaloids containing one secondary and one tertiary




MeN

R

145 R = H

159 R = D

MeN

H

’ H

160

D

161

amine function, treatment with formaldehyde-d, and NBD introduces

a trideuteriomethyl group on the secondary nitrogen. Oxidative photol-

ysis (see nex t section) and NMR studies of the products may then be

used to establish the nitrogen alkylation pat tern of the original alkaloid

( I 0 , I I ) . Use of this procedure made possible the assignment of the

correct structure to micranthine(11).

2 . Photooxidative Degradation

Sodium-ammonia cleavage has long been the dominant method for

the chemical degradation of bisbenzylisoquinoline alkaloids. Oxidation

procedures have been of limited utility in the past and have seldom

resulted in the isolation of fragments derived from all parts of the origi-

nal alkaloid. A mild photooxidative degradation has been reported

recently that promises to complement sodium-ammonia cleavage as ageneral degradative method for bisbenzylisoquinoline alkaloids (97) . In

a model case, isotetrandrine (59) was irradiated with a Hanovia lamp

in dilute methanol solution at room temperature in the presence of




oxygen. The diphenyl ether portion of the molecule was isolated directly

as the dialdehyde 14 in 50y0 yield. After borohydride reduction, the

crystalline head-to-head isoquinoline fragment 162 could also be iso-lated. Phenolic alkaloids also seem amenable to photooxidative degra-

dation. For example, berbamine (103) gave the phenolic aldehyde 163

(35%)as well as the lactam base 162 (15%).

59 R = Me103 R = H

162

14 R = M e163 R = H

VI. Pharmacology

Thalidasine and obamegine were found to be active in vitro against

Mycobacterium smegma tis; thalrugosine, thalrugosamine, and thalrugo-

sidine were all very weakly active against the same organism(7'6, 77, 98).

Tetrandrine showed strong tuberculostatic activity againsta number of

strains of Mycobacterium tuberculosis in vitro; it also found to signifi-

cantly prolong the life expectancy of mice infected with various tuber-

culosis strains (99).Thalsimine, dihydrothalsimine, and hernandezine were found to

inhibit the conditioned avoidance reactions and the motor conditioned

reflexes associated with movement and eating in rats. In addition,




thalsimine and dihydrothalsimine were found to temporarily reduce the

time for dogs to run through a labyrinth ( 100) .

The tertiary bases tetrandrine, cycleanine, and dauricine exhibitedantiinflammatory and anesthetic properties; the related quaternary

salt cycleanine dimethiodide was a curare-like agent ( 1 0 1 ) .Thalmine

and 0-methylthalicberine were active against experimental idamma-

tion in mouse paw ( 1 0 2 ) .The cardiovascular and hypotensive activity of thalicarpine has been

studied in the isolated dog heart and in the rhesus monkey. Thali-

carpine hypotension appears to be due to a nonspecific vasodilation and

myocardial depression ( 1 0 3 ) .Fetidine is claimed to have hypotensive

activity ( 104) . Both thalisopine and fetidine depress high nervous

activity in mice ( 1 0 5 ) .The toxicity of thalicarpine has been examined in monkeys and in

dogs. Lethal doses in monkeys and maximum nonlethal doses in both

species were determined ( 106) .The alkaloids thalicmine, dihydrothalicmine, hernandezine, thalmine,

thalictrinine, and fetidine were more active against experimental

inflammation than either aminopyrine or sodium salicylate ( 107) .

VII. Bisbenzylisoquinoline Alkaloids Tabulated by Molecular W eight

This table includes all reported bisbenzylisoquinoline alkaloids;

references are to the most recent compilation in which each alkaloid is

discussed. Molecular weights cited for alkaloids that have not been

examined by mass spectrometry must be regarded as provisional unless

corroborated by synthetic studies. Also, assignments based on corre-

lation with alkaloids of subsequently revised structure (e.g., micranthine)

should be considered questionable.

MW Formula Alkaloid Ref. ( M W Formula Alkaloid Ref.

548 C34H3zNz05 12’-O-Desmethyltrilo-

bine

Micranthine

Tricordatine

562 C,SH,,NzO, Cocsuline 2 rigille-

tine, effirine)

0-Methylmioranthine

Nortiliacorine-A

Nortiliacorinine-A

Nortilimorinine-B

a

a

a

a

a

a

a

a

Telobine

Trilobine

566 C34H34Nz06N,N-Bisnoramoline

576 C35H3zNz06 Normenisarine

576 C36H3SNz0s 0,N-Dimethylmicran-

thine

Isotrilobine

Tiliacorine

Tiliacorinine

578 C35H,4Nz0s No name

C

b

a

e

(conrinued )




MW Formula Alkaloid Ref.~580 C35H36N206Cycleacurine a

Daphnoline ( = triloba- c

mine)

2-N-Norobamegine

582 C35H38NzO6 Ocotine

590 C36H34Nz06 Menisarine

592 C36H36N206Cepharanoline

Stebisimine

Hypoepis ephanine

Thalmethine

Tiliarine

Atherospermoline

Base A

Chondrocurine

Curine (F bebeerine,

chondrodendrine)

Daphnandrine

Demerarine

Dinklageine

Dryadodaphnine

Hayatine (= ( & ) -

Isochondrodendrine

Neoprotocuridine

2-N-Norberbamine

Obamegine

Ocoteamine

Protocuridine

Sepeerine

Thalicrine

Tomentocurine

Toxicoferine

Dauricoline

Espinine

Magnoline

606 C36H34N207Stepinonine

Cancentrine

606 C3.,H3,NZ06 Cepharanthine

Cissampareine

Coclobine

Epistephanine

(- -Epistephanine

594 C36H38N206Aromoline

~ur ine]

596 C36H40Nz06Berbamunine

a

C

C

b

a

C

b

C

C

b

d

&

C

C

b

e

b

b

b

d

a

C

d

e

d

a

b

a

a

b

a

a

b

b

b

b

C

a

MW Formula Alkaloid Ref.

Insulanoline C

0-Methylthalmethine b

608 C37H40N206Belarine a

Berbamine b

Chondrofoline a

Cycleadrine a

Cycleanorine a

Cycleapeltine a

Dryadine b

Fangchinoline bHayatidine b

Hayatinine b

Himanthine e

Homoaromoline C

Homothalicrine e

Lauberine b

Limacine b

Limacusine b

Menisidine d

4"-O-Methylbebeerine b

Nemuarine aNorcycleanine C

Ocodemerine b

0 ocamine b

Oxyacanthine b

. Pakistanine a

Penduline a

Pycnamine b

Repandine b

Thalicberine b

Thalmine b

Thalrugosamine a

Thalrugosine ( = hali- a

609 C37H41N20tProtochondrocurarine e

Tubocurarine a

610 C37H42N206 uspidaline b

Dauricinoline a

Daurinoline b

N'-Desmethyl- &

Dirosine b

( = thalmidine)

gine)

dauricine

Espinidine a





612

612

616

620

620

622

622

624

624

624

632

Isoliensinine

Liensinine

Norrodiasine

C35H36Nz08 Base B

C36H40Nz07Aztequine

C38H36N20~Phaeantharine

C37H36Nz0, Oxoepistephanine

C38H40N206Insularine

C3,H38N207 De-N-methyltenuipine

Magnolamine

Repanduline

Nortenuipine

Thalsimidine

C38H42Nz08 Cycleanine ( = O-me-

thylisochondroden-

drine

Funiferine

Isotetrandrine

Melanthioidine

Menisine

0 Methylisothalic

berine0-Methylrepandine

0-Methylthalicberine

Obaberine

Pakistanamine

Phaeanthine

Rodiasine

Tetrandrine

C3,H4,Nz0, Thalidopidine

C38H44N206Dauricine

C38H44Nz0zChondrocurarine

Isochondrocurarine

Neochondrocurarine

C3,H4,NzOS Pycnarrhenamine

b

b

b

d

b

b

d

a

b

d

b

b

C

C

a

b

b

d

b

d

b

b

a

b

b

b

a

b

a

e

e

b


636 C38H40N20, Isotenuipine

tenuipine)

Repandinine (= (k ) .

Tenuipine

Thalsimine

637 C39H45NzOs+ ycleahomine

638 C38H42N207Thalfoetidine

Thalidezine

Thalisopine

Thalrugosidine

Neferine638 C39H4BN206 -Methyldauricine

642 C38H46N207Thalictrinine

646 C36H42N209 ycnarrhenine

648 C38H36N208Thalfine

652 C39H44N207Hernandezine

666 C39H42N208Thalfinine

668 C39H44N208bhalibrunine

674 C40H38N20iBisjatrorrhizine

680 C40H44N208Dehydrothalmelatine682 C40H46N208 halictropine

Thalixodine

Thalmelatine

Thalidasine

Thalictrogamine

694 C41H46N208 Dehydrothalicarpine

696 C41H48N208Fetidine

Thalicarpine

698 C40H46N20s Thaldimerine

712 C41H48N209O-Desmethyl-

720 C43H32N209Chelidimerine

726 C42H50N209Adiantifoline

740 C42H48NZ010halmelatidine

742 C42H50Na0~0halmineline

adiantifoline

a

d

C

b

a

a

b

b

a

ab

e

b

a

b

b

a

b

a

a

ba

a

b

a

b

b

a

a

b

a

a

C

References; (a) This work. (b) M. Curcumelli-Rodostamo, in “The Alkaloids” (R. H. F.

Manske, ed.), Vol. XI II, Chapter 7. Academic Press, New York, 1971. (c) M. Curcumelli-Rodo-

stamo and M. Kulka, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. I X , Chapter 4. Academic

Press, New York, 1967. (d ) M. Kulka in “The Alkaloids” (R. H . F . Manske, ed.), Vol. VII ,

Chapter 21. Academic Press, New York, 1960. (e) T. K ametani, “The Chemistry of the Isoquino-

line Alkaloids,” Chapter 6 . Elsevier, Amsterdam, 1969.

Corrected molecular formula; th e formula cited in reference b is in error due to a n internal

inconsistency in the original paper.




VIII. Appendix

It is the function of this appendix to abstract papers on bisbenzyliso-quinoline alkaloids that appeared in 1974 and the first half of 1975, as

defined by the Chemical Abstracts coverage stated in Section I, and also

amend the text. The structural formulas, basic physical constants, and

plant sources of new alkaloids are noted, but the reader is referred tothe original papers for details of structural elucidation. It is intended

that material included here will be incorporated in expanded form in

an appropriate later volume of this treatise. This appendix has been

organized in conformity with the plan of the foregoing main discussion,

and a miscellaneous section has been included to draw attention to someinteresting transformations of particular alkaloids that were recently

reported.

1. NEWALKALOIDS

a. Sanguidimerine (164)

+21.2O (pyridine)] was isolated fromrhizomes of Sanguinam'a canadensis L. and is diastereomeric with the

meso alkaloid chelidimerine (46) (108) . These natural products along

with 48 are the first representatives of the class of bisbenzophenanthri-

dine alkaloids and are included in our review because of their dimeric

nature and their formal 4-phenethylisoquinoline structure unit.

This alkaloid [mp 174°C;

164




b. Cocsulinine (165)

Cocsulinine [mp 260-263OC; [.ID +312" (CHCl,)] was isolated fromCocculus pend ulus ( 108)and possesses anticancer activity. The structure

was assigned from spectral data, deuterium exchange experiments,

Hofmann degradation, and sodium-ammonia cleavage.

165

c. Cocsoline (166)

Isolated also from Cocculus pendulus (110) was cocsoline [mp 197-199°C; [.ID + 204" (CHCl,)]; it was assigned st,ructure 166 on the basis

of MS and NMR data and conversion to isotrilobine (50).

AH

166

d. Tiliageine (167)

+ 132.6" (pyridine)] (111).The structural assignment was based on IR

and NMR data and conversion to O-methylfuniferine (94). The stereo-

chemistry is still undetermined.

Tiliacora dinklagei Engl. has yielded this alkaloid [mp 270°C;



3 0 6 M . P. CAVA, K. T. BUCK, AND K . L. STUART

167

e. Pennsylpavine (168) and Pennsylpavoline (169)

Thalictrum polygamum afforded the first two aporphine-pavinedimers; pennsylpavine (168) [mp 122-123°C; [a]g5 - 74" (MeOH)] and

pennsylpavoline (169)[mp 145-146°C; [a]g5 - 45" (MeOH)].Structural

assignments were based entirely on spectral data (UV, NMR, mass,

C D ) . The related alkaloids pennsylvanine (170) and pennsylvanamine

(171) were also reported from T . polygamum (112).

f . Pennsylvanine (170) and Pennsylvanamine (171)

The chemical and spectral data leading to the structures of these twonew alkaloids have now appeared ( 1 1 3 ) :pennsylvanine (170) [mp 112-

113°C (ether); [a]g4 + 131" (MeOH)] and pennsylvanamine (171)

[mp 128-129°C (acetone-ether), 107-108°C (ether); + 119"

(MeOH)].

170 R = M e

171 R = H

168 R = M e169 R = H




g. Monomethyltetrandrinium Chloride (172)

The Thai Menispermaceae drug krung kha mao yielded this alkaloid[mp 208°C; [a]gO+ 51.5 (MeOH)] (114).This new berbamine alkaloid

was assigned structure (172) ased on spectral data and partial syn-

thesis from tetrandrine (64); he nitrogen methylation pattern was not

established.

OMe

172 R = H, R, = Me, or vim versa

h. Baluchistanamine (173)

Baluchistanamine (173) mp 122-124°C (cyclohexane-benzene)] has

been reported from Berberis ba~ u~ hi ~t an ic a.D data are given for thisfirst example of an isoquinoline-benzylisoquinoline type of alkaloid

(115).

173 R = H

174 R = Me

MeNp LMe q N M e

3 8 R = M e176 R = H



308 M . P. CAVA, K. T.BUCK, AND K. L. STUART

Oxidation of obaberine (38) with KMnO, in acetone afforded 0-methylbaluchistanamine (174), while corresponding treatment of

oxyacanthine (175) gave 173 in low yield. Apparently, 173 arisesbiogenetically from the cooccurring oxyacanthine (175).

i. Phlebicine

Cremastosperma polyphlebum (Diels) Fries yielded phlebicine (176)

(mp 195°C; sint, 180"C), for which ORD and CD data are given.

Partial methylation of 176 afforded rodiasine (97) and NMR and M Scomparisons of 176 and its dideuterio, deuteriomethyl, 0-acetyl, and

0-ethyl derivatives permitted unambiguous assignment of it s skeleton( 116) .The stereochemistry of the asymmetric centers, however, is not

yet determined.

176 R = H97 R = Me

j . Thalibrunine (177)

Thalibrunine (177) from Th ali cfr um ochebruniannum Franch. e t Sav.

has been assigned the structure shown on the basis of chemical andspectral data ( 117) .

MeN O M eM e o q N & f e

H - * H

177




2. KNOWN LKALOIDSROM NEWSOURCES

Reference Plant Alkaloids

~

118 Triclisia gillettii

118 27. patens Oliver

118 T . subcordata

119 Anisocycla grandidieri

120 Cyclea barbata Miers

(C.peltata Hk. f. et.

Thorns).

121 C. barbata

~ -Stebisimine, isotetrandrine, cocsuline (49)

Pycnamine, cocsuline (49)

Fangchinoline, tricordatine

( -)-Epistephanine ( 8 5 ) , stebisimine

( + )-Tetrandrine, sotetrandrine, limacine,

berbamine, homoaromoline

( & )-Fangchinoline, ( + )-isofangchinoline

[thalrugosine (151)]

3. PHARMACOLOGY

Kupchan and Altland (122 ) have made a study of the structural

requirements for tumor-inhibitory activity among bisbenzylisoquinoline

alkaloids and related compounds. Pharmacological evaluations of a

number of bisbenzylisoquinolinealkaloids and synthetic analogs againstWalker carcinosarcoma 256 in rats were used to study structural

requirements for therapeutic activity. Only one linkage of the iso-

quinoline unit appears necessary, and activity is seemingly unaffected

by the configurationof the asymmetric centers or whether the nitrogens

are secondary or tertiary. However, the presence of two methylimino

groups destroys activity.

Thalmine has been shown to be significantly active against ascites

lymphoma NK/Ly in mice and rats. Thalsimine, thalmidine, thalic-

trinine, and hernandezine were weakly active against lymphoma NK/Ly,alveolar hepatoma PC-1, or Pliss lymphosarcoma (123 ) .

Two new reports of antimicrobial studies have appeared. Thali-

carpine isolated from Thalictrum polygamum was shown to be active

against Mycobacterium smegmatis but not against five other bacterial

species (124 ) . Extracts of Berberis vulgaris have been examined for

antibiotic activity; oxyacanthine chloride at 1 :10,000 dilution killed

Bacillus subtilis and Colpidium colpoda (125 ) .

The effects of thalicarpine on the heart and carotid artery flow in

anesthetized monkeys and on isolated dog hearts has been studied. The

principal activity seemed to reside in the aporphine portion of the

molecule (126 ) .

The action of hayatine methochloride and ( + )-tubocurarine chloride



310 M. P. CAVA, K . T. BUCK, AND K . L. STUART

on autonomic ganglia in cats has been examined. Hayatine metho-

chloride was 2.5-4 times less active than tubocurarine chloride on

sympathetic ganglia of cats. Details are given in the Chemical Abstract(1 2 7 ) ..

Toxicity studies by Menez et al. (1 2 8 ) on (+)-tubocurarine labeled

with iodine or tritium showed that tritium in the 13’ position had no

effect on its acute toxicity. Tubocurarine chloride, when given intra-

venously to rabbits or subcutaneously to rats, induced hypercalcemia

and hypophosphatemia but did not affect blood pH ( 1 2 9 ) .The lymphotoxic effect of d-tetrandrine in dogs and monkeys has

been demonstrated, as was related toxicity levels on these test animals

(1 3 0 ) . Phaeanthine, isolated from Phaeanthus ebracteolatus, has beenshown to have anticancer activity, and in a review of the chemistry and

biochemistry of alkaloids from this plant, this property was discussed

in relation to structurally similar bisbenzylisoquinolines ( 1 3 1 ) .

The neuromuscular blocking potencies of (+ )-tubocurarine chloride,

N,N’-dimethyl-(+ )-chondrocurine and N,N’-dimethyl-(- -curine have

been evaluated on rat diaphram, cat tibiales, and superior cervical

ganglion ( 1 3 2 ) . In another related study, the same authors (1 3 3 )examined five bisbenzylisoquinolines that have head-to-head and tail-

to-tail linkage and were shown to have negligible blocking action on cat

tibiales and superior cervical ganglion in relation to ( + )-tubocurarine.

N,N ‘-Dimethylberbamine, however, showed substantial activity.

4 . MISCELLANEOUS

a. Hofmann Elimination Effected by Diazomethane

When the quaternary curare bases ( + )-tubocurarine chloride l),

( + )-isotubocurarine chloride 178),nd chodrocurarine chloride (4) were

treated with excess diazomethane, in addition to the expected O-methyl

derivatives, the respective Hofmann elimination products 179),

180),nd 181) ere also produced (1 3 4 ) .The nature of the products

(styrene versus stilbene) is apparently governed by steric factors.

b. Conversion of Stepinonine 120)nto a ConventionalBisbenzylisoquinoline Skeleton

As a sequel to their full account of the structural elucidation of

the novel benzylisoquinoline-2-phenyl-sec-homotetrahydroisoquinoline



5 . BISBENZYLISOQUINOLINEALKALOIDS 311

1 R1 Me, R, = H ( Cl - )

178 R1 = H, R, = M e ( C l - )

4 R, = R, = M e ( C l - )

M e o p N M ee 0 .H

Me,N

180

179

181

alkaloid, stepinonine ( 135) , Inubushi and co-workers have succeeded

in a chemical conversion of stepinonine to identifiable bisbenzyliso-

quinoline alkaloids ( 1 3 6 ) .Stepinonine (120) was first converted to its

reduced derivative (121) and then oxidation by Jones' reagent fol-

lowed by reduction (zinc-acetic acid, then sodium borohydride) gave

a mixture of the enantiomer (68)of 0-methylrepandine and O-methyl-

oxyacanthine (145).




H

68

MeN OMee o G N M e

H 'H

145

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106055 (1971).

C A 77, 98905 (1972).

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72, 97303 (1970).

72, 55716 (1970).

(1970).

Med. 22, 402 (1972); C A 78, 69230 (1973).

(1971);C A 75 , 148465 (1971).

(1972).

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(1970); CA 74, 1042 (1971).

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SOC., erkin Trans. 1 5 9 7 (1972).

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17, 2120 (1969); C A 72, 2092 (1970).

(1971).

( M o s c o w ) 36,74 (1973);CA 78,106079 (1973).

132 (1971); CA 78, 79631 (1973).



316 M. P. CAVA, K. T. BUCK, AND K . L. STUART

101. V. V. Berezhinskaya, Postep Dziedzinie Leku Rosl ., Pr . Ref. Dosw. Wygloszone

102.F.

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B. Sultanov,Farmakol. Alkaloidow Serdechnykh Glikozidov

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120. T. Yupraphat, P. Pachaly, and F. Zymalkowski, Planta Med. 2 5 , 315 (1974); C A

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128. A. Menez, F. Bouet, J. P. Changeux, A. M. Rousseray, P. Boquet, and P. From-

129. P. Szabo an dT. Ferenczy, Acta Biol.Debrecina9, 101 (1973);CA 81, 114747 (1974).

Symp., 1970 164 (1972);C A 7 8 , 119087 (1972).

120 (1971); C A 7 8 , 66916 (1973).

C A 76, 17765 (1972).

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81, 136346 (1974).

81, 152477 (1974).

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(1974).

81, 82289 (1974).

(1974);CA 81, 87983 (1974).

(1972); C A 80, 103857 (1974).

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81, 100062 (1974).

CA 80, 103855 (1974).

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79 (1974); C A 82, 51463 (1975).



-CHAPTER 6---

SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS

MAURICESHAMMA

ThePennsylvania State University

University Par k, Pennsylvania

AND

VASSILST. GEORGIEVU S V Pharmaceutical Corporation

Tuekahoe, N e w York

I. Introduction. . . . . .............................................. 319

11. Dauricine-Type A1 oids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

IV. Berbamine-Oxyacanthine-TypeAlkaloids. . . ...................... 341

V. Thalicberine-Type Alkaloids . . . . . . . . . . . . . . ...................... 348

VII. Menisarine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

VI II . Tiliacorine-Type Alkaloids ....................... . . . . . . . . . . . . . . . . 359

X. Curine-Chondocurine-TypeAlkaloids. ................................ 363

383

XI II . Synthesis Using Electrolytic Oxidation. ....................... . . 387

XIV. Use of Pentafluorophenyl Copper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387

References . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . 389

111. Magnolamine-Type Alkaloids. ....................................... 336

VI. Trilobine-Isotrilobine-Type Alkaloids . . . . . . ...................... 354

IX. Liensinine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

XI. Miscellaneous Syntheses ............................................ 381

XI I. Syntheses Using Phenolic Oxidative Coupling .........................

I. Introduction

Well over a hundred bisbenzylisoquinoline alkaloids are presently

known. The two benzylisoquinoline units may be bonded together by

one, two, or three diaryl ether linkages. When only one diaryl linkage

is present, this bond is involved in tail-to-tail or head-to-tail coupling

and never in head-to-head coupling. When linked by two or three diarylether linkages, the two benzylisoquinoline units can be bonded either

head-to-head or head-to-tail. The resultant diversity in the structures of

the bisbenzylisoquinoline alkaloids, coupled with their known or



320 MAURICE SHAMMA AND VASSIL ST.GEORGIEV

potential pharmacological activity, has stimulated substantial interest

in their synthesis. This chapter will deal with the preparation of bis-

benzylisoquinolines in the order of their structural complexity.Although several interesting and reliable syntheses of bisbenzyliso-

quinolines have been worked out, e.g., those of ( )-cepharanthine,

( +)-isotetrandrine and related bases, ( + )-0-methylthalicberine, ( k -

N-methyldihydromenisarine, ( k -0-methyltiliacorine, and ( k -cycle-

anine, no reliable synthesis of the pharmacologically important

( + )-tubocurarine as yet exists. Furthermore, the complexity of the

synthetic problem is such that the successful syntheses referred to above

are invariably long and must involve the judicious use of several

functional protective groups.

Biogenetic-type syntheses using phenolic oxidative coupling of

monomeric benzylisoquinolines have unfortunately proven of limited

value due sometimes to low yields, bu t more importantly because it is

head-to-head coupling that occurs most readily in vitro, a mode of

coupling not encountered in nature.

A novel approach to bisbenzylisoquinoline synthesis concerns the

electrolytic oxidation of the salts of monomeric phenolic benzyliso-

quinolines, but so far only one such example has been reported. The

most promising new route t o the bisbenzylisoquinolines involves the use

ofpentafluorophenyl copper in the formation of the diary1 linkage and

this method will be discussed toward the end of this chapter.

11. Dauricine-Type Alkaloids

The first att empt a t the synthesis of a dauricine degradation product

was carried out a number of years ago when dauricine methyl methine

(2) was prepared and was found to be identical with material derivedfrom naturally occurring ( - -dauricine (3),Scheme 1 ( 1 ) .

The sequence in Scheme 1 represents one of the early pioneering

efforts in the bisbenzylisoquinoline series. The use of the Erlenmeyer

azlactone synthesis in the preparation of th e dicarboxylic acid 1 should

be noted. Several syntheses of enantiomeric and diastereomeric mixtures

of dauricines ( 5 ) are available. The first synthesis was accomplished

through the Ullmann -+ Arndt-Eistert +Bischler-Napieralski sequence

(Scheme 2) . It was not possible to separate the components of the final

mixture (2-5).The second synthesis is a variation of the one described above (4-6) .

Condensation of the diacid chloride of 6 with homoveratrylamine gave

the required diamide 4.



0 X

-

0 /\ \5



U

N m



6. SYNTHESES OF BISBENZYLISOQUINOLINE ALKALOIDS 323

6

In the third instance, Ullmann condensation of the racemic bromo-

tetrahydrobenzylisoquinoline 7 with racemic armepavine (8) yielded,

following hydrolysis, a mixture of dauricines (4-6) .

7

R = benzyl or scetyl

8

The first synthesis of a clean optically active derivative of dauricineinvolves the preparation of (- -O-methyldauricine ( l l ) ,dentical with

material derived from the natural product (7 ) . Controlled bromination

of ( - -armepavine yielded ( - -3'-bromoarmepavine (9).O-Methylation

then furnished 10, which was condensed under Ullmann conditions with

( - -armepavine to supply 11, Scheme 3.

Several other syntheses of O-methyldauricine are also available. The

first of these follows the now well established route involving initial

synthesis of the diacid chloride of 1 and its further condensation with

homoveratrylamine. The ultimate product was again a product withmixed stereochemical landscape-an enantiomeric-diastereomerk

mixture (8). A more arresting approach to O-methyldauricine was

carried out primarily to prove the usefulness of Reissert intermediates

(9). _+ )-Armepavine was first prepared in high yield through a Reissert

sequence as indicated in Scheme 4 . The other required moiety, ( f -lo,was generated by either of the two routes described in Scheme 5.

A related approach to O-methyldauricine involves a rare instance of

bis-Reissert reaction. The dialdehyde 13 was first prepared and then

condensed with 2 moles of 12 to yield th e dibenzoate 14. The corre-sponding diol (15)was hydrogenolyzed with hydrogen bromide and zinc

in acetic acid to the bisbenzylisoquinoline 16. N-Methylation and

reduction then furnished a mixture of O-methyldauricines (9). The



m

c E- - 0X

fp




CH30

1. K O H ,ethanol,water

CH,OH30Q N , c , P h -ldehyde,0°C CH30$r 2. zn. nnr

3-Rromoanis-

phenyi lithium,

0--CPh -0

CH30CN II

012

CH30

CH30r

3.. C H JaBH,

cH3Or CH3

\CH3OCH30

( k1-10

or

CH30%aH, Br@ NaBH4

CH30

0 CH,O

1 . Zn,H B r2. CH.13. NaBH+

-+ ) - l oBr

CH30

SCHEME 5

yields were unusually high throughout this sequence and represent a

distinct improvement over the previous syntheses.

Yet another synthesis of an 0-methyldauricine mixture utilizing

Reissert intermediates proceeded via the condensation of 2 moles of theanion of 12with the diphenyl ether 17. Basic hydrolysis then yielded

the bisbenzylisoquinoline 16 (9 ) .The use of Reissert compounds in the

synthesis of bisbenzylisoquinolines has been recently further extended

(94.




oHcOCH,

13

R*o<R \ OCH,

14 R = P h - C O O

15 R = O H

16 R = H

17

A synthesis of (- -0-methyldauricine (11)was achieved as a result of

preparative work in the berbamunine series. Ullmann condensation of

(-)-18 with (-)-armepavine yielded the dimer 19 which upon acid

hydrolysis, and diazomethane 0-methylation supplied (- -0-methyl-

dauricine 11) ( 1 0 ) .

Br



\

W




Sodium in liquid ammonia reduction of the synthetic dimer 20, a

diastereomeric racemate prepared as indicated, afforded diamines

21 and 22. Compound 21 corresponds to a mixture of dauricines, while22 is a mixture of deoxydauricines, Scheme 6 ( 1 1 ) .An alternate syn-

thesis of 22 is also available through Ullmann condensation of ( k -23

with (k -24 ( 1 2 ) . The latest and most efficient synthesis of ( f -0-

OH

23 24

methyldauricine follows the classical lines outlined in Scheme 7 above.

The final product was a mixture of diastereomers from which

( & )-0-methyldauricine could be separated ( 1 3 ) .The diary1 ether 25, obtained through an Ullmann sequence, was

condensed with two moles of 3-methoxy-4-benzyloxyphenethylamine.

The product was the diamide 26, which was converted stepwise into a

mixture of 0-methyl-0,O-dibenzylmagnolamine27), Scheme 8 ( 1 4 ) .

The dimeric immonium hydrochloride 28 had previously been obtained

by a similar sequence ( 1 5 ) .

H C1010 H OCHaPh PhCHaO

28

A first attempt to synthesize magnoline followed the course outlined

A modified route was then adopted which eventually provided a

in Scheme 9 but aborted when dimer 29 failed to debenzylate ( 1 6 ) .

mixture of magnolines (30), Scheme 10 (16).



OCH,

0

/pc1‘ G C H S> C H a - C \ ’-‘ CH, \

25 2

SCHEME



332 MAURICE SHAMMA AND VASSIL ST. GEORGIEV

H o o G c H 2 D o a C H & O O H 2.. 9061.thylhloroformate

\H

O\\ No 3-Methoxy-4-,C-CH,benzyloxy.

c1 \C1 phenethylamine

OCH, CH,O

1 . POCI.pN\.. CH.1a R H,

Fo H 4. E O H , ethanol

SCHEME




0 0

C1

//CHz--6, 3-Methoxy-4-hydroxy-

c1 phenethylaminef

OCOOC,H,

1. Ethyl chloroformatem1r3 H3.. CHDIOCla

H / t b o & H 5.. N a OH,aBH, ethanol +

\\ OCOOCzH5

H3C’

30

SCHEME0

3 1 31

33

SCHEME1



334 MAURICE SHAMMA AN D VASSIL ST.GEORGIEV

The alternate pathway to a bisbenzylisoquinoline, namely, condensa-

tion of two tetrahydrobenzylisoquinoline units by means of an Ullmann

reaction, was also tried and provided a mixture of magnolines (30)( 1 7 ) .The same sequence was then applied using optically active inter-

mediates. Thus, ( + )-31was condensed with (-)-32.- -Magnoline(33)was generated following hydrolysis of the benzyloxy protective groups,

Scheme 1 1 (18).It should be noted here that (-)-magnoline 33) s

enantiomeric with ( + )-berbamunine. In related work, ( 5 )-34 was

condensed with ( _+ )-35 o give rise to a mixture of daurinolines 36,

Scheme I 2 ( 1 9 ) .Daurinoline itself has the (- - or (R, ) configuration.

34 35

36

SCHEME2

The alkaloid (- -cuspidaline is representedby expression 37, nd a

synthesis of ( f -cuspidaline was carried out through a bis-Bischler-

Napieralski reaction. Following reduction, h7-methylation, and

catalytic debenzylation, it was possible to separate the diastereo-

meric mixture of ( 5 )-cuspidaline by fractional crystallization, Scheme

13 ( 2 0 ) . ( & )-4’-O-Methylberbamunine (38) has also been obtained byessentially the same route ( 2 0 ) .An alternate but closely related prepara-

tion of a mixture of cuspidalines is also available using the intermediate

39 (21).




COOH

3-Methox y-4-benzyloxy-

decalin, ACHaCOOH phcnethylamine.

I

P

1

Fractionalcrystallization

_____j

/H3C

SCHEME 13




0 C H 3

40

OCH,

4 1

and

OH

42



PhCH2CI,COOCH, NaOH,

CHBOH

-H300C

I

OH

c H 3 o o c ~C O O C H 3 2.. BasicOCl,,hydrolysisyridine

3. CAaN2t

OCH,Ph

OCH,Ph

3-Methoxy-4-benzyloxy-phenethylamine,

silver benzoate,N(C2Hda

(Arndt-Eistert)

OCH,Ph

1. POC13

3. NaRH,4. Conc. HCI,

ethanol

-

2. C H ~ I

OCHaPh

H3C CH3

OH

Mixture of enantiomeric and diastereomeric magnolamines

SCHEME4



OCH,

c ’ - c H z ~ o ~ ~ ~ &CN,cetonethanol,

OCH,

OCH,

CHa-CN

Hydrolysis

-OCH,

HOOCCH,poa\

\ OCH,I

OCH,

44or alternatively,

Br

OCH,

C H 3 0 0 C - H ~ C ~ o ~ C H 2 C O O C H 3-ydrolysis 44

\ OCH,

OCH,then,

1. 3-Methoxy-4-benzyloxyphenethylamine

S 0 C l 2 2. PC15, CHCI. (Bischler-Napieralski)44 Diacid chloride 9

OCH,

45

SCHEME6




also been prepared through Ullmann condensation of two tetrahydro-

benzylisoquinoline units. This sequence, which uses both benzyloxy and

ethoxycarbonyloxy protective groups, is shown in Scheme 16 ( 2 7 ) .Thesimple analog 46 of magnolamine has also been prepared through the

Ullmann condensation of two tetrahydrobenzylisoquinoline units and

was obtained a s an isomeric mixture (28).

PhCH,O’

3H30

P hCH,O

1. POCI., toluene2. CH313. N a R H ,

t

H O,H,OOCOwthen,

ylC H z P h

C H 3 0

C H 3hCH,O

+H O

OCH,Ph

1. Ullmann2. Hydrolysis

Mixture of enantiomeric and

diastereomeric magnolamiries

SCHEME6

P o d\

46




IV. Berbamine-Oxyacanthe-Type Alkaloids

Initial efforts in this series provided preparations of such inter-mediates as 47 to 50 (29-34) . The first synthesis of ( + )-tetrandrine (54)

was achieved in low yield by Ullmann condensation of ( + )-N-methyl-

coclaurine (53)with (- )-3’,8-dibromo-N,O,O-trimethylcoclaurine51)

48

H O O C C O O H

49

50

obtained by bromination of 53 followed by 0-methylation. 0 , O -

Dimethylbebeerine (55) should have been a by-product of this con-

densation but was not actually isolated and characterized, Scheme 17

An interesting total synthesis of optically active natural ( + )-

isotetrandrine (65) (- -phaeanthine ( 6 6 ) ,and ( + )-tetrandrine (54) has

been achieved ( 3 6 ,3 7 ) .The first required intermediate, ( - -0-benzyl-8-

bromolaudanidine (56),was prepared through exploitation of a Will-

gerodt reaction as shown in Scheme 18.

(35).



342 MAURICE SHAMMA A N D VASSIL ST. GEORGIEV

rtl. K I . K ~ ( : o ~ .pyridinr. A

SCHEME7

Another intermediate was N-tert-butoxycarbonyl-4-hydroxy-3-

methoxyphenethylamine (57) and the preparation of this urethan is

given in Scheme 19. The tert-butoxycarbonyl group is removable by acid

but is resistant to hydrogenolysis and base hydrolysis under relatively

mild conditions. Ullmann condensation of 56 with 57 furnished the

diary1 ether 58 in good yield. Catalytic debenzylation was followed by

55



6. SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS 343

S

ll ACF,--CN 0

CHa

c=o

9, morpholine, A NaOH

OCHIPh OCH,Ph

OCH3 OCH,

OCH,Ph

OCH,

1. P O C l 32. NaBR,3. Resolution via

I-(+ )-tartaricacid salts

4. HCOH.NaBH,

Br

/

H3C H-

a:-56

SCHEME8

another Ullmann condensa-ion with the -bird required intermediate,

namely, methyl p-bromophenylacetate, to supply the bisdiaryl ether

59, again in good yield, Scheme 20.

When the bisdiaryl ether 60 was heated, the amide 61 was produced,

which generated the key imine 62 upon Bischler-Napieralski cyclization.

tcrt-Rutyl aaidoformate, Hz.N(CzH,)3, cthyl acetate

PhCH,OH 3 0 p N H z PhCH,O

0- tert-butyl

HO

0-&t-butyl

57



1 . H z

Cu

/

2. MCUO. KzCOa,pyridine, A

56 + 57

58

1 . OH(hyd

2. p-N(est

fo 3. CF,O--t&-butyl (rem

/N

/ tcrt

59

SCHEME0




D M F ,pyridine, A

60- POCI3,CHC13A

61

The reduction of imine 62 was studied under a variety of experimental

conditions. With sodium borohydride in methanol, a 3 : 2 ratio of

bisbenzylisoquinolines 63 and 64 was obtained, which wereN-methylated to ( + )-isotetrandrine (65) and ( - -phaeanthine (66),

respectively. But when zinc in sulfuric acid was utilized on the racemate

of 62, only 64, as the racemate, could be isolated. No stereospecificity

in the reduction of 62 was observed with Adains catalyst containing a

trace of concentrated hydrochloric acid. AT-Methylationof racemic 64

gave a racemic compound composed of ( - )-phaeanthine (66) and its

enantiomer (+)-tetrandrine(54), Scheme 21 ( 3 7 ) .Since ( )-66has been

isolated from a natural source and resolved into its optical antipodes

( 3 7 a ) , the present synthesis amounts also to a total synthesis of( + )-tetrandrine.

The first successful syntbssis of (i -cepharanthine (73),belonging to

the oxyacanthine series, w5Fachieved through the Bischler-Napieralski

cyclization of the key bislGtam 72. One precursor of this important

intermediate was the substituted aminourethan 69, which was prepared

from species 67 and 68 as shown in Schemes 22 and 23 ( 3 8 , 3 9 ) .

The lower half of cepharanthine was prepared as in Scheme 24,

taking advantage of the fact that a benzyloxy group can be hydrogen-

olyzed while a tert-butyl ester is immune.Condensation of 69 with90 furnished the urethan 71, which was

converted to the bislactam 32. Bischler-Napieralski cyclization gave a

bisimine, which could be rexuced to a bis secondary amine either with




I

Br Br

67

SCHEME2

Adams catalyst or with sodium borohydride. Since the ratios of the two

diastereomers obtained from each of these reductions were different,

the available mixtures of secondary amines were combined, N -methylated, and then separated by chromatography. One of the prod-

ucts isolated proved to be ( & )-cepharanthine (73), cheme 25 (38'39).

It was found possible to convert the unusual bisbenzylisoquinoline

alkaloid stepinonine (74) to N,O-dimethyltetrahydrostepinonine 75),

which in turn could be selectively oxidized with Jones' reagent to the

H0. Ethyl

2. Zn /Hn , HCI CI

Ph-CH, -0- CH 3 0 r o1 chloroformate,yridine

C,H,OCOI t

O

0

C H 3 0

H O

0 O C H p P h O C H I P h

68

then,

1 . CuO, K1C03. pyridine, A2. Dil. HCI (formyl hydrolysis)

67 + 68

OCH,Ph

69

SCHEME3




COOH CO O - t e r t - Bu

ter2-Butyl alcohol,

H a , PdtC

bOCH2€?h AOC13, pyridine ~

O C H S P h

COO- tert-Bu ~ O O C H .

p-Toluen esulfonic

acid (removal of+

CU,A ( ~ l ~ r n a n n ) tcrl-Bu group)

7 0

SCHEXE 4

ketone 76. R e d u c h n of this ketone first with zinc in acetic acid andthen with sodium borohydride yielded a mixture of O-methylrepandine

(77) and O-methyloxyacanthine (78) (39a).

A mixture of enantiomeric and diastereomeric berbamines (82)

and oxyacanthines (83) was obtained through the following sequence.

Schotten-Baumann reaction of the diamine 47 with the diacid chloride

79 gave amides 80 and 81,which could be separated. Bischler-Napieralski

cyclization using phosphorus oxychloride produced the corresponding

3,4-dihydroisoquinolines. -Alkylation with methyliodide, borohydride

reduction, and subsequent acid hydrolysis generated isomeric mixturesof berbamine 82 and oxyacanthine 83, respectively (39b).

V. Thalicberine-Type Alkaloids

( + )-Thalicberine (84) and ( +)-O-methylthalicberine (85) are repre-

sentative of a group of bisbenzylisoquinoline alkaloids found in

Thalictrum species (Ranunculaceae), and a synthesis of ( + )-O-methyl-

thalicberine has been reported ( 4 0 ,4 1 ) . Ullmann condensation of( + )-O-benzyl-8-bromolaudanidine (86) with the phenolic tert-butyl-

urethan 87 afforded the diary1 ether 88, which was then hydrogenolyzed

to the phenol 89, Scheme 26.



CH,O'

1. POClD2. H., Pt or NaRHI3 . HCOH.NaBH, H3C

4. ChromatographyH

HN

79.

SCHEME5



352 MAURICE SHAMMA AN D VASSIL ST. GEORGIEV

84 R = H

85 R = CH,

CuO, K,CO.,

+0-tert-Bu

OCHaPh

86 87

0- tert-Bu

OCH,Ph88

0- ert-Bu

OH

89

SCHEME 26



m

\

a



354 MAURICE SHAMMA AN D VASSIL ST. GEORGIEV

Phenol 89 was condensed in a second Ullmann condensation with

methyl-p-bromophenylacetate to yield the ether 90, which was con-

verted to the amide 91 by the p-nitrophenyl ester method. Bischler-Napieralski cyclization then gave the imine 92. Reduction of this

imine with sodium borohydride gave only a single compound, namely,

the desired amine 93. N-Methylation furnished the final product,

(+ )-O-methylthalicberine ( 8 5 ) ) identical with the natural material,

Scheme 27.

VI. Trilobine-Isotrilobine-TypeAlkaloids

The alkaloids ( + )-trilobine (94) and ( + )-isotrilobine (95) possess a

diphenylenedioxy bridge connecting the two top aromatic rings. It has

been possible to interrelate chemically bases of the berbamine-

oxyacanthine group, which contain two diary1 ether linkages, to those

belonging to the trilobine-isotrilobine series, and these interrelationships

will be discussed briefly here. When naturally occurring ( + )-iso-

tetrandrine (65) was heated with hydrobromic acid at lOO"C, the

demethyl derivative 96 was obtained. This derivative cyclized to the

trilobine-type compound 97 upon more drastic treatment with hydro-bromic acid, and diazomethane O-methylation yielded the methyl ether

98, Scheme 28 ( 4 2 ) .

94 R = H95 R = CH,

In a similar vein, ( + )-tetrandrine (54)) which is diastereoisomeric

with ( + )-isotetrandrine (65),was converted to the diphenylenedioxy

derivative 99 ( 4 3 ) .

The starting alkaloids in the two examples above belong to theberbamine series, but diphenylenedioxy formation can also be brought

about in the oxyacanthine series. Thus, oxyecanthine (100)itself was

converted into the derivative 101 ( 4 4 ) while N-methyldihydro-

epistephanine 102) ed to the levorotatory antipode 103 of natural




CH3 HBr, 100°C,3 hoursH

3C

65

H3C /NH / HBr. 130-135°C, 3 hours

/

\\ OH 0

96

97 R = H98 R = CH3

SCHEME8

54




104

1. HBr, HOAc, 100°C

2. HBr, 140-145°C

3. CHaNat (+-1-95

SCHEME9

( + )-isotrilobine ( 4 5 ) .Finally, taking advantage of the known fact that

in dilute acid (+ )-oxyacanthine (100) undergoes isomerization to

( - -repandine (104), t was found possible to convert ( + )-oxyacanthine

into natural ( + )-isotrilobine, Scheme 29 ( 4 6 ) .

Inubushi and co-workers have recently adapted their synthesis of

( + )-isotetrandrine and (- -phaeanthine to preparations of ( + )-

obaberine and ( -t -trilobine (46a).

VII. Menisarine-Type Alkaloids

The alkaloid (+ )-menisarine possesses the structure 105, which

incorporates a diphenylenedioxy bridge, and an interesting synthesis of

( )-N-methyldihydromenisarine (107) has been achieved. The firststage of the synthesis concerned the preparation of the diamine 106,

which was carried out via a double Ullmann, as shown in Scheme 30

(4 7 , 4 8 ) . The lower half (1) of the molecule was prepared using a

Willgerodt reaction as per Scheme 31.

105



358 MAURICE SRAMMA AND VASSIL ST. OEORGIEV

cu, pyridine.

A t

Br OCH,

OH OH

OCH, OCH,

106

SCHEME0

Condensation of the diacid chloride of 1 with the diamide 106 a t high

dilution, followed by Bischler-Napieralski ring closure, reduction, and

Eschweiler-Clarke N-methylation furnished the desired racemic

product 107, Scheme 32 ( 4 7 , as) , which was spectrally identical with

the product derived from the reduction and N-methylation of natural

( + )-menisarine (105).

1. CH&OCI, AICI.,

d o n. DlmethylS. sulfate

0

II

' ~ 0 0 c ~ c H 3illgerodt



6. SYNTHESES O F BISBENZYLISOQUINOLINE ALKALOIDS 359

108 + Diacid chloride of 1

2. NaBH,

107

SCHEME2

VIII. Tiliacorine-TypeAlkaloids

( + )-Tiliacorine and it s diastereomer ( + )-tiliacorinine have been

assigned structure 108 on the basis of extensive degradative studies

( 4 t h ) .These two alkaloids are unusual in having a biphenyl system inlieu of the usual diary1 linkage. A total synthesis of ( k -O-methyl-

tiliacorine (109) has been described in detail ( 4 9 ) . Unsymmetrical

Ullmann condensation of the bromophenols 110 and 111 yielded a

mixture of three products from which the desired diester 112 was

isolated by chromatography. Homologation and conversion to the

diamine 113 was followed by condensation with the diacid chloride 114.

The resulting bisamide 115 was converted to a mixture of ( f)-0-methyltiliacorine and O-methyltiliacorinine by well established trans-

formations. Careful chromatography of this mixture yielded ( f -0-methyltiliacorine, spectroscopically and chromatographically identical

with material derived from the alkaloid. The diastereoisomeric ( f)-0-

methyltiliacorinine was obtained only in trace amounts, Scheme33 ( 4 9 ) .



360 MAIJRICE S H A M M A AND VASSIL ST.GEORGIEV

1. K salts formation

C H 3 O O C ~ O C H a BrDc c.. Cu-bran=,hromatographyiphenyl ether, A

t

\H HO

Br

110 111

1 . LiAlH,

C H 3 0 0 C v C O O C H , 2.. S 0 C l zC N

4. H., NYR)

-o\

112

113

then,

113 + COCl

__f

114

115




1. CHJ2. Na B H ,3. POC1.

4. H2, Pt5. HCOH, HCOOH

t

108 R = H109 R = CH,

SCHEME3

IX.Liensinine-Type Alkaloids

The alkaloid ( + )-liensinine (118) incorporates head-to-tail coupling

through a diary1 ether linkage. A total synthesis of this alkaloid was

achieved on the heels of the initial isolation and characterization reports.

Ullmann condensation of ( - -116with ( - -117followed by hydrolysis

gave the optically active alkaloid (50 ,5 1 ) . A synthesis of a diastereo-

meric mixture of liensinines, by a somewhat similar pathway, is alsoavailable ( 5 2 ) .

The related alkaloid ( - -isoliensinine (122)yields ( - -O,O-dimethyl-

isoliensinine (121)on treatment with diazomethane. Derivative 121 was

synthesized by Ullmann condensation of (- -119 with ( - -120 (53).Finally, optically active (- -isoliensinine (122) was obtained by the

sequence in Eq. 1 ( 5 4 ) .Worthy of attention are the new conditions for

the Ullmann condensation ( 5 2 , 5 4 ) nvolving the use of copper powder,

potassium carbonate, a small amount of potassium iodide, and dry

pyridine heated to 155-160'c in a current of nitrogen. These conditionsgive better yields (about 15y0) han the usual Ullmann condensation.

The newer base (- -neferine (123), related to liensinine and isolien-

shine, was synthesized by a similar approach (Eq. 2 ) (55).



CH,O

1. Ullmann

2. H,OBHO \

Y~ c H ,I I I I Y \ C H 3r /

-\ PhCH,O \PhCH,O

116 117

cH30CH,

O b F O O HHac,5:>

OCH,

119 120




CH,O PhCH,O

CuO, K.COa.

-CH, pyridine, A

HOH30LYCH30

0 \ C H ,

1CH, OCH,

OCH,

123

X. Curine-Chondocurine-Type Alkaloids

It was conclusively demonstrated in 1970 that the hitherto accepted

structure for the alkaloid ( + )-tubocurarine,which had been represented

as 124, was in error and that the correct structure is 125 ( 56 ,57) . This

finding was of particular interest not only because of the importance of( + )-tubocurarine as a neuromuscular blocking agent, but also because

of the fact that supposed total syntheses of the racemic di-0-methyl

ether of tubocurarine iodide as well as of racemic tubocurarine iodide




X 0

c H 3 0 m m ,H

\0

4

124 125

had been claimed previously. A description of the synthetic work on

tubocurarine follows. This description is complicated not only because

of the above mentioned change in structural assignment, but also by

the failure of the workers involved in the synthetic work in clearly

differentiating between enantiomers, racemates, and diastereomers

while comparing samples (58-62) .As a preliminary attempt at th e synthesis of the dimethyl ether of

tubocurarine, the simple dimer 126 was constructed as described in

Scheme 34. The product 126 was obtained as a mixture of two diastereo-

mers from which the predominant racemate (mp 96-99°C) could be

isolated (58).

Essentially the same approach was utilized in the preparation of the

so-called “di-0-methyl ether of tubocurarine iodide ’) (127), Scheme 35

( 5 8 ,59). The UV spectrum of one salt so obtained was apparently close

to or identical with the spectrum of an authentic sample of the di-0-

methyl ether of ( + )-tubocurarine iodide, and this finding was taken as

proof of structure.* It must be pointed out, however, that most

tetrahydrobenzylisoquinolines, as well as bisbenzylisoquinolines such

as tubocurarine or its dimethyl ether, exhibit a maximum absorption

near 280 nm, so that UV spectroscopy is not a reliable basis for com-

parison. Another criterion used was a mixture melting point between the

* There seems to be some confusion in the assignments of melting points of the final

products. I n reference ( 5 8 ) , two supposed diastereomeric tubocurarine iodides wereobtained (m p 131-135°C and 223-228°C). But in reference ( 5 9 ) ,only one melting point

was quoted [mp 257-268°C (ethanol)]. This la tt er material apparent ly gave no melting

point depression with a sample of the natural sa lt (mp 262-264”C), even though no fo rmal

resolution was carried out on the synthetic material.




CH,O CH,O3C H , O P " r ~

N,C H3 C H 3 0

h C H, O HO

___, +

CH,O CH,O

I . H,, P t

N\CH3 2 . HC'OH,HCOOH,..jCx; -

2. PO('I3 5'C H 3 0 \ /

1. Homoveratrylaminr

(636N \ C H ,

\ /

CH, OCH, CH, OCH3

I

OCH,

COOCH,

SCHEME4



FOOH

cH30)3?JyHO ' N H a PhCH,O

PhCH,OLy



. 209. HCI, A , 2 hours

OCH,Ph

OCH,

OCH,

1. Zn, dil. HOAc,A , 1.5 hours

2. CHJ.CH30H

OCH,

S CH E M E5



em a0m

w

U

m



t




naturally derived dextrarotatory di-0-methyl ether of tubocurarine

iodide and the synthetic isomer, in which apparently no depression was

observed. Such a comparison is, of course, invalid since (a)a racemateusually has a different melting point from th at of a pure enantiomer, (b)

melting points of bisbenzylisoquinoline salts are often unreliable and

difficult to reproduce, and (c) the structure assigned to ( + )-tubocurarine

and its di-0-methyl ether was in error in the first place. A synthesis of

the unsubstituted tubocurarine analog 129 is also known, Scheme 36

(63).The product proved to be a mixture of two racemates, mp 225-

227°C and 121-124°C.

As an extension of the synthetic work on the so-called “di-0-methyl

ether of tubocurarine,” a preparation of the di-0-methyl ether of racemicchondodendrine (130)was carried out, Scheme 37 ( 6 4 ) .

A slightly different approach t o the so-called “di-0-methyl ether of

tubocurarine” has also been recorded, Scheme 38 (60).The starting

material was the diimine 131, which was known from previous work.

Each of the two diastereomeric racemates of 132 gave two bis-

methiodides upon treatment with methyl iodide, a result that is some-

what difficult to rationalize; and one of these four isomeric salts,

namely, tha t melting 257.5-259”c, was claimed to be identical with the

dextrorotatory di-0-methyl ether iodide of natural ( + )-tubocurarineiodide. The criteria for comparison were simply closeness of UV spectra

and melting points.

A claim of a synthesis of a material assumed to be identical with

natural ( + )-tubocurarine iodide was put forward, even though an actual

CH, % ismethiodide

1. Cu, K,COa,

2. Z n , H O A c

salts

131 133

SCHEME8



372 M A U R I C E S H AM M A A N D V A S S I L ST. G E O R G I E V

CH30

K@ ‘0 ,Cu, A

+

OCHaPh

CH,O

Ac.0,pyridine----.-+

0

A

OCHaPhOCHaPh

CHa

COOCH,Ha

H OCH,

133

C H d , NaOH,C H 3 0 H , A

OCH,

OCH,PhH,CH,Ph3”’ Br

OCH, H CH,

135HNd

184




Finally, a synthesis of racemic so-called ( ( N , N ’-demethylchondo-

dendrine ” (137))erroneously assumed by the authors to be identical

with chondrofoline, has also been advanced and is described in Scheme40( 6 2 ) .T w o products were obtained a t the conclusion of the sequence, and

one of them was assumed to correspond t o chondrofoline on the basis of

UV spectral comparisons and a negative Millon test. It was later shown

by other workers th at the correct structure for chondrofoline is 138 (65))so that the claim of a synthesis of chondrofoline is unfounded ( 6 2 ) .

H 3 c , : ~ 3

OCH,

138

In other attempts at the synthesis of tubocurarine-type bases,

Ullmann condensation of the dibromotetrahydrobenzylisoquinoline 139

with the N-methylcoclaurine salt 140 was investigated but did not lead

to characterizable product (66).Studies of the efficient Ullmann con-

densation of phenols with aromatic halides substituted a t the ortho

position(s)with nitro group(s)have been carried out and have culminatedin the preparation of the imide 141 (67-69).

0,O-Dimethylcurine (143)was presumably obtained in the course of

the previously described syntheses. But a more reliable preparation of

this compound involves the Ullmann condensation between the levo-

rotatory dibromotetrahydrobenzylisoquinoline 139 and the levorotatory

diphenolic tetrahydrobenzylisoquinoline 142 (70). When the catalyst

for the condensation consisted of cuprous chloride in the presence of

potassium carbonate and pyridine and the conditions were heating a t

155-165’C for 24 hours, a small yield of optically active 0,O-dimethyl-curine (143)together with a larger amount of 144 was obtained. When,

however, the two starting tetrahydrobenzylisoquinolines were racemic

rather than levorotatory and the catalyst was cupric oxide in pyridine




141

heated at 160-170°C for 50 hours, the products consisted of a small

yield of a mixture of 0,O-dimethylcurines together with a mixture of

tetrandrines and isotetrandrines (54), as well as a mixture of 144.

Ullmann condensation of 2 moles of the racemic phenolic tetrahydro-benzylisoquinoline 145 followed by N-methylation yielded the hayatine

analog 146 (2'1).

Turning now to the structurally simpler alkaloid (- -cycleanbe (147),a promising route to i ts preparation appeared to be Ullmann condensa-

tion of 2 moles of 8-bromoarmepavine, since the alkaloid is symmetrical.



376 MAURICE SHAMMA AND VASSIL ST. G EO R G I EV

1. Cu, aq. Na O H , A2. C H J

c1145 OCH, 'o

O CH 3

146

One such attempt using ( k -8-bromoarmepavine (148)and the superior

cupric oxide-potassium carbonate-pyridine catalyst gave some of the

dimer 149 but none of the expected mixture of cycleanines (72).

A fully authenticated first total synthesis of ( k -cycleanine (147)

involved as a first hurdle the synthesis of the amino acid 151as well as

that of its corresponding methyl ester 155 (73, 7 4 ) . The aldehyde 150was condensed with nitromethane to give a yellow nitrostyrene.

Catalytic hydrogenation over Adams catalyst in acetic acid then gave

the required amino acid 151, Scheme 41.

Furthermore, the methyl ester 155 of the acid 151was synthesized by

the following alternate route. 3,4-Dimethoxy-5-bromophenethylamine,

prepared by the reduction of the nitrostyrene 152 under Clemmensen

CH,O

C H 3 0 :\CH3 ::::r CH, cH3H,O CH3

+ I 6H 44H 3 c \ : M 0 C H 3 CH,

OCH, OCH,

147 I4948




C H 3 0 1. CH3NOa T N H ,H 3 0

cH30vc. Ha, Pt, HOAc

4H,COOH *(IH,COOH

150 151

SCHEME1

conditions, was converted to the N-carbobenzoxy derivative 153.

Ullmann condensation between 153 and methyl p-hydroxyphenyl-

acetate afforded the product 154, and catalytic removal of the blocking

group gave rise to the desired methyl ester 155, Scheme 42.

The amino acid 151 was next protected as its N-carbobenzoxy

derivative 156. Condensation between 155 and 156 furnished the amide

1. Zn/Hg, HCl

c H 3 0 T v " 0 2 2. Ph-CHP-O-C '01

C H 3 0

Br

152

CH,OH o ~ c H 2 - - C O O C H I .

c H 3 0 q T uO, K.CO3, pyridine t

Br OCH,Ph

153

C H 3 0

CH&OOCH, CH2COOCHS

154 155

SCHEME2



0

=I IG




157, which was converted to the carboxylic acid 158. Esterification of

158with p-nitrophenol and DCC was followed by treatment with hydro-

gen bromide to remove the carbobenzoxy group. The resulting aminehydrobromide 159 readily suffered cyclization to the bisamide 160, and

Fischler-Napieralski cyclization followed by reduction led to a mixture

of tetrahydroisoquinolines. N-Methylation finally furnished a mixture

CH,O

cH30 P o C H 3 0cH3\ C H 3

44 66

HN z”̂

H C N )

OCH,Ph OCH,Ph

OCH,163 164

O C H a P hI

I

H,CLN& CH ,

OCH,

165




of products which generated ( -cycleanhe (147)after chromatography.

T w o other products obtained from the chromatographic separation

were the dimers 161 and 162, Scheme 43.A later study in the cycleanine series demonstrated that Bischler-

Napieralski cyclization of the amide 163 proceeds in two directions to

supply ultimately amines 164 and 165 (75).

XI. Miscellaneous Syntheses

The alkaloid aztequine was supposedly isolated from the leaves of

yoloxochitl, Tabma mexicana Don. (Magnoliaceae) and was assigned

structure 166 with no delineation of stereochemistry. This assignment

is certainly in error, since in the same paper the unlikely claim was made

that hydroiodic acid ruptured the diaryl ether linkage of the alkaloid

without touching the methoxyl groups (?‘G).

I IO H O H

166

Attempted syntheses of 166 either involve initial preparation of the

diaryl ether corresponding to the two bottom rings, followed by further

elaboration to construct the two tetrahydroisoquinoline units, or

include an Ullmann condensation to bond together the two tetrahydro-

benzylisoquinoline units (77-79).The bisbenzylisoquinolines167, 168, and 169, which have no analogs

in nature, have been synthesized through Ullmann condensation between

170 and 171 in the case of 167; 172 and 173 in the case of 168;and 174

and 175 in the case of 169 ( 8 0 , S l ) .

167




168

169

170 R, = OH, R, = H

171

173

175

R1 = Br, R, = H

R, = H, R, = Br

R, = Br, R, = H

172 R, = H, Ra = OH

174 R1 = H, RP = OH

The dimer 176 has also been prepared in the course of a study ofstructural requirements for tumor-inhibitory activity among bis-

benzylisoquinolines ( 1 3 ) .

Lastly, an important related synthesis that should be a t leastmentioned here in passing is that of the alkaloid ( + )-thalicarpine(177),which is an aporphine-benzylisoquinoline rather than a bisbenzyliso-

quinoline (82-84).




XU. Syntheses Using Phenolic Oxidative Coupling

Historically, significant attempts a t the phenolic oxidative coupling

of tetrahydrobenzylisoquinoline free bases were reported as early as

1932, but they generated only dibenzopyrrocolines (85, 8 6 ) . The first

phenolic oxidative coupling leading to a bisbenzylisoquinoline was not

reported until 1962, when i t was shown that ferricyanide oxidation of

the quaternary salt ( +_ )-magnocurarine iodide (178)at pH 10 yieldedthe dimer 180 n 1Sy0yield (87, 88).

RO

-0‘178 R = H

179 R = CH3

OR

XQ

0180 R

181 R

RO

#@

= H

= CH,




Similarly, ( f -4’-O-methylmagnocurarine iodide (179) furnished the

corresponding dimer 181, while ( )-armepavine methiodide, which has

a methoxy group at C-7 and a hydroxy at C-4‘ , could not be dimerized(87-89) .

In a variation on this theme, and using the free base instead of the

quaternary salt, it was demonstrated that ferricyanide oxidation of

( f -4’-O-methyl-N-methylcoclaurine182) in a two-phase system of

chloroform-0.1 N sodium carbonate (pH 11.4) a t or below room tem-

perature resulted in formation of the racemic diastereomers 183 and

184 in about 15% yield and separable by chromatography, Scheme 44

It will be recalled that in an initial attempt i t had been found th at( k -armepavine methiodide did not dimerize at room temperature.

Reexamination of this oxidation under more severe conditions, namely,

0.1 N sodium carbonate solution and potassium ferricyanide on a steam

bath or 1 N sodium hydroxide and silver nitrate a t room temperature,

produced the carbon-carbon dimer 185 in about 15y0 yield ( 9 1 , 9 2 ) .

(901.

185

In an atte.mpt to prepare the aporphine base ( f -N-methylcaaverine

(186) by phenolic oxidative coupling, the ferric chloride oxidation of

racemic tetrahydrobenzylisoquinoline 187 was investigated. The

products were the dienone 188 in 2.4y0yield and the dimeric benzyliso-

quinoline 189 in 1.1% yield, Scheme 45 (93).

A few studies have also been concerned with the enzymatic oxidation

of tetrahydrobenzylisoquinolines. Oxidation of ( 5 )-N-norarmepavine

(190) a t pH 6.5 with crude horseradish peroxidase and hydrogen

peroxide yielded a complex mixture that included small yields of theisoquinolines 191, 192, and 193, Scheme 46 (94). Other investigations

have dealt with the enzymatic oxidation of phenethyltetrahydroiso-

quinolines ( 9 5 ,96).



c H 3 0 p N \ C H 3O aq. FeCl,, 30:40'C CH3

188187

+ H3C' N&KJHO \

186

SCHEME5




H OJ9190

191

H O

O H

192

SCHEME6

cH30H,O

O H

198

XIII. SynthesisUsing Electrolytic Oxidation

The first preparation of a naturally occurring bisbenzylisoquinoline

alkaloid, namely, dauricine, using an oxidative method occurred when

the sodium salt of ( )-N-carbethoxy-N-norarmepavine (194) was

subjected to electrolysis using tetramethylammonium perchlorate as

the electrolyte, a graphite anode, and a platinum cathode (97). Amixture of the dimers 195 and 196 was obtained and separated. The

dimer 196 then furnished a racemic and diastereomeric mixture of

dauricines 3 following 0-benzylyation, reduction, and catalytic de-

benzylation. Such an electrolytic oxidative dimerization was unsuccess-

ful when the nitrogen function was not protected, Scheme 47 .

XIV. Use of Pentafluorophenyl Copper

The most promising avenue to the bisbenzylisoquinolines presently

appears t o be via a n improved Ullmann diary1 ether synthesis utilizing

pentafluorophenyl copper in dry pyridine. Thus condensation of




CaH5OOC /N

mzElectrolysisn wet

acetonitrile-b O e ee

194

C 2 H , 0 0 C / N O C H , CH,O

195

+

196

then,

1.. PhCH.CI,miAIH4 base H3C’ N O C H 3CH3 cHH3O

3. H., PdIC196 t

SCEEME7




( + - 6'-bromolaudanosine (197)with ( + )-armepavine and pentafluoro-

phenyl copper in dry pyridine gave an impressive53y0yield of the dimer

198, the S,S isomer of tetra-0-methylmagnolamine (98). Analogous

condensations have also led to the preparation of aporphine-benzyliso-

quinoline dimers (98).

IOCH,

198

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88. B. Franck and G. Blaschke, Ann. 668, 145 (1963).

89. B. Franck, G. Blaschke, and G. Schlingloff, Angew. Chem., Int. Ed. Engl. 3, 192

90. M. Tomita, Y . Masaki, K . Fujitani, and Y. Sakatani, Chem. Pharm. BuZZ. 16, 688

91. A. M. Choudhury, I. G. C. Coutts, A. K. Durbin, K . Schofield, and D. J. Humphreys,

92. See also M. Tomita, Y. Masaki, and K. Fujitani, Chem. Pharm. BuZZ. 16, 257 (1968) ;

93. T. Kametani and I. Noguchi, J . Chem. SOC. 502 (1969).

94. Y. Inubushi, Y. Aoyagi, an d M. Matsuo, Yet. Lett. 2363 (1969).

95. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC. 9 (1969).

96. T. Kametani, H. Nemoto, T. Kobari, and S. Takano, J . HeterocycZ. Chem. 7, 181

97. J. M. Bobbitt and R. C. Hallcher, Chem. Commun. 543 (1971).

98. M. P. Cava and A. Afzali, J.Org. Chem. 40, 1553 (1975).

(1964).

(1968).

J.Chem.SOC. 2070 (1969).

M. Tomita, I(.Fujitani, Y. Masaku, and K.-H. Lee, ibid. 251.

(1970).



-CHAPTER 7-

THE HASUBANAN ALKALOIDS

YASUONUBUSHIND TOSHIROBUKA

K y o t o U n i v e r s i t y

S a k y o .k u . K y o t o . J a p a n

I. Introduction ........................................................ 393

395

395

395

398

414

415

416

418419

419

A. Cepharamine .................................................... 420

B. Hasubanonine a nd Aknadilactem .................................. 422

C. Metaphanine .................................................... 424

V I. Biosynthesis ....................................................... 427

References ......................................................... 428

I1. Occurrence and Physical Constants of Hasubanen Alkaloids ..............I11. Structure Elucidations ...............................................

A. Mass Spectroscopy ...............................................B. Structures of Hasubenan Alkaloids .................................

IT. Synthesis of the Hasubanan Skeleton ................................. 414

A. Synthesis via Ketolactones ........................................B. Synthesis via'Ketonitriles .........................................

Synthesis v ia Cyclic Enrtmines .....................................

D. Synthesis via Spiroketone..........................................E. Synthesis by Phenol Oxidation .....................................V. Synthesis of Hasubanan Alkaloids .....................................

C.

I. ntroduction

Work on alkaloids of the hasubanan group up to 1970 have been

reviewed in Volume XI11 of this treatise ( 1 ) In the succeeding four

years that are covered in the present review. significant advances in this

field have been made in discovering thirteen new congeners and also in

synthetic studies of the hasubanan skeleton and of this type of

alkaloids.So far as we know. the occurrence of the hasubanan alkaloids has

been noted in Stephania species only. and no alkaloid has been found in

other species of Menispermaceae of special interest from the chemo-

taxonomical viewpoint.



TABLE IPLANTOURCEND PHYSICALROPERTIES

Plant species Alkaloid

Meltin

Formula point ("

Stephania abyssinica Walp. Metaphanine

StephabyssineStephaboline

Prostephabyssine

Stephavanine

Stephania cephalantha Hayata Cepharamine

Stephania delavayi Diels Delavaine

16-Oxodelavaine

Stephania hernandifolia Walp. Aknadicine

Aknadinine

Hernandine

Methylhernandine

Hernandolinol

Hernandifoline

Hernandoline

3-0-Demethylhernandifoline

Protostephabyssine

S ephisoferuline

Prome taphanine

16-Oxoprometaphanine

Homostephanoline

Hasubanonine16-Oxohasubanonine

Miersine

Stephasunoline

S epham iersine

Epistephamiersine

Oxostephamiersine

Alrnadinine

Stephania japonica Miers Metaphanine

Stephania sasakii Hayata Aknadilactam

233

178-18186-18

196-198

229-23

186-1 8

140-15

221-22

156

7 0

197-19

152-15

114-11

227-22

19G19

148-14

196-19

133-13

232

207

115

233

116-11

161

222

233

165

98

290

2 0-21

-

" Constants for methiodide. Constants for hydrobromide.



7. HASUBANAN ALKALOIDS 395

The numbering system of the hasubanan skeleton (1) (2,3,4,5-

tetrahydro-3a,9b-butano-l-benz[e]indole), which is used throughout

this review, is that proposed by Tomita et al. in their earlier paper ( 2 , 3 2 ) .

3

IH1

11. Occurrence and Physical Constants of the

Hasubanan Alkaloids

Table I gives a survey of the occurrence and physical constants of

hasubanan alkaloids.

III. Structure Elucidations

A . MASS SPECTROSCOPY

From the measurements of IR, UV, and NMR spectra, i t is difficult

to determine the hasubanan skeleton of unknown alkaloids. The mass

spectral feature, however, exhibits a very characteristic fragmentation

pattern and therefore provides a rapid and convenient method for

structure elucidation of hasubanan alkaloids, especially that of alka-

loids obtained in small amounts ( 3 ,5 , 1 3 , 1 6 , 4 0 ) .

1 . Hasubanan Derivatives Possessing No Oxygen Function at C Ring

In the mass spectra of 3,4-dimethoxy-N-methylhasubanan 2),

3-methoxy-4-hydroxy-N-methylhasubanan3), nd lO-oxo-3,4-dimeth-

oxy-N-methylhasubanan (4), the most abundant and diagnostic

peak appears at m/e M-56. The first rupture occurs in ring C to

furnish an ion, a or e . The additional loss of methyl or hydrogen from

the fragment ion a must give rise to ion b or c and the loss of a methoxylradical from the ion c produces ions d and/or d' . The fragmentation

pattern of these compounds is a primary breakdown path for all

hasubanan alkaloids ( 4 4 , 4 5 ) .



396 YASUO INU BUSH I AND TOSHIRO IBUKA

O M e O M e

r J *

& 3

f NM e

;.19+ /

I I

M e

M e

2 R = M e a m/e 245 ( R = M e ) d m/e 2133 R = H M - 5 6

(?Me

+ /

O M e

M e M eb m/e 230 c m/e 244

& &_f + /

0

Iu:

t N

M e

Me

4 e m/E 259

SCHEME

O M e

IM e

d' rn/e 213

O M e

Me

e' m/e 259

2. Alkaloids Possessing a Hemiketal or .a Ketal Ether Linkage

between C-8-C-10: Metaphanine ( 5 ) and Stephamiersine (6)

The mass spectrum of metaphanine ( 5 ) (3, 20, 21, 4 4 ) exhibits themost abundant ion peak (aor a') a t m/e 245, which may arise from the

intermediatef by homolysis of the C-5-C-13 bond and the associatedhydrogen transfer from C - 5 or C-6 to C-10 or (2-13. The hydro,aen source



398 YASUO INUBUSHI AND TOSHIRO IBUKA

derived from the intermediate f by the loss of hydrogen and the

associated C-5-C-13 bond fission (5 , 40, 44, 45 ). The cleavage mode

mentioned above is quite common for all metaphanine type alkaloidspossessing an ether linkage between c-8and C-10, and a ketone function

at (2-7. By contrast, the fragmentation of stephamiersine (6)and episte-

phamiersine (7)) which possess an ether linkage between C-8 and C-10

and a ketone function at C-6, produces the most abundant ion, i at

mle 243 rather than an ion a' a t m/e 245. This difference may be of

diagnostic significance, as it demonstrates the presence of a ketone

function a t C-6 in metaphanine type alkaloids (4U).

3. Alkaloids Possessing an +Unsaturated Ketone Group a t C Ring:

Iso-6-dehydrostephine (8) and Hasubanonine (129)

Alkaloids such as hasubanonine (129), possessing an a,/?-unsaturated

carbonyl group a t C ring, show a similar breakdown pathway as that of

metaphanine and others. An important feature of the spectra of these

alkaloids is that two intensive ion peaks are observed-one is an ion aor a' and the other is an io nj, which occurs by the loss of the ethanamine

chain from the molecule. In the case of isodehydrostephine (8)) the

most abundant ion peak, j , was found at mle 301 ( 6 ) .

0 1 +

IH

8

SCHEME

j mle 301

B. STRUCTURESF HASUBANANLKALOIDS

1. Stephisoferuline (9)

Stephisoferuline was isolated from Stephania hernandifolia, and thepresence of four methoxyl groups, one secondary amino group, an

a$-unsaturated ester moiety, and two phenolic hydroxyl groups was

shown (19).A new hasubanan ester-ketal structure (9) was assigned to




stephisoferuline on the following evidence. Hydrolysis of stephiso-

feruline afforded stephuline (10) and isoferulic acid. The former gave

N-methylstephuline (11) on methylation, confirming the presence of asecondary amino group. Treatment of 10 with dilute hydrochloric acid

led to facile demethylation of acetalmethyl t o give 8-demethylstephuline

(12) and oxidation of 10 with Jones’ reagent provided 6-dehydro-

stephuline (13).On the other hand, acetylation of 10, followed by acid

treatment, resulted in the triacetyl derivative 14, and the downfield

shift of the signal for the C-7 H (6 4.20) of 14 in its NMR spectrum

compared with that of stephisoferuline (6 3 .75) supported the assignment

of the ketone function a t C-8. ydrogenation of the triacetyl derivative

14 furnished the dihydrotriacetyl derivative 15, which on treatmentwith acetone dimethylacetal in the presence of p-toluenesulfonic acid

afforded the rearrangement product 16.The compound 16 was identified

with the base derived from aknadicine (= 4-demethylnorhasubanonine)

(17) ( 1 0 , 1 1 ) as follows. Reduction of 17 with N R H gave the C-6

epimeric alcohols 18. Acetylation of 18 gave the products that were

converted to the triacetyl derivative 16 by letting their chloroform

solution stand. This chemical correlation established the planar structure

of stephisoferuline, the stereochemistry a t C-8, C-10, -13, nd C-14,

and the absolute configuration of the molecule. Since reduction of6-dehydrostephuline (13)with NBH gave stephuline (10)solely, and the

hydride attack from the a side of 13 was predictable from inspection of

the molecular model, th e /3 configuration of the C-6 hydroxyl group was

suggested. On the other hand, chemical, spectral, and crystallographic

examinations suggested the same configuration of five of the six asym-

metric centers of stephisoferuline (9) with those of stephavanine (19)

( 6 ) .From the biogenetic analogy, the /3 equatorial configuration of the

C-7methoxyl group of 9 was presumed ( 1 9 ) .

OMe

H

9

R210

11 R, = R, = M e

12

R, = Me, R, = H

R1 R, = H




M e 0 k

HI

18

AC

14

Ac

15

AcO

\M e 0

M e 0 N M e 0 N

HI

HI

Ac

16 17 1s

2 . Stephavanine (19)

Stephavanine was isolated from Stephania abyssinica grown in

Eastern and Southern Africa, and the presence of one methylenedioxy,

two hydroxyl, one secondary amino, and two methoxyl groups in its

molecule was shown (6) .The mass spectrum of stephavanine revealed a

diagnostic fragment ion k for hasubanan alkaloids at m/e 2 1 4 (44 ,45 ) .Alkaline hydrolysis of stephavanine gave vanillic acid and stephine (20),

and the 6,7-bistrirnethylsilyl ether 21 was derived from the latter. The

NMR spectrum of 21 showed two unsplit aromatic proton signals,

indicating the methylenedioxy group attached to C-2 and C-3 of an

aromatic ring. Oxidation of 20 with Jones’ reagent provided 6-dehydro-

stephine (22), which on treatment with sodium hydroxide solution gave

isodehydrostephine (8). Of six chiral centers of 19, the relative con-

figurations of C-8, (2-10, C-13, and C-14 were inevitably established

because of the cage ring system of the stephavanine moIecuIe. The/%axial configuration of the C-6 hydroxyl, which forms an ester linkage

with vanillic acid, was deduced from the NMR spectral examination and

the /I-equatorial configuration of the C-7 hydroxyl group was suggested




by the fact that oxidation of the diol20 provided selectively the mono-

ketone 22. Thus, the structure 19 was assigned to stephavanine ( 6 ) .

This conclusion was supported by X-ray crystallographic study ofstephavanine hydrobromide ( 6 ) .

M e 0

H O G

IH

19

?"\

"H

M e 0 N

IH

22

"H

RO

M e 0 N

IH

20 R = H

21 R = &(Me),

c/

H

k mle 214

3 . Stephabyssine (23), Stephaboline (24), and Prostephabyssine (25)

Examination of basic constituents of Stephania abyssinica. collected

in Ethiopia resulted in the isolation of three new phenolic hasubanan

alkaloids-stephabyssine, stephaboline, and prostephabyssine ( 5 ) .

Stephabyssine (23) had one N-methyl, one methoxyl, one saturated

ketone, and two hydroxyl groups. The presence of a phenolic hydroxyl

group with an unsubstituted para position was presumed by a positive

color reaction with Gibbs' reagent. Methylation of 23 with methyl

iodide in the presence of potassium carbonate provided O-methyl-stephabyssine, which was identified with metaphanine (5)

(4 ,20 -25 , 46 , 47 ) . Thus, the structure of stephabyssine was established

as 4-demethylmetaphanine (23).




OM e OMe

"H HO "H. .HO N HO N

I I

0J 3 3 $ . H..HO

I

HO

I

M e

23 R = H

5 R = M e

Me

24

Stephaboline (24) was shown to possess one N-methyl, one methoxyl,and three hydroxyl groups ( 5 ) .The close relationship of stephaboline

with stephabyssine (23)was indicated by similarities in their NMR

spectra as well as positive reactions of each compound with ferric

chloride and the Gibbs reagent. Since NBH eduction of stephabyssine

gave stephaboline in a high yield, the structure of stephaboline was

established except for the configuration of the C-7 hydroxyl group. The

NMR pectrum of 24 exhibited a diffused multiplet a t S 4.4 assignable

to the C-7 H. This signal changed to a pair of doublets (JAx= 5 Hz,

J B X = 1 1 Hz)by treatment with D,O, and the magnitude of the couplingconstant of J B X suggested the axial configuration of the C-7 H, hus

confirming the equatorial configuration of the C-7 hydroxyl group (5).When treated with aqueous hydrochloric acid solution under mild con-

ditions, prostephabyssine (25) gave stephabyssine (23)with loss of the

elements of methanol in high yield. This facile hydrolysis demonstrated

the presence of an enol methyl ether located at C-6-(2-7. Consequently,

the structure 25 was assigned to prostephabyssine. Determination of the

NMR pectra of prostephabyssine in a variety of solvents gave complex

patterns indicative of the presence of the hemiketal25a and ketone 25bforms in equilibria similar to the solvent-dependent equilibria observed

in prometaphanine (26,27).

?Me ?Me

OH

HO N

I IMe Me

258 25 25bSCHEME




4. Stephamiersine (6), Epistephamiersine (7), Oxostephamiersine (26),

and Stephasunoline (28)

Reinvestigations of basic constituents of Stephania japonica grown

in Kagoshima Prefecture (the sourthern part of Japan) resulted in

isolations of four new hasubanan alkaloids: stephamiersine, epistepha-

miersine, oxostephamiersine, and stephasunoline (4 0 ,41). That the

structures of these alkaloids were closely related to each other was

presumed on the basis of their spectral data which are summarized in

Table I1 and Table 111.

TABLE I1

PHYSICALONSTANTS ND SPECTRALATA F SOMEALKALOIDSFROM Stephania japonica Miers

mp [aID IR Y : W EtoHsx MS m l e ) M+,

A1kaloid ("C) (CHCl,) (cm-') (nm) ( 6 ) base peak

Stephamiersine (6) 165 +33 1725 286 2200 389,243

Epistephamiersine (7 ) 98 +64.1 1735 286 2300 389,243

Oxostephamiersine 26) 290 +88.3 1730, 1680 286 2000 403,257

Stephasunoline (28) 233 $121.4 3550 286 2000 377,245

TABLE I11

NMR SIGNALSF SOME LKALOIDSROM Stephania japonica Miers4

Aromatic

protons N-Methyl

Alkaloid (2H) C-7-H C-10-H Methoxyl groups group

6 6.67 3.52 4.72 3.92, 3.82, 3.34, 3.31 2.64

7 6.66 4.27 4.82 3.89, 3.76, 3.52, 3.45 2.63

26 6.77 3.63 4.79 3.92, 3.83, 3.33, 3.29 3.1228 6.67 3.62 4.88 3.90, 3.82, 3.46 2.57

O Chemical shifts are quoted in 6 values.

Equilibrium experiments of either stephamiersine (6)or epistephamier-

sine (7) with 1yosodium hydroxide solution gave an equilibrium mixture

consisting of 6 and 7 in a 1:3 ratio. Consequently, 6 and 7 were epimers

attributable to an asymmetric center adjacent to a carbonyl group, and

7 was thermodynamically more stable. Furthermore, permanganate

oxidation of stephamiersine (6) gave the lactam, which was identifiedwith oxostephamiersine (26). Reduction of epistephamiersine (7) with

NBH provided dihydroepistephamiersine (27),* which on treatment

J. von Wyk.* Later. this compound waa obtained in nature from Stephuniu abyssinica by Dr. A.




with methanolic hydrochloric acid solution under mild conditions gave

stephasunoline (28).This facile hydrolysis of dihydroepistephamiersine

suggested the presence of the labile acetal methyl ether in its molecule.Thus, the chemical correlations among6,7,26,and 28 were established.

Acetolysis of stephamiersine (6) and epistephamiersine (7) provided

1,3-diacetoxy-2,5,6-trimethoxyphenanthrene29) and 1,2,3-triacetoxy-

5,6-dimethoxyphenanthrene 30), respectively. On the other hand,

acetolysis of dihydroepistephamiersine (27)gave the known 1 acetoxy-

2,5,6-trimethoxyphenanthrene (31) (26,27). On the occasion of

acetolysis of morphinan and hasubanan series alkaloids,it is well known

that a ketone function in the original molecule remains an acetoxyl

group on the phenanthrene nucleus, and an alcoholic hydroxyl group isremoved by dehydration in the course of the aromatization process

( 2 0 , 2 1 , 2 6 , 2 7 , 1 , 4 8 , 4 9 ) .From the structures of these phenanthrene

derivatives derived from 6 ,7 ,and 27, the positions of five of six oxygen

functions were confirmed, and particularly, the C-3, C-4, and C-7

positions of three of four methoxyl groups and the C-6 position for an

oxygen function in the original alkaloid molecule were established.

In the NMR spectra of 6 , 7 , and 28, a signal due to C-10 H appeared

around 6 4.8 (doublet, J = 6.5 Hz). In the spectrum of 7, the NOE

[I3y0enchancement of the signal of this doublet ( 6 4.82)] was observedwhen irradiated a t the aromatic proton signal. The signals a t 6 1.47

(doublet,J = 10.5 Hz) and 6 2.46 (double doublet,J = 10.5 and 6.5 Hz)

were assigned to the C-9 methylene protons by the double resonance

technique. From these assignments, it is obvious that an acetal ether

linkage attaches to C-10.

NBH reduction of oxostephamiersine (26) provided compound 33,

which on treatment with perchloric acid-acetic anhydride gave com-

pound 34. Oxoepistephamiersine (32) derived from epistephamiersine

(7) by permanganate oxidation was reduced with NBH to give com-

pound 35, which on treatment with perchloric acid-acetic anhydride

also afforded compound 34. Catalytic hydrogenation of 34 provided the

conjugated ketone 36. On the other hand, NBH reduction of 16-

oxohasubanonine (37) (28,38) gave epimeric alcohols (38), which on

treatment with dilute mineral acid gave the same conjugated ketone

36. From these results, the skeletal structure and the attached positions

of oxygen functions, C-6, C-7, C-8, and C-10 of oxostephamiersine (26)

were established.

The configurations of the C-7 OCH, group of these alkaloids were

deduced from the NMR spectral experiments. In the spectrum of

stephamiersine (6), signals due to the C-5 methylene protons were

observed at 6 2.86 ( l H , double doublet, J = 11.5, 1.5 Hz) and 6 3.67



7 . HASUBANAN ALKALOIDS 405

( l H , doublet, J = 11.5 Hz). The long-range coupling between the C-7

H and one of two C-5 methylene protons ( 6 2.86) was observed by the

homonuclear INDOR technique. On the other hand, the spectrum ofepistephamiersine (7)evealed signals assignable to the C-5 methylene

protons a t 6 2.99 (IH, doublet, J = 11.5 Hz) and 6 3.18 ( IH, doublet,

J = 11.5 Hz) and the NOE (6.5y0 nhancement) of the C-7 H signal

was observed when irradiated the signal a t 6 3.18 but no signal enhance-

ment was observed between the C-7 H and the signal at 6 2.99. From

these findings, together with the equilibrium experiments previously

discussed, the configuration of the C-7 OCH, was established to be a-

axial in 6 and p-equatorial in 7.The configurations of C-6 O H and

C-7 OCH, of stephasunoline (28) were also deduced from the NMRspectral examinations. The spectrum of stephasunoline exhibited signals

assignable to the C-5 methylene protons a t 6 2.46 ( IH, double doublet,

J = 14.3, 2.4 Hz) and 6 2.82 ( lH , double doublet, J = 14.3, 3.8 Hz).

When irradiated at the signal appearing at 6 2.46, the NOE (120J,

enhancement) of the C-7 H signal (6 3.62, doublet, J = 3.9 Hz) was

observed. This result, together with analysis of coupling constant values

of the signals for four protons attached t o C-5, c-6, and C-7, led to the

conclusion that the C-7 OCH, group should be p-equatorial and the

C-6 OH p-axial. Thus, the structure 28 was assigned to stephasunoline

( 4 0 , 4 1 ) .The planar structure of stephasunoline (28) is the same as that

proposed for miersine (39) ut the stereochemistry of C-6 OH and

C-7 OCH, of the lat ter has not been established (1,39).

5 . 16-Oxohasubanonine(37)

This alkaloid was isolated from Stephania japonica and identified

with 16-0xohasubanonine, which had been derived from hasubanonine

by permanganate oxidation (28, 38) .

6. 16-Oxoprometaphanine (40)

This alkaloid was isolated from Stephaniajaponica (28) .On hydrolysis

with dilute mineral acid 16-oxoprometaphanine gave known oxo-

metaphanine (41) (50, 51) and compound 34, which had been derived

from stephamiersine (6)and epistephamiersine (7 ) 4 0 , 4 1 ) . Acetylation

of 16-oxoprometaphanine gave acetyl-16-oxoprometaphanine (42),

which on treatment with dilute hydrochloric acid afforded compound

34. These chemical correlations and the NMR spectral examinations of

16-oxoprometaphacine and its transformation products supported the

structure 40 for 16-oxoprometaphanine (28).



On-

4 i

0

+ ;b Ot? O

?

2

30a



408 YASUO I NUB USHI AND TOSHIRO IBUKA

?Me ?Me

M e 0

IMe

40s 40

SCHEME

IMe

40b

@ &* .H M e 0 OAc

. .HO Fi ‘ 0 O N ‘0

I

M e

I

Me41 42

7. Delavaine (43)

Delavaine was isolated from Stephania delavayi (8) and its IR

spectrum exhibited bands at 1670 cm- (cr,p-unsaturated ketone) and

1608 cm-l (C=C double bond) (8).Hydrolysis of the methylenedioxy

group of delavaine with sulfuric acid and phloroglucinol gave the corre-

sponding dihydroxy derivative 46, which on acetylation afforded thediacetyl derivative 47. The IR absorption of the ester carbonyl (1775-

1780 cm-l) in 47 showed the phenolic nature of the hydroxyls, from

which it follows that the methylenedioxy group is attached to an

aromatic ring. On the other hand, the NMR spectrum of delavaine

exhibited two unsplit aromatic proton signals a t 6 6.41 and 6 6.64.

Consequently, it is obvious that the methylenedioxy group is at the

C-2 and C-3 position of the aromatic ring. The Hofmann degradation of

delavaine methiodide formed the methine base 44,which on acetolysis

furnished the acetoxy-methoxy-phenanthrene derivative 45 (8),suggesting that delavaine belongs to the hasubanan alkaloids. In the

NMR spectrum of delavaine, signals were present for N-methyl (6 2.49)

and methoxyl(6 4.06 and 6 3.60) groups, and the C-5 methylene proton




0 1

IMe

43

M e 0

M e 0& M e 0/ \

Me Me

4 4

45M e

46 R = H47 R = Ac

signals appeared a t 6 2.46 (doublet, J = 16 Hz) and 6 3.00 (doublet,

J = 16Hz). However, no C-9 H signal of the morphinan skeleton

between 6 3.00 and 6 4.00 (52-55) was observed, thus demonstrating

the hasubanan skeleton for delavaine. Consequently, structure 43 was

proposed for delavaine ( 8 ) , but no positive evidence regarding the

stereochemistry of the ethanamine bridge is presented.

8. 16-Oxodelavaine(48)

16-Oxodelavaine was isolated from Stephunia delavayi grown in

Transcaucasia ( 9 ) .The UV spectrum of this alkaloid was similar to that

of delavaine (8), and the IR spectrum showed bands for an a,/?-

unsaturated ketone (1686 cm-') and a lactam carbonyl (1670 cm-l)

function. In the NMR spectrum, signals were present for two isolatedaromatic protons ( S 6.64, 1H, singlet and S 6.46, 1H, singlet), methylene-

dioxy ( 6 5.88, 2H, singlet), two methoxyl ( 6 4.10 and 3.66 each 3H and

singlet), and an N-methyl (6 2.96, 3H, singlet) groups, and the c-5




methylene protons (6 2.90, lH, doublet, J = 16 Hz and 6 2.66, lH,

doublet, J = 16 Hz). After various chemical, physicochemical, and

spectral investigations, the structure 48 was proposed for16-oxodelavaine (9).

M e

48

9. Hernandifoline (49)

Hernandifoline was isolated from Stephania hernandifolia grown in t h e

Black Sea littoral of Caucasia ( 1 6 ) .The presence of four methoxyl, onesecondary amino, two hydroxyl, and one a,p-unsaturated ester groups

was shown. Methylation of hernandifoline (49) with methyl iodide

afforded A'-methylhernandifoline (50), and alkaline hydrolysis of 49

gave a base (51) and hesperetic acid. The NMR spectrum of 51 revealed

signals for two aromatic protons (6 6.49, 2H, singlet), C-10 H (6 4.76,

doublet, J = 5.8 Hz) , C-6 H (6 4.07, multiplet), C-7 H ( 6 3.62, doublet,

J = 4.0 Hz), C-3 OCH, (6 3.67, singlet), C-8 OCH, ( 6 3.50, singlet),

C-7 OCH, (6 3.38, singlet), C-5 methylene protons (6 3.04, 1H, quartet ,

J = 14.9, 3.5 Hz and 6 1.85, 1H, quartet , J = 14.9, 2.8 Hz), C-6 OH(6 2.13, l H , double t,J = 10.0 Hz), C-9 methylene protons (6 2.34, 1H,

quartet, J = 10.8, 5.8 Hz and 6 1.80, lH, doublet, J = 10.8 Hz). The

mass spectrum of 51 showed the pattern characteristic for the hasuba-

nan alkaloids (44 ) ,m/e 363 ( M + ) ,217, and 216. Methylation of 51 with

methyl iodide in methanol gave substance52and the further methylation

of 52 with diazomethane gave compound 53. Following spectral investi-

gations of the alkaloid and its degradative compounds, the structure of

hernandifoline except the configuration at the C-7 OCH, group was

proposed as 49 (16).This structure is the same as that proposed forstephisoferuline (9) ( 1 9 ) ,except for the configuration of the C-7 OCH,

group. The reported melting points of hernandifoline (49) (227-227.5"C),

the compound (51) (225-226"C), and the compound (52) (154-155°C)




HO

M00Q7=~Lo@\ Ho&

* .H.H

. . M e 0 . :

IR2

M e 0

* .M e 0 N

R

M e 0 kI

49 R = H

50 R = M e51

52

53

R, = R, = H

R, = H, R, = M e

R, = R, = M e

differ from those of stephisoferuline (9) (133-135OC), stephuline (10)

(223-225°C)) and N-methylstephuline (11) (126-128%), but there has

been no report of direct comparisons of these alkaloids.

10. 3-0-Demethylhernandifoline (54)

3-0-Demethylhernandifoline was isolated from Stephania hernandi-folia,and the presence of three hydroxyls, one secondary amino, and

three methoxyl groups was shown ( 1 8 ) . The IR spectrum exhibitedbands for OH and NH a t 3560, 3440, and 3200-2700 cm-l, a carbonyl

group at 1695 crn-l, and a conjugated double bond a t 1640 cm-l. In

the NMR spectrum signals were present for three methoxyls (6 3.89,

3.41, and 3.40), ortho-coupled aromatic protons (6 6.50, lH, doublet,

J = 8.0 Hz and 6 6.60, 1H, doublet, J = 8.0 Hz), the C-5 methylene

protons (6 2.02, lH, double doublet, J = 15.0, 2.3 Hz and 6 3.17,1H,

double doublet, J = 15.0, 4.1 Hz), C-6 H (6 5.40, lH, multiplet), C-7 H(6 3.74), and C-10 H (6 4.88, l H , doublet, J = 5.8 Hz) .

On alkaline hydrolysis, 3-0-demethylhernandifoline gave hesperetic

acid and an amine (55))which gave an intense color reaction with ferric

IH

54

IH

55




chloride characteristic for o-phenols. Methylation of 55 with methyl

iodide, followed by treatment with diazomethane, furnished the

N,O,O-trimethyl derivative, which was identical with compound 53 ( 1 6 )derived from hernandifoline. From these chemical correlations, structure

54 was proposed for 3-0-demethylhernandifoline.

11 . Hernandine ( 5 6 )

Hernandine was isolated from Xtephania hernandifolia, and the pres-

ence of one N-methyl, two methoxyl, and three hydroxyl groups was

suggested ( 1 3 ) .The mass spectrum of this alkaloid revealed a character-

istic fragment ion peak for hasubanan alkaloids a t m/e 231 (13 , 44 , 45).The NMR spectrum of hernandine showed signals for C-10 H (8 4232,

OMeI

. :/J

R20 N

M e

56

I

R, = H, R, = M e

R, = Me, Ra = Hr

1H, doublet, J = 6.2 Hz), C-9 methylene protons (8 1.51, lH, doublet,

J = 10.8 Hz and S 2 . 8 5 , 1H, double doublet, J = 10.8, 6.2 Hz), C-6 H

( 6 4.15, lH, multiplet), C-7 H (8 3.58, lH, doublet, J = 3.8 Hz) , and

C-5 methylene protons (6 3.09, lH, double doublet, J = 14.6, 3.5 Hz

and 6 1.95, l H , double doublet, J = 14.6, 2.4 Hz) . The axial con-

figuration of C-6 OH was determined from the values of th e spin-spin

coupling between the C-5 methylene protons and c-6 H . From these

results, st ructure 56 was proposed for hernandine ( 1 3 ) ,but the absolute

configuration of the ethanamine bridge, the configuration of the C-7

oxygen function, and the position of one of two methoxyl groups have

not been definitely established.

12. Methylhernandine (57 )

Methylhernandine was isolated from Steph ania hernandifolia, and the

presence of one N-methyl, two hydroxyl, and three methoxyl groups

was suggested ( 1 4 ) . On acetylation, methylhernandine gave diacetyl-




methylhernandine, the IR spectrum of which showed carbonyl bands

a t 1775 and 1730 cm-l, indicating that one of two hydroxyl groups is

phenolic and the other alcoholic. In the NMR spectrum of methylhern-andine, signals were present for C-5methylene protons (S 1.93,lH, double

doublet, J = 14.8, 2.9 H z and 6 3.00, lH, double doublet, J = 14.8,

: : /M e 0 N

M e

57

3.4 H z ) , C-6 H ( 6 4.05, H, multiplet), C-6 O H (6 2.24, doublet, J =

9.8 H z ) , C-7 H (6 3.62, lH, doublet, J = 4.1 Hz), C-10 H (6 4.81, lH ,

doublet, J = 6.2 H z ) , and C-9 methylene protons ( 6 1.45,1H, doublet,

J = 10.8 Hz and 6 2.63, l H , double doublet, J = 10.8, 6.2 Hz). Since

methylhernandine was identified with compound 52 ( 1 6 )derived fromhernandifoline (49) ( 1 6 ) , structure 57 was proposed for methyl-

hernandine ( 1 4 ) .

13. Hernandolinol (58)

Hernandolinol was isolated from Stephunia hernandifolia grown in

Caucasia, and the presence of one N-methyl, three methoxyl, and two

hydroxyl groups was suggested. On Hofmann degradation, hernandol-

in01 gave the methine base (mp l14-115°C), which on acetolysisafforded the diacetoxydimethoxyphenanthrene derivative (mp 163-

164OC) ( 1 5 ) . This methine base and phenanthrene derivative were

OMe

Me

58




identified with the methine base and phenanthrene derivative derived

from hernandoline, respectively (I? ),and hernandolinol was proved to

be identical with the reduction product of hernandoline with sodiumborohydride. Thus, structure 58, without stereochemical implications,

was proposed for hernandolinol (15 ) .

IV. Synthesisof the Hasubanan Skeleton

The synthesis of the hasubanan skeleton has been undertaken in

several laboratories with a remarkable degree of variability in thesynthetic schemes.

A. STNTHESISIA KETOLACTONES

Annelation reaction of the ketoester 59 with methyl vinyl ketone

provided the ketolactone 60. Three methods available for introduction

of the nitrogen atom into this ketolactone have been reported. The first

method was reported by Inubushi et al. Treatment of the ketal lactone61 from the ketolactone 60 with methylamine in the presence of methyl-

amine hydrochloride gave the ketolactam 63 and the ketal amide 68

(56-58). Similarly, the ketoester 64 rovided the ketal lactone 66 and the

ketolactam 67 via the ketolactone 65. The second method was developed

by Evans et al. Reaction of the ketolactone 60 with methyl iodide in the

presence of potassium carbonate gave the unsaturated ketoester 62,

which on treatment with LAH-methylamine furnished the ketolactam

63 ( 5 9 , 6 0 ) .The last method was reported by Tahk et al. Reaction of the

ketal lactone 61 with a large excess of methylamine gave the ketal amide68, which was reduced with LAH to give the amino alcohol 69, acid

R R R

59 R = H 60 R = H64 R = OMe 65 R = OMe

61 R = H66 R = OMe




62

M e

63 R = H

67 R = OM e

IMe

68 R = O69 R = Hz

IMe

70

treatment of which afforded 7-0x0-N-methylhasubanan (70) ( 6 1 ,6 2 ) .The main disadvantage of these three methods was the low yield in the

nitrogen introduction step.

B. SYNTHESISIA KETONITRILES

This procedure consists in the Robinson annelation reaction of the

ketonitrile (71 or 72) with methyl vinyl ketone. Treatment of the

ketonitrile 71 with methyl vinyl ketone provided the separable stereo-

isomeric mixture 73.Treatment of the mixture with sodium alkoxide

NC

4Nc8H

&%

Mo OH IH

71 R = H 73 R = H

72 R = O M e 74 R = O M e

75 R = H

76 R = OMe




gave the ketolactam 75. Similarly, the ketonitrile 72gave the ketolactam

76 (57, 5 8 ) . This procedure is of practical value because of acceptable

yields and simpler operations compared with the former methods.

C. SYNTHESISIA CYCLICENAMINES

1. Stork-Robinson Annelation Reaction

Synthesis of the key intermediate, the cyclic enamine 79, is analogous

to that of 3-arylpyrroline in the mesembrine synthesis (63-65) . Three

methods available for synthesis of this intermediate have been developed.

Reaction of /3-tertralone (77)with 1,2-dibrornoethane gave the

spiroketone 78, which on treatment with methylamine furnished the

cyclic enamine 79 ( 6 1 ) .On the other hand, ketalization of the ketoester

77 R = H 78

59 R = CH,CO,Et

80

M e

79

Me

81

59, followed by treatment with LAH-methylamine, afforded the ketal

amide 80. Successive treatments of 80 with LAH and aqueous acid

solution provided the cyclic enamine 79 (59, 60). Further, reaction of

p-tetralone (77) with excess methylamine, followed by treatment with

titanium tetrachloride, yielded the enamine 81. When reacted with iso-

propylmagnesium chloride, this enamine gave the "bidentate" nucleo-

phile which on treatment with bromochloroethane gave the cyclicenamine 79 (60). The cyclic enamine 79 thus synthesized was reacted

with methyl vinyl ketone to yield 7-oxo-N-methylhasubanan (70) in a

moderate yield (60-62).




2 . [4 + 21 Cycloaddition and [2,3] Sigmatropic Rearrangement

A unique and elegant synthesis of hasubanan derivatives was re-

ported by Evans e t al. (66).Upon heating equimolar quantities of the

sulfoxide 82 with the cyclic enamine 79, diastereoisomer mixture of

the sulfoxide 83 as well as some rearrangement amino alcohol 84 was

obtained, indicating that [4 + 21 cycloaddition and [2,3] sigmatropic

rearrangement were occurring consecutively. When heated with sodium

sulfite, the unpurified reaction product from 79 and 82 afforded the

<82 R = S-CSH,

J.0

85 R = C 0 ,Me

. .C,H,-S N

10 Me

83

M e84

M e86

desired amino alcohol 84. The evidence th at 84 is a single isomer rather

than an epimeric mixture was derived from its behavior on tlc, its

cleanly resolved NMR spectrum, and the sharp melting range of the

amine salt. The syn relationship between hydroxyl and nitrogen func-

tion was deduced from the observance of intramolecular hydrogen

bonding in the IR spectrum. Similarly, addition of methyl pentadienoate

to the cyclic enamine 79was also found to afford the nicely crystallinetetracyclic ester 86 in 50% yield. Qualitatively, it appeared that the

sulfoxide-substituted diene 82 was slightly less reactive than the ester-

substituted diene 85 (66) .




D. SYNTHESISIA SPIROKETONE

Another synthetic route for hasubanan derivatives was devised re-cently by the Bristol-Myers group. Alkylation of 7-methoxytetralone

(87)with 1,4-dibromobutane n the presence of sodium hydride gave the

87

OMeI

91

88 89 R = CN90 R = CH2NH,

OMe

(-yg. Br

IH

92

spiroketone 88, which was transformed into the hydroxynitrile 89 by

treatment with acetonitrile in the presence of n-butyllithium. LAH

reduction of 89 furnished the amine 90, which on treatment with con-

centrated hydrochloric acid gave the amine 91. Treatment of 91 with

one equivalent of bromine yielded 3-methoxy-9-bromohasubanan92)

in good yield (67, 74 ) .

A new synthetic method of dl-3-methoxy-N-methylhasubananas

been explored recently (75). Treatment of 91 with formalin in formicacid afforded dl-9,10-dehydro-3-methoxy-N-methylhasubanan,hich

was derived into dl-3-methoxy-N-methylhasubanan y catalytic

hydrogenation (75).




E. SYNTHESISY PHENOLXIDATION

Treatment of reticuline (93) with trifluoroacetic anhydride, followedby catalytic hydrogenation yielded the amide 94. Treatment of 94 with

vanadium oxytrichloride gave rise, by phenol oxidation, to the dienone

95, which was transformed into the enone96 by treatment with aqueous

potassium carbonate solution. When reacted with methanolic hydro-

chloric acid, the enone 96 provided the cepharamine analog 97 (68).

O M e

HO

M e 0 )y93

M e 0 ,M e 'COCF3

Md3(3Ho / , /

M e 0u

94 95

O M e O M e

I

M e96

IM e

97

V. SynthesisofHasubanan Alkaloids

The syntheses of hasubanan alkaloids are of interest in connection

with their pharmacological activities, since these alkaloids involve the

structural unit of prafadol (98) (69) ,which is used as a potent analgesic.

Hasubanan alkaloids are classified into three groups-the cepharamine,

hasubanonine, and metaphanine types-on the basis of the oxidationstage at the B and C rings. The representative of each group has been

synthesized from the common intermediate, the ketolactam 67, with an

exception of one of two cepharamine syntheses.




OMe OMe OMe

Me

106

Me

107

IMe

108

Another synthetic route to cepharamine utilizing photocyclizationwas designed. Heating of 2’-bromoreticuline (109) with trifluoroacetic

anhydride, followed by catalytic hydrogenation, provided the dihydro-

methine 110. Irradiation of 110 with a mercury lamp in the presence of

sodium hydroxide and sodium iodide gave the dienone 111. Hydrolysis

of the amide function of 111 caused the Michael addition to yield an

isomer of cepharamine. Transesterification of 112with hydrochloric acid

in methanol provided a mixture of cepharamine (108)and the starting

material 112, from which cepharamine was isolated in a pure state (7 1 ) .

M e 0

HO

H o d

M e 0109

?Me

M e 0

ICOCF,

111

HO

yJJM e 0

110

M e 0&I

M e

112




B. HASUBANONINEND AKNADILACTAM

In the synthesis of hasubanonine (129) from the ketolactam 67,introduction of two more oxygen functions at the C-6 and C-8 positions

are required. Oxidation of the ketolactam 67 with lead tetraacetate in

the presence of boron trifluoride etherate gave three acetates-l13,114,

and 115. In order to avoid the production of the undesired acetates 114

and 115, a lowering of the electron density of an aromatic ring was

preferable. Thus, similar oxidation of the ketolactam 104 possessing an

acetoxy group a t C-4 with lead tetraacetate was tried, and the acetoxy-

ketone 116was solely obtained in 65% yield. Treatment of 116with two

equimoIar quantities of bromine, followed by heating with sodiumacetate, provided the enol acetate 117 and the bromoacetate 118 in a

1 O : l ratio, but the yield of 117 was rather poor. However, the acetoxy-

ketone 116 was brominated with pyridinium hydrobromide perbromide,

and the reaction product 119 was heated with sodium acetate to give

solely the enol acetate 117. Partial hydrolysis of the enol acetate func-

tion of 117 provided the a-diketone 120, which was brominated to give

@\ o& o&A(

N/-0. .H . f

\O- .

R N \O AcO N

I I I

Me

67 R = H

113 R = OAc

Me

114

Me

115

R O RO. .R N

I IMeMe

104 R = H 117 R = AC 118 R = AC

116 R = OAc 120 R = H 121 R = H

122 R = Me

M e




O MeM eM e

Br\

&0 . :

0

M e 0

Br

M e 0. :fro

AcO NI I

M eI

M ee

1 1 9 1 2 3 1 2 4

OMe OM0 ?Me

0

M e 0

M e 0

M e 0

IM eMe

IM e

1 2 925 R = M e

127 R = H

126 R = M e1 2 8 R = H

the bromoketone 121 in high yield. Methylation of 121 with diazo-

methane furnished compound 122, which was heated in an aqueous

sulfuric acid according to the Hesse’s procedure to produce pre-dominantly the p-diketone 123 together with the compound 124. The

p-diketone 123 was methylated with diazomethane, and silica gel

chromatographic separation gave 16-oxohasubanonine (125) and its

isomer (126) from the earlier eluate in a 1:1 ratio, and continued elution

provided aknadilactam (127) and its isomer (128) in a 1 1 ratio. On the

other hand, permanganate oxidation of hasubanonine produced optically

active 16-oxohasubanonine (28,38),a sample of which was proved to be

identical with th at of the synthetic one (125)except in optical rotation.

Since LAH reduction of 16-oxohasubanonine followed by oxidationwith activated manganese dioxide regenerated hasubanonine, the syn-

thesis of 16-oxohasubanonine is equivalent to the complete synthesis of

hasubanonine (129) (38, 72).




C. METAPHANINE

The ketolactam 67 was also chosen as the starting material for themetaphanine synthesis. Since the introduction of an oxygen function

at the C-S position of 67 had been established during the synthesis of

hasubanonine, the major problems are the stereoselective introduction

of the C-10 hydroxyl group trans to the ethanamine bridge and the

selective reduction of the lactam carbonyl group when both the lactam

carbonyl and the hemiketal ring are present. Oxidation of 100 and 130with chromic anhydride-acetic acid gave lo-0x0 compounds 131 and

132, espectively, but the yields were rather poor and irregular. The

synthetic intermediate that had been utilized for the hasubanoninesynthesis was converted to its ketal derivative 133.Chromic anhydride

oxidation of 133 provided the 10-0x0 ketal lactam 134 in high yield.

Hydrolysis of the acetoxyl groups of 134, ollowed by methylation with

diazomethane, produced 10-0x0 compound 135.For the purpose of the

hemiketal formation between C-8 and C-10, the relative configuration of

the hydroxyl group derived from C-10 0x0 group must be trans to the

ethanamine bridge. (The terms “cis” and “trans” in this section are

H

Me Me Me

100 R = H, 130 R = H, 133 R = H,131 R = 0 132 R = 0 134 R = 0

“OR

M e Me Me

135 136 R = H 137

143 R = Ac



7 . HASUBANAN ALKALOIDS

O M e O M e

425

OMo

M e

138 R = H

139 R = AC

140 R = THP

M e

141 R = Ao

142 R = THP

IM e

144

used to express the relative configuration of the C-10 hydroxyl group to

the ethanamine bridge.) Reduction of 135 with various metal hydrides

was tried, but the major product was the undesired cis C-10 hydroxyl

compound 136, although the cis-trans ratio varied depending on sol-

vents and metal hydrides used. Catalytic hydrogenation of the C-10

0x0 compounds 135 and 137was unfruitful. Next, reduction of 135 with

sodium in various alcohols was examined, and in this case, the yield of

the trans isomer was superior to that of the cis isomer. However, thetotal yield was rather poor. Finally, reduction of 135 was successfully

carred out by the Meerwein-Varley procedure to give the trans C-10

hydroxyl compound 138 in an excellent yield. After the hydroxyl

group at C-10 of 138 was protected as an acetoxyl group or a pyranyl

ether group, the acetate 139 or the pyranyl ether 140 was oxidized to

produce the C-8 0x0 compound 141 or 142, Removal of the protected

group afforded 16-oxometaphanine.

Jones’ oxidation of the cis C-10 acetoxyl compound 143 gave the

ketoacetate 144, which on treatment with aqueous sodium carbonatesolution produced the C-10 0x0 compound 135.This rearrangement was

assumed to be caused by an intramolecular 1,4 hydride shift from C-10

to C-S of compound 144. In order to demonstrate this mechanism, 135

was converted to the deuterated c is C-10 hydroxyl compound 145,

which gave the deuterated cis C-10 acetate 146 by acetylation. Jones’

oxidation of 146 gave the C-S 0x0 compound 147, which on treatment

with aqueous sodium carbonate solution produced quantitatively the

C-10 0x0 compound possessing deuterium a t C-S with the ,l3 configura-

tion, as indicated by the mechanism shown in 148.Thus, validity of the1,4-hydride shift was verified, and the stereochemistry of the C-10

oxygen functions, which was based on the NMR spectral analyses, was

chemically established.




OR

M eI

Me Me

147 14845 R = H

146 R = Ac

"H OTHP

M e Me Me

149 150 R = 0 151155 R = S

. H

HO N

Me Me

156 157

IMe

152 Rl = <:I, R, = 0

153 Rl = 0, R, = S

154 1, 0, R, = H,

The last step of this synthesis was reduction of the lactam carbonyl

group of 150. Since this compound possesses a masked carbonyl group,

the protection of the C-8 hemiketal hydroxyl group was examined, bu tall trials were unfruitful. Reduction of the pyranyl ether 142 with LAHand then oxidation of the resulting amine 151did not lead to the desired

(2-8 0x0 compound. Furthermore, Raney nickel reduction of the thio-




lactam 153 derived from the ketal lactam 152 gave the amino ketone

154, whereas a similar reduction of the thiolactam 155 derived from the

compound 150 did not give the corresponding amino ketal. Finally, thelactam carbonyl group of 150 was converted to the imino ether by

treatment with th e Meerwein reagent, and reduction of this imino ether

with NBH resulted in the amino ketal 156. Finally, hydrolysis of the

ketal function provided metaphanine (157) (50, 5 1 ) .

VI. Biosynthesis

Although the biosynthesis of the hasubanan alkaloids has not beenfully established, hasubanonine (158) and protostephanine (159) have

been shown by tracer experiments to be biosynthesized from two

different C-6-C-2 units (73).The nature of the building block of 158 and 159 was examined by

feeding (2RS)-[2-14C]tyrosine (160), (2RS)-[2-14C]dopa (161), [2-14C]-

tyramine (162),and [2-14C]dopamine 163) to Stephaniajaponica plants.

The results from these experiments showed that (a) both alkaloids are

built from two different C,-C, units derivable from tyrosine; (b) one

unit is a phenethylamine formed from both tyramine (162)and dopamine(163), and it generates ring C with i ts attached ethanamine residue for

both natural products; and (c) dopa (161) affords only this same

phenethylamine unit.

OMe

IMe

158

OMe

@ e

MeO" OMe

159 160 R = H161 R = OH

162 R = H

163 R = O H

H O R2

166 R, = OH, Rz = OMe64 R = OH

165 R = O M e 167 R1= OMe, F22 = OH



428 YASUO INGRUSHI AND TOSHIRO IBUKA

168

R = H or OMe HoDc‘

169

R = OH or OBIe

Four I*C-labeled amines (164-167) and the putative isoquinoline

intermediates were synt,hesized and tested in Stephania japonica plants.

None of the isoquinolines was incorporated, but the amines 164 and

165 acted as precursors of 158 and 159. Degradation of hasubanonine

proved th at the trioxygenated C,-C, unit had been built specifically

to form ring C and its ethanamine side chain. These findings show thatthe biosynthesis of hasubanonine (158) and protostephanine (159) in

Xtephania japonica involves the first of the two alternatives above, and

rejection by the plants of bases 166 and 167 indicates t ha t further 0-methylation is not the next step. By combining building block 165

with residue 168 or 169, a set of isoquinolines and bisphenethylamines

can be designed to allow selection of the natural advanced inter-

mediatefs)for the biosynthesis of 158 and 159 from the large number of

structures that are possible (73) .

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7 . HASURANAN ALKALOIDS 429

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Khim. Prir. Soedin. 8, 130 (1972); CA 77, 72561w (1972).

19. S. M . Kupchan and M. I. Suffness, T e t . Le t t . 4975 (1970).

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21. M . Tomita, T. Ibuka, Y. Inubushi, and K. Takeda, Chem. Pharm. Bull. 13, 695,

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27. M . Tomita, Y. Inubushi, and T. Ibuka, J. Pharm. SOC. pn. 87, 381 (1967); CA

28. Y. Watanabe, M. Matsui, and M. Uchida, Phytochemistry 14, 2695 (1975).

29. M. Tomita, Y. Watanabe, and K . Okui, J. Pharm. SOC. pn. 76, 856 (1956); C A

30. Y. Watanabe, M. Matsui, and K. Ido, J . Pharm. SOC. pn. 85, 584 (1965); C A

31. T. Ibu ka and M. Kitano, Chem. Pharm. Bull. 15, 1939 (1967).

32. M. Tomita, T. Ibuka, Y . Inubushi, Y. Watanabe, and M. Matsui, Tet. Lett. 2937

33. T. Ibu ka, M. Kitano, Y. Watanabe, and M. Matsui, J . Pharm. SOC.513%. 7, 1014

34. H. Kondo and M. Satomi, Annu. Rep. I T S U U L a b . 8 , 6 (1957);C A 51, l7956i (1957).

35. Y. Watanahe and H. Matsumura, J . Phurm. Soc. Jpn. 83, 991 (1963);C A 60,4201d

36. T. Ibuka and M.Kitano, Chem. Pharm. Bull. 15, 1809 (1967).

37. D. H. It. Barton, G . W. Kirby, and A. Wiechers, J . Chem. SOC.C 2313 (1966).

38. T. Ibuka, K. Tanaka, and Y. Inubushi, Chem. Pharm. Bull. 22, 782 (1974).

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40. M.Blatsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Tet. Lett. 4263 (1973).

41. M . Matsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Chem. Pharm. Bull. 23, 1323

42. J.Kunitomo, Y. Okamoto, E. Yuge, and Y. Nagai, T e t . L e t t . 3287 (1969).

43. J. Kunitomo, Y. Okamoto, E. Yuge, and Y . Nagai, J. Pharm. SOC. pn. 89, 1691

44. 31. Tornita, A. Kato, and T. Ibuka, T e t . Lett . 1019 (1965).

45. 11. Tomita, A. Kato, and T. Ibuka, M a s s Spectrose. (Tokyo) 13, 115 (1965).

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(1964).

work: C. W. Thornber, Ph.ytochemistry 9, 157 (1970).

(1975).

(1969);C A 71, 113125d (1969).




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51. T. Ibuka, K. Tanaka, and Y. Inubushi, Chem. Pharm. Bull. 2 2 , 907 (1974).

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J. Am . Chem. SOC. 5, 7910 (1973).



-CHAPTER 8-

THE MONOTERPENE ALKALOIDS

GEOFFREY. CORDELL

University of Illilzois

Chicago. Illinois

I. Introduction ........................................................ 432

432

A. Skytanthine ..................................................... 432

B. Tecomine and Tecostanine ........................................ 435

C. Tecostidine ...................................................... 437

D. Hydroxy- a nd Dehydroskytanthines ................................ 438

E. Actinidine ....................................................... 440

F. The Quaternary Alkaloids of Valeriana oflcinalis .................... 442

G. Boschniakine (Indicaine) an d Boschniakinic Acid (Plantagonine) . . . . . . . 443

H. N.Normethy1skytanthine .......................................... 445

I. 4-Noractinidine .................................................. 446

J. Cantleytine ...................................................... 446

K. Venoterpine (Gent ialutine) an d Isogentialutine ....................... 448

L. Leptorhabine .................................................... 450

M.Bakankoside ..................................................... 450

N. Gentianine ...................................................... 452

0 . Fontaphilline .................................................... 454

P. Gentianadine .................................................... 455

Q. Gentianidine ..................................................... 456

R

.Gentianamine ................................................... 457

S. Gentioflavine .................................................... 457

T. Gentiocrucine, Enicoflavine, and Gentianaine ........................ 458

U. Jasminine ....................................... ............. 462

V. Gentiatibetine and Oliveridine ..................... . . . . . . . . . . . . . 463

w .Unnamed Alkaloids from Gentiana tibetica .......................

I1. Isolation an d Structure Elucidation of the Monoterpene Alkaloids .........

..............................................d Pediculinine ...................................... 466

111- Biosynthesis and Biogenesis of the Monoterpene Alkaloids ................ 470

A. Skytanthines .................................................... 470

B. Alkaloids of Tecoma st am ......................................... 487c. Actinidine and the V a l e k n a Alkaloids ............................. 487

D. Gentianine ...................................................... 488

E. Gentioflavine .................................................... 489

. Pedicularine, Pedicularidine, and Pediculine ......................... 467

F. Biogenesis. . . . . . . . . . . . ................................... 492



432 GEOFFREY A. CORDELL

IV. Pharmacology of the Monoterpene Alkaloids. ...........................A. Actinidine .......................................................

B. Tecomine and Tecostanine ........................................C. Gentianadine ....................................................D. Gentianine ......................................................E. Skytanthine .....................................................F. Summary .......................................................References .........................................................

499

500

500500

500

502

502

502

I. Introduction

Original thoughts on the biogenesis of the monoterpene alkaloids, inparticular gentianine (l), entered on the prephenic acid hypothesis.

When Thomas ( 2 )and Wenkert ( 3 ) ntroduced their theories on indole

alkaloid biosynthesis from an iridoid precursor, i t became clear that the

other alkaloids could also be derived from the iridoids. The alkaloids,

rather than condensing with tryptamine/tryptophan with subsequent

reaction, would condense with ammonia and give a series of alkaloids

containing a C,, unit. Since these early days, a substantial number of

alkaloids formed in this manner have been isolated. As further com-

pounds of this type were isolated, two distinct types became apparent,the iridoids and those with a cleaved cyclopentane ring, the secoiridoids.

The organization of this chapter is based on this distinction as applied

to the monoterpene alkaloids. Thus, the alkaloids derived from a

secoiridoid are treated later. This approach is continued in the section

dealing with the biosynthesis and biogenesis.

Original interest in many of the plants from which these alkaloids

have been isolated was in most cases based on experimental or folkloric

experience with the crude drug. This data and subsequent work on the

pharmacology of the alkaloids isolated from these drugs concludes thischapter. A number of reviews of this general area are available (4-18) .

11. IsoIation and Structure Elucidationof theMonoterpene Alkaloids

A, SKYTANTHINE

Coincidentally, in 1961, two groups (19-22) isolated “skytanthine”

from the Chilean shrub Skytanthus acutus (Apocynaceae)and a year later

a third isolation was reported (23).Degradation of skytanthine demon-

strated the bicyclic nature and the location of one of the methyl groups



8. MONOTERPENE ALKALOIDS 433

and permitted formulation 1 in which the methyl group on the five-

membered ring could not be placed ( 2 0 , 2 2 ) .

One of the first applications of NMR spectroscopy in the area ofnatural product structure elucidation was used successfully for sky-

tanthine ( 2 0 , 2 2 ) .The NMR spectrum of the dehydrogenation product

established the presence of thirteen protons, and together with the

analytical data for the picrate, supported a molecular formula of

C1,H,,N. Five lines of a sextet were visible in the NMR spectrum at

6 3.2 ppm. Thus, the dehydrogenation product could be represented as

either 2 or 3,and the latter was favored on biogenetic grounds. Com-

pound 3 was very similar to the actinidine isolated by Sakan ( 2 4 ) .

Direct comparison of the natural actinidine and the dehydrogenationproduct of skytanthine confirmed their identity. Skytanthine, therefore,

has structure 4, for which no stereochemistry could be assigned.

CH3

1 2 3

A different approach was used by the Italian workers ( 1 9 , 2 1 ) .

Analytical data indicated two C-methyl and one N-methyl groups and

a molecular formula C,,H,,N. Dehydrogenation afforded a substituted

pyridine, which must also be joined to a five-membered ring. On this

basis, it was suggested that skytanthine was a monoterpene alkaloid,

and three structures were proposed in accordance with the isoprene rule.

Once again, the dehydrogenation product was established as actinidine.Differences in the physical constants of the materials isolated by the

Italian group (19 , 21 ) and by Appel and Miiller (23)led to a more careful

examination of the problem.




Gas chromatography of skytanthine indicated the presence of four

peaks ( 2 5 ) .A number of stereochemical possibilities are available for

skytanthine, and four of these were synthesized ( 2 5 ) from the a-, ?-,y-, and 6-nepetalinic acids ( 2 6 ) by LAH reduction, ditosylation, and

cyclization with excess methylamine. I n this way the pure skytanthines

5 ,6 , 7 ,and 8 were obtained having [.ID and picrate properties as shown

( 2 5 ) . Similarly, the Italian group also synthesized a-, ?-, -, and

S-skytanthine (2 7 , 2 8 ) . Preparative gas chromatography demon-

strated that a-, ?-,nd &skytanthine were present in the original

skytanthine, the /? isomer 6 predominating (25). Later, gas chromatog-

raphy (2 9 , 3 0 ) and thin-layer chromatography (31 , 32) were used to

demonstrate that the percentages of /3-, a-, nd &isomers were 70, 20,and 3oJ, respectively.

CH,

5

a

r a 1 D + 79"

Picrate mp 120°C

CH,

B

6

+ 16'

135°C

ICH3

7

Y

+59

162°C

I

CH38

6

+ 9"

139°C

A study of the Hofmann elimination of a-,?-,- , and 6-skytanthines

( 3 0 ) unearthed pronounced differences in product composition. These

subtle differences were correlated with the stereochemistry of the

starting materials, resulting in differences in the elimination versus

regeneration of tertiary amine reactions.Careful isolation work demonstrated that both the a- and /?-Sky-

tanthines were absent from freshly collected roots of Skytanthus acutus( 3 3 , 3 4 )but were present in the dried branches.




Aspects of the early work on Skytanthus alkaloids have been

summarized ( 4 ,6) .

Oxidation of /3-skytanthine (6)with 30y0 ydrogen peroxide affordedthe N-oxide (9) and this process was reversed with Zn/dilute HC1

( 3 3 , 3 5 ) . 3-Skytanthine N-oxide was also obtained from the leaves ( 3 3 )and roots ( 3 5 )of S. acutus. The precursors of a- and /3-skytanthine in

S. acutus are still unknown, but it has been suggested that the N-oxide

(9) is the natural product, which is reduced during steam distillation by

the sugars present.

Further investigation of S. acutus by Gross and co-workers ( 3 6 )afforded a base, which by its mass spectrum was shown to be a fully

saturated skytanthine derivative. The characteristic ions a t m/e 84 dueto 10 as well as smaller fragments at m/e 58, 11, the base peak, and

mle 44, 12, were observed in the mass spectrum.

The base formed a picrate (mp 144-146°C) and a methiodide (mp 300-

302°C). This information together with the low optical rotation

+ loo) ndicated that the free base was &skytanthine (8) ( 3 6 ) .

‘‘(@,cH3 7 CHZN ,CH3

CH3 N @

N@ CH3Y\o@ CH,’ \CH,CH3

9 10 11

12

B. TECOMINE13) AND TECOSTANINE16)

Tecoma stuns (Bignoniaceae) and a number of other Tecoma species

are used in Mexico by the natives for the control of diabetes (3 7 ,3 8 ) .The two alkaloids tecomine (tecomaine) and tecostanine have been

isolated and characterized and are apparently responsible for hypo-

glycemic activity of the plant (see Section IV) .




Tecomine was isolated by Hammouda and Motawi in 1959 (39) by

chromatography of the alkaloid fraction. Little structure work was

attempted except for the demonstration of the presence of a carbonylgroup and the formation of several derivatives. Subsequently, Jones

and co-workers ( 4 0 , 4 1 ) obtained an unstable liquid alkaloid from

T. stuns. The alkaloid formed both a picrate and a methiodide, and the

UV and I R spectra indicated the presence of an cc$-unsaturated cyclo-

pentenone. Only one aromatic proton was present in the NMR spectrum

together with two three-proton doublets and an N-methyl group.

Reduction in acetic acid and subsequent Huang-Minlon reduction gave

a mixture of three bases which upon Pd-C dehydrogenation gave actini-

dine (3).The gross structure of tecomanine was therefore establishedas 13 ( 4 0 , 4 1 ) .Catalytic reduction in ethanol added one molar equivalent

of hydrogen, and the major dihydro derivative was obtained by re-

crystallization of the picrate. Huang-Minlon reduction gave a single

base, which again was characterized as the picrate. Comparison with the

four known synthetic ( 2 5 ) skytanthine picrates indicated that the

derivative was new.

Tecomanine and tecomine were subsequently shown to be identical

by direct comparison of their I R spectra and mixed melting point

determination of their picrates ( 4 2 ) . t remains to determine the stereo-chemistry of tecomine. A study of the stability of tecomine indicated

that degradation is pH dependent, being most rapid at high pH, and

that antioxidants are beneficial in preventing decomposition ( 4 3 ) .

Tecostanine, a crystalline base, was also obtained by Hammouda

( 4 2 ) , and its structure was subsequently established in collaboration

with Le Men and Plat ( 4 4 ) .The I R spectrum indicated the presence of

an alcohol function, and this was confirmed by the facile acetylation to

give a monoacetate derivative ( 4 2 ) .The oxygen atom was removed by

tosylation and LAH reduction. The resulting deoxy base was dehydro-

genated (Pd-C), and the product was shown to be identical with actini-

dine (3).The deoxy base therefore has structure 4, but again, the deoxy

compound was not identical with any of the synthetic skytanthine

isomers ( 2 5 )or the deoxy derivative of tecomine ( 4 0 , 4 1 ) .

Tecostanine is therefore a hydroxyskytanthine derivative, and the

nature of the hydroxyl function was readily determined to be a primary

alcohol from the NMR spectrum (broad two-proton doublet a t 3.56 ppm).

A decision on the position of the hydroxyl function was made after

careful examination of the mass spectrum ( 4 4 ) . Fragment ions were

observed at m/e 100, 58 (11),and 44 (12).The ion a t m/e 100 was shifted

to m/e 84 in deoxytecostanine and to m/e 85 when LAD was used in

place of LAH in the formation of deoxytecostanine. These data are in




H0cHa??cH3 CH3

16

accord with a fragmentation such as 14 to give the ion 15 as shown in

Scheme 1. The primary hydroxyl function is therefore located as shownin 16 ( 4 4 ) , nd i t remains to determine the stereochemistry of tecostanine.

C. TECOSTIDINE

A further alkaloid of the actinidine type has also been isolated from

T . tuns ( 4 5 ) .From the mother liquor after crystallization of tecostanine,

an unstable base was obtained that gave a crystalline picrate and

showed a small negative rotation. The UV spectrum indicated thepresence of a 3,4,5-substituted pyridine, and the IR spectrum showed

the presence of an alcohol function. The base could not be reduced

catalytically, and the presence of an actinidine-type structure was

suggested. Thirteen protons could be observed in the NMR spectrum

and this, together with an observed molecular ion of m/e 163, suggested

a molecular formula of C,,H,,NO. The NMR spectrum proved defini-

tive in determining the structure, €or two singlets were observed at

6 8 . 2 2 and 8.27 ppm corresponding to the 2- and 6-protons of the

pyridine ring and a three-proton doublet at 6 1.27 ppm. The methyl

group is therefore in the cyclopentane ring and the hydroxyl group

(singlet for two protons at 6 4.65 ppm) on the carbon attached to the

pyridine nucleus. Tecostidine therefore has structure 17 (45 ) .




From Pedicularis rhinantoides, Abdusamatov and Yunusov ( 4 6 )

isolated a base having a molecular formula Cl,,Hl,NO and showing

hydroxyl absorption in the IR spectrum. Oxidation of the base withalkaline permanganate afforded a carboxylic acid that was shown to be

identical with boschniakinic acid (18) ( 4 7 ) .The base from P. hinan-

toides therefore has the gross structure 17, but since the [ of this base

was +59”, i t is the optical antipode (19) of the material from T. tuns.

17 18

C H 1 O . i p 3 goCH, CH3

IS 20

Confirmation of the structure of tecostidine was obtained by syn-

thesis of the d isomer (19) from d-pulegone (20) ( 4 8 , 4 9 )using a route

similar to that used for actinidine ( 50 ,5 1 ) (see below, Section E,Scheme 2).

D. HYDROXY-ND DEHYDROSKYTANTHINES

In 1961 Appel and Muller isolated from S. acutus a crystalline

nonvolatile alkaloid (23)and suggested that i t was a hydroxy derivative

of skytanthine. Subsequently, this compound, alkaloid D, was subjected

to more careful analysis (52). The IR spectrum confirmed the presence

of a hydroxyl group, and the NMR spectrum indicated th at this group

was probably tertiary and attached at the site of one of the methyl

groups (three-proton singlet at 6 1.24 ppm). Also observed were a

secondary methyl group (three-proton doublet at 6 0.85 ppm) and an

N-methyl group (three-proton singlet at 6 2 . 3 ppm). On this basis,structures 21 and 22 were proposed for alkaloid D ( 5 2 ) .

In 1967, alkaloid D was reisolated from S. acutus together with a

second isomeric alkaloid (53).The NMR spectrum of this alkaloid was




similar to that of alkaloid D, showing methyl singlets a t 6 2.18 ppm for

the N-methyl group and at 6 1 . 1 2 ppm for the methyl group of the

tertiary alcohol. Thus, alkaloid D, renamed hydroxyskytanthine I, andthe isomer hydroxyskytanthine 11, had structures 21 and 22 or the

reverse ( 5 3 ) .A decision on these structure assignments was made on

the basis of NMR and mass spectral analysis.

In the NMR spectrum of hydroxyskytanthine I, the 3a- and 3p-

protons were readily discerned to be doublets, whereas in hydroxy-

skytanthine I1 both doublets are further coupled. Hydroxyskytanthine

I, therefore, has the structure 22 (53). The mass spectrum of hydroxy-

skytanthine I1 (21) showed ions at mle 84 and mle 110 ascribed to the

species 15 (R = H ) and 23.These ions were not observed in the massspectrum of hydroxyskytanthine I.

A s well as the hydroxyskytanthines I and I1 isolated from Skytanthus

acutus, two additional hydroxyskytanthines have been isolated from

Tecoma stuns (41). Both bases showed no UV absorption and had

ICH,

21

ICH,

22

ICH,

23

m/e 110

molecular formulas of C,,H,,NO. The oxygen function was traced to a

hydroxyl group from the IR spectrum. Two C-methyl doublets and a n

N-methyl group were observed in the NMR spectrum, and in the

absence of low-field methine or methylene protons, the hydroxyl

function must be tertiary. This data and consideration of the massspectrum led to structures 24 and 25 for the two hydroxyskytanthines.

A distinction between these two possible structures was made on the

basis of an examination of the IR spectrum. In the spectrum of the




base mp 82-94'C, intramolecular hydrogen bonding was observed,

suggesting structure 25 for this compound and structure 24 for the base

mp 91-99"C (41).Two other skytanthine-type alkaloids have been isolated and shown

to be dehydroskytanthines. Casinovi and co-workers ( 2 9 , 5 2 )obtained

a base by preparative gas chromatography and showed th at i t had the

molecular formula C,,H,,N. The NMR spectrum indicated the presence

of an olefinic methyl group (singlet at 6 1.50 ppm integrating for three

protons), and reduction with PtO, in acetic acid afforded 6 skytanthine

having the configuration 8. On this basis, the structures 26 and 27 were

suggested for this dehydroskytanthine (2 9 , 5 2 ) .

Treatment of hydroxyskytanthine I (alkaloid D) with thionyl

chloride gave dehydroskytanthine identical with that obtained pre-

viously ( 5 2 ) .The elucidation of the structure of hydroxyskytanthine I as

22 permitted deduction of the structure of dehydroskytanthine to be

27 (53).

cH3fl+' C H 3 f l HOH CH3 czQfl:ICH3

I ICH3 CH,

26 27 28

In 1973, Gross and co-workers ( 3 6 )obtained another alkaloid, which

by the molecular ion a t mle 165 suggested th at i t was a dehydroskytan-

thine. The base formed a picrate and a methiodide. Catalytic hydrogena-

tion (5y0Pd-C) gave a dihydro derivative identical with a-skytanthine

(8).The NMR spectrum indicated the presence of two secondary methyl

groups and only one oIefinic proton ( 6 5 .5 ppm). Since the mass spectrumshowed the presence of ions a t mle 58 and 44, the double bond must be

at the A5 position, and this dehydroskyanthine therefore has the

structure 18 ( 3 6 ) .

E. ACTINIDINE37)

Actinidine, one of the simplest monoterpenoid alkaloids, was fistisolated from Actinidia polygama ( 2 4 , 54 , 55 ) and subsequently from

A . arguta ( 5 6 ) ,Valeriana oflcinalis (5 7, 5 8 ), Tecoma radicans (56),and

T . u lva (59 ) .Co-occurring with actinidine in A . polygama was a non-

nitrogenous neutral substance, metatabilactone ( 2 4 , 55) (from the




Japanese colloquial name for A . polygama, matatabi). Hydrolysis ofmatatabilactone gave a hydroxy acid, which upon permanganate

oxidation afforded two isomeric dicarboxylic acids identical with thenepetalinic acids (26) obtained from nepetalactone. On this basis,

structure 29 was suggested for matatabilactone ( 2 4 , 5 5 ) .

CH3 0 COaH CH3 0i’G ‘ +

CH3 CH3

29 30 31

Permanganate oxidation of actinidine gave, among other products,

5-methylpyridine-3,4-dicarboxyliccid, and on the basis of biogenetic

considerations, the probable structure 3 was suggested for actinidine

( 2 4 ) .Confirmation of this gross structural assignment was obtained by

synthesis. Nepetalinic acid imide (31) on treatment with PCl, a t 100°C

afforded a 2,6-dichloropyridine, which was dehalogenated with Pd-C

to give actinidine ( 2 4 , 6 0 ) .

I n 1960, Sakan and co-workers published a series of papers describingfully their work on actinidine (51,55, 60-62). Synthetic dl-actinidinewas prepared in five steps from 32 and resolved with dibenzoyl-1-tartaric

acid ( 6 2 ) (Scheme 2). The absolute configuration of natural actinidine

7H3 7H3 0”1 . NaCN/H,SOI

3. HCI, A 2. PdCI,/KOAc

q C O z C 2 H 6 OH

2. SnC1,lpyridine 1 . POCID, 200°C+ 3

CH3

32

CH3

35



442 GEOFFREY A . CORDELL

was also determined by synthesis ( 5 0 , 5 1 ) (Scheme 2 ) . (+)-Pulegone

(20) was converted to methyl pulegenate (33), hich was ozonized, and

the ketone was treated with the potassium salt of ethyl cyanoacetate togive 34, he sodium salt of which on treatment with methyl iodide

followed by hydrolysis gave optically active 35, which was transformed

into d-actinidine (36) s before. Natural actinidine, therefore, has the

I-configuration and the structure 37. A number of monoterpenoid

alkaloids have been correlated with actinidine. These include bosch-

niakine ( 6 3 ) , ecomine ( 4 0 ) ,skytanthine ZO ) , tecostidine (as), nd an

unnamed Valerianu alkaloid ( 64 , 65 ) . The chemistry of Actinidia

polygama has been reviewed (9 , 6 6 ) .

36 37

F. THEQUATERNARY LKALOIDSF Valerianu oficinalis (38 and 39)

I n addition to actinidine ( 5 7 , 5 8 ) , two other alkaloids in this series

have been isolated from the roots of Valeriana oficiana lis (57 , 6 4 , 6 5 ) .

Both alkaloids are quaternary, and because of their close similarity,

they will be discussed together. One of these alkaloids showeda molecular

formula of C18H2,NOCI and the other C18H2,N02C1, indicating the

presence of a hydroxyl group in the second isolate.

The first alkaloid isolated ( 6 4 , 6 5 ) showed strong hydrogen bonding

in the IR spectrum in addition to characteristic aromatic bonds indi-

cating the presence of a para-substituted aromatic ring. Nn carbonylbands were observed. The UV spectrum also indicated the presence of

cH3flH,R

I

38 R = H

39 R = O H




both pyridine and phenolic chromophores, the latte r shifting from 222

and 267 nm to 242 and 292 nm on addition of alkali. Essentially

identical data were observed for the second alkaloid (65),but in the IRspectrum, further absorptions at 3200 and 1047 cm-l confirmed the

presence of an additional nonphenolic hydroxyl group.

The NMR spectra of the alkaloids and their derivatives was par-

ticularly revealing. Two singlets at 6 8.90 and 8.83 ppm were ascribed

to the 2,6 protons on a pyridine nucleus and two doublets ( J = 8.8 Hz)

a t 6 7.04 and 6.73 pprn to a para-substituted aromatic nucleus. Both

compounds showed a complex four-proton multiplet in the region

6 4.70 ppm, which could be ascribed to two low-field methylene groups,

and each compound showed a three-proton doublet a t about 6 1.23 ppm,indicative ofa secondary methyl. However, whereas the first (and major)

alkaloid showed a three-proton singlet at 6 2.34 pprn for an aromatic

methyl group, the second compound showed the presence of a two-

proton singlet at 6 4.68 ppm, indicating th at the second hydroxyl group

was on the aromatic methyl ( 6 5 ) .Strong peaks in the mass spectrum of the trifluoroacetate of the

major alkaloid were observed at m/e 268 (parent pyridinium species)

147, 132 (base peak), and 120. It was clear that cleavageof the molecule

tQgive m/e 147 and 120 had occurred, the latter being the phenolic partand the former the pyridine nucleus ( 6 4 ) . n the mass spectrum of the

minor alkaloid, the pyridine fragment was shifted to m/e 163 and the

base peak to m/e 148 ( 6 5 ) .Pyrolysis ( 6 4 , 65) of the major alkaloid and isolation of the base as

the picrate indicated an identity with (8 ) - () actinidine (37). On this

basis, structure 38 was proposed for the major alkaloid and structure

39 for the minor alkaloid. Treatment of (IS)-() actinidine (37) with

p-hydroxyphenylethyl bromide and formation of the picrate confirmed

structure 38 for the major alkaloid ( 6 5 ) .The enantiomer of 38 has alsobeen synthesized ( 57 ) .

G . BOSCHNIAKINEINDICAINE)44) ND BOSCHNIAKINICCID

(PLANTAGONINE)IS)

Indicaine was first isolated in 1952 from Plantago indica ( 67 ) . The

Russian workers suggested a molecular formula of C,,H,,NO. Sub-sequently, indicaine was isolated from Plantago ramosa (68)and Pedicu-

laris olgae (69-71). Preliminary structure work demonstrated that

indicaine was an amino aldehyde. The compound gave a picrate




(mp 151-153OC) (6 7 , 68) and could be oxidized with silver oxide or

nitric acid to an acid (68). This acid, called plantagonine, was also

obtained as a natural product, initially from P. ramosa (68) and subse-quently from P. olqae (69, 7 0 ) .

On the basis of degradative and spectral evidence, structure 40 was

proposed for plantagonine ( 7 0 )and by inference 44 or indicaine. The

UV spectrum was characteristic of a pyridine and supported the

presence of a methyl group at a secondary carbon atom. Exhaustive

KMnO, oxidation gave an amino acid, which was decarboxylated to

nicotinic acid on heating. The amino acid was identified as pyridine-3,

5-dicarboxylic acid (42) by comparison with an authentic sample ( 7 0 ) .

In 1968, the structures for plantagonine and indicaine were revisedwhen it was demonstrated that alkali permanganate oxidation ofplantagonine gave pyridine-3,4,5-tricarboxyliccid (43), and therefore

to have structures 18 and 44, respectively ( 4 7 ) . ndependently, Torssell

arrived at the same structural conclusions for plantagonine and indi-

caine based on examination of their spectral properties ( 7 1 ) and by

comparison with the ethyl ester of plantagonine (45), which had been

prepared independently ( 4 8 ) .Also isolated at this time was an alkaloid, boschniakaine, from

Boschniakia rossica ( 7 2 ) .This base formed a picrate and a carbazone,

thereby indicating that it was an amino aldehyde, and this was con-

firmed by the I R spectrum. Also isolated was an acid that could be

derived from the aldehyde by silver oxide oxidation. The structures 18

and 44 were assigned to these compounds ( 7 2 ) . n order t o confirm the

40 R = CO,H 42 R = H I8 R = CO,H

41 R = C H O 43 R = C O p H 44 R = C H O45 R = CO,C.H,

structure assignments and determine the absolute stereochemistry,

boschniakine (dl and d ) was synthesized by a route analogous to that

used for the synthesis of actinidine ( 5 0 , 5 1 ) Scheme3 ) . The product was

identical with the natural boschniakine(44) nd therefore belongs to the

opposite antipodal series than the other actinidine-type alkaloids.

Boschniakine has also been isolated from Tecoma stuns ( 4 4 , where it

co-occurs with a d-actinidine derivative, and from T. radieans ( 5 6 ) .




1. Oa/CCI*

2. K CH,CO.C.HS

~

QOH . POCla8 2. PdC12IKOAc

40

I ,NH.CN

CN

CH,

SnCl./HClQ- 4

CN

SCHEME

In 1973, Gross and co-workers (73) demonstrated that in spite of

apparent differences in the physical properties of boschniakine and

indicaine, they were in fact identical. I n particular, recrystallization of

the picrate from ethanol gave a product of mp 126OC. Plantagonine and

boschniakinic acid are also probably identical, bu t no direct comparison

has been made.

Isolated from P . olgae as a picrate (mp 125-127°C) was a quaternary

alkaloid analyzing for Cl2H1,NO+ ( 7 4 ) .The I R spectrum indicated th e

presence of an aldehyde, and this was confirmed by the NMR spectrum

(singlet at 6 3.49 ppm and a six-proton multiplet at 6 1.25 ppm,

suggesting the presence of a N-ethyl and a methyl group). Oxidation of

I

CZHS

46

indicainine, as the compound was named, gave boschniakinic acid (18).

Indicsinine was therefore assigned the structure 46. The correctness of

this structure has been questioned (73).

H. N-NORMETHYSKYTANTHINE (47)

A further alkaloid from Tecoma stuns analyzed for C,,HI9N (41).The

IR spectrum indicated the presence of NH, and no N-methyl group was

observed in the NMR. Dehydrogenation afforded actinidine (3),




identified as its picrate. The base was therefore identified as N-

normethylskytanthine (47). N-Methylation afforded a skytanthine

derivative, which was similar to the skytanthine derived from tecost-anine ( 4 4 ) .The stereochemistry of N-normethylskytanthine remains to

be determined.

CH3

47

I. 4-NORACTINIDINE (48)

From Tecoma stuns, Dickinson and Jones ( 4 1 ) isolated an alkaloid

C9H,,N as the picrate. The UV spectrum at 259.5 and 267 nm indicated

a 3,4-disubstituted pyridine, and this assignment was confirmed by the

NMR spectrum, which showed three aromatic protons. A three-proton

doublet was observed 6 1.6 ppm, and five other protons were observed

as multiplets, including three “benzylic” protons in the 6 3.2-3.8 ppmregion. The structure 4-noractinidine (48), with the d configuration, was

assigned to this compound ( 4 1 ) . Its picrate showed no melting point

depression with a synthetic sample of 8-epi-4-noractinidine picrate

derived from asperuloside (75) .

c p 3

48

J . CANTLEYINE 50)

From an unidentified Jasminum species (designated N G F 29929)

Johns and co-workers ( 7 6 ) solated a new pyridine derivative. The new

alkaloid had an elemental composition of C,,H,,NO, by analysis, and

this was supported by a molecular ion at mle 207. The IR spectrumindicated the presence of hydroxyl and ester functions. The UV spec-

trum was identical with that of 49, a synthetic compound.A study of the

NMR spectrum confirmed the 3,4,5-trisubstitution, the methyl ester,




and a secondary methyl group. The magnitude of the coupling con-

stants as determined by double resonance studies revealed the cis nature

of the methyl and hydroxyl functions and confirmed that the methylenegroup is on the carbon adjacent to the ester function. The alkaloid

therefore has structure 50, with absolute stereochemistry as shown ( 76 ) .The possibility of its artifactual nature was noted.

co2c*cH3 co2c*3 co2c*3

N N 0 OGlu49 50 51

The same alkaloid was also isolated by Potier and co-workers (77)from Cantleya corniculata (Icacinaceae) and given the name cantleyine.

Three principal fragmentation ions were observed in the mass spectrum

of cantleyine (50),and these are thought to arise as shown in Scheme

4 (77). The location of the C-methyl group was deduced from an absence

r.

na/e 207I r n l e 179

mle 207

l+. r

mle 175 mje 147

SCHEME

t .

of nuclear Overhauser effect ( N O E ) when the methyl protons of the

ester group were irradiated. Cantleyine(50),dentical with the “natural ”

material, was obtained by treatment of loganin (51) with ammonia for

2 hours (77) . The compound was not isolated from C . cornicuEata in the

absence of ammonia.




Two further isolations of cantleyine have been reported from

Dipsacus azureus ( 7 8 )and Strychnos n u x vomica ( 7 9 ) . n both instances,

ammonia was used in the work-up.

K. VENOTERPINEGENTIALUTINE)52) AND ISOGENTIALUTINE55)

Another alkaloid of this same general type but lacking the carbo-

methoxyl side chain present in cantleyine 50)s venoterpine (gentia-

lutine) (RW-47) (52). Venoterpine was first isolated from RauwolJia

verticillata (Apocynaceae) by Arthur and Loo in 1966 ( 8 0 ) under the

designation RW-47. Although some physical data were obtained, nostructure work was carried out. Collaborative work on RW-47 with

Johns and Lamberton ( 8 1 )deduced two plausible structures for RW-47,

of which one was favored on biogenetic grounds.

The molecular ion a t m/e 149 in the mass spectrum and elemental

analysis gave a molecular formula for RW-47 of C,H,,NO. Hydroxyl

but no carbonyl absorption was observed in the IR spectrum. The UVspectrum indicated t he presence of a pyridine and the 3,4 disubstitution

was confirmed by the NMR spectrum. A secondary methyl group

(doublet a t S 1.32 ppm) as well as a hydroxyl were observed (singlet6 .96 ppm, removed with D,O). This hydroxyl group was shown to be

secondary, with the methine proton as a multiplet a t S 4.50 ppm.

Double irradiation of this methine proton simplified the remaining

benzylic region to an AB system and a quartet, the la tter coupling with

the methyl group. On this basis, the relative stereochemistry of the

methyl and hydroxyl groups, which must be on adjacent carbons, was

deduced to be cis. Biogenetic reasoning suggested structure 52 for

One feature remained to be explained, namely, the base peak in themass spectrum at m/e 120, a loss of 29 mu from the molecular ion.

Deuteration shifted the base peak to mle 121, indicating that the

hydroxyl proton was transferred in this process and -CHO lost.

In 1968 Ray and Chatterjee ( 8 2 ) isolated venoterpine (52) from

Alston ia venenata (Apocynaceae). Once again, the NMR spectrum gave

important information for the purposes of structure elucidation, but the

upfield shift of the hydroxyl group deceived the Indian workers into

believing that they had a different stereoisomer than the Australian

group. The coupling constants for the methylene and methine protonsmitigated against this, however.

Finally, RW-47 and venoterpine were compared directly ( 8 3 ) and

found to be identical. In addition, the ORD-CD spectrum of veno-

RW-47 ( 81 ) .



449. MONOTERPENE ALKALOIDS

terpine demonstrated that it was of the opposite absolute configuration

to (A')-( - actinidine (38) ( 2 4 ,50). Structure 52 therefore also represents

the correct absolute configuration of venoterpine (83).Gentialutine was first isolated from Gentiana Zutea (84) and has

subsequently been isolated from G. tibetica, G. asclepiadea (as), nd

Henyanthes trifoliata (86). The molecular weight was determined to

be 149 ( 8 4 ,87), which by elemental analysis could be ascribed to

C,H,,NO. The compound lacked carbonyl absorption, but showed

substantial hydroxyl absorption ( 8 4 ,87). The UV spectrum was th at of

a vinyl pyridine, and on this basis, structure 53 was proposed ( 8 4 ) .

This structure was not supported by the NMR spectrum, which showed

two a-pyridine protons at 6 8 .22 and 5.25 ppm and the /3-pyridineproton at 6 7.15 ppm. The vinyl protons were not found. Instead, a

methyl doublet was observed at 6 1.35 pprn and the alcohol methine

proton at 6 4.60 ppm. Although these data negate structure 53 for

gentialutine, no new structure was proposed at this time.

These data are, however, in agreement with the gross structure 52

for gentialutine, rather than that previously assigned (84). No stereo-

chemical work has been carried out, but the close melting point of

gentialutine with that of venoterpine indicated the probable identity of

the two compounds. Recently, the structure of gentialutine was revised(88)and determined to be the same as venoterpine (52),although no

direct comparison was made.

oH

52 53 54 55

Also obtained a t this time from Gentiana tibetica was a new alkaloid,

isomeric with gentialutine, which was named isogentialutine (88).The

IR spectrum indicated the presence of a hydroxyl function but absence

of other functional groups. The UV spectrum demonstrated the

presence of a pyridine derivative and from the NMR spectrum the

substitution pattern was determined to be 3,4. In addition, a three-

proton doublet at 6 1.33pprn (secondary methyl) coupled to a protonat 6 3.18 ppm (benzylic methine) indicated a close similarity to gen-

tialutine (52). Indeed, CrO,/pyridine oxidation of isogentialutine and

gentialutine afforded an identical product, the five-membered ketone




54, albeit a t differing rates. Gentialutine and isogentialutine, therefore,

differ in the configuration of t he hydroxyl group. Further evidence for

this was obtained from the NMR spectrum, where the pyridylic methineproton appeared as doublet of doublets ( J = 7 Hz and 5H z) . The

hydroxymethine proton gave coupling constants of 5 Hz and 3 Hz,

indicating two trans- and one cis-oriented protons on adjacent carbon

atoms. Isogentialutine therefore has structure 55 (88) .

L . LEPTORHABINE57)

From the epigeal part of Leptorhabdos parvijlora (Scrophulariaceae),the Tashkent group recently isolated another new monoterpene pyridine

alkaloid, to which the name leptorhabine was given (89) .Permanganate

oxidation under alkaline conditions pyridine 3,4-dicarboxylic acid (56),

56 57

thereby defining the substitution on the pyridine ring. The NMRspectrum confirmed this substitution pattern and also indicated a sec-

ondary methyl group and a benzylic hydroxyl group showing a methine

proton at 5.06 ppm. Two methylene protons were observed as a

multiplet at 1.98 ppm. On the basis of this and substantiating spectral

evidence leptorhabine was assigned the structure 57, without stereo-

chemistry.

M. BAKANKOSIDE60)

Bakankoside was one of the first monoterpene alkaloids isolated,

being obtained from seeds of the Madagascan Strychnos vacacoua (90) .The name arises from the local name for seeds, bakanko. The highly

stable crystalline compound was hydrolyzed by dilute acid to afford

d-glucose (90) .Hydrolysis with emulsin was not complete after 7 weeks(90) . The high negative rotation [.ID - 195") clearly aroused the

attention of these workers. A further sample was obtained from the

fruits of S. vacacoua (91) ,and subsequent work indicated a molecular




weight of 359. Analytic data suggested (correctly)a molecular formula

C,,H,,NOB + H,O for the parent compound and C,,H,,N03 for

bakankoside itself ( 9 1 ) .It was forty-four years before the work on bakankoside was resumed,

this time by Prelog’s group ( 9 2 ) . t was demonstrated t hat bakankoside

had no alkoxy, AT-methyl, r C-methyl groups; that i t was neither acidic

nor basic; and that i t did not give derivatives for a carbonyl group or a

color reaction with ferric chloride. Catalytic hydrogenation gave a

dihydroderivative, and both bakankoside and the dihydroderivative

formed tetraacetates. Osmium tetroxide oxidation of bakankoside and

acetylation afforded hexaacetate, indicating the presence of a vinyl

group.Dihydrobakankoside was hydrolyzed by emuslin to dihydrobakanko-

genin. In 0.1 N sodium hydroxide, the UV maximum was shifted from

238 nm to 276 nm. No shift was observed for bakankosin. The shift is

characteristic of the addition of a double bond in conjugation. Prelog

and co-workers interpreted this as conversion of 58 to 59 ( 9 2 ) .The IR

spectrum confirmed the presence of an a$-unsaturated amide, showing

two carbonyl bonds at 1670 and 1625 cm-l. Zinc dust distillation of

bakankoside gave crotonaldehyde, pyridine, and ,3-picoline.

Several structures were proposed a t this time for bakankoside, butneither the carbon skeleton nor the relationship of the glucose to the

rest of the structure could be deduced. Biichi ( 9 3 , 9 4 ) subsequently

suggested structure 60 for bakankoside, which accounts for the physical

and degradative work, and this structure has remained unchallenged.

The probable stereochemistry of bakankoside will be discussed later

when biosynthetic aspects of the monoterpene alkaloids are discussed.

/ /

CC-C=C-C-N\ + = C C = C C - N \

0II0

II0

I

58 59

OGlu

H

60




N. GENTIANINE62)

Gentianine is the best known of the monoterpene pyridine alkaloidsand is possibly the most widely distributed. Much of the early structure

work on gentianinine was done by Proskurnina ( 9 5 ) . Hydrogenation

gave a dihydro derivative having a molecular formula CloH,,N02. Oxi-

dation with permanganate gave an acid C,H,NO,. Distillation of this

acid with zinc gave pyridine ( 9 5 ) ,and decarboxylation gave 4-vinyl-

pyridine ( 9 6 ) . Proskurnina and co-workers ( 9 6 ) originally assigned

structure 61 to gentianine, but later (92') amended this to 62, since

gentianine was optically inactive. In addition, the IR spectrum also

supported the presence of a 6 rather than a y-lactone (absorption at1715 cm-l).

61 62 63

At this time, Govindachari and co-workers (9 8 ,9 9 ) synthesized

dihydrogentianine (63) from 5-ethyl-4-methylnicotinic acid (64) bytreatment with formaldehyde, thereby establishing the structure of

gentianine (62). Subsequently, Govindachari and co-workers ( 100)synthesized gentianine by the route shown in Scheme 5 .

In 1963, the first NMR study of gentianine was published ( 101) .The

vinylic protons were observed a t 6 5.77,5.95, and 7.08 ppm, the pyridine

protons at 6 4.67 and 3.24 ppm. Prior to a study of the biosynthesis of

gentianine, Marekov and Popov investigated the products of its oxida-

tion (102) .

Gentianine, as can be seen from Table I, has been isolated from anumber of plants, but often the question is raised as to its natural

occurrence. Much of the early isolation work on the crude alkaloid

fraction was done with the aid of ammonia, and there is no doubt th at




+ 1. POCI.

2. PdCL, K O A cHO

\CONH,

SCHEME

in many instances gentianine was isolated as an artifact. Evidence for

this comes from a number of sources.

Swertiamarin, a secoiridoid isolated from Swertia japonica (103-109)and other species (110-115), was treated with ammonia for 3 days a t

room temperature to give gentianine ( 1 1 6 , 1 1 7 ) .Subsequent work with

Anthocleista procera and Enicostemma littorale (1 1 8 ) indicated thatswertiamarin was probably responsible for the gentianine isolated in

these cases, since no gentianine was isolated in the absence of ammonia.

The relationship to gentianine helped to establish the structure of

swertiamarin as 65 (1 1 2 ) .Similarly, another secoiridoid glycoside, gentiopicroside, has been

shown to be transformed into gentianine by treatment with ammonia

(119-121).Gentiopicroside has been isolated from a number of genera in

the Gentianaceae (1 2 2 ) and has structure 66 (109 , 123 , 1 24) . As far as

possible, the isolation of gentianine from plants that contain swertia-marin or gentiopicroside and that have involved ammonia in the isola-

tion procedure are designated by an asterisk in Table 1 .

A further problem has also been uncovered in the isolation of genti-

anine ( 8 1 ) .The chloroform residue, after thorough extraction with acid

buffer and treatment with methanol, deposited crystals having the

elemental composition C,,H,,NO,Cl,. The UV spectrum indicated a

great similarity to dihydrogentianine (63),and the IR spectrum indi-

cated the presence of an unsaturated lactone and the pyridine nucleus.

Oxidation with permanganate in acetone gave an acid (67) identicalwith that obtained from gentianine. The NMR spectrum confirmed the

substitution showing two singlets a t 6 9.06and 8.84 ppm. One methylene

group was observed at 6 4.54 ppm and three methylene groups centered




65

OGlu

66 67

68

at 6 3.00 ppm. On this basis, structure 68 was proposed for this chloro-

form adduct of gentianine ( 8 6 ) .Treatment of a chloroform solution of

gentianine with benzoyl peroxide also gave 68 (86) .

0. FONTAPHILLINE69)

Another plant in the Oleaceae giving rise to monoterpenoid alkaloids

is Pontanesia phillyreoides, and this species has been investigated by

Budzikiewicz (1 2 5 ) . n addition to gentianine, a new crystalline alkaloid,

fontaphilfine, was isolated. Elemental analysis indicated a molecular

formula C18H,,N0,, and this was confirmed by the mass spectrum

which showed an M + a t mle 327. Acid hydrolysis of fontaphillineafforded two components, identified as 4-hydroxybenzoic acid and

gentianine (62).Fontaphilline was therefore suggested to be 69, and this

structure was substantiated by spectroscopic data (1 2 5 ) .

The I R spectrum indicated a para-substituted benzene (850 cm- l) ,

an aromatic carboxylic ester (1723 cm-I ), and a hydroxylic group. The

NMR spectrum indicated two pyridine a-protons as singlets at 6 8.75

and 9.0 ppm, two pairs of ortho-aromatic protons a t 6 6.80 and

7.85 ppm, and a carbomethoxyl group as a singlet a t 6 3.95 ppm. A

two-proton multiplet a t 6 5.60 pprn and ;t highly deshielded multipleta t 6 7.30 pprn confirmed the presence of a vinyl group. The remaining

two groups of methylene protons were observed as multiplets a t 6 3.60

and 4.55 ppm.




The mass spectrum showed a molecular ion a t m/e 327 and a base peak

a t m/e 121 having sructure 70. The electronegative mass spectrum how-

ever was more informative. The base peak appeared at mle 137 corre-sponding to the p-hydroxybenzoyl anion. Three other fragment ions were

observed at m/e 206 (ion 71), m/e 189 (fragment 72), and m/e 174 (ion

73), in agreement with the assigned structure of fontaphilline ( 125) .

P. GENTIANADINE74)

Gentianadine was first isolated from the aerial parts of Gentiana

turkestanorum by Yunusov and co-workers (1 2 6 ) .The crystalline base

showeda carbonyl absorption at 1730 cm -l characteristic of a &lactone.

The UV spectrum was similar to that of dihydrogentianine (63),but theelemental composition of C,H,NO, indicated a loss of two-carbon units

(1 2 6 ) .The base was apparently very similar to 74, a compound pre-

synthesized by Govindachari and co-workers (99). Slight differences in

physical properties were noted, however, and thus gentianadine was

degraded to confirm this structure assignment. Alkali potassium per-

manganate gave pyridine-3,4-dicarboxylic cid and decarboxylation

gave an oily product identified as 4-vinylpyridine. Gentianadine there-

fore has structure 74 ( 1 2 6 ) .

This structure was further confirmed by the NMR spectrum ( 1 2 7 ) ,which showed two-proton triplets at 6 4.52 nd 3.04 ppm for the lactone

methylene groups and three pyridine protons at 6 9.12, 8.64, and

7.19 pm with coupling as expected. I ts mass spectrum (128 )gave the




molecular ion m / e 149 as the base peak and important fragment ions by

ring expansion and loss of CO a t m/e 120 and further losses of CO to

m/e 92 and H C N to m / e 6 5 .Gentianadine also occurs in G. olgae (129 , 130) and G . olivieri ( 1 3 1 ) .

A novel route to its synthesis was recently described by Dolby and

co-workers ( 1 3 2 , 1 3 3 ) . The quaternary 2-dehydroquinuclidine-3-

carboxylic acid ester 75, when heated, rearranges via two consecutive

1,3 sigmatropic shifts to a mixture of 76 and 77, the former pre-

dominating. Palladium-carbon dehydrogenation afforded gentianadine

(74) in 9% overall yield (132 , 133) .

74 75 76 77

Q. GENTIANIDINE 79)

From Gentiana macrophylla, Chinese workers isolated another mono-

terpene alkaloid type (134 ) . Gentianidine was obtained in crystalline

form and was optically inactive. The IR spectrum indicated the presence

of a &lactone and alkali permanganate oxidation gave berberonic acid

(78). N M R spectral evidence indicated probable structure 79 for

gentianidine, and support for this came from condensation of 4,6-

dimethylnicotinic acid (80) and formaldehyde at 100°C ( 1 3 4 , 1 3 5 ) .The

78 79 80

mass spectrum of 79 has been described (136 ) . Gentianidine (79) hasalso been isolated from Erythraea centaurium (137 ) ,Menyanthes trifoliata(138 ) , G . asclepiadea (112 ) , and Xwertia japonica, but not from X.

japonica in the absence of ammonia (139 ) .




R.GENTIANAMINE81)

A further novel type of Gentiana alkaloid has been obtained fromG. oliuieri (86,126, 131) and G . turkestanorum (126).Gentianamhe is a

crystalline alkaloid having a molecular formula C,,H,,NO,. The IR

spectrum indicated the presence of hydroxy and %lactone functions

and a double bond. The UV spectrum was very similar to gentianine.

Monoacetylation confirmed the presence of a hydroxyl group ( 126) ,and

catalytic reduction afforded a dihydro derivative, which contained a

C-methyl group, thereby confirming the presence of a vinyl group.

Alkali oxidation afforded pyridine 3,4,5-tricarboxylic acid (43).

On this basis, gentianamine was assigned structure 82, and this wassupported by the mass spectrum. The molecular ion, m/e 205, succes-

sively lost CH,O and CO, to give m/e 131 (126). n addition, dihydro-

gentianamine (12) was syntheszed from dihydrogentianine (63);

treatment with formaldehyde at 100°C gave a 50% yield of dihydro-

gentianamine identical with th at prepared from the natural material.

The NMR spectrum of acetylgentianamine (83) (127) indicated the

presence of a vinyl group (absorption at 6 5.8 and 6.94 pprn), two a-

pyridine protons (8 9.06 and 8.85 pprn), and the acetate ( 6 2.04 pprn).

Further assignments were not made.

+ q&Lo CH, r f i o

C H O f i oH3

N N

81 R = H 82 84

83 R = Ac

H H

85

S. GENTIOFLAVINE8 5 )

Gentioflavine was first isolated as Alkaloid IV from a number of

Gentiana species ( 1 4 0 ) .A molecular ion of C,,H,,NO, was derived from

elemental analysis and mass spectrometry ( 1 4 0 , 1 4 1 ) . The IR spectrum




shows the presence of an NH group (3235 m-l), conjugated lactone

(1700 m-l) , and a conjugated carbonyl group (1640 m-l).

The NMR spectrum showed two methylene groups (4.35 nd 3 ppm),a methyl doublet (1.3 pm) with the corresponding methine proton a t

5 . 2 ppm. A singlet 10.1ppm was ascribed to an aldehyde group. The

other two singlets a t 8.45 and 8.8 ppm were assigned to an NH and

another highly deshielded proton (1 4 1 ) .The aldehyde group was con-

firmed by the formation of semicarbazone and oxime derivatives.

Oxidation of gentioflavine with nitric acid gave pyridine 3,4,5-

tricarboxylic acid (43),and treatment with bromine water gave a basic

compound, bromogentioflavine (C,H,BrNO,). The I R spectrum of this

derivative indicated a S-lactone (1740 m-l) and a pyridine ring. The

NMR spectrum showed an aromatic methyl 6 2.76ppm), the two

methylene groups (6 4.57 and 3.16 pprn), and an a-pyridine proton

(6 9.03ppm). On this evidence, structure 84 was assigned to bromo-

gentioflavine ( 1 4 1 , 1 4 2 ) .Treatment of bromogentioflavine with Raney

nickel afforded gentianidine (79), identical with the natural product.

Gentioflavine was therefore assigned the novel structure 85 ( l a l ) ,

bromine water affecting an oxidative decarboxylation of the aldehyde

group (1 4 3 ) .The mass spectrum of gentioflavine (1 3 6 ) showed an initial loss of

15 m u to m/e 178 with subsequent losses of formaldehyde, CO, CO, and

finally HCN t o give the cyclopentadienyl ion, m / e 65.

T. GENTIOCRUCINE87),ENICOFLAVINEgo),AND GENTIANAINE92)

Gentiocrucine was originally isolated by Marekov and Popov from

Gentiana cruciata ( 1 4 2 , 1 4 4 ) , and on the basis of spectral evidence

structure 86 was assigned. Ghosal and co-workers have recently re-investigated the structure of gentiocrucine isolated from Enicostemma

hyssopifolium (1 4 5 ) and have concluded that in fact 87 is the correct

structure for th is compound.

Gentiocrucine gave two 2,4-dinitrophenyIhydrazones 1 4 5 ) , ndicating

th at the formulation as an amide was erroneous. In the mass spectrum,

a substantial loss of 27 mu was observed, and this could not be accounted

for on structure 86 bu t could be accounted for by the loss of HCN from

87 (1 4 5 ) .

The PMR spectrum indicated the presence of adjacent methylenegroups at 6 2.4 and 4.3 ppm, two exchangeable proton a t 6 9.2 and

10.0 ppm, and a complex multiplet a t S 8.1 ppm. The lat ter was simpli-

fied to two doublets ( J = 9 and 17 HE)on addition of D,O, indicating




the presence of cis and trans isomers of the methine proton on the

vinylogous amide. The CMR spectrum of gentiocrucine conclusively

demonstrated the existance of two isomers, fourteen carbon resonancesbeing observed (88 and 89) ( 145) .

CONH,no86

cis and trans

87

H. 97.42\

35.70-

\

35.70-

63.59 ‘168.69 63.48 ‘168.49

88 89

It should be noted t hat hydrogen bonding of the nonlactonic carbonyl

in the cis isomer shifts this resonance downfield by 3 ppm to 194 ppm.

As we shall see, gentiocrucine, although not apparently a monoterpene

alkaloid turns out to be intimately involved with this group of

compounds.

Recently, Ghosal and co-workers have examined some of the more

reactive monoterpene alkaloids, the concept being tha t there must be a

number of intermediates between the secoiridoids and the normally

isolated monoterpene alkaloids. From Enicostemma hyssopifolium, a newalkaloid, enicoflavine, was isolated, and the structures 90 and 91 were

proposed for the isomeric mixture ( 146) .Elemental and mass analysis established the molecular formula as

C,oH,lNO,. Selective tlc sprays indicated the presence of an aldehyde

(2,4-DNP and Tollens test) and the absence of a conventional nitrogen

function (negative Dragendorf). The UV spectrum indicated the

presence of a vinylogous amide cross-conjugated to a lactone group, a

system found in gentiocrucine ( 1 4 5 ) .In the IR spectrum, bands were

observed for NH/OH, an aldehyde, an unsaturated lactone function,and a vinyl group.

The NMR spectrum ( 146) supported these functionalities, showing

an aldehyde a t 6 9.3 ppm and vinylic and allylic methine proton in the



8. MONOTERPENE ALKALOIDS 46 1

methylene adjacent to nitrogen. A further signal at 6 8.50 ppm was

ascribed to the aldehyde proton, which was confirmed by reaction with

Tollens reagent.The spectrum of gentianaine in deuteropyridine showed two addi-

tional one-proton signals at 6 4.88 ppm for the hydroxy proton and

8.26 ppm for the amide proton. The enolic nature of the 1,3-dicarbonyl

function could not be deduced from the spectrum (1 2 7 ) .The mass spectrum of gentianaine (129)showed losses of CHO and

CO to give ions m/e 1 2 and m/e 1 13 from the molecular ion at m/e 1 4 1 .

The base peak was at m/e 69, and the structure 93 was suggested for

H

92 93

this ion. This seems highly unlikely, since two protons would need to be

lost from adjacent methylenes. More probable appears to be a syn-

chronous loss of ethylene and HNCO from the M + - peak as shown(Scheme 7 ) to give th e ion 94. Gentianaine is therefore another simple

H m/e 69

94

SCHEME

derivative of a monoteqene unit, probably arising by loss of croton-

aldehyde by retroaldol reaction from a compound such as 95, i.e., a

hydroxybakankoside derivative.

H o A C H O




U. JASMININE96)

In 1968, Lamberton and co-workers ( 1 4 8 ) isolated another alkaloidderived from the secoiridoid skeleton. Jasminine, as the alkaloid was

named, was obtained from a number of J a s m i n u m species and from

Ligustrum novoguineense. Subsequently, the same compound was iso-

lated from a third member of the Oleaceae, Olea paniculata ( 1 4 9 ) .

Unique among the monoterpenoid alkaloids, jasminine was found to

contain two nitrogen atoms and has the molecular formula C,,H,,N,O,

( M + , m/e 220) . Two intense carbonyl bands were observed-at

1725 cm-l attributed to an ester and at 1680 cm-l attributed to an

amide ( 1 4 8 ) .In the NMR spectrum ( 1 4 8 ) two a-pyridine protons were found at

S 9 .0 1 and 8.57 ppm together with a broad signal at S 8 .17 ppm, ex-

changeable with D,O and assigned to the amide NH. A three-proton

doublet at S 1 .5 8 ppm was assigned to a secondary methyl group, and

a three-proton singlet at 8 3.93 ppm was assigned to the methyl ester

function. The methylene protons were deshielded, appearing as quartets

at 8 5 . 1 2 and 4.87 ppm, and the methine proton was also deshielded

appearing as a broad multiplet at 8 4.75 ppm. Double irradiation

studies confirmed the proton assignments. On this basis two struc-tures, 96 and 97, were proposed ( 1 4 8 ) for jasminine, the former being

considered more likely on biosynthetic grounds.

96 97 98

The mass spectrum ( 1 4 8 )of jasminine shows a base peak of m/e 205

(loss of methyl radical) and subsequent important fragments a t

m/e 173, 145, 118, 117, and 9 0 . For structure 96, these fragments can be

rationalized as in Scheme 8. Confirmatory evidence for the structure

came from an examination of the concentrated acid hydrolysis product

of jasminine, which, on the basis of spectroscopic evidence, was assigned

the structure 98 ( 1 4 8 ) .Chemical considerations indicate t hat hydrolysiswould not be expected to result in decarboxylation of the acetic acid

residue. Jasminine was not considered to be an artifact of isolation

( 1 4 8 , 1 4 9 ) .




mle 205 m/e 173

m/e 90

SCHEME

m/e 145

pc,

wle 118

v. GENTIATIBETINE100) ND OLTVERIDINE (103)

In 1967, Rulko and co-workers ( 150) described the isolation and

characterization of a further type of monoterpene alkaloid. From theroots of Gentiana tibetica, a crystalline alkaloid was isolated (150)showing a molecular ion at mle 165, which by elemental analysis corre-

spond to C,H,,N02. The I R spectrum indicated the presence of a

pyridine derivative and a hydroxyl group. The NMR spectrum sub-

stantiated the presence of a pyridine ring, but in this case substitution

was 2,3,4, since two doublets ( J = 5 Hz) were observed at 6 6.85 and

8.21 ppm. A methyl singlet was observed at 6 2.53 pprn and was

assigned to a methyl group at the 2-position on a pyridine ring sub-

jected to additional deshielding. A sharp singlet was observed at6 5.94 ppm, suggesting a methine proton attached to two oxygen atoms.

That one of these oxygens was a hydroxyl function was demonstrated

by deuterium exchange. The four remaining protons were observed as

separate, complex multiplets indicative of two adjacent methylene

groups with differing chemical shifts. One pair of protons ( 6 2.56 and

2.98 ppm) was apparently benzylic, whereas the other pair (6 4.29 and

3.88 ppm) was adjacent to oxygen. In the absence of carbonyl and vinyl

groups, the structures 99 and 100 were proposed (1 5 0 ) , he latter being

favored on the basis of an enhanced deshielding of the methyl group bythe proximate hemiacetal. Oxidation with chromium trioxide afforded

a lactone 101.

An interesting observation was made in the mass spectrum of this




compound. The parent ion mle 165 loses 31 mu initially and subse-

quently 28 mu, but in the monodeutero compound (sample crystallized

from C,H,OD) both these ions were shifted by one mass unit. Thissomewhat surprising result was rationalized in terms of a loss of form-

aldehyde from an M + - 1 species giving a species 102, which may lose

CO, retaining the label (150) .

HO

D

102 103

This alkaloid (100)has been named gentiatibetine (1 5 0 ) ,and has beenisolated from a number of other species in the Gentianaceae (see

Table I).Also isolated from G . oliwieri (1 3 1 )was an alkaloid oliveridine,

which gave spectral data similar to those of 100, but which from the

mass spectrum was 14 mu larger. Loss of methoxyl from the molecular

ion gave the base peak mle 148, which subsequently lost C2H, and CO.Structure 103 was proposed on this evidence and Scheme 9 was sug-

gested to account for the mass spectral breakdown ( 131) .This scheme

should be compared with that proposed for the de-0-methyl derivative

m/e 179 mle 148 m/e 120

mle 91SCHEME




W . UNNAMEDLKALOIDROM Gentiana tibeticu

Chinese workers have isolated a n alkaloid having the st ructure 104from Gentiana tibetica (151) . Evidence for the s tructure came mainly

from the spectral properties after elemental analysis indicated a

molecular formula C,,H, 1N03.The I R spectrum indicated th e presence

of a pyridine nucleus and a conjugated carbonyl. The latter functionality

104

was traced to an aldehyde (6 9 .7 ppm) from the NMR spectrum. Also

observed were a deshielded N-methyl group (6 3.26 ppm) and a slightly

deshielded C-methyl doublet at 6 1.20 ppm, with the methine proton

appearing at 6 4.66 ppm, indicating proximity to both an oxygenfunction and an aromatic system. The remaining protons were observed

as two methylene groups a t 6 3.02 and 4.33 ppm. These da ta are in

agreement with structure 104.

X. OLIVERAMINE105)

Isolated from the chloroform-soluble alkaloids of G. olivieri ( 1 5 2 )was

a crystalline base that analyzed for C,,H,,NO, bu t that by massspectrometry had a molecular weight of 352. The molecular formula

was therefore C2,H2,N204,so th at the compound is dimeric.

Oliveramine, as the compound was named, gave a typical pyridine

UV spectrum and showed the presence of a 6-lactone in the IR spec-

trum, and from the E value, two of these functions were demonstrated.

Four aromatic 2,6-pyridine protons were observed, bu t no olefinic

protons. A three-proton doublet at 6 1.44 ppm indicated a secondary

methyl, and four-proton multiplets a t 6 2 .97 and 1 .98 ppm accounted

for the methylene groups of the 6-lactone. Two two-proton multipletswere also observed, corresponding to two adjacent methylenes, and the

remaining methine proton was masked by other absorptions a t about

6 3.00 ppm. These data suggested structure 105 for oliveramine (152),

which is therefore a reduced dimer of gentianine (62).




105

296 mle

106

Mass spectral analysis of oliveramine indicated that a cleavage

predominates to givemle 1 7 6 as the base peak. A predominant alternate

mode of fragmentation gives rise to m/e 296 (106) by successive losses

of two carbon monoxide molecules (1 5 1 ) .

Y. PEDICULIDINE108)AND PEDICULININE109)

Two further alkaloids of novel structure were isolated from Pedicularis

olqae (153 , 154 ) . As we shall see, although both are C,, alkaloids, their

terpenoid derivation is questionable in view of their structural nature.

Pediculidine (1 5 3 ) , having the molecular formula C,,H,NO, showed

three maxima in the UV for an extended pyridine chromophore, and

this was supported by the IR spectrum which indicated an unsaturated

carbonyl function.

The NMR spectrum of pediculidine confirmed the presence of anolefinic band, and from the observed coupling constant ( J = 12.2 Hz),it was cis-disubstituted. Three aromatic protons were observed, and

from their chemical shift the pyridine ring was 3,4-disubstituted. The

four remaining protons were in the 6 2.45-3.15 ppm region, correspond-

ing to two deshielded methylene functions. On this basis, structures 107

and 108 were proposed (153)for pediculidine, the latte r being favored

on biogenetic reasons. No degradations were performed.

Pediculinine (1 5 4 ) ,also isolated from Verbascum nobile (1 5 5 ) ,on the

other hand, showed a characteristic pyridine UV spectrum and nobands in the carbonyl region of the IR spectrum. The molecular formula

(C,,H,,NO) indicated the presence of a single oxygen atom and this was

traced to a hydroxyl group from the IR and NMR spectra. Acetylation




gave a monoacetyl derivative in which the methine proton had shifted

from 6 4.01 ppm to 6 5.08 ppm. Substitution of the pyridine ring was

found to be 3,4 from the NMR spectrum, and alkali permanganateoxidation t o pyridine 3,4-dicarboxylic acid (56). The remaining protons

were observed as a four-proton multiplet in the region 6 3.05-2.40 ppm

and as two two-proton triplets at 6 1.98 and 1.57 ppm.

107 10s 109

Structure 109 was assigned (154) to pediculinine on the basis of this

evidence. Pediculidine was not interrelated with pediculinine. Although

structure 108 was chosen on the basis of biogenetic reasoning, it is not

immediately obvious what the biosynthesis of these compounds

involves. They are included here because of their Cl0 skeleton, and their

co-occurrence with monoterpene alkaloids.

Z. PEDICULARINE110),PEDICULARIDINE113),

AND PEDICULINE

Pedicularine was first isolated from Pedicularis olgae in 1963 by the

Tashkent group (69)after separation of plantagonine (18)and boschni-

akine (44). The base was optically inactive and contained a carboxylic

acid group. Subsequent work (156)indicated th at the original materialwas a mixture. Separation by repeated recrystallization afforded pure

pedicularine (mp 207"-209"C). The molecular formula was established

to be C,,H,,N02, supported by a molecular ion a t m/e 177. The UVspectrum indicated a simple pyridine derivative, and the IR spectrum

the presence of a carbonyl function (1710 cm-l).

Alkali oxidation afforded pyridine 3,4-dicarboxylic acid (56) thereby

establishing the substitution. The NMR spectrum confirmed this sub-

stitution, showing three pyridine protons a t 6 8.92, 8.47, and 8.07 ppm,

the latter being coupled doublets. At 6 1.07 ppm, a three-protondoublet was observed corresponding to a secondary methyl group. TWO

One-proton multiplets a t S 1.67 and 2.18 ppm were assigned to two

nonequivalent methylene protons, and the methine group for the




methyl was observed a t 6 3.08 ppm. Also at 6 3.08 ppm, a second methine

signal was observed, and on the basis of the two proposed structures 110

and 111, this would have to be assigned to the methine adjacent to thecarboxylic acid (156) .

110 111 113

The mass spectrum (156 ,157) ndicated losses of methyl radical, Hradical, and carbon dioxide by one fragmentation pathway and carbon

dioxide followed by methyl radical in a second pathway, as shown in

Scheme 10. Biogenetic consideration suggested th at structure 110 was

the more likely. The methyl ester of pedicularine (112)showed losses of

methyl and carbomethoxyl as expected (157)(Scheme 10).

Pedicularis olgae also afforded (158) an alkaloid, pedicularidine,

closely related to pedicularine (110).The base was optically active and

had a molecular formula C,,H,,NO. The UV spectrum confirmed thepresence of a pyridine ring, and the oxygen function was traced to a

saturated aldehyde or ketone from the IR spectrum. The mass spectrum

showed losses of 1mu and 29 mu, indicating the presence of an aldehyde,

and this was confirmed when silver oxide oxidation afforded an amino

acid identical, except for optical rotation, with pedicularine (110).The

gross structure 113 was suggested (158)for pedicularidine. No stereo-

chemistry was derived for this compound.

In 1968 the Tashkent group isolated from Pedicularis olgae a com-

pound th at they named pediculine (159) .Elemental analysis and massspectrometry indicated a molecular formula C,,H,,NO. The UVspectrum demonstrated the presence of a pyridine nucleus, and the IRspectrum indicated the presence of a hydroxyl group and no carbonyl

group, thereby assigning the oxygen function. Hydrogenation gave an

uptake of one molecule of hydrogen.

The mass spectrum showed the molecular ion as a base peak and

important fragment ions at m/e 146 and mle 117. These ions were

thought to be due to losses of methyl and formyl radicals. No NMR data

were reported for pediculine. On the basis of this evidence, the impossiblestructure 114 was proposed (159) or pediculine.

A number of possible alternative structures could be proposed for

pediculine, and of these 115 seems reasonable as a working structure.



T xu




CH,OH

114 115

The isolation and physical data for the monoterpenoid alkaloids are

summarized in Tables I (160-198) and 11, respectively. Table I11

(199 ,200) summarizes the isolation of a number of alkaloids of unknown

structure from plants shown to contain monoterpene alkaloids.

111. Biosynthesis and Biogenesis of the Monoterpene Alkaloids

The biosynthesis of the monoterpene alkaloids has been the subject

of only limited study, and yet a considerable number of reviews of

varying degrees of completeness have appeared ( 5 - 8 , 1 0 , 1 1 , 1 3 - 1 8 , 5 7 ,

12 2, 201-204). This biosynthetic work is reviewed here and is followed

by a brief discussion of related areas of iridoid biosynthesis and an

outline of the biogenesis of the monoterpene alkaloids.The problem that possibly some or even all of the monoterpenoid

alkaloids may be the result of addition of ammonia to a preformed

iridoid or secoiridoid during work-up has been the subject of some

discussion. Whereas yields of alkaloid isolated are sometimes unaffected

by the use of sodium carbonate in place of ammonia ( 7 6 , 1 1 9 ) , n other

cases, no alkaloids are isolated in the absence of ammonia ( 7 7 , 1 1 8 , 1 1 9 ) ,and in some instances the yield of alkaloid is merely increased by the use

of ammonia (1 9 7 ) .

The leading work in this area is that of Floss and co-workers (1 1 9 ) ,who found that 91% D [15N]gentianine(62) from G. lutea was from

added labeled ammonia. Only G. fet isowii afforded similar quantities

of gentianine by procedures involving ammonia and sodium carbonate.

A . SKYTANTHINES

In 1961, the skytanthines were suggested as belonging to the mono-

terpene group of alkaloids ( 2 1 ) , nd subsequent work has confirmed thisconcept. Feeding [2-14C] mevalonate (116) to Skytanthus acutus (2 0 5 )afforded, as predicted (2 0 6 ) , radioactively labeled skytanthine (a),whereas labeled phenylalanine and acetate gave an inactive product



TABLE I

ISOLATIONF MONOTERPENELKALOIDS

lkaloid Plan t name

I. Iridoid-derived

Actinidine (37)

(+)-Boschniakine (44) (indicaine)

Actin ida arguta Franchiet Sav.

A . polygama Miq.

Tecoma fu lva G . Don

T . radicans Juss.

Valeriana oficinalis L.

Boschniakia rossica G . Beck

Pedicularis ludwigi Regel

P. olgae Regel

Plantago albicans L.

P . indica L.P. major L.

P. notata Lag.

P . psyllium Dene.

P. ramosa Aschers.

(- )-Boschniakine

( + )-Boschniakinic acid (18) (plantagonine)

Tecoma rndicans J u s s .

T . stuns J u s s .

Incarvillea olgae Regel

Boschniakia rossica

Pedicularis dolichorrhiza Schrenk.

P. ludwigi Regel

P. olgae Regel

Plantago albicans

P . coronopus L.

P. crassifolia Roth

P. crypsoides Boiss.

P. cylindrica Forsk.

P. indica

P. major



TABLE I (continued)

Alkaloid Plant Name

P. notataP. ovata Forsk.

P. psyllium

P. ramoea

(-)-Boschniakinic acid

Cantleyine (50)

A5-Dehydroskytanthine 28)

A'-Dehydroskytanthine (27)Hydroxyskytanthine I (22)

Hydroxyskytanthine I1 (21)

Indioainine (46)

Isogentialutine (55)

Leptorhabine (57)

4-Noractinidine (48)

N-Normethylskytanthine (47)

Skytanthine (4)

S-Skytanthine(8)

8-Skytanthine-N-oxide(9)

Tecomine (13)

Tecostanine (16)

(- -Tecostidine(17)

(+)-Tecostidine (19)

Venoterpine (52) (gentialutine)

Verbascum songaricum Schrenk.

Incarvillea olgae

Cantleya corniculata

Dipsacus azureus Schrenk.

Jasminum species NGF 29929

Strychnos nu x v o m i c a L.

Tecoma stam

Skytanthus acutue MeyenSkytanthus acutus

Skytanthus acutus

Pedicularis olgae

Gentiana tibetica King

Leptorhabdos parwifolia

Tecoma stans

Tecoma stans

Skytanthus acutus

Skytanthus acutus

Skytanthus acutus

Tecoma fu lva G . Don

Tecoma etans

Tecoma stuns

Tecoma stuns

Pedicularw rhinantoides Hook. f

Alstonia venenata R. Br.

Gentiana asclepiadea L.

G. utea L.



Unnamed I (24)

Unnamed I1 (25)

Unnamed I (38)Unnamed I1 39)

11. Secoiridoid-derived

Bakankoside (40)

Enicoflavine (90)

Fontaphilline

Gentianadine (74)

Gentianaine (92)

Gentianamine (81)

Gentianidine (79)

Gentianine (62)

G. ibetica

Menyanthes trifoliata L.

Rauwolfia verticillata (Lovr.) Baill.

Tecoma stans

Tecoma stam

Valeriana oflcinalisValeriana oflcinalis

Strychnos vacacoua Baill.

Enicostemma hyssopifolium (Willd.) Ve

Fontanesia phillyraeoides Labill.

Gentiana olgae Regel

G. livieri Griseb.

a. turkestanorum Gandoger

Gentiana caucasa Bieb.

G. aufmanniana Regel e t Schmalh.

G. lgae

Q. olivieri

G. urkestanorum

Gentiana olivieri

G. urkestanorum

Erythraea centaurium Pers.

Gentiana asclepiadea

G.macrophylla Pall.

Menyanthes trifoliata

Swertia japonica MakinoAnthocleista procera Lepr.

A . rhizophoroides Baker

Centaurium pulchella Hayek

Dipsacus azureus

Enicostemma littorale 331.

Erythraea centaurium



TABLE I (continued)

Alkaloid Plant Name

Fagrea fragrans Roxb.

Fontanesia phillyreoides Labill.

aentiana angu.stifoZiaMichx.

C . asclepiadea

G . axillariJora Lev. et Van.

B. xillaris Reichb.

0. barbata Froel.

a. biebersteinii Bunge

a. bulgarica Velon

0. clusii Perr. et Song.

a. cruciata L.a. decumbens L. f.

8. inaerica G. Beck

G . fetisowii Regel e t Winkler

G .freyniana Bornm.

0. gracilipes Turrill

Q. kauffmanniana

U. Zutea

a. macrophylla Pall.

Q . olivieri

B. neumonanthe L.

a. punctata L.

Q. purdomrii Marquand

a.purpurea L.

a. scabra Bunge

B. chistocalyx C. Koch

0. septem$dea Pall.

a. sino-ornata Balf.

a. straminea Maxim.



Gentiatibetine (100)

Gentiocrucine (86)

Gentioflavine (85).

B. ianschanica Rupr.

B. ibetica

Q. turlcestanorum

G . vvendenakyi Grossheim

B.wutaiensis Merquand

Ixanthus wiscosus Griseb.

Lomatogonium rotatum Fries.


Ophelia diluta Ledeb.

Swertia connata Schrenk

S. raci$ora Gontsch.

S. berica Fisch.

8.aponica Makino

S.marginata Schrenk

Bentiana mclepiadea

0.uteaB.olivieri

B.punctata

B. purprea

B. ibetica

Menyanthes trgoliata

Enicostemma hyssopifolium

Qentiana cruciata

Erythrea centaurium

Bentiana mclepiadea

B.bulgarica

B. cruciata

B. utea

Q. olgae

a. olivieri

B. unctata

Q . tianshanica

a. viriiowi



TABLE I (continued)

lkaloid Plant Name

Jasminine (96)

Oheramine (105)

Olivericline (103)Pedicularidine (113)

Pedicularine (110)

Pediculidine (108)

Pediculinine (109)

Unnamed I (104)

111. Unknown structures

Alkaloid I

Alkaloid I1

Alkaloid IVb

Alkaloid V

Swertia connata

S. racilifolia Gentsch.

8. arginata

Ja sm in u m d o ma t iigerum Lingelsh.

J. gracile Andr.

J. lineare R . Br.

J . schumanni i Lingelsh.

Lingustrum novoguineense Lingelsh.

Olea panicula ta R. Br.

Gentiana olivieri

Gentiana oliveriPedicularis olgae

Pedicularis olgae

Pedicularis olgae

Pedicularis olgae

Ver basc um nobile Vel.

Gentiana tibetica


G. puncta ta


0 . bulgarica

G. cruciata

G. lutea .G. puncta ta

Gentiana cruciata




Alkaloid VI

Alkaloid B

Alkaloid B

Alkaloid C

Alkaloid E

Gentianamine (81)

Indicanine

cf. bulgarica

B. cmciata

B. luteaB. punctata

B. bulqarica

Q. cruciataQentiana macrophylla

Skytanthus acutus

Bentiana macrophyllaSkytanthus acutus

Bentiana caucasia

B . kauffmnniana

B . olqae

Q. olivieri

a. tianthanica a. turkestanorum

0. vvedenskyi

Swertia conmta

S . qraciJEora

S. marginata

Pedicularh dolichorrhiza

Plantaqo albicans

P . indica

P . notata

P . ovata

P . psyllium

Oliverine (105) Bentiana olivieri

Pediculine (115) Pedicularis olqae

Spicatine Centaurium spicaturn Fritsch.

Bentiana aaclepiadea

a Asterisk indicates that ammonia was involved in the isolation procedure.



TABLE I1PHYSICALROPERTIESF THE MONOTERFENEALKALOI

uv NMR MassMolecular IR spectrum spectrum spectrum

lkaloid Formula mp/hp (mm) spectrum A,,, (log c) ( 6 ppm) W e )

I. Iridoid-DerivedActinidine (37) 100-103°C 191 ( 6 4 )

( 2 4 , 5 4 , 5 5 ,6 1 , 6 2 )

1.27(d, 3)

2.18 (s,3)8.01 (s, 1)

8.11 (9, 1)

( 2 0 )

147, 120 ( 6 4 ) -

-

Boschniakine(44)(indicaine)

SO-90°C [3]

214-216°C

( 2 4 )

( $ 9 )

( z j r , 4 1 )

( 2 4 , 6 9 , 1 6 2 )

239, 268, 282

( 2 4 )

(70, 1, 62)

1.38 (d, 3)8.77 (9, 1)

8.99 (9, 1)10.45 (s,1)

( 4 1 )

(70)

1.15 (d, 3)

1.32 (d, 3)

161, 146, 132,118, 117, 91,

77 (70, 3,196)

oschniakinic acid (18)

(plantagonine)

177, 162, 146,

133. 118. 91.( + ) 218-220°C

( - ) 218-22ooc

( 2 4 , 62, 7,

69, 60)

(162)

( + ) 226-227°C

( 1 6 2 )

77 (70,Y1,196)9.15 (s, 1)

8.64 (8,l)

(71)

Methyl ester

( 4 7 )

1.31 (d, 3)3.78 (s, 3)

8.29 s , 1 )

8.77 s , 1)

(76, 7)

207, 179, 176,

147, 132, 117,

91, 77 (76,

77)

antleyine (50) 132-133OC

130°C (77)( 7 6 )

( 7 6 , 77) 271 (3.39)

(76 , 77)



(36)s-Dehydroskyt anthine CllHlsN (36) _-(28)

A7-Dehvdrosk~tanthine C,,H,.N (29. - -. .. _ _ . ,

(29) 52, 53)

(22) (alkaloid D)

Hydroxyskytnnthlne I CllHPINO (52) 93°C (23, 52) (52)

94-95OC (53)

Hydroxyskytanthine I1 Cl1HlaNO (53) 119-120°C (53) -(21)

( 7 4 )ndicainine (46) CiaHieN + 0 -( 7 4 )

Isogentialutine ( 5 5 ) CsIIllNO ( 8 s ) 131°C (88) ( 8 8 )

5CD

Leptorhabine (57) CsIIiiNO (89) - ( 8 9 )

261 (3.52)

268 (3.48)

( 7 4 )

254,260,267

( 8 8 )

263,269 (89)

( 4 1 )-Noractinidine (48) CBHIIN 4 1 ) - -

1.0 (d, 3)

1.3 (d , 3)

2.9 (9, 3)5.5 (m, 1 )

(36)

1.50 (s, 3)

0.82 (d, 3)

1.24 (s, 3)

2.3 (s, 3)

1.00 (d, 3)1.12 (5, 3)2.18 (s, 3)

(53)

3.498.55 (s , 1)8.75 (9 , 1)10.13 (s, 1)

( 7 4 )

1.33 (d, 3)3.05-2.98

(m, 2)3.18 (m, 1)

3.69 (b, 1)4.53 (td, 1 )

7.15 (d, 1)

8.28 ( 8 , 1)8.28 (d, 1 )

( 8 8 )1.20 (d, 3)1.97 (m, 1)

3.30 (m, 2)

5.06 (m, 1 )6.94 (bs,1)

7.15 (d , 1)8.07 (d, 1 )

8.11 (4, 1)

( 8 9 )8.03 (d, 1)8.8 ( 5 , 2)8.85 (d, 1)

1.6 (d, 3)

( 52)

(52)

( 4 1 )

165, 150,12 2, -89"

107, 79, 58,44 (36)

-+35.8

(23+ 38.

(53)

110, 84, 58, 44 -38.5

(53)

190,162,161, +14.146, 133,132, ( 7 4

118, 117 , 91,77 ( 7 4 )

149, 120, 105, -98, 79 ( 8 8 )

149, 132,131,

118,117,106,

79 (89)

- +3"



TABLE II ( con t inued )

uv NMR Mass

Molecular I R spectrum spectrum spectrumAlkaloid Formula mp/ bp (mm) spectrum A,,, (logs) (8 ppm) (mid

N-Normethylskytan- CloHlsN (41 ) 125130' (3) ( 4 1 ) - 0.9 (d, 3) 153 (41 ) +3

Skytanthine (4) ClIHZ1N 54" (1.5 ) (21 , (19 , 165 ) - 1.27 (d, 3) - +4

1.02 (d, 3)hine (47) ( 4 1 )( 4 1 )

(19,-21, 165) 22) 2.18 (s, 3) 262" (1) (23) (19 , 20, 1 6 5 ) + 3

62 (1.5) (19, +2

21, 165)

a-Skytanthine(5)

@-Skytanthine6)

y-Skytanthine (7)

+7

- ( 3 0 ) +1

+5( 3 0 )



&Skytanthine (8) -

&Skytanthine "oxide C l lH2 , N O- 218-222% ( 3 5 )

Tecomine (13) CI1Hl7NO 125°C (0.1) (39-41)(9) 2H20 ( 3 3 , 3 5 ) ( 3 3 , 3 5 )

(tecomanine) ( 3 9 - 4 1 ) ( 4 0 , 4 1 )

Tecostanine (16) CllHllNO 82OC ( 4 2 , 4 4 ) ( 4 2 , 4 4 )

( 4 ~ ~ 4 4 )

Tecostidine (17) and (19) CIOIIllNO

ifr ( 4 5 , 4 6 )

co

Venoterpene (52) C & l l N O 13&132OC (81-85 , 88)( 8 0 , 8 1 , 8 4 ) ( 8 0 . 8 1 )

128-130°C

(82 , 84 ,86-

88, 1 3 8 )

Unnamed I from CloHziNO 91-92OC ( 4 1 )( 4 1 ) ( 4 1 )ecoma slam (24)

Unnamed I1 from Cl oIIz l NO 82-94' ( 4 1 )T e c m slam (25) ( 4 1 ) ( 4 1 )

-226 (4.1)

(39-41)

-

( 4 5 , 4 6 )

259 (3.50)( 8 1 - 8 5 , 8 8 )

( 4 1 )

( 4 1 )

-

-1.07 (d , 3)

1.12 (d, 3 )

2.75 (5, 3)5.95 ( 8 , 1)

( 4 0 , 4 1 )

0.98 (d, 3 )2.25 ( 9 , 3)3.56 (d, 2)

( 4 4 )

1.27 (d, 3)

4.65 ( 8 , 2)

8.22 ( s , 1)8.27 ( s , 1)

( 4 5 )1.32 (d, 3)2.9-3.3

(m, 3)4.50 (m, 1)5.60 (6,l)

7.09 (d. 1)

167,186,152, +10

110, 84, 58, (244 (30 , 36)

4

- 0' (

-17

- 1

00. 58.44 ( 4 4 ) 0 (

163 (45 , 46) -4"

+5.

+ 2149, 134,132,120,106.77

(80-82)

8.18 id, 1)

8.21 ( 8 , 1)

(81-83. 85.88)

(Benzoate) (41)0.9 (d, 3)

1.0 (d, 3)

2.3 ( 8 , 3)

( 4 1 )

0.95 (d, 3)1.24 (d, 3) 74,55 ( 4 1 )2.27 (9, 3)

183, 166, 150,



TABLE I1 (confinued)

uv N M R Mass

Molecular IR spectrum spectrum spectrumAlkaloid Formula mp/bp (mm ) spectrum Amax (log e) ( 8 ppm) (mle)

222, 267 ( 6 4 ) 1.23 (d, 3) 288, 147, 132, 4.120 ( 6 4 . 6 5 ).34 (s. 3)

Unnamed I fromVnleriana ofleinalii,(88)

Unnamed I1 fromValeriana offkinalin(39)

11. Secoiridoid-derived

Bakankoside (60)

,+ Enicoflavine(90)

00N

Fontaphilline (69)

Gentianadine (74)

ClsHazNOCl 201-203°C ( 6 4 )

157" and 200°C -( 9 0 )

162" and 211OC( 9 3 )

80" and 121°C ( 1 2 5 )

(125)

C8H7NOz (126) 77-78°C ( 1 2 6 , (126)129)

76-77°C ( 1 3 2 ,1 3 3 )

8748°C ( 9 9 )

. .

4.73 im, 4)6.73 (d , 1)

7.04 (d, 1)

8.83 (8 . 1)

8.90 (s, 1)( 6 4 , 6 5 )

(65 ) ( 6 5 ) +

40, 270 ( 1 4 6 ) 1.6 (m, 2) ( 1 4 6 )

2.45 (b, 1 )

212 (4.49)

257 (4.25)

( 1 2 5 )

( 9 9 )

4.4 (m, 2)5.8-5.96 (dd, 2)6.9-6.98 (m, 2)

8.2 (m, 1)

8.9 (b, 1)

9.3 s , 1)10.1 (b, )

(116)3.60 (t, 2)3.95 (s, 3)4.55 ( t , 2) ( 1 2 5 )

5.60 (m, 2)6.80 (d, 1)7.30 (m, 1)

7.85 (d, 1)

8.75 (9, 1)9.00 (5, 1)

3.04 ( t , 2)

4.52 ( t ,2) ( 1 2 8 )7.19 (9. )

8.64 (d, 1)9.12 (d, 1)

( 1 2 5 )149, 120, 92, 65

(127)



Gentianaine (92) CeH,NO, ( 1 2 7 , 149-150°C ( 1 2 9 )1 2 9 ) ( 1 2 7 , 1 2 9 )

Gentianamine (81) CIIH~INOB 149-150°C ( 1 2 6 )

( 1 2 6 ) ( 1 2 6 )

231 (4.16) 2.88 (4.16) 141.113. 112. 9268 (4.1)' 4.70m, 2) ( i z . 9 )

( 1 2 9 ) 8.50m, 2)( 1 3 7 )

( 1 2 6 ) 5.80 q, 2) 205, 75, 31,

117, 1 1,OG).94 (rl, 1)8.85 a , 1)

9.06 a , 1)( 1 2 7 )

Gentianidine(79) CgHsN02 129-13OoC ( 1 3 4 , 1 3 7 ) ( 1 3 4 ) ( 1 3 4 ) ( 1 3 6 )

Gentianine (62) CIOH.O, ( 9 5 , 8042°C 8 4 , ( 8 4 , 8 5 , 9 7 , ( 8 4 . 8 5 , 99, ( 1 0 1 , 1 1 3 ) 175,147,117,( 1 3 4 , 1 3 9 ) ( 1 3 7 -1 3 9 )

1 2 5 , 1 7 6 ) 8 5 , 85 , 9 9 , 9 9 , 1 0 1 , 1 7 5 , 1 0 1 , 1 4 7 , 91 ( 1 2 5 )1 0 1 , 113, 1 9 1 ) 1 6 9 )

1 3 8 , 1 4 7 ,1 6 8 , 1 7 1 ,1 7 6 , 1 8 1 ,1 8 3 , 1 X 6 )

83°C 1 3 8 , 1 9 3 )

Gentlatibetine (100) CsHllNOa 159-160°C ( 1 5 0 )

( 1 5 0 ) ( 1 3 1 )161.5"C

( 8 6 , 1 3 8 , 1 5 0 )

( 1 5 0 ) 2.53 a, 3) 165

2.56 m, 1) 134

2.98 m, 1) 1063.88 (m, 1) ( 1 5 0 )4.29 m, 1)5.94 a , 1)6.85 d, 1)8.21 d, 1)

( 1 5 0 )



TABLE I1 cont inued)

uv N M R MassMolecular I R spectrum spectrum spect,rum

(midlkaloid Formula mp/bp (mm) spectrum Amax (log 6) ( 8 ppm)

Gentiocrucine (86) CeR7N03 1 4 4 ) - ( 1 4 4 ) 232, 283 ( 1 4 4 ) 2.58 (m, 2)

4.40 (m. 2)

Gentioflavine 85) CioHllNOB 207-208°C ( 1 4 0 , 1 4 1 ) 235,298, 410( 1 4 0 , 1 4 1 ) ( 1 7 1 ) ( 1 4 0 , 1 4 1 )

218-220°C

(140-I42)

Jasrninine (96) CiiHmNzOQ 175-176OC ( 1 4 8 )( 1 4 8 ) ( 2 4 8 , 1 4 9 )

Ollveridine(103) C ~ O H ~ O N O ~60°C ( 1 3 2 ) ( 1 3 1 )

( 1 3 1 )Pedicularidiue (113) CloH1,NO 211-212OC ( 2 5 8 )

( 1 5 8 ) ( 1 5 8 )

Pedicularine (110) C I O H ~ ~ N O Z203-204°C ( 1 5 6 , 1 5 8 )( 1 5 6 , 1 5 7 ) ( 1 5 8 )

207-209°C(dec.) ( 6 9 ,1 5 6 )

Pediculidine (108) CioHgNO ( 1 5 3 ) 74-75°C ( 2 5 3 ) ( 2 5 3 )

( 1 3 1 )

236 (3.36)270 (3.32)

( 1 5 8 )272 ( 1 5 6 ,

1 5 8 )

268 (3.97)273 (3.96)

293 (3.36)

( 1 5 3 )

8.10 (bd, 1)

( 1 4 4 )

1.3 (d, 3)

3.0 ( t , 2)4.35 ( t ,2)

5.2 (9, 1)8.45 9,1)8.80 (a, 1)10.10 (8, 1)

( 1 4 1 )1.58 (d, 3)

4.75 rn, 1)

4.87 ( % I )

5.12 ( I)8.57 (8 , 1)

9.01 (8 , 1)

( 1 4 8 )1.44 (d, 3)

1.98 (m, 2)2.67 (m, 2)2.96 (m, 5 )4.46 (m, 4)

8.43 (8 , 1)

8.76 (8 , 1)8.94 (8, 1)9.00 (s, 1)

( 1 5 2 )-

-

8.07

8.478.92

( 1 5 6 )

2.45-3.15 ( m )6.34 (d)

141,113

111,97 ( 1 4 4 )

-

20,205, 173, -33"

145, 118,117,91 ( 2 4 8 ) - 3 7 .

352, 296,176

( 1 5 2 )

179, 151, 148,

120, 91 ( 1 3 1 ) 67.1 5 8 )

(156-158) 0 (

- 5

( 2f 52

( 1159, 158, 131, Picr

30. 118. 117.7.12 id j 104,' 103,' 102,'7.15 (d) 77 ( 1 5 3 )



Pediculinine (109) CIOHI~NO 133-134°C ( 1 5 4 )

( 1 5 4 ) ( 1 5 4 , 1 5 5 )

Unnamed from G'entiana CloH,,NO3 208-210°C ( 1 5 1 )

tibetica ( 1 0 4 ) ( 1 5 1 ) ( 151 )

111. Unknown Structures

Alkaloid I C13HteNaO3

Alkaloid I1 -1 4 0 )

183-187°C

( 1 4 0 )

138-140°C

( 1 9 7 )240°C ( 1 9 7 )

248-252OC

128-130°C

( 1 4 7 )190°C (15)

(23)206-208°C

( 1 4 7 )120-140°C

(28)375-380°C

-

( 1 4 0 )

( 1 2 6 , 1 2 9 )-

206-207°C

( 1 3 1 )188-189T

( 1 8 9 )182-183°C

( 1 9 8 )

262 (3.33)

269 (3.23)

( 1 5 4 )

234 (4.21)

296 (4.32)

402 (3.95)

( 1 5 1 )

269,316 ( 1 4 0 )

-

234, 266 ( 1 4 7 )

8.41 (d )8.51 (9)

( 1 5 3 )1.57( t , 2)

1.98 (t , 2)

3.05-2.10

( m , 4)

4.01 (m, 2)6.93 (d , 1)8.19 (rn, 2)

( 1 5 4 )1.20 (d , 3)3.02 (m, 2)

3.26 (s, 3)

4.33 ( m , 2)

4.66 (u . 1)7.74(s, 1 )

9.70 (s, 1)

( 1 5 1 )

-

-

-

-

-

-

-

-

--

-

---

161, 146, 145,131, 130, 118,

117, 91, 77

( 1 5 4 )

- 0.80

-

-

61, 146, 117, + 6

91 ( 1 5 8 )




TABLE I11

POSSIBLE ISOLATIONS O F MONOTERPENELKALOIDSUNIDENTIFIED)

Compound Pla nt name mp/bp ("C) Reference

Alkaloid I11

Alkaloid I11

Alkaloid I11 (aerial

Alkaloid I11 (roots)

Alkaloid 111-1

Alkaloid 111-2

Alkaloid IVa

Alkaloid VIIAlkaloid E-2

Base A

Base B

E-1

E-2

J-5-2

Substance V

Substance V I

Substance VII

VP-2

VP-3

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

Unknown

UnknownUnknown

TJnknown

parts)

Centiana bulgarica

G . cruciata

G. punctatu

Q. punctata

G. asclepiadea

C. asclepiadea

G . punctata

C . punctataErythraea celztaurium

Plantago notata

P. albicana

Erythrae centaurium

E . centaurium

Jasmi num fruticans

J . fruticans


M . trifoliata

M . trifoliata

Va le ri am stolonifera

V . stolonifera

Anthocleista rhizophoroides

Qentiana asclepiadea

G . asclepiadea

Qentiana sp.

Qentiana sp.

Gentiana sp.

Skytanthus acutus

S. acutus

Swertia japonicaTecoma stana

Verbascum songaricum

---

-

157-160---

72

106-

-

260

143-144

oil

---

-

-

249-252

240

189-191

Picrate, mp 125-127-

--

-

197

197

197

197

197

197

194

140137

61

61

178

178

199

199

138

138

138

200

200

169

86

86

142

142

142

166

33

19339

164

(205,207).Work with S. acutus in vitro gave a labeled product from

[2-14C]rnevalonate(2 0 8 ) . Skytanthine is therefore derived from a

terpenoid precursor.

Similar results were subsequently reported by Waller and co-workers

(209);[2-14C]mevalonatewas incorporated, but [2-14C]lysinewas not.

Different specific activities of the skytanthines from different plantparts were observed both from feeding labeled mevalonate and labeled

methionine. The latter was shown to be a specific precursor of the

N-methyl group (209).




A further complication was also uncovered, for considerable random-

ization of the label in the monoterpene terminal carbon atoms was

observed in 3-year-old plants, yet essentially no randomization wasfound in experiments with 1.3-year-old plants (209). In the biosynthesis

of iridoids (12 4, 210-214) and indole alkaloids (201 ) , andomization of

label is consistently observed. Some of these problems have been

discussed by Appel (215 ) ,who considers that multiple labeling must

have occurred in order to have labeled the methyl group, C-9. Much of

this work on skytanthines has been summarized by Marini-Bettolo ( 6 ) .

B. ALKALOIDSF T. stuns

A more extensive study of the biosynthesis of the alkaloids of Tecomastuns, has been carried out by Gross and co-workers (216) . [2-I4C]-

Acetate and [2-14C]mevaIonate ach labeled the alkaloids %skytanthine

(8), tecostanine (16),ecomine (13), and boschniakine (44). 2-14C]-

Acetate was also incorporated into A5-dehydroskytanthine (28). The

monoterpenoid nature of these alkaloids is therefore established. The

N-methyl groups in 8, 28, 13, nd 44 were derived from methionine.

Neither loganin ( 5 7 ) , uniformly labeled, nor actinidine (3) wereincorporated into these alkaloids. Thus, the branching point for the

formation of the skytanthine-type alkaloids occurs at a stage prior to

formation of loganin, and the oxidation of the piperidine ring to a

pyridine ring is not reversible. Uniformly-labeled &skytanthine (8),

however, gave rise t o moderate incorporation into tecostanine (16)and

tecomine (13),bu t almost no incorporation into 44 or 28. N-Normethyl-

skytanthine (47), on the other hand, gave excellent incorporation into

tecostanine, moderate incorporation into 13 and 8, but very low

incorporation into 44 (216) .

C. ACTINIDINE3) ND THE Vuleriuna ALKALOID8

The biosynthesis of actinidine was first studied by Waller and CO-

workers (217 ) ,who demonstrated that i t was not derived from lysine,

aspartic acid, or quinolinic acid, but rather by a monoterpene route.

Thus, [2-14C]acetate, 2-14C]mevaIonate 116),and [ 1-14C]geranylpyro-

phosphate (117) were each incorporated into actindine in Actinidiupolygumu. [2-14C]Mevalonate abeled actinidine (3) o the extent of

0.12% after only 24 hours, indicating the quite rapid alkaloid formation

in this plant.



488 GEOF FREY A. CORDELL

Experiments by Gross and co-workers ( 5 7 )with Valeriana o#cinalis

demonstrated that [2-14C]mevalonatewas an effective precursor of both

actinidine and the quaternary alkaloid 38 to the extent of 0.1 and0.47%, respectively. Phenylalanine was not a precursor of the phenyl

ring in 38, but tyrosine was found to be incorporated. Uniformly-

labeled actinidine (3) was also incorporated into 38.

C H 3

H O C H x WIII Hs Gy./ \ 0Hs Hr Hr CO,H

C H , C H 3 N

116 117 118

0 = degraded, active

A = degraded, inactive

0 '4 'OH H0''''''B7\\ 0 G l u HY%H, CO&H3

3G l u 0 0OGlu CO,R \ o

66 R = O H120 R = H

51 R = C H 3119 R = H

1 2 1

D. GEENTIANINE62)

The incorporation of glycine into a number of terpenoid-derived

alkaloids has been observed ( 2 0 1 ) .When [2-14C]glycinewas administered

to young Gentiana asclepiadea plants ( 1 8 2 ) labeled gentianine was

produced ( 1 8 2 ) . Degradation and isolation indicated the labeling ofgentianine as shown in 118. This labeling corresponds to a biosynthesis

from [2J4C]acetate, but in the formation of acetate, current theories

suggest that labeling should be at the 1 position of acetate ( 2 1 8 ) .

Clearly there is much to learn about the utilization of glycine in terpine

biosynthesis. Further work by the Bulgarian group ( 2 1 9 )was aimed at

evaluating the role of pyruvate in gentianine biosynthesis. Neither

[l-14C]pyruvatenor [1-l4C]formatewas incorporated.

It was mentioned previouly that both gentiopicroside (66) and

swertiamarin (65)are in vitro precursors of gentianaine (220 , 221 ) .It istherefore pertinent to comment on some aspects of the biosynthesis of

gentiopicroside. A number of labeled mevalonates have been shown to

be precursors ( 1 2 4 , 2 1 2 - 2 1 4 , 2 2 1 - 2 2 3 ) . Experiments with [4-3H,2-14C]-

(4R)-nd (4s)-mevalonates (116) indicated that as expected the 48-




protons were lost and only one 4R-proton was retained. This tritium

was located a t the ring junction hydrogen as indicated by conversion to

a tritiumless gentianine (221 ) . Similar experiments with [2-2H,2-14C]-(2R)- and (2s)-mevalonates indicated th at the tritium was lost from

the 2S-labeled species and approximately half of the tritium from the

2R-labeled species. There was no tritium loss between loganic acid (119)

and gentiopicroside, and subsequent work deduced that most of the

tritium was at C-7 (224 ) .

Loganin (51) ( 2 2 0 , 2 2 1 )and loganic acid ( 2 2 1 , 2 2 3 )are also excellent

precursors of 66. [5,9-3H, 3,7,1 -14C]Loganic acid was incorporated into

66 with loss of half the tritium label (221 , 223 ) ) so that oxidation is

regiospecific. Sweroside (120) is also a precursor of gentiopicroside(225 ,226 ) .

More recently an iridoid gentioside (121) was isolated from three

Gentiana species ( 2 2 7 )and shown to be a precursor of gentiopicroside

and, by implication, of gentianine.

E. GENTIOFLAVINE85)

The novel monoterpene alkaloid gentioflavine was investigated by the

Bulgarian group (142 , 194 , 228 ) . [l-14C]Geraniol (122) and [1-14C]-linalool (123) were each incorporated. Degradation of the labeled

gentioflavine indicated that the activity was specifically a t the aldehyde

group, thereby demonstrating the monoterpene derivation of gentio-

flavine (194 ) . It was also demonstrated that a t least some of the

biosynthetic reactions of the alkaloids may be reversible. Feeding uni-

formly labeled gentiopicroside to G. asclepiadea gave a 23% incorpora-

CH, A H,

123

tion into gentioflavine ( 2 2 8 ) .Previously, however, it had been demon-

strated that gentioflavine was also a precursor of gentianine, gentian-

idine (79), and possibly gentianadine (74) (229 ) .Labeled gentioflavine

was not incorporated into gentiopicroside (228 ) hence, another routenot involving gentiopicroside must exist for the conversion of 85 to 62.

Experiments using 14C0, indicated that labeling of the alkaloids ap-

peared in gentioflavine before gentianine (229).The biosynthetic data

for the monoterpene alkaloids are summarized in Table I V .



TABLE IV

INCORPORATIONATA OR MONOTERPENE LKALOIDS

Incorporationa

Alkaloid precursor Pl an t % Reference

Actinidine

[2-14C]acetate

[2-14C]aspartate

[2- 14C]lysine

[2-'4C]mevalonate

[ l-14C]geranyl pyrophosphate

[2,3,5,7-'4C4]quinolinic cid

[' 4C methionine

[2 - 4C]acetate

[2-14C]mevalonate

[U-3H]loganin

[U-3H]N-normethylskytanthine

[U-3H16-skytanthine

[U-3H]actinidine

A'-Dehydroskytanthine

[14C]methionine

[2-14C]lysine

[2-14C]mevalonate

A5-Dehydroskytanthine

['4C]rnethionine

[2-14C]aceate

[2- 4C]mevalonate

[W3H loganin

[U-3H N-normethylskytanthine

[U-3H1G-sl~ytanthine

[U-3H]actinidine

[U-'4C]gentioflavine

[U-'4C]gentioflavine

Boschniakine

Gentianadine

Gentianine1 4 ~ 0 ,

[14C]formate

[ -14C]acetate

[2-14C]acetate

[2-14C]glycine

[I-"%Tpyruvate

[2-'*C]mevalonate

[U 4C]gent oflavine

Gentioflavine

1 4 ~ 0 ,

[1-14C]geraniol

[1 14C]nerol

[U-'4C]gentiopicroside

Actinid ia polygama

A . polygama

A . polygama

A . polyrJamu

Valeriana osci nal is

A . polygama

A . polygama

Tecoma stans

T . stans

T . stans

T . stans

T . stans

T . stans

T . stans

Skytanthus acuttu

S. acutw

S. acutus

Tecoma stans

T . stans

T . stans

T . stans

T . stans

T . stans

T . stans


G. asclepiadea

G . asclepiadea

G. asclepiadea

G . asclepiadea

G. asclepiadea

G. asclepiadea

G. asclepiadea

G . asclepiadea.

G. aactepiadea


G. asclepiadea

G. asclepiadea

0 . aaclepiadea

0.04

0

0

0.17

0.47

0.06

0

L

L

L0

0

0

0

4.0

0

0.2

LL

L

0

0.03

0.04

0

NG

NG

NG

0

L

NG

NG

0

NG

NC

NG

3.0

3.0

2.3

2 1 7

2 1 7

21 7

57

21 7

21 7

216

2 1 6

216

21 6

2 1 6

216

2 1 6

209

209

209

2 1 6

21 6

2 16

216

21 6

2 1 6

2 1 6

229

2 2 9

2 2 0

220

1 9 9

1 1 9

1 8 2

2 1 9

1 8 2

1 9 4 ,

2 2 8 ,

229

2 2 9

1 9 4

194

2 2 8

21 7

490



TABLE I V (conrinued)

Incorporationa

Referencelkaloid precursor Pl an t %

Skytanthine

[2-'4C]acet.ate

[2-'*C]mevalonate

a-Skytanthine

[14C]methionine

[2-'4C]lysine[2-'4C]mevalonate

['4C]methionine

[2-l4C]1ysine

[2-14C]mevalonate

[14C]methionine

[2-14C]acetate

[2-14C]mevalonate

[U-3H]loganin


[U-3H]G-skytanthine

[U-3H]actinidine

[14C]methionine

[2-'4C]acetate

[2-'4C]mevalonate

[U-3H]loganin


[U-3H]G-skytanthine

[U-3H]actinidine

8-Skytanthine

6-Skytanthine

Tecomine

Tecostanine

[ 4C]methionine

[2-14C]acetate

[2-'4C]mevalonate

[U-3H]loganin


[U-3H]6-skytanthine

[U-3H]actinidine

Valeliana alkaloid (38)

[Z-4C]mevaIonate[U-'4C]phenylalanine

[2-'4C]tyrosine

[U-3H]actinidine

Skgtanthw aeulus

S. acutw

S. acutus

S . acutus

Skytanthus acutils

S . acutusS. acutus

Skytanthus acutus

S. acutus

S . a e u t u s

Tecoma stuns

T . stam

T . stans

T . stuns

T . stans

T . stuns

T . stans

Tecoma stuns

T . stuns

T . stuns

T . stuns

T . stuns

T . slam

T . stuns

Tecoma stuns

T , stuns

T . stans

T . stuns

T . s tam

T . stuns

T . stam

Valeriana of lc ina l isv.oflcinali.9

v. o f i c i n a l i s

V. oficicinalis

0

L

L ( ~ T Z itro)

0

4.0

00.17

10.0

0

0.2

1 .1

L

L

00.1

0.9

0

0.2

L

L

0

0.1

0.1

0

0.6

L

L

0

1.4

0.6

0

0.10

0.02

0.04

6, 206,

208

6 , 205 ,

207

208

6 , 205 ,

20 7

209

209209

209

209

209

216

216

216

21 6216

21 6

216

216

216

216

216

216

216

21 6

216

216

216

216

216

216

216

5757

57

57

a L = low incorporation; NG = not given.

491




F. BIOGENESIS

It was mentioned in the introduction to this chapter that much ofthe stimulation of interest in these alkaloids came as a result of the

general interest in the iridoids and indole alkaloids following the pro-

posals of Thomas ( 2 ) and Wenkert ( 3 ) . The biogenesis of the mono-

terpene alkaloids, a frequently discussed topic ( 1 , 1 0 , 11, 14, 15 , 44 , 48 ,

5 7 , 8 1 , 8 4 , 8 6 , 1 1 2 , 1 2 5 , 1 3 7 , 1 4 1 , 1 4 8 ) , is intimately entwined with the

biosynthesis of the iridoids and secoiridoids. It is therefore pertinent a t

this point to summarize briefly some of the results and biosynthetic

schemes developed in this area that are applicable to the monoterpene

alkaloids.A scheme for the formation of the iridoids and secoiridoids from

geraniol is shown in Scheme 1 1 . The scheme highlights some of the

potential precursors of the monoterpene alkaloids, and each of these is

discussed sequentially. (R)-()-Mevalonic acid 116) s sequentially

phosphorylated to 5-phosphomevalonic acid and 5-phosphomevalonic

124 125

OPPCHa '1$ . "'Hs

, Hr

4 2 5 126

CH,OPP CH,OPP

117 R = PP

122 R = H

127

SCHEME1




$f

&LH,OH rc--

6H,OH

CHO CH20H CHaOPP

CH, Hr CH, Hr CH3

132 131

COaRISkytanthines

CH3 OGlu

154 128 R = CH3

137 R = H

Hr y2R iH O X o +-- HO-@ C 51

OGlu H°CH2 OGlu

129 R = CH,

130 R = H

I139

120- 5 ---+ Monoterpem alkaloids

SCHEME1 ( conr inued)

acid (124). rans elimination ( 2 3 0 , 2 3 1 ) ffords isopentyl pyrophosphate,

which undergoes enzyme-mediated stereoselective loss of the pro-4S

hydrogen (2 3 2 )and stereoselective addition of hydrogen t o the re side

of the double bond (2 3 3 ) o produce dimethylallyl pyrophosphate ( 2 3 4 ) .

Stereoselective loss of the pro-48 (in mevalonate) proton ( 2 2 1 , 2 2 3 , 2 3 0 ,2 3 5 , 2 3 6 ) from isopentyl pyrophosphate (125) in the coupling-

elimination reaction with dimethylallyl pyrophosphate (126) roduces

geranyl pyrophosphate (117) n which both pro-4S hydrogens of




mevalonate have been lost, and this has been confirmed using doubly-

labeled mevalonates into loganin (51)and loganic acid (119) (221 , 223).

After trans-cis isomerization of the 2,3 double bond in geranylpyrophosphate (97) to give neryl pyrophosphate (127),cyclization and

formation of the cyclopentanol ring occurs. I n the case of the iridoids

and indole alkaloids thus far studied, this cyclization is stereospecifically

cis and proceeds with retention of both hydrogen atoms as indicated.

Steps after the cyclization and prior to the formation of deoxyloganin

(128)are still in some doubt.

Deoxyloganin is a precursor of loganin (237 ) and a number of

secoiridoids (224,238-240) ,and it has been demonstrated tha t hydroxyl-

ation of deoxyloganin is stereospecific (225 ) .The derivation of loganin(124, 222, 241) and secologanin (129) (242) from [2-14C]mevalonate is

well established, as is their formation from variously labeled geraniols

( 2 2 2 , 2 3 5 , 2 4 2 - 2 4 4 ) . Loganin is a precursor of secologanin, ( 2 4 5 )

secologanic acid (130) ( 2 4 2 , 2 4 6 ) ,and a number of other secoiridoids

( 2 2 0 , 2 2 1 , 2 2 3 , 2 2 4 , 2 3 9 , 2 4 7 - 2 4 9 ) . ecologanin has been demonstrated

to be a precursor of a number of secoiridoids ( 2 4 9 )and this route from

loganin to the secoiridoids as well as another route have been investi-

gated by Inouye and co-workers (249 ) .

Returning to a point in the biosynthesis scheme where the cyclo-pentane ring has just formed, we observe that a number of possible

routes exist, depending upon the various stages of oxidation of the two

alcohol functions and the methyl group in 131. In the formation of the

Skytanthus alkaloids, oxidation of the two alcohol functions occurs to

the dialdehyde 132, with subsequent condensation with ammonia.

The labeling a t C-9 of skytanthine (4) from [2-14C]mevalonate(209)

would imply a randomization a t some point and would involve an

unlikely oxidation, subsequent reduction of the methyl group, and

N-methylation with methionine. Oxidation after condensation with

ammonia, rather than reduction, affords actinidine (3).Several oxidized

actinidine/skytanthine-type lkaloids are known; for example, teco-

stanine (16)and tecostidine (17), n which one of the ring methyl groups

has been hydroxylated. This oxidation may occur after formation of the

nucleus, but it seems more probable that a hydroxydialdehyde such as

133 is involved.

It has been implied that the series of compounds, actinidine, teco-

stidine, boschniakine (44), boschniakinic acid (18),and 4-noractinidine

(48) forms a neat biosynthetic oxidative series. No experiments to

prove or disprove this concept have been reported. However, it seems

more likely that oxidation of the C-8 methyl group of nerol occurs after

formation of the cyclopentane ring and before alkaloid formation; thus,




species of the type 133 and 134 and other highly oxidized species should

be involved.

A number of hydroxyskytanthines are known (see earlier), and againthe problem arises as to their derivation from an alkaloid (skytanthine)

precursor or an oxidized monoterpene. No experiments in this area have

been reported. I n the case of hydroxyskytanthines I and I1 (22 and 21),

i t may be tha t hydroxylation is part of the initial cyclization reaction

giving 135 and 136, which subsequently condense with ammonia and

are reduced.

133 135 136

In the hydroxyskytanthines, where the ring junction is hydroxylated,

it seems more probable that a preformed alkaloid is a precursor.

Cantleyine (50) was shown to be an artifact in Cantleya corniculata

formed by ammonia addition to loganin (51) (77) . In a similar manner,

boschniakinic acid (18)may be derived by ammonia condensation with

deoxyloganic acid (137) ( 224) .Decarboxylation of 18 leads to 4-noractinidine (48) as noted pre-

viously. A number of 4-noriridoids are also known, so that again this

presents an alternative biosynthetic route. The same comments apply

to the formation of venoterpine (52), which may or may not be derived

from the carboxylic acid corresponding to cantleyine (138).

50 R = CH,

138 R = H140

Cleavage of the cyclopentane ring of loganin probably proceeds via

10-hydroxyloganin(139)(250)to give secologanin (129).The subsequentelaborations of secologanin by condensation and rearrangement are

numerous and are evidenced by the wide array of known secoiridoids.

This structure diversification is almost matched in the monoterpene




alkaloids. There are six basic structure types of monoterpene alkaloids

derived from the secoiridoid skeleton thus far isolated. In simple terms,

we can envisage the formation of these skeleta as occurring from theester trialdehyde 140 by selective condensation reactions. This highly

functionalized compound is merely the hydrolysed version of seco-

loganin, and it serves a useful purpose in analyzing the probable bio-

synthetic origin of the monoterpene alkaloids.

For the purpose of deriving the alkaloid skeleta, we will consider five

different orientations of this unit in condensation with ammonia. These

orientations are depicted in Scheme 1 2 and the primary alkaloid from

this orientation is shown. This, of course, is only a schematic representa-

tion, and we must look more carefully if we are to discern the probableiridoid precursors of each alkaloid. Unlike the indole alkaloids where

structure diversification takes place a t the alkaloid level, it appears that

structure modification in the monoterpene alkaloids occurs a t the

iridoid level.

0

Fontaphilline (69)

/*

Gentianine (62)

Jasminine (96)

SCHEME2. Biogenesis of the monoterpene alkaloids.




Gentiatibetine (100)

CHO COaCH3

NH3 H

Bakankoside (60)

'02CH3 CH$

&A o 2 P C H 3

CHO CHO

NH3N

Pedicularine (110)

rH0\

CH3

104

SCHEME2 (continued)




A s was mentioned previously, both gentiopicroside (66) and swertia-

marin (65) condense readily with ammonia to give gentianine, thereby

delineating a possible biosynthetic precursor. Swertoside (119) is at alower oxidation state than 66, and condensation of the lactone ring with

ammonia would give bakankoside (60) having the absolute stereo-

chemistry indicated. Similar condensation with ammonia in the lactone

ring of kingiside (142) would give jasminine (96).

A study of the iridoids of Gentiana punctata (195) afforded a new

secoiridoid, gentioflavoside (142). Treatment with aqueous ethanolic

ammonia afforded gentioflavine (95)) but no details are available on

the formation of 141. Condensation with ammonia in the lactol ring of

$CH3 o

HCH, OGlu

141 a-CH3

146 /I-CH,

142

secologanin (129), reduction of the aldehyde, and condensation with

p-hydroxybenzoic acid would lead t o fontaphilline (69).

The biogenesis of gentiatibetine (100) presents an interesting prob-

lem. One possibility is shown in Scheme 12, but a second possibility

also exists involving a compound such as tetrahydroantirride (143) as a

precursor as shown in Scheme 13. The probable biogenesis of enico-

flavine (90) and gentiocrucine (87) was mentioned previously. It is

pertinent to note here the isolation of erythrocentaurin (144) from

E . hyssopifolium and Swertia lawii ( 251) , ince this is another compound

derived from swertiamarin (65) via the lactonic dialdehyde 145.

OGlu CH, OGlu

143

SCHEME 13

100




The existence of optical antipodes of some of the alkaloids also pre-

sents a slight problem. In most instances, this is due to the opposite

configuration at C-8. There are several examples of iridoids in whichboth C-8 epimers occur naturally, and the situation with kingiside (141)

(252) and epikingiside (146) has been studied by Inouye’s group ( 2 5 3 ) ,

who demonstrated the operation of two separate routes for the forma-

tion of these substances.

144 145 147

For the situation in the series of a monoterpene alkaloids that are

formed from a monoterpene prior to iridoid formation, we must

envisage a different biogenesis in which 8-epiiridoidal (147) is an inter-

mediate. It was suggested by Inouye (253) that d- and Z-citronellals are

the intermediates which give rise to the opposite C-8 configurations.

Citronella1 (148) was not a precursor of the indole alkaloids ( 2 5 4 ) .Ex-tensive further work is required before the subtle details of the bio-

synthesis of both the monoterpene alkaloids and the iridoids are clarified.

IV. Pharmacology of the Monoterpene Alkaloids

The original interest in the plants of the Gentianaceae arose because

of the widespread use of gentian in Europe ( 2 5 5 ) .At the turn of the

century, Gentiana spp. were current in no less than twenty pharmaco-paeias, the important species being Gentiana lutea, G. purpurea , G .

punctata , and G. panon ica (256).A discussion of the pharmacological

action of these alkaloids concludes this review.




A. ACTINIDINE3)

Actinidia polygama is a potent feline attractant ( 2 5 7 ) , and theprincipal alkaloid, actinidine, has been shown to exhibit strong at tr act-

ant activity for several species of Felidae, including the cat, lion, tiger,

and leopard ( 5 4 ) .Actinidine also has a marked effect on the EEG of the

cat (258 , 259) , since during EEG flattening positive spikes were

distinctly observed similar to those obtained with acetylcholine. A

number of side effects have been observed (260 ) . The pharmacology

of actinidine has been reviewed ( 2 6 1 ) .

B. TECOMINE13) AND TECOSTANINE16)

The leaves of various Tecoma species have enjoyed a wide and

prolonged use by the natives of Mexico in the control of diabetes ( 3 7 , 3 8 ) .

Tecomine citrate and tecostanine hydrochloride were examined for

hypoglycemic activity in rabbits ( 2 6 2 , 2 6 3 ) . Both alkaloids showed

activity at 20 mg/kg intravenously and 50 mg/kg orally in fasting ani-

mals. In depancreatized rabbits, the compounds were ineffective.

Alloxan-induced hyperglycemia was effectively reduced at a dose of20 mg/kg. Problems associated with the stability of tecomine have also

been examined ( 4 3 ) .

C. GENTIANADINE74)

Gentianadine, isolated from several Gentiana sp., exhibits hypo-

thermic ( 2 6 4 , 2 6 5 ) ,hypotensive (264) ,antiinflammatory ( 2 6 4 , 2 6 6 ) , nd

muscular relaxant actions ( 2 6 4 ) . t is only very mildly toxic and shows

no effect on behavior or growth on prolonged administration (267).

D. GENTIANINE42)

Gentianine is the most widely studied of the Gentiana alkaloids.

Preliminary examination indicated no antifungalor antibacterial effects.

LOW oxicity was observed, and gentianine exhibits a central nervous

system stimulant action, but in higher doses has a paralyzing a d o n . A t

a dose of 90 mk/kg, gentianine reduces formalin-induced rat hind legswelling ( 1 8 7 , 2 6 8 ) ,and i t was suggested to act via the nervous and

hypophyseal system ( 2 6 8 ) .Simihr to gentianadine (74), i t exerts hypo-

tensive, antiinflammatory, and muscular relaxant actions but is more




effective than 74. Prolonged administration of gentianine had no

effect on behavior or growth (267).

A comparative study (266)of the antiinflammatory activity of severalpyridine alkaloids indicated that the most active alkaloids (25 mg/kg,

oral) were oliverine and gentianine, followed by gentianadine and

gentianamine (81 .

TABLE V

PRARMALOGICALROPERTIESF MONOTERPENEALKALOIDS

Alkaloid Pharmaoological action Reference

Gentianadine (74)

Gentianamine (81)

Gentianaine (92)

Gentianine (62)

Oliverine

Skytanthine (4 )

Actinidine (37) Feline attractant

Affects cholinergic neurons of t he brain

Sialogogue

No feline attraction

Vomiting (on parenteral administration)

Olfactory reflex stimulation

Anesthetic potentiator

Decreased motility

Hypothermic

Hypotensive action

Antiinflammatory effectMuscular relaxant

No effect on behavior or growth

Antiinflammatory

Low antiinflammatory effect

Central nervous system

Hypothermic

Hypotensive

Antiinflammatory

Antihistamine

Decreases motility

Muscular relaxantNo effect on growth or behavior

No antibacterial action

No antimalarial activity

No antifungal activity

No antiamoebic effect

Antiinflammatory

Nicotine-like conditioned discriminated

Sedative action

Toxicity

No psychotropic effects

avoidance behavior

Tecomine (13) Hypoglycemic

Tecostanine (16) Hypoglycemic

Valerianu alkaloid (38) Cholinesterase inhibitor

54, 55, 6 2

258, 259

260

260

260

27 3

264

264, 265

264, 265

264

264, 266265

267

266, 274

266, 274

271

264, 265

264, 271

268

1 1 3

264, 265

264, 265264 , 267

2 71

175

271

179

266

272

272

272

272262, 263

262, 263

65



502 G E O F F R E Y A. CORDELL

The principal folkloric reputation of Gentiana sp. is as a tonic, which

may be related to the hypotensive and muscle-relaxant activity of

gentianine ( 2 6 4 ) . Enicostema littorale is used in Indian traditionalmedicine as an antimalarial ( 2 6 9 ) ,and this activity was traced to the

chloroform-soluble alkaloid fraction ( 2 7 0 ) . Gentianine, the principal

alkaloid, had no affect on Ptasmodium gallinaceum (271) or P . berghei( 1 7 9 ) , o th at the activity must be attributed to some other constituent.

Further work ( 2 6 5 )on gentianine and gentianadine has indicated that

both compounds exhibit central muscle-weakening action, inhibition of

provoked aggression, and analgesic potentiating effects.

E. SKYTANTHINE4)

The pharmacology of the skytanthine alkaloids has been investigated

by Gatti and Marotta (272 ) .It exhibits no curare-like action but does

induce tremors. It has a facilitating effect on the rate of acquisition of

avoidance behavior (like nicotine). Low toxicity was observed. Its

pharmacology has been reviewed ( 6 ) . Valerian preparations are widely

used as a mild sedative. The major alkaloid (38) is a highly active

inhibitor of cholinesterase activity but shows less acetylcholinesteraseactivity ( 6 5 ) .The available data on the pharmacology of the isolated

alkaloids are summarized in Table V .

V. Summary

The monoterpene alkaloids are a comparatively undeveloped group

of alkaloids. Although some forty alkaloids have been isolated andcharacterized mostly from pharmacologically active plants, more data

are required to evaluate their potential usefulness.

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57. D. Gross, G. Edner, and H. R. Schuette, Arch. Pharm. (Weinheim) 304, 19 (1971).58. R. D. Johnson and G . R. Waller, Phytochemistry 10, 3334 (1971).

59. W. Hilz, G. Edelmann, and H. H. Appel, Rev. Latinoam. Quim. 4, 28 (1973).

60. T. Sakan, A. Fujino, and F. Murai, Nippon Kagaku Zasshi 81, 1444 (1960);CA 56,

61. A. Fujino, Nipp on Kagaku Zasshi 81, 1327 (1960); CA 56, 11644f (1962).

62. T. Rakan, A. Fujino, A . Suzui, and Y . Butsugan, Nippon Kagaku Zasahi 81,

63. R. R.-J. Nu, Dhs. Abstr. 25, I578 (1964).

64. K. Torssell an d K. Wohlberg, Tet. Lett. 445 (1966).

65. K. Torssell and K. WahIberg, Acta Chem. Scand. 21, 53 (1967).

66. S. Isoe, Kagaku 20, 145 (1965); CA 64, 12743 (1966).

67. A. N. Danilova and R.A. Knomlova, Zh. Obshch. Kh im. 22, 2237 (1952).

68. A. V. Danilova, Zh. Obshch. Kh im. 26, 2069 (1956); CA 51, 5098d (1957).

69. Kh. Ubaev, P. Kh. Yuldashev, and S. Yu. Yunusov, U z b . Khim. Zh. 7, 33 (1963);

70. K. L. Lutfnllin, P. Kh. Yuldashev, and S. Yu. Yunusov, Khim. Prir.Soedin. 1,

71. K. Torssell, Acta. Chem. Scand. 22, 2715 (1968).

72. T. Sakan, F. Murai, Y. Hayashi, Y. Honda, T. Rhono, M. NakaJima, and M. Kato,

73. D. Gross, W. Berg, and H. R. Schutte, 2. Chem. 13, 296 (1973).74. S. Khakimdzhanov, A. Abdusamatov, and S. Yu. Yunusov, Khi m. Prir . Soedin. 7,

75. L. H. Briggs, B. P. Cam, P. W. LeQuesne, and J. N. Shoolery, J. Chem. SOC. 595

51805k (1970).

265 (1968); C A 70, 68580g (1969).

Chem Soc. J. 33, 712 (1960).

Zmshi 81, 1447 (1960); CA 56, 11645d (1960).

Appel, Chem. I d . London)984 (1963).

23, 3147 (1967).

11644a (1962).

1164411 (1962).

1445 (1960); CA 56, 116441 (1962).

C A 59, 15602a (1963).

365 (1965);CA 64, 3620c (1966).

Tetrahedron 23, 4635 (1967).

126 (1971); CA 74, 1 4 2 1 1 8 ~1971).

(1965).




76. N. K. Hart, S. R. Johns, and J. A. Lamberton, A wt . J . Chem. 22, 1283 (1969).

77. T. Sevenet, B. C. Das, J. Parello, and P. Potier, Bull. SOC . him. F r . 3120 (1970).

78. T. V. Rakmatullaev and S. Yu. Yunusov, Khim. Prir. Soedin. 8, 400 (1972).79. N. G. Bisset and A. K. Choudhury, Phytochemistry 13, 265 (1974).

80. H. R. Arthur and S. N. Loo, Phytochemistry 5 , 977 (1966).

81. H. R. Arthur, S. R. Johns, J . A. Lamberton, and S. N. Loo, A w t . J . Chem. 20,

82. A. B. Ray and A. Chatterjee, Tet. Lett. 2763 (1968).

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84. J. Cieslak, J. Kuduk, and F. Rulko, Acta Pol. Pharm. 21, 265 (1964);C A 62, 13507

85. F. Rulko and K. Nadler, Dks. Pharm. Pharmacol. 22, 329 (1970).

86. T. U. Rakhmatullaev and S. Yu. Yunusov, Khim. Prir. Soedin. 8, 350 (1972).

87. F. Rulko, Diss. Pharm. Pharmacol. 19, 195 (1967); CA 67, 29849c (1967).88. F. Rulko and K. Witkiewicz, Pol. J . Pharmacol. Pliarm. 26, 561 (1974).

89. Kh. A. Kadyrov, V. I. Vinogradova, A. Abdusamatov, and S. Yu. Yunusov,

90. E. Bourquelot and H . Herissey, C . R . Hebd. Seances Acad. Sci. 144, 575 (1907).

91. E. Bourquelot and H. Herissey, C . R.Hebd. Seances A c d . Sci. 147, 750 (1908).

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93. G. Buchi and R. E. Manning, Tet. Lett. (26) , 5 (1960).

94. G. Buchi and R. E. Manning, Tetrahedron 18, 1049 (1962).

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98. T. R. Govindachari, K. Nagarajan, and S. Rajappa, Chem. Ind. (London) 1017

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101. D. Lavie and R. Taylor-Smith, Chem. tnd. (London) 781 (1963).

102. N. Marekov and S. Popov, C . R. Aead. Bulg. Sci. 20, 707 (1967); CA 68, 49831q

103. T. Kariyone and G. Matsushima, J . Pharm. Soc. Jpn. 47, 133 (1927).

104. T. Kubota and Y . Tomita, Chem. Ind . (London) 229 (1958).

105. Y. Tomita, Nippon Kagaku Zasshi 81, 1726 (1960);CA 57, 8650a (1962).

106. T. Kosuge, Japanese Pat. 10,927; C A 68, 16140k (1968).

107. Y. Araki, Japanese Pat. 10,926 (1967);CA 68, 16139s (1968).

108. H. Inouye, S. Ueda, A. Nakamura, T. Ashida, and S. Tobita, Japanese Pat. 10,517

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113. M. Koch, Trav. Lab. Matiere Med. Pharm. Galenigue Pac. Pharm. Parw 50, 94pP

2505 (1967).

(1965).

Khim. Pri r. Soedin. 10, 683 (1974).

Aeta 3 5 , 2519 (1952).

72132 (1946).

SSSR 66, 437 (1949).

1065 (1956).

(1956).

(1968).

(1970); CA 73, 38533w (1970).

(1963).

(1965).




150. F. Rulko, L. Dolejs, A. D. Cross, J. W. Murphy, and T. P. Toube, Rocz. Chem. 41,

151. 2. Xue a nd X.-T. Liang, K’o Hsueh Pung Pa0 19, 378 (1974).

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153. A. Abdusamatov, M. U. Rashidov, and S. Yu. Yunusov, Khim. Prir. Soedin. 7 ,

154. A. Abdusamatov and S. Yu. Yunusov, Khim. P1.i~. oedin. 9, 306 (1971); C A 75,

155. P. Ninova, A. Abdusamatov, a nd S. Yu. Yunusov, Khim. P er .Soedin. 7,540 (1971);

156. A. Abdusamatov, S. Khakimdzhanov, and S. Yu. Yunusov, Khim. Prkr. Soedin. 5,

157. S . Khakimdzhanov, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Sod in .

158. S . Khakimdzhanov, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin.

159. A. Abdusamtov, Kh. Ubaev, and S. Yu. Yunusov, Khim. Prir. Soedin. 4, 136

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165. C. G. Casinovi, J. A. Garbarino, and G. B. Marini-Bettolo, Gazz. Chim. Ztal. 91,

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172. T. U. Rakmatullaev, S. T. Akramov, and S. Yu. Yunusov, Khim. Prir. Soedin. 5,

173. P. K. Alimbaeva and R. F. Eremina, Fiziol . Akt. Soedin. Rast. Kirg. 56 (1970);C A

174. P. K. Alimbaeva, Zh. S. Nuralieva, and M. M. Mukhamedziev, Fizdol. Akt. Soedin.

175. R. Sita, R. Iyer, B. Pathak, and A. K. Boxe, Naturwissemrhaften 43, 251 (1956).

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181. E. Steinegger and T. Weibel, Pharm. Acta Helv. 28, 259 (1951).

567 (1967).

78, 15995 6~1973).

304 (1971).

110477s (1971).

C A 76, 1812x (1972).

457 (1969).

6, 142 (1970).

8, 132 (1973).

(1968).

SSR 23, 36 (1966); CA 67, 8680a (1967).

CA 78, 13729e (1973).

195 (1968).

1037 (1961); CA 58, 12612g (1963).

Sanita 2, 195 (1962); CA 60, 574c (1964).

43, 2213c (1949).

64, (1969).

75, 148463~1971).

Rast. Kirg. 88 (1970); CA 75, 14859a (1971).




182. N. Marekov, M. Arnaudov, and S. Popov, Dokl. Bolg. Akad. Nauk 2 3 , 169 (1970);

183. S. Shibata, M. Fuji ta, and H. Igeta, J. Pharm. Soc. Jpn. 77, 116 (1957).184. V. N. Karpovich, Tr . Leningr. Khim.-Farm. Inst. 12, 201 (1960); C A 57, 12631i

185. I. K. Nikitina, Tr.Leningr. Khim.-Farm. Inst. 21, 159 (1967); C A 69, 74504p

186. N. V. Kurinnaya, Nek. Yopr. Farm. 197 (1956); CA 53, 20695d (1959).

187. C.-Y. Sung, H.-C. Chi, an d K.-T. Liu, Sheng Li Hsueh Pa0 22, 201 (1958); C A 53,

188. N. V. Kurinnaya, Aptechn. Delo 3 (4) , 15 (19.54);CA 49, 2677g (1955).

189. D. S. Sargazakov, Izv. Akad. Nauk Kirg. SSR, Ser. Estestv. Tekh. Nauk 2, 103

190. I. T. Eskin, Tr. Inst. Kraev. Eksp. Med., Akad. Nauk. Kirg. SS R No. 2, 75 (1959);

191. C. Casanova and A. G. Gonzalez, An. R . SOC.Espan. Fis. Quim., Ser. B 60, 607

192. Kyoshin Seiyaku Co., Japanese Pat. 18,497 (1962); CA 59, P7323e (1963).

193. Yamashiro Pharmaceutical Co., Japanese Pat. 10,925 (1967);CA 68, 16138r (1968).

194. N. Marekov, L. Mondeshki, and M. Arnaudov, Dokl. Bolg. Akad. Nauk 23, 803

195. S. S. Popov and N. L. Marekov, Chem. Ind . (London) 655 (1971).

196. A. Abdusamatov and S. Yu. Yunusov, Khirn. Pr ir . Soedin. 4, 392 (1968).

197. N. Marekov, N. Mollov, and S. Popov, C . R.Acad. Bulg. Sci. 18, 999 (1965).

198. S. M. Khafagy and H. K . Mnajed, Acta Pharm. Suec. 5 , 135 (1968);CA 69, 80134j

199. S. S. Popov, N. Marekov, and P. Panov, Dokl. Bolg. Akad. Nauk 23, 1247 (1970).

200. Yu. I. Kornievskii, A. G. Nikolaeva, an d K. E. Koreshchuk, Farm. Zh. (Kiev)27,

81 (1972); CA 77, 2804d (1972).

201. G. A. Cordell, Lloydia 37, 219 (1974).

202. D. V. Banthorpe, B. V. Charlwood, and M. J. 0. Francis, Chem. Rev. 72, 115 (1972).

203. A. R. Battersby, Bwchem. J. 111, 26P (1969).

204. I. D. Spenser, Compr. Biochern. 20, 231 (1968).

205. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Gazz. Chim.

206. G. B. Marini-Bettolo, in “Biologenesi delle Sostanze Naturali,” Corso Estivo di

207. C. G. Casinovi, G. Giovannozzi-Sermanni, and G. B. Marini-Bettolo, Rend. Acead.

208. M. A. Luchetti, Ann. Ist . Super. Sanita 1, 563 (1965); CA 65, 9349a (1966).

209. H. Auda, H. R. Juneja, E. J. Eisenbraun, G. R. Waller, W. R. Kays, and H. H.

210. D. A. Yeowell an d H. Schmid, Ezperientiu 20, 250 (1964).

211. J. E. S. Hiini, H. Hilterband, H. Schmid, D. Groger, S. Johne, and K. Mothes,

212. C. J. Coscia an d R. Guarnaccia, J. Am . Chem. SOC. 9, 1280 (1967).213. H. Inouye, S. Ueda, and Y. Nakamura, Tet. Lett. 3221 (1967).

214. H. Inouye, S. Ueda, and Y. Nakamura, Chem. Pharm. Bull. 18, 2043 (1970).

215. H. H. Appel, Scientia 35, 128 (1968); CA 71, 124733b (1969).

216. D. Gross, W. Berg, and H. R. Schutte, Biochem. Physiol. Pflanz. 163, 576 (1972).

CA 73, 11391m (1970).

(1962).

(1968).

134156 (1959).

(1960);CA 5 5 , 202i (1961).

CA 54, 12490e (1960).

(1964).

(1970);C A 74, 20401n (1971).

(1968).

Ital. 94, 1356 (1964).

Chimica, Academia Nazionale Dei Lincei ’(1962).

Naz. Yo (Quaranta)16-17, 89 (1965-6); C A 68, I0289u (1968).

Appel, J. Am . Chem. Soc. 89, 2476 (1967).

Ezperientia 22, 656 (1966).




217. H. Auda, G. R. Waller, and E. J. Eisenbraum, J. Biol. Chem. 242, 4157 (1967).

218. S. P. J. Shah and L. J. Rogers, Biochem. J. 114, 395 (1969), and references therein.

219. N. Marekov, S. Popov, a nd G. Georgiev, C. R. Acad. Bulq. Sci. 19, 827 (1966);CA

220. D. Groger and P. Simchen, 2. Naturforsch., Teil B 24, 356 (1969).

221. C. J. Coscia, L. Bot ta, and G. Rocco, Arch. Biochem. Bwphys. 136, 498 (1970).

222. C. J. Cosia an d R . Guarnaccia, Chem. Commun. 138 (1968).

223. R. Guarnaccia, L. Botta, and C. J. Coscia J . Am . Chem. SOC . 1, 204 (1969).

224. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Tet. Lett. 2351 (1969).

225. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 3453 (1968).

226. H. Inouye, S. Ueda and Y. Takeda, Chem. Pharm. Bull. 19, 587 (1971).

227. S. Popov and N. Marekov, Phytochemistry 10, 3077 (1971).

228. N. Marekov, S. Popov, an d M. Arnaudov, Dokl. Bolg. Akad. Nauk 23, 955 (1970).

229. N. Marekov, N. Arnaudov, an d S. Popov, Dokl. Bolq. Akad. Nauk 23, 81 (1970).230- G. Popjak an d J. W. Cornforth, Biochem. J. 101, 553 (1966).

231. J. W. Cornforth, R. H. Cornforth, G. Popjak, and L. Vengoyan, J.BioL Chepn. 241,

232. J.W. Cornforth, R. H. Cornforth, C. Donninger. and G. Popjak, Proc. R. Yoc., Ser.

233. K. Clifford, J. W. Cornforth,R.Mallaby. and G. T.Phillips, Chens. Concmun. 1599

234. B. W. Agranoff, H. Eggerer, V. Henning, and F. Lynen, J. Biol. Chem. 235, 326

235. A. R. Battersby, T. C. Byrne, R. S. Kapil, J.A. Martin, T. G. Payne,D. Arigoni, and

236. M. J. 0. Francis, D. V. Banthorpe, an d G. N. J. LePatourel, Nature (London)228,

237. A. R. Battersby, A. R. Burne tt, and P. G. Parsons, Chem.Commun. 26 (1970).


239. H. Inouye, S. Ueda, and Y. Takeda, Tet . Lett. 4073 (1971).

240. H. Inouye, S. Ueda, Y. Aoki, and Y. Takeda, Chem. Pharm. BUCI. 20, 1287 (1972).

241. R. Guarnaccia, L. Botta, and C. J. Coscia, J. Am . Chem. SOC. 4, 6098 (1970).

242. R. Guarnaccia and C. J. Coscia, J. Am. Chem. SOC. 3, 5320 (1971).

243. A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Martin, and A. 0 . Plunkett,

244. A. R. Battersby, E. 8. Hall, and R. Southgate,J.Chem. SOC. 721 (1969).

245. A. R. Battersby, A. R. Burnett, and P. G. Parsons, J. Chem.SOC. 1187 (1969).

246. R. Guarnaccia, L. Botta, and C. J. Coscia, J . Am. Chem. SOC. 6, 7079 (1974).

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249. H. Inouye, S. Ueda, K. Inoue, and Y. Takeda, Chem. Pharm. Bull. 22, 676 (1974).

250. L.-F. Tietze, J. Am. Chem. SOC . 6, 946 (1974).

251. S. Ghosal, A. K. Singh, P. V. Sharma, and R. K. Chaudhuri, J. Pharm. Sci. 63,

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66, 8845j (1967). .

3970 (1966).

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(1971).

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1005 (1970).

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201 (1974).

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256. R. Osterwalder, Schweiz. Apoth.-Ztp. 58, 201 (1920).

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259. N. Yoshii, K. Hano, and Y. Suzuki, Med. J. Osaka Univ. 15, 155 (1964); CA 65,

260. T. Khayashi, Rejleksy Golovn. Mozga, Dokl. Mezhdunur. Konf., 1963 431 (1965);CA

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266. F . Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 146 (1971); C A 78,

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268. H.-C. Chi, K.-T. Liu, an d C.-Y. Sung, Sheng Li Hsueh Pa0 23, 151 (1959); C A 57.

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274. F. Sadritdinov, Farmakol. Alkaloidov Serdechnykh Glikozidov 151 (1971); C A 78,

CA 61, 13376g (1964).

6138g (1966).

67, 10216x (1967).

C A 70, 2217v (1969).

Serdechnykh Glikozidov 148 (1971); C A 78, 66918~1973).

Serdechnykh 79634b (1973).

Serdechnykh Glikozidov 153 (1971); C A 78, 924 81 ~1973).

11821g (1962).

(1966).

(1967).

92480t (1973).



---CHAPTER9-

ALKALOIDS UNCLASSIFIED AND OF UNKNOWNSTRUCTURE

R . H. F. MANSKE

University of Waterloo

Waterloo, Ontario, Canada

I. Introduction ........................................................ 511

11. Plants a nd their Contained Alkaloids ................................... 511

References .......................................................... 551

I. Introduction

Much of the data collected in this chapter was gleaned from ChemicalAbstracts and is so indicated by listing a Chemical Abstracts reference,

although such a reference is often included for the convenience ofreaders even where the original was available. Many of the alkaloids

are of structural types not treated in recent chapters of earlier volumes.

This chapter is supplementary to Volume XV, Chapter 6.

11. Plants and Their Contained Alkaloids

1 . Adaline (XV,264)*

The ketone Me(CH,), .CO -CH=CH,, prepared from the correspond-ing carbinol by Jones oxidation, was cyclized with methoxyethylene to

the dehydropyran 1, which upon acid hydrolysis generated the keto-

aldehyde Me(CH,),CO(CH,),CHO, which underwent a Mannich reaction

with p-ketoglutaric acid and ammonium chloride to give ( f -adaline

(2) (1).

2

* The roman numeral followed by a n arabic number refers to volume number and page

where the subject of t he heading has been treated in previous volumes.



512 R. H.F. MANSKE

2. Alphonsea ventricosa Hook. f. et Thorns. (Anonaceae)

Norglaucine and glaucine (2).

3. Ancistrocladus hamatus Gilg. (A . ahlii Am.)

(Ancistrocladaceae; Dipterocarpaceae) (XIV,509; XV,265)

Hamatine (3) CZ5Hz9O4N; p 250-252'C). It is phenolic and its 0-

methyl derivative is enantiomeric with 0-methylancistrocladine (3).

OMe GMe

OMe Me

a

4. Ancistrocladus heyneanus Wall.

- 149.7') has structure 4 s determined on spectral evidence (4).

(XIV,509; XV,265)

The new alkaloid ancistrocladidine (Cz5Nz,0,N; mp 245-247OC;

O Me OH

M e

4

5. An iba duckei Kostermans (Lauraceae) (XI,496)

The new 3-pyridyl ketone, duckeine (5; I3Hl1O4N;mp 243-245'C),

was isolated from this plant. 2,6,4'-Trihydroxy-4-methoxybenzophenone

was also isolated (5) .

OH

OH

5



9. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE 513

6. Ankorine (X,546; XIII,191)

The structure of this alkaloid has been revised to 6 on th e evidence

that none of the four possible synthetic racemic forms represented by the

earlier structure are identical with the natural alkaloid (6).

HO

CH2I

CH,OH6

7. Ant irrh inum spp. (Scrophulariaceae) (XIV,511)

Some tertiary bases or mixtures of bases were present in A . molle L.,

A . moll iss imum (Pau)Rothm., and A . hispanicum Chav. One of these

bases was identified as 4-methyl-2,6-naphthyridinend another was

given the impossible formula C,,H,,O,N, (7).

8 . Ariocarpus agavioides (Castaii.) E. F. Anders

(Neogomesia agavioides Castaii.) (XIV,512; XV,293)

This plant yielded N,N-dimethyl-4-hydroxy-3-methoxyphenethyl-

amine and the related Pelecyphora aselliformis Ehrenb. yielded N , N -

dimethyl-3-hydroxy-4,5-dimethoxyphenethylamine.n addition, seven

previously known alkaloids were isolated from these plants ( 8 ) .

9. Aristolochia argentina Griseb. (Aristolochiaceae)A reexamination of this plant has yielded four closely related lactones

(7, mp 271°C; 8, mp 275°C; 9, mp 247-25OOC; 10, mp 225°C) which

(XII,460)

7 R = R ’ = H

8 R = H , R ’ = OMe

9 R = M e , R ’ = H

10 R = Me, R’ = O Me



514 R. H. F. MANSKE

presumably arise from catabolism of preformed aporphines or analogous

bases. They were separated on a column of silicic acid (9).

10. Ata lantia monophylla Correa (Rutaceae)

(XII,500; XIV,513; xV,267)

Atalaphyllinine (C,,H,,O,N; mp 205-207°C). I ts structure 11)was

indicated by an examination of its spectra and was confirmed by con-

version to bicycloatalaphylline (10) .

11

11. Azureocereus ayacuchensis Johns. (Cactaceae)

tyramine (0.135y0) n this cactus (11).

Though mescaline was absent there was a comparative abundance of

12. Bathiorhamnus cryptophorw (H.Perrier) R. Capuron (Rhamnaceae)

Two new piperidine-type alkaloids were isolated and their structures

indicated by spectral examination and confirmed in part by chemical

reactions; cryptophorine (C,,H,,ON; mp l l&l lS°C; [a]578 61'; 0-

acetyl-, mp 103-104'c) (12); cryptophorinine (C,,H,,O,N; [ a ] 5 7 8- 8")(13). The former yielded an octahydro derivative (14) upon catalytic

reduction which upon catalytic dehydrogenation generated a pyridine

derivative ( 1 2 ) .

M e 0 RI

M e

12 R = W

OH

14 R = n-C,,H,,




13. BauereZZa baueri (Schott) Engler (Rutaceae)

Melicopidine (mp 121-122"C) and acronycine (mp 172-175°C) ( 1 3 ) .

14. Bruguiera cylindrica L. (Rhizophoraceae) (XIII,353)

Brugine, a n unusual tropeine, was isolated from the stems and bark

( 1 4 ) -

15. Bur kea africana Hook. (Leguminosae)

Tetrahydroharman, harman, and harmalan (15 ) .

16. Gadia eZZisiana Baker (Leguminosae)

This very toxic plant yielded some fifteen bases, three of which were

identified as multiflorine, 13-hydroxylupanine, and its pyrrole carboxylic

ester calpurnine ( 1 6 ) .The last is highly toxic to mice and fish ( 1 7 ) .

(IX,206)

17. Camptothecine (XII,464; XIV,515; XV,269)

Yet another synthesis of this alkaloid has been reported in which

2,5-pyridine dicarboxylic acid was the starting material, being convertedinto 15 in 8 5 yield in three steps. Subsequent steps involved several

convergent routes which gave, as a late intermediate, compound 16.

The ingenuity shown in the choice of reactions was equaled only in the

experimental skill necessary to bring them about, even though only

300 mg of dl-camptothecine was obtained ( 1 8 ) .

0

5B o

C Oa H

0

15 16

18. Cannabis satiwa L. (Urticaceae)

This much investigated plant has now yielded an alkaloid. Cannabis-ativine (C,,H,,O,N,; m p 167-168°C; + 55.1") (17) was obtained

from the roots and its structure was determined by an X-ray study of

the base crystallized from acetone, Other spectral data are consistent



516 R. H. F. MANSKE

with this structure. Its presence in the leaves was indicated by thin-

layer chromatography. It is the first example of a palustrine-type base

from flowering plants (19).

19. Cathu edzdis Forskal (Celastraceae)

(111,343; XI,489; XII,539; XV,280)

The alkaloid previously named cathidine has been shown to be a

mixture comprised of a polyalcohol esterified with different amounts

of acetic, benzoic, trimethoxybenzoic, evoninic, and nicotine acids.

Reductive hydrolysis generates a polyalcohol which on acetylation

provides an octaacetate identical with that similarly obtainable fromevonine ( 2 0 ) .

20. Cephalotaxus harringtoniana (Forbes) K. Koch (Cephalotaxaceae)

(X,552; XIII,400; XIV,319; Xv,272)

The new alkaloid, desmethylcephalotaxinone (C,,H,,O,N; mp 102-

+213"),was given structure 18 on the basis of its spectra0 7 O C ;

and on its partial synthesis from cephalotaxine ( 2 1 ) .

9O 0

18

21. Cephalotaxus harringtonia Sieb. e t Zucc.

The variety drupacea of this plant was found to yield the new

alkaloids 1 1-hydroxycephalotaxine (C,,H,,O,N; [a]i6- 139') (19) and

drupacine (C,,H2,0,N; [ c z ] ; ~ - 137') (20) whose given structures were




determined largely by spectral methods and partly confirmed by

hydrolysis of 19 to 20 (22).

““ if O

Ho

OMe bMl3

19 20

22. Clausena heptaphylla Wt. and Am. (Rutaceae)

(XII,467 ; XII17274;XV,273)

Heptazolidine from the above plant was given structure 21, largely

on the basis of spectral methods (23).

23. Clausena indica O h . (XII,467; XIII,274; xV,2 73)

Indizoline (22), a new alkaloid, was isolated along with 3-methyl-

carbazole ( 2 4 ) .

22

24. Clitocybe fasciculata Bigelow

(L ep ista caespitosa (Brosadola) Singer) (Agaricaceae)

This fungus proved to be rich in alkaloids yielding 2.4Yo7 he major

component being lepistine (C,,H,,O,N,, liquid, bp 140-150°C/0.01 mm;

B . HCl, mp 242°C; B .HI, mp 250-253°C; B.MeI, mp 198-199°C). A n



518 R.H. F. MANSKE

X-ray examination of the hydrobromide defined its structure (23) nd

other spectral properties are consonant therewith (25).

mco.M 23

25. Cocculus laurifolius DC. (Menispermaceae)

Three new dibenz(d,f )azonine alkaloids were reported-laurifonine

(C,oH,,03N; perchlorate, mp 182-185OC, [elD 10”) (24); laurifine

(C,,H,,O,N, amorphous, [elD f ) (25); and laurifinine (C1,HZ3O3N,perchlorate, mp 243-245OC) (26). The structures were arrived at by

spectral studies and confirmed in part by interconversions ( 2 6 ) .

(X,406)

OR‘

24 R = R‘ = M e

25

26

R = H , R = M e

R = Me, R’ = H

26. Cocculus carolinus DC. (XII,468; XIII,325)

The new alkaloid carococculine (27) (C,,H,,O,N; mp 219-220°C).

The spectral properties of the alkaloid and of its 0-methyl and 0-acetyl

derivatives indicated its structure. Its relation to other morphinane

alkaloids is apparent (27).

MOoO

OH

27




27. Codonocarpus australis A. Cunn. (Phytolaccaceae) (xIV,579)

The structure of codonocarpine, previously reported, ha5 been con-firmed and the N-methyl base (C,,H,,O,N,; mp 167-171°C) (28) has

been isolated from the plant and prepared from codonocarpine by

N-methylation with formic acid followed by NBH reduction. Acetyl

and other methyl derivatives have been described and extensive chemical

degradations are reported (28).

b04H O M e

28

28. Coryphantha calipensis H. Bravo (Cactaceae) (XII,468; XV,274)

Normacromerine, N-methyl-3,4-dimethoxyphenethylamine,nd two

new alkaloids, namely, (- -N-methyl-3,4-dimethoxy-~-methoxyphen-

ethylamine and (- - N,N-dimethyl-3,4-dimethoxy-~-methoxyphen-

ethylamine. It is noted that the new alkaloids are /I-methoxy derivatives

of macromerine (29).

29. Couroupita guianensis Aubl. (Myrtaceae)

Couroupitine A (C,,H,0,N2; mp 265-266°C; [a],, f ). Spectral

examination was consistent with structure 29. A second base (mp >340°C; [.ID f ; N-acetyl, mp 186°C) of molecular weight 304 ( M + ) of

unknown structure was also obtained ( 3 0 ) .

29

30. Crotalaria assarnica Benth. (Leguminosae) (XII,247; XV,274)

Monocrotaline (31).



520 R. H. F. MANSKE

31. Crotalaria burhia Buch.-Ham. (XII,247; XIV,522)

Crotalarine (30). ts structure was based on its alkaline hydrolysis andother chemical transformations ( 3 2 ) .Another examination of the same

plant yielded monocrotaline and an alkaloid, croburine (mp 167-1 68°C).

Hydrolysis of i t generated retronecine and 2,3-dihydroxy-4-ethy1-2,3,4-

trimethylglutaric acid, also new. Structure 30 was also proposed (33).

30

32. Crotalaria m adu ronsis Wight

Isocromadurine (C,,H,,O,N; mp 135-1 36°C; [elk5+43.5 ), solated

from the seeds of this plant, on alkaline hydrolysis generated retronecine

and the symmetrical HO,C .CH(Me)C(OH)Me-CHMe .CO,H (mp 129-

130OC). Therefore its structure is 31 ( 3 4 ) .

(XII,247; XIV,522)

31

33. Crotalaria spp.

Seeds of C . leioloba Bartl. (C. ferruginea R. Grah.) yielded mono-

crotaline while those of C. tetragona Roxb. gave integerrimine and

trichodesmine, two alkaloids previously isolated only from Senecio spp.

( 3 5 ) .

34. Cryptocarya alba Auth? (Lauraceae) (X,577; XIII,403; XIV,522)

( + )-Reticdine was the only base isolated from the leaves and bark

(36).



522 R. H. F. MANSKE

37. Dendrobates histrionicus (XIII,405 XV,277)

The frogs of the genus Dendrobates elaborate a series of toxins of

importance in the study of neuromuscular transmission. The venom of

D . histrionicus has yielded histrionicotoxin (38), its octahydro derivative

(39), and its perhydro derivative (40). A synthesis of the last, the

optically inactive form, had been achieved starting from the known

compound 41. By a series of ingenious steps this was converted t o 42,

and after another four steps the perhydro compound was isolated by

chromatography on silica (39). A more extensive examination of the

alkaloids from the frog has yielded four analogs of histrionicotoxin

whose structure (43) was determined by an X-ray analysis of its

hydrochloride. A fifth compound, HTX-D [mp 231-232°C (dec.)],

corresponds in empirical formula to tetrahydrohistrionicotoxin but its

mass spectrum indicates a different structural pattern ( 4 0 ) .

CH2.R

0

41

42 43

38. Dendrobates pumilio (XIII,405;XV,277)

Pumiliotoxin C, the toxic base isolated from the above-named frog,has been synthesized as its dl form. The starting material was a mixture

of the known cis and trans forms of tetrahydro-1-indanone ( M ) , he

oxime of which generated a hydroquinolone. Further transformations,



9. ALKALOIDS UNCLA SSIFIED AND OF UNKNOWN STRUCTURE 523

over ten in number and utilizing some novel reactions and skilful

techniques, finally generated the dl base (45) with the correct stereo

structure (41 ) .

& &H H M e

44 45

46

39. Dendrobine (XII,475; XIII,406; XIV,525; Xv,277)

The total synthesis of this ( ) base has been reported. The starting

material t o achieve this in twenty steps was the ketol 41, which by aseries of standard reactions was converted to the ketolactam 47. Another

series of reactions converted 47 into the enone 48 and subsequently into

the hydroxyester 49 which on hydrolysis and lactonization generated

( k -oxodendrobine (50, X = 0) and which was converted to (4 -dendrobine (50, X = H,) on Birch reduction (42 ) .

The biosynthesis of this alkaloid is consistent with its derivation from

: :;1*' fi0M e0

H Me H

47 48

0

49 50



524 R. H. F. MANSKE

mevalonate involving successive transformations to farnesol, germa-

crane, and cadalane skeletons. Degradation of the labeled dendrobine

confirmed that the labeled carbon of [4-14C]mevalonate ppeared in theanticipated positions ( 4 3 ) .

40. Dendrobium chrysanthum Wall. (Orchidaceae)

Exhaustive spectral studies and a synthesis of ( ~fr -trans-dendro-

chrysine obtained from this plant proved the structures of the cis and

trans alkaloids (51). They were obtained only as viscous oils with

[a]:, - 19" and with [ a ] i 2- 1l0 , respectively ( 4 4 ) .

(XV,279)

IpJJ-jN N

M eoI

ICH=CH. Ph

51

41. Dendrobium crepidatum Lindl.

Crepidine (C18H2502N,mp 107-109"C, [a] 500-600) , crepidamine(C,,H,,O,N, mp 221°C) [a ]g4 - 2(MoH)), and dendrocrepine

(C33H4403N, p 158-163"C, [4]~~0-600) were isolated from this plant.

An X-ray study of its methiodide showed th at crepidine has structure

52. Crepidamine was shown to have structure 53 on the basis of a mass

spectrum. Dendrocrepine, on the basis of a more elaborate spectral

study, was given structure 54 ( 4 5 , 4 6 ) .

(XIV,525; Lv,297)

Me

;:f i-3HO' ::a

HO

Ic=o

Me*-H

M e

Me

52 53 54

42. Dendrobium nobile Lindl. (XII,475; XIII,406; XIV,525; XV,279)

4-Hydroxydendroxine (55) and nobilomethylene (56) were isolated.

Spectral methods were used in determining these structures and 56 was

prepared from nobilinone (57) ( 4 7 ) .



9. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE 525

55 56 57

43. Desmodium cephalotes Wall. (Leguminosae)

(XI,] ;XIII,406; XV,279)

/3-Phenethylamine, salsolidine, hordenine, tyramine, candicine,

choline, and several unidentified quaternary bases, many only in trace

amounts ( 4 8 ) .

44. Dolichothele sphaerica Britton et Rose (Cactaceae)

When selected precursors are presented to this plant it generates

“unnatural ” alkaloids. When simultaneously given the lower homolog

of histamine and isocaproic acid it produced 58, an analog of dolicothe-line. Similarly, the aberrant alkaloid 59 was formed when 3-amino-

ethylpyrazole was fed ( 4 9 ) .

(XIV,526)

H NllCH, .NH .CO .CH2 .CH, .CHMe,

58

45. Dolichotele surculosa (Boed.) Buxb.

The four major alkaloids from the above-named plant were N-

methylphenethylamine, hordenine, N-methyltyramine, and synephrine.

Four other plants of the genus, namely, D . longimamma (DC.)Br. e t R.,

D . uberiformis (Zucc.) Br. et R., D . melaleuca (Kar.) Craig, and D .haumii (Boed.) Werd. et F. Buxb. were also examined. They were rich

in alkaloids but the constituent bases differed essentially from those of

Mammillaria and these differences appear tohave taxonomic significance

(XIV,526)

(50) .



526 R. H. F. MANSKE

46. Doryphora sassafras Endl. (Monimiaceae) (XIV,228)

A total of eleven crystalline alkaloids was isolated from the bark ofthis plant. The four alkaloids from the nonphenolic fraction were

liriodenine, doryanine, ( + )-isocorydine,and (- -anonaine. The phenolic

fraction yielded ( + )-reticuline, corypalline, doryphornine (60)(mp 215-

217OC), and two bases, A (mp 169-171°C) and B ( m p 201-203"C, [a]z5

- 15.6'), not further examined. Extensive use was made of

chromatography ( 5 1 ) .

60

47. Erythrophleum chlorostachys Baill. (Leguminosae)

(X,561; XII,533; XIV,528)

The structure of norerythrostachaldine (61) was established by LAHreduction to a tetrol (62) identical with one prepared from norerythro-

stachamine (63)52).

R'

61

63

R = CHO. R' = CO, .CHa.CH, .NHMe

R = C02Me, R' = C O , . CH,. CH, .NHMe

62 R = CHSOH, R' = CH,.OH

48. Erythrophleum ivorense A . Chevalier (X,561; XII,533; XIV,528)

Two new variants of the cassaine-type alkaloids have been isolated

from this plant. They are 3-(3-methylcrotonyl)cassaine 64) and 19-

hydroxycasesine (65) (53).




64

65

66

R = CO.CH=CH,, R = M e

R = H , R' = CHzOHR = H, R' = CO,Me, C O is -OH

49. Erythrophleum chlorostachys Baill.

Norerythrostachamine, a new alkaloid (C,,H390,N, amorph.), was

shown to have structure 66. The nonnitrogen fragment was identical

with the N B H reduction product of erythrophlamic acid. In addition

there were isolated cassaidine, cassamidine, norcassamidine, and a

number of amides ( 5 4 ) .

(x,561; XII,533; XIV,528)

50. Ery throxy lum monogynum Rox b. (Erythroxylaceae)

(XII,476; XIII,355)

The 3,4,5-trimethoxybenzoyl and 3,4,5-trimethoxycinnamoy1de-

rivatives of laH,5aH-tropen-3~~-01(67)ere isolated from the roots ( 5 5 ) .

67

51. Eschscholtzidine (x,478; XII,371)

A synthesis of'this alkaloid by standard methods has been announced.

The optically inactive base was characterized as its methiodide

(mp 305OC) ( 5 6 ) .

5 2 . Euxylophora paraensis Hub. (Rutaceae)1 -Hydroxyrutaecarpine (68)(Cl8Hl3O2N3,mp 3 1 8-32OoC; O-methyl,

mp 2 5 3 °C) was isolated. Its structure was derived from a spectral

exa.mination and confirmed by a synthesis (57').

(XII,477)



528 R . H. F. MANSKE

68

53. Fagara xanthoxyloides Lam. (Rutaceae)

Another examination of this plant yielded the alkaloid fagaronine, aquaternary base (chloride, mp 200°C, followed by solidification and

remelting at 26OoC) which proved to be an extremely active anti-

leukemic (58 ) . t s proposed structure (69)was confirmed by a synthesis.

The known compound 70 (R = H) was prepared by a new route and the

hydroxyl was protected by the isopropyl group. Condensation of 70

(R = Pr') with o-bromveratraldehyde and subsequent cyclization with

sodamide in liquid ammonia followed in turn by reaction with dimethyl

sulfate generated the 0-isopropyl ether of fagaronine methosdfate as

well as the methosulfate of fagaronine (59) .

(XIV,530; XV,300)

M e 0

69

P O RMe

NO270

54. Fagopyrum esculentum Moench. (Polygonaceae)

The basic fraction obtained from buckwheat seed provided a crystal-

line base, fagomine (C,H,,03N; B .HCl, rno 176-177OC). Its structure

(71) was arrived a t by an exhaustive spectral study and confirmed in

part by chemical reactions ( 6 0 ) .

71




55. Gentiana sp. (Gentianaceae)

A new alkaloid (CloHllO,N, mp 208-210°C, [a],, .8") has been iso-lated from a Chinese gentian. I ts structure (72) as revealed by spectral

methods. Like at least some other gentian alkaloids, i t may be an

artifact ( 6 1 ) .

(XI,487; xV,282)

H

72

56. Gymnocactus (Cactaceae)

known 8-arylethylamines along with traces of unidentified bases ( 6 2 ) .Seven species of this genus were shown to contain predominantly

57. Haloxylon persicum Bunge ( H . ammodendron Bunge)

(Chenopodiaceae) (XI1,480; XIV,534)

Anabasine was the major component of a total of 5.4y0 alkaloids in

this plant. Traces of nicotine were also detected ( 6 3 ) .

58. Haplamine

4-Hydroxy-6-methoxy-2-quinolinewas alkylated with Me,C=

CH .CH,Br and the resulting mono-0-alkyl ether cyclized by

reaction with dichlorodicyanobenzoquinone to yield haplamine

(mp 199°C)(72a) 6 4 ) . t had been isolated from Ha plophyllum perfora-

t u m Kar. et Kir. and the correct struction had been proposed ( 6 5 ) .

(IX,229; X,565; XII,480; XII1,408; XIV,534)

59. Haplophyl lum fol iosum Vved. (Rutaceae)

Folirninine, isolated from the aerial parts of the above plant, was given

structure 72b on the basis of a spectral examination. Hydrogenation

(IX,225; XV,284)



530 R. H. F. MANSKE

generated a tetrahydro derivative (73) nd reaction with methyl iodide

gave 74 (66).

p -p:H pMe

72b 73 74

60. Hap lophyl lum perforatum Kar. e t Kir.

The 7-isopentyloxy derivative of y-fagarine was isolated and pre-

pared by the 0-alkylation of haplopine with Me,C=CH .CH,Cl. Its

structure (75)was determined on the basis of spectral data. Hydrogena-

tion generated the quinolinone 76 ( 6 7 ) .Methylevoxine, a new alkaloid

from this plant, is 77 as determined by spectral methods ( 6 8 ) .Glycoperine 78) nd haplophydine (79) were later isolated from this

plant. Their structures are based on spectral data and upon the hydrol-

ysis of 78 to haplopine and L-rhamnose (69, 7 0 ) .

(IX,229; XV,283)

?Me O M e

Me,CH. C O z .CH,O@:J IJ OMeM e

Me$: CH.C H I O

7 5 76

?Me

\ IC .C H CH,O

Me’ I OMeO M e

77

RhO*JO M e OCH,. CH:CMez

78 79




61. Haplophyllum latifolium Kar. et Kir.

haploperine, and dubamine were identified from this plant ( 7 1 ) .

(x ,565;XIV,535)

In addition to six unknown compounds the known skimmianine,

62. Hedera helix L. (Araliaceae)

been reported (72).

The unusual occurrence and isolation of emetine from this plant has

63. Heimia salicifoliaLink e t Otto (Lythraceae)

Abresoline (C,,H,,O,N, amorphous) was isolated in very low yield.

Hydrolysis in the presence of alkali generated transferulic acid and the

quinolizidol 80 so that its structure is 81. This was confirmed by a

synthesis of its dihydro derivative (73).

(X,566; XIV,525)

9,.OMe

80 R = O H

81 R = M e 0

HO

64. Heimia salicifolia Link et Otto

In addition to the known sinicuichine, cryogenine, and nesodine, there

were isolated two new alkaloids, ALC-I (C,,H,,O,N, mp 335-345"c,

+ 115.6", [a]436 235") and ALC-2 (C2,H2g0,N, mp 309-310"C7

[a]589 72.3", [a]436 154.6")which were shown to be stereoisomers

of lythrine. The former yielded a monomethyl ether melting at 230-

233°C and that of the latter melted at 235-237°C ( 7 4 ) .

(X,566; XIV,525)

65. Hippodamine (XIV,518; XV,284)

An X-ray diffraction analysis of crystals of convergine hydrochloride,

the N-oxide derivative of hippodamine, showed that it is 82 and

consequently the structure of hippodamine is also known (75).



5 3 2 R. H. F. MANSKE

AM e

82

66. Hydrastis canadensis L. (Ranunculaceae)

Canadaline (C2,H230,N, mp 117-1 lS°C, [.ID + 43O), a new alkaloidfrom this much investigated plant, was shown to have structure 83.

Spectral examination and chemical manipulation served this purpose

( I V , 8 7 ; IX,49; X,423)

( 7 6 ) -

O M e

83

6 7 . Indicaine ( X I I I , 4 1 7 )

The alkaloid described as boschniakine was shown to be identical

with the previously known indicaine (84) ( 76a ) .

84

68. Isoharringtonine (XIV,SI9)

This alkaloid ( 8 5 ) s an ester of cephalotoxine, the acid component of

which is dibasic, contains two asymmetric carbons, and is also a methyl

ester. Methanolysis of the alkaloid generated a dimethyl ester that was




shown, by a synthesis, to have the erythro configuration 86. This was

achieved by hydroxylating the corresponding maleic acid with osmium

tetroxide and hydrogen peroxide. Hydroxylation of the corresponding

fumaric acid generated an acid of t,hreo configuration (77) .

0053)--

85 86

69. K nig htin deplanchei Vieill. (Proteaceae) (XV,287)

Two tropane alkaloids (87 and 88) were isolated. Their structureswere determined by spectral methods ( 7 8 ) .

Ph. COz

O R

'CH(0H)Ph

87 R = CO.CH:CH.Ph

88 R = H

70. Kreysigia rnulti ora Reichb. (Liliaceae)

(X,569; XII,483; XIII,146; XIV,268; XV,298)

In addition to the alkaloids previously isolated from this plan t there

have been isolat,ed hree new ones: ( - -multifloramine (89)(C21H,505N,mp 209-2 12°C) [a]g - 1og ) , kreisiginone (90) (mp 193-1 94°C)) and

deacetylcolchicine. Methylation of 89 and of Aoramultine with diazo-

methane gave a mixture of kreisigine (91)an d 0-niethylkreysigine (92).

Spectral examination, culminated by a synthesis, confirmed the struc-

t,ures and ascertained that of the previously known floramultine (93)( 7 9 ) .Extensive biosynthetic studies showed th at these homoaporphines

arise from 1 -phenethylisoquinolines, specifically from automnaline (94)

labeled as shown (SO).




72. Leptorhabdos parvijlora Benth. ( L . benthumiana W a l p . )(Scrophulariaceae)

The structure of t,he new alkaloid, leptorhabine (98), was determined

by spectral methods and confirmed in part by permanganate oxidation

to pyridine-3,4-dicarboxylic cid (82).

98

73. Lindera benzoin Meissn. (Benzoin aestivale Nees.) (Lauracea,e)

(XIII,412; XV,287)

Laurotetanine was isolated (83).

74. Liriodendron tulipifera L. (Magnoliaceae)

The leaves of this plant yielded lirinine N-oxide (99) and lirinine

0-methyl ether which was also obtained by reducing the AT-oxide to

lirinine (100).Spectral methods were employed in the structural deter-

mination ( 8 4 ) . In addition to the known nonphenolic alkaloids (iso-

remerine, liriodenine, lysicamine) the new isolaureline (101) was also

isolated. It s structure is based on spectral data ( 8 5 ) .

(XIV,227)

M e O pO H-- H O

c : g r : e/

\ \ \

OMe OMe O M e

99 100 101

7 5 . Lophophora diffusa (Croizat)H. Bravo (Cactaceae)

(XII,488; xv,288)

naturally, was isolated (86).

O-Methylpellotine (102), an alkaloid not previously known to occur




O M e M e

102

76 . Magnolia obovata Thunb. (Magnoliaceae)

(X,407; XII,489; XIV,228)

In addition to the known bases, liriodenine, anonaine, glaucine,

asimilobine, reticuline, and magnocurine, this plant yielded a new

alkaloid, obovanine, whose st,ructure (103) was determined from itsspectral data (87).

103

7 7 . Mappia foetida Miers (Oliacinaceae)

In addition to the previously reported camptothecine (88,89) this

plant has yielded mappicine (C,,H,,O,N,, mp 251-252°C). It forms an

acetyl derivative (mp 191-1 92°C) and on exhaustive spectral examina-

tion proved to be a relative of comptothecine with structure 104. Apartial synthesis from camptothecine was achieved (90).

Et .CHOH

104

78. M ay ten us arbutifolia (A. Rich.) R. Wilczek (Celastraceae)

(XI,460; XIV,541; XV,Z89)

Celacinnine (C,,H,O,N,, mp 203-204"C, - 19") (105) was iso-

lated from this plant and also from Tr ip terygium wilfordii Hook.




Spectral studies of i t indicated structural features that were consonant

with chemical degradations. It yielded a dihydro derivative (mp 172°C)

and vigorous acid hydrolysis generated spermidine. The isomericcelallocinnine (mp 172-173"c, [a]g5 -24) (106), also present in M .

arbutifolia, differed from 105 in that the cinnamoyl group is cis oriented.

Its dihydro derivative is identical with that of 105. Two analogous

alkaloids isolated from T . wilfordii are celabenzine (C23H,902N3,

mp 156-158"C, [a] i5 0 ) (107) and celafurine (C,,H,,O,N,, mp 154-

155OC, [a]g5- 11 ) (108), whose structures were assigned on the evi-

dence of spectral and chemical properties ( 9 1 ) .

R

105 R = t m m - P h . C H : C H . C O , R' = H

106 R = c - P h . C H : C H . C O , R' = H

107

108 R = 0 : R ' = H

R = P h . C O , R' = H

79. Melicope perspiczsinerva Merr. et Perry (Rutaceae) (XIV,542)

In addition to a new flavone (melinervin) and other neutral compounds

this plant yielded skimmianine, kokusaginine, ( )-platydesmine, and

halfordinine (mp 150-152°C) the last of which was shown to be 6,7,8-

trimethoxydictamnine ( 9 2 ) .

8 0 . Murraya koenigii Spreng (Rutaceae)

(XI I,49 1; XIII ,54 4; XIV,274,414; XV,290)

The new murrayacinine is given structure 109 on the basis of its

spectra and on a synthesis from 2-hydroxy-3-methylcarbazole93).

M e

109




81. J l y r rh a octodecimguttata (XIV,518)

The report of the chemical study of the above Coccinellidae containsthe isolation of a new alkaloid, myrrhine (C13H2,N, iquid) (110),and a

review of the relationship that exists among the alkaloids that have

been isoated from a number of arthropods, namely, coccinelline,

convergine, hippodamine, and propyleine. The structure of 110 was

confirmed by correlation with propyleine (precoccinelline) as well as by

varied spectral studies. Coccinelline was shown to be biosynthesized via

the polyacetate pathways. These alkaloids have been shown to be

involved in the defensive behavior of the insects (94) .

H

110

82. Oncinotis nitida Benth. (Apocynaceae)

Three new spermidine alkaloids have been isolated. The structural

assignments are based on spectral studies and upon chemical degrada-

tion to known fragments. Oncinotine (111) (C,3H,50N,, oil, [.ID - 3");

neooncinotine (112),obtained only in admixture with 111; isooncinotine

(112a) (C2,H,,0N3, mp 66-71°C, [a],, - 37"). Acetyl and reduced

derivatives as well as hydrolytic products were prepared (95). Asynthesis of ( )-oncinotine was also achieved. Some fifteen steps were

involved in which one of the starting substances was HO(CH,),CO,H.

An isomer of oncinotine was shown to be present in the natural base ( 9 6 ) .

(XIII,415; XIV,546)

G - y y JR O

111 R = (CH,),NH,

112 R = (CH,),NH,

H H

l l 2 a




83. Op untia clavata Eng. (Cactaceae)

M-Methyltyramine was isolated (97) .

84. Pandaca calcarea (Pichon) Mgf. and P. debrayi Mgf.

(Apocynaceae) (VIII,203; XI,14 7)

(- -Apparicine and ( - -dregamine, known alkaloids, and the new

pandoline (C21H2s03N2, amorphous, [ID +417') and pandine

(C21H,,03N,, mp 108-1 13°C; [ID + 273") (98).

85. PassiJlora sp.

Traces of harman were detected in P. caerulea I,., P. decaisneana

Hyb., P. edulis Sims, P . oetida L., P. incarnata I,., P. subpeltata? ( P .

subulata Masf.), and P. warmingi i Masf., but neither harmine, harma-

h e , harmol, nor harmalol could be detected (99).

86. Pau ridiantha lyall i i (Baker) Bremek. (Rubiaceae)

lated ( 1 0 0 , 1 0 1 ) .

(XIV,547)

Two new indole alkaloids lyaline (113) and lyadine (114) were iso-

C0,Me

113 R = CH=CHg

114 R = C H ( 0 H ) M e

87. Pelea barbigera Hillebr. (M elicope barbigera A. Gray) (Rutaceae)

(IX,229; XIV,542)

Kokusaginine, isoplatydesmine (115), and eduline, which was re-

garded as an artifact ( 1 0 2 ) .

M e

115




8 8 . Penicil l ium oxalicum

The alkaloid oxaline (C,,H,,O,N,, mp 2 2 0 °C, [a];, - 45') is unique ina number of respects, as is evident upon an inspection of its structure

(116) which was determined by X-ray methods. Spectral methods and

particularly mass spectra are consonant with this structure (103,104).

116

89. Pergularia pallida Wight et Am. (Asclepiadaceae)

(IX,518; XIII,425; XIV,562)

Three major alkaloids proved to be tylophorine, tylophorinidine, and

O-methyltylophorinidine. Minor constituents proved to be 3,6,7-

trimethoxyphenanthroindolizine and one of uncertain structure with

four methoxyls in the phenanthrene portion and an alcoholic hydroxyl

a t C-14 (105) .

90. Peripterygia marginata Loes. ( Pterocelastrus m argina tus Baill.)

(Celastraceae)

The alkaloid periphylline isolated from this plant has structure 117

as determined by spectral methods. Alkaline hydrolysis gave trans-

cinnamic acid and alkali fusion of its tetrahydro derivative generatedspermidine ( 1 0 6 ) .

H

H

1 7

91. Petteria ramentacea Presl. (Leguminosae)

stages of this plant. Anagyrine and lupanine appeared later ( 1 0 7 ) .

Cystine and its N-methyl derivative appeared in the early growth



542 R. H. F. MANSKE

96. Poranthera corymbosa Brogn. (Euphorbiaceae)

(XIV,551; XV,294)

The plant yielded porantherine, porantheridine, porant,hericine (121)

(C,,H,,ON, amorphous [.ID - 20"; B.HBr, mp 308"C), O-acetyl-

poranthericine (amorphous, [a],,+ 2 ) , porantheriline (C,,H,,O,N, mp

76-77°C; [.ID + 87 ) ,and porantherilidine (CzzH,302N, morphous, [.ID

-47 ; B.HBr, mp 251-252°C) (122). The structure of 122 was arrived

a t on the basis of an X-ray study of its hydrobromide. Porantherline on

hydrolysis generates acetic acid and an alcohol (mp 124-126°C) which

was shown to be enantiomeric with 121 a t the hydroxyl position (116).

H

Et

HO-

121 12%

97 . Porantherine (XIV,551; XV,294)

This tetracyclic base (123), whose structure was determined largely

by X-ray analyses, has been synthesized. Not only was there involved

a multitude of intermediates, new to chemistry, but the experimental

skill was evidently of a high order. The sequence of reactions was based

upon a retrosynthetic analysis involving five key intermediates which

were obt,ained from the first reaction product 124 of the Grignard

reagent derived f rom 5-chloro-Z-pentanone ethylene ketal with ethyl

formate (1.27).

Me

123 124




98. Prosopis nigra (Gris.) Hieron. (Leguminosae)

/3-Phenethylamine, harman, tryptamine, N-acetyltryptamine, andtyramine all separated in the order given from a column of alumina (118).

(XI,12,492)

99. Prosopis spicigera L. (XI,492)

The new amino acid spicigerine was given structure 125 (219).

125

100. Ptelea trifoliata L. (Rutaceae)

This much-investigated plant has yielded a new quaternary base,

O-methylptelefolium (126) (220).Another examination of P . trifoliatasubsp. pallida disclosed the presence of hydroxylunine and balfouridine

(XIII,417; XIV,553)

(121).

OM0

126

101. Retama monosperma Boiss. (Genista monosperma Lam.)

(Leguminosae) (IX, 99; XV,276)

The subspecies rhodorrhizoides yielded d-sparteine, retamine, ana-

gyrine, sophocarpine, a,nd traces of sophoridine, N-methylcytisine,

cytisine, and sophoramine (122).

102.Retan illa ephedra Brogn. (Rhamnaceae)

The following were isolated and identified: boldine, norboldine,

armepavine, norarmepavine, coclaurine, and N-methylcoclaurine, as

well as two cyclopeptides-integerresine and crenatine A (223).

(XV,295)



544 R. H. F. MANSKE

103. R u ta bracteosa DC. (R . halepensis L. (Rutaceae)

(IX,224; XII,462; XIV, 5 5 3 ; XV,283)

In addition to three furocoumarins this plant yielded rutamine (127)( 1 2 4 ) .

Me

127

104. Rutaceae (XII,503; XIII,423; XV,292)

A number of plants of this family when examined for alkaloids and

triterpenes yielded results of possible taxonomic significance.Araliopsis

tabouensis AubrBv. e t Pellegr. yielded ( - - )-A'-methylplatydesminium

ions, a second furoquinoline, and flindissol. Diphasia lclaineana Pierre

yielded lupeol, evoxanthine, arborinine, and skimmianine. Teclea

verdoorniuna Excell. et Mendonga yielded lupeol and exoxanthine (125) .

105. Sceletium Alkaloids (IX,468; XIV,554; XV,296)

Three new alkaloids were isolated from S . namaguense (L . ) Bolus in

addition t o other known bases and sceletium A,, whose structure (128)was revealed largely by spectral methods; A7-mesembrenone (129)(C,,H,,03N, oil) previously prepared from mesembrine;N-formyltor-

tuosamine (130) C21H,,0,N,, oil); and sceletenone (131)C,,H,,O,N,oil). S. tricturn (L.) Bolus also yielded a number of known alkaloids

and the new 41-O-demethylmesembrenone (132) (C,,H,,O,N, oil)methylation of which generated mesembrenone (126) .

128 129




130 131 R = H

132 R = OMe

106. S e d u m m a x i m u m Suter (Crassulaceae)

The alkaloids, sedamine, sedinine, and sedridine were identified in the

alkaloid mixture which was present to the extent of 0.008 to 0.01% in the

dry plant ( 1 2 7 ) .

(XI,462)

107. Senecio cineraria DC (Compositae) (XII,256)

Jacobine, senecionine, seneciphylline, and retrorsine ( 2 2 8 ) .

108. Senecio erraticus Bertol. (XII,245,251; XV,297)

Three alkaloids of mp 229-231°C, 221-222"C, ([a],,+ 1 l 0 ) , and 192-

193°C were isolated. Apart from limited IR data no identities were

suggested (2 2 9 ) .

109. Senecio petasitis DC. (XII,245; XV,297)

The alkaloid from this plant on hydrolysis generated retronecine and

isolinecic acid and in consequence its structure is 133, n full conformity

with spectral data (2 3 0 ) .

OH Me ?H

I nEt ---fl--CH,--CH-$-Me

IcoI

I 0

Ico

133



546 R. H. F. MANSKE

110. Senecio swaziensis Compton

(XII,245; XlII,400; XIV,537; XV,297)

Swazine (C,,H,,O,N, mp 165"C, [a],, - 103.5"), which had been

isolated from the above-named species and also fromS. barbellatus DC.

(1 3 1 ) ,has been subjected to chemical degradation and to spectral study.

Acid hydrolysis generated retrorsine and a spirodilactone (134). Of the

possible structures that could be derived from the above fragments

th at represented by 135 is favored (1 3 2 ) .

O J ' i CQ CHz

co II 0

134 135

111. Sida cardifolia L. (Malvaceae)

/3-Phenethylamine, ephedrine, #-ephedrine, methyl ester of N,-

methyltryptophan, hypaphorine, vasicinone, vasicine, vasicinol, and

liberal amounts of choline and betaine (1 3 3 ) .

(X,581)

112. Skimmianine and y-Fagarine

These alkaloids were found in the following species of Haplophyllum :

H . schelkovnikovii Grossheim, H . villosum G . Don( ?), H . kowalenskyi

(Auth?), nd H . t enue (Auth?) 1 3 4 ) .

(X,565; XlI,480; XV,284)

113. Sophora a l o ~ o c u r ~ d e s. (Leguminosae)

(VII,258; IX,208; XIV,557; XV,298)

In addition to the known sophoridine, sophoramine, sophocarpine,

and aloperine there was isolated neosophoramine (C,,H,,ON,) whichwas regarded as the 5-epimer of sophoramine ( 1 3 5 ) . Tricrotonyl-

tetramine (136) (C,,H,,N,; mp 101-103°C) was later reported as a

constituent of this legume ( 1 3 6 ) .



9. ALKALOIDS UNCLASSXFIED AND O F UNKNOWN STRUCTURE 547

M eI

jJ.-J.-.M e M e

H H

136

114. Sophora proda nii E. Anders

Sparteine and cytisine (1 3 7 ) .

(IX,208; XIV,257)

115. Streptomyces Species N 337 (XIII,421)

The structure of the base from this Streptomyces, M. ich had been

regarded previously as a pyrrolidine derivative, has been revised to

( E , )-2-pentadienyl-3,4,5,6- etrahydrop yridine (137) ( 1 3 8 ) .

137

116. Sw ain son a galegifolia R. r. (S.coronillaefolia Salisb.)

(Leguminosae) (X,581; XIV,558)

Spherophysine was identified as a constituent (139).

1 17 . Syneilesis palma ta Maxim. (Compositae) (XII,245)

Syneilesine (C,,H,,O,N; mp 195"C),a highly cytotoxic alkaloid, was

shown to have structure 138.Aside from spectral studies, hydrolysis and

?H H ?H

E t - C H - C - C - C - M e

H M e C O

II I I

A A I

I0

coI

138



548 R. H. F. MANSKE

hydrogenolysis gave critical information. Hydrolysis gave three new

closely related lactones which confirmed the nature of the acid moiety.

Hydrogenolysis generated dihydrodeoxysyneilesine-11,14-olide (139)(mp 109°C) which on hydrolysis also yielded three lactones and the

necine, dihydrodesoxyotonecine (140) (140 ) .

I

co

Me

139

I

M e

140

118. Talaum a mex icana G. Don (Magnoliaceae) (VII,445; XIV,227)

Liriodenine ( 1 4 1 ) .

119. Teclea boiviniana (Baill.) H. Perrier (Evodia boiviniana Baill.)

(XII,503 XIII,423;XV,292)Rutaceae)

Malicopine, tecleanthine, and evoxanthine, all known acridones, were

isolated. In addition, this plant yielded 6-methoxytecleanthine (141)

and 1,3,5-trimethoxy-lO-methylacridene142) (142 ) .

0 OMe

M e 0

1 4 1 142

120. Teclea grand ifolia Engl.

Tecleanone (C,,H,SO,N; mp 190OC) was obtained in 0.00670 yield in

the form of yellow crystals. Its structure (143) was determined largelyfrom its mass spectrum and other spectral data. It bears a formal

resemblance to tecleanthine in that it is the open form of a possible

acridone ( 1 3 ) .

(XIII,423; XV,292)




121. Teclea un ifoliata Auth 1

alkaloid mixture which was obtained in 0.5y0 1 4 4 ) .

(XXI,503; XIII,423; XV,292)

Maculine, skimmianine, and kokusaginine were separated from the

122. Tem pletonia retusa (Vent.) R. Br. (Leguminosae)

A new alkaloid, (- -templetine (C20H35N3;mp 120-3 22OC; [.ID- 2 O ) , was isolated in 0.02y0 yield as well as the known ( - -cytisine,

(- -anagyrine, ( + )-lupanine, and ( & )-piptanthine. Vigorous dehydra-

tion of it afforded ( - -dehydropiptanthine (CZ6Hz3N3). pectral

methods including an X-ray analysis indicated the complete stereo

structure (144) f this alkaloid. Since this alkaloid has now been related

to ( - )-ormosanine and to (-)-panamine, i t is possible to assign thecorrect stereo structure to those as well ( 1 4 5 ) .

(IX,213)

144

123. Trichocereus pachano i Britten et Rose (Cactaceae)

(XII,506;XV,298)

The presence of mescaline and 3-methoxytyramine was proved (1 4 6 ) .

124. Tylophora cordifolia Thw. and T. Eava Trirnen (Asclepiadaceae)

(IX,518; XIII,425; XIV,562; XV,298)The former yielded tylophorinine and three unidentified alkaloids on

a chromatogram. Similar examination of T . ava gave tylophorine and

four unidentified alkaloids ( 1 4 7 ) .



550 R. H . F. MANSKE

125. Tylophora indica Merrill (T.sthmatica)(IX,518; XIII,425; XIV,562)

A reexamination of the structure of tylophorinidine by an X-ray study

of its methiodide diacetyl derivative confirmed it to be 145 ( 1 4 8 ) .Other

spectral methods are consonant with that structure (1 4 9 ) .

IOMe

145

126. Ulugbekia tschimganica (B. Fedtsch.) Zakirov (Boraginaceae)

determined by spectral methods ( 150) .Uluganine from this plant has structure 146 (R = trachelanthoyl) as

CH(0H)Me/

90.

WaoR46

127. Vaccinium (Cranberry) (Ericaceae)

A new alkaloid (mp 168-170°C) was obtained from the leaves of a

cranberry native to New Brunswick. It s structure (147)was determined

almost exclusively by spectral methods and confirmed by a synthesis.

Tryptamine was condensed under physiological conditions with glu-

tardialdehyde and the condensation product reduced with NBH. The

147



9. ALKALOIDS UNCLASSIFIED AN D OF UNKN OWN STRUCTURE 551

resulting base was methylated with methyl iodide in the presence of

sodium amide and the 1-methyl base (147)was identical wit'h the natural

product (1 5 1 ) .

128. Zanthoxylum americanum Mill. (Rutaceae)

Nitidine and laurifoline were isolated from the root and stem bark as

well as the coumarins xanthyletin and xanthoxyletin. The presence of

chelerythrine, tembetarine, magnoflorine, and candicine was demon-

strated. The root bark of Z . clava-herculis was shown to contain lauri-

foline, magnoflorine, tembetarine, and candicine (152) .

(XII,478; XIV,530)

129. Zanthoxylzcm arnottianum Maxim.

In addition to a host of neutral compounds and a quaternary iso-quinoline derivative isolated as picrate (C,,H,GO,N+ C,H,O,N; ;

mp 256-26O0C), this plant yielded dictamnine, robustine, and haplopine

(1 5 3 ) .

(X,423; XII,478; XIV,530)

130. Zanthoxylum tsihanimposa H . Perr.

(XII,506; XIII,427; XIV,530)

The bark of this plant yielded y-fagarine, skimmianine, and 1 1 -

dihydrochelerythrinylacetone, as well as two further derivatives of

chelerythrine which appear t o be artifacts (1 5 4 ) .

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23 (1973);CA 81, 1663042 (1974).

82, 1 0 8 8 1 0 ~1974).

Phytother. 9, 37 (1975); CA 83, 5028p (1975).

Slatkin, Tet. Lett. 2815 (1975).

(1975).

( 1974).

Chem. 39, 676 (1974).

303 (1974); CA 81, 1367311 (1974).

(1974); CA 82, 82982b (1975).

Beal, Tetrahedron30, 3229 (1974).

Lett. (9) 923 (1975); CA 83, 203767s (1975).

Acta 57, 2597 (1974).

Pharm. Bull. 22, 349 (1974): C A 80, 121154~1974).




43. 0. . Edwards, J. L. Douglas, and B. Mootoo, Can. J. Chem. 48, 2517 (1970).

44. U. Ekevag, M. Elander, L. Gawell, K. Leander, and B. Liining, Acta Chem. Scand.

45. P. Kirkegaard, A. M. Pilotti, and K. Leander, Acta Chem. Scand. 24, 3757 (1970);

46. M. Elander, K. Leander, J. Rosenblum, and E. Ruusa, Acta Chem. Scand. 27, 1907

47. T. Okamoto, M. Natsume, T. Onaka, F. Uchimaru, and M. Shimizu, Chem. Pharm.

48. S. Ghosal and R. Mehta, Phytochemistry 13, 1628 (1974);C A 81, 166408m (1974).

49. H. Rosenberg and S. J. Stohs, Phytochemistry 13, 823 (1974);CA 81, 47456r (1974).

50. J. J. Dingerdissen and J. L. McLaughlin, LEoydia 36, 419 (1973); CA 80, 68386n

51. C. R. Chen, J. L. Beal, R. W. Doskotch, L. A. Mitscher, and G. H. Svoboda,

52. J. W. Loder and H. R. Nearn, Aust. J.Chem.28,6 51 (1975); C A 82, 140344h (1975).

53. A. Cronlund, Acta Pharm. Suec. 10, 507 (1973); C A 80, 80085w (1974).

54. J . W. Loder, C. C. J. Culvenor, R. H. Nearn, G. B. Russell, and D. W. Stanton,

55. J. T. H. Agar, W. C. Evans, and P. G. Treagust, J. Pharm. Pharmacol. 26, Suppl.,

56. M. S. Prernila and B. R. Pai, Ind ianJ. Chem.11,1084 (1973);C A 80,108721b (1974).

57. B. Danieli, G. Palmisano, and G. Rainoldi, Phytochemistry 13, 1603 (1974); CA

58. W. M. Messmer, M. Tin-Wa, H. H. S. Fong, C. Bevelle, N. R. Farnsworth, D. J.

59. J. P. Gillespie, L. G. Amoros, and F. R. Stermitz, J . O r g . Chem. 38, 3239 (1974).

60. M. Koyama and S. Sakamura, Agric. Biol.Chem. 38, 1111 (1974); C A 81, 148445s

61. Z. Xu e and X.-T. Liang, K’o Hsueh T’ung Pao 19, 378 (1974);CA 82,13964k (1975).

62. L. G. West, R. L. Vanderveen, and J. L. McLaughlin, Phytochemistry 13,66 5 (1974);

63. A. A. M. Habib, M. M. A. Hassan, and F. J. Muhtadi, J. Pharm. Pharmacol. 26,

64. P. Venturella, A. Bellino, and F. Piozzi, Heterocycles 3, 367 (1975);C A 83, 435548

65. V. I. Akhamedzhanova, J. A. Bessanova, and S. Yu. Yunusov, Khim. Prir. Soedin.

66. I. A. Bessanovaand S. Yu. Yunusov, Khim. Prir.Soedin. 52 (1974);CA 80,121152m.

67. I. A. Bessanova, V. I. Akhamedzhanova, and S. Yu. Yunusov, Khim. Pri r. Soedin.

68. V. I . Akhamedzhanova, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pr ir. Soedin.

69. K. A. Abdullaeva, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pri r. Soedin. 680

70. K. A. Abdullaeva, I. A. Bessanova, and S. Yu. Yunusov, Khim. Pr ir . Soedin. 684

71. E. F. Nesrnelova and G. P. Sidyakin, Khim. Prir. Soedin. 9, 548 (1973); C A 80,

72. G. H. Mahran and S. H. Hilal, Egypt. J . Pharm.Sci.13,32 1 (1972);CA 81, 169679m

27, 1982 (1973), CA 8 0 , 27416d (1974).

C A 75, 26524x (1971).

(1973); CA 8 0 , 27413a (1974).

Bull. 20, 418 (1972) ; CA 77, 5645p (1972).

(1974).

Lloydia 37, 493 (1974); CA 82, 82983C (1975).

Aust. J. Chem. 27, 179 (1974); CA 80, 68397s (1974).

ll lP -1 12 P (1974); CA 82, 167464j (1975).

82, 28576j (1975).

Abraham, and J. Trojanek, J . Pharm. Sci.61, 1858 (1972).

(1974).

C A 81, 1309s (1974).

837 (1974); CA 82, 108817d (1975).

(1975).

10, 109 (1974); C A 80, 121153n (1974).

677 (1974); CA 82, 86462e (1975).

272 (1975); CA 83, 97662s (1975).

(1974);C A 82, 73261n (1975).

(1974); C A 82, 73260n (1975).

105845J (1974).

(1974).



554 R. H. I?. MANSKE

73. R. B. Harhammer, A. E. Schwarting, and J. M. Edwards, J . Org. Chem. 40, 156

74. X. A. Dominguez, J. Marroquin, B. S. Quintero, and B. S. Vargas, Phytochemistry

75. B. Tursch, D. Daloze, J. C. Bralkman, C. Hootele, A. Cravador, D. Losman, and

76. J. Gleye, A. Ahond, and E. Stanislas, Phytochemistry 13, 675 (1974); C A 81,

76a. D. Gross, W. Berg, and H. R. Schuette, Z . Chem. 13, 296 (1973); C A 80, 3679r

77. T. Ipaktchi and S. M. Weinreb, Tet. Lett. 3895 (1973); CA 80, 71001p (1974).

78. M. Launasmaa, Planta Med. 27, 83 (1975); C A 83, 4938y (1975).

79. A. R. Battersby, R. B. Bradbury, R. B. Herbert, M. H. G. Muro, and R. Ramage,

80. A. R. Battersby, P. Bohler, M. H. G. Munro, and R. Ramage, J. Chem. Soc.,

81. M. Hanaoka, H. Sassa, N. Ogawa, Y. Arata, and J. P. Ferris, Tet . Lett. 2533 (1974);

82. K. A. Kadyrov, V. I. Vinogradova, A. Abdusamatov, and S. Yu. Yunusov, Khim.

83. A. Philip and A. B. Segelman, J. Pharm. Sci. 63, 1495 (1974);CA 82, 13999a (1975).

84. R. Ziyaev, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 505 (1973);

85. R. Ziyaev, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 685 (1974);

86. J. G. Brun and S. Agurell, Phytochemistry14, 1442 (1975); CA 83, 1607608 (1975).

87. K. It o and S. Asai, Yakugaku Zamhi 94, 729 (1974); C A 81, 166344n (1974).

88. T. R. Govindachari and N. Viswanathan, Indian J. Chem. 10, 453 (1972).

89. T. R. Govindachari and N. Viswanathan, Phytochemistry11, 3529 (1972).

90. T. R. Govindachari, K. R. Ravindranath, and N. Viswanathan, J. Chem. Soc.,

91. S. M. Kupchan, H. P. J. Hintz, R. M. Smith, A. Karim, M. W. Cass, W. A. Court,

92. S. T. Murphy, E. Ritchie, and W. C. Taylor, A w t .J.Chem. 27, 187 (1974); C A 80,

93. D. P. Chekraborty, P. Battacharya, A. Islam, and S. Roy, Chern. Ind. ( L o n d o n )

94. B. Tursch, D. Daloze, J. C. Braekman, C. Hootele, and J. M. Pasteels, Tetrahedron

95. A. Guggisberg, M. M. Badawi, M. Hesse, and H. Schnid, Helw. Chim. Acla 59, 414

96. F. Schneider, K. Bernauer, A. Guggisberg, P. van den Brock, M . Hesse, and H.

97. R. L. Vanderveen, L. G. West, and J. L. McLaughlin, Phytochemistry 13, 866

98. M. J. Hoizey, M. M. Debray, L. LeMen-Olivier, and J. LeMen, Phytochemistry13,

99. J. Loehdefink and H. Kating, Planta Med. 25, 101 (1974); CA 81, 355313' (1974).

100. J. Levesque, J. L. Pousset, A. Cave, and A. Cave, C. R. Acad. Sci. (Ser. C ) 278, 959

(1975); C A 82, 112187r (1975).

14, 1833 (1975); CA 84, 2212d (1976).

R. Karrlson, Tet . Lett. 409 (1974).

1327643 (1974).

(1974).

J . Chem. SOC ., erkin Trans. 1394 (1974).

Perkin Trans. 1 1399 (1974).

CA 82, 4445q (1975).

Prir. Soedin. 683 (1974); C A 82, 73262q (1975).

CA 80, 60055h (1974).

CA 82, 8640c (1975).

Perkin Trans. 1 1215 (1974).

and M. Yatagai, J. Chem. Soc., Chem. Commun. 329 (1974).

80074s (1974).

165 (1974); C A 81, 4103f (1974).

31, 1541 (1975).

( 1974).

Schmid, Helw. Chim., Aeta 57, 434 (1974).

(1974);CA 81, 35584t (1974).

1995 (1974);C A 82, 829723. (1975).

(1974); CA 81, 74819u (1974).




101. J. L. Pousset, J. Levesque, A. Cave, F. Picot, P. Potier, and R. R. paris, plants

102. T.Higa and P. J. Scheuer, Phytochemistry 13, 1269 (1974); A 81, 166385b (1974).

103. P. S. Steyn, Tetrahedron 26, 51 (1970).

104. D. W . Nagel, K. G. R. Pachler, P. S. Steyn, P. L. Wessels, G. Gafner, and G . J .

Kruger, Chem. Commun. 1021 (1974).

105. N.B.Mulchandani an d S. R. Venkatachalam, India, A.E.C., Bhabha &.R ~ .ent.

[Rep.]B.A.R.C.-764, 8 (1974); A 82, 108862q (1975).

106. R. Hocquemiller, M. Leboeuf, B. C. Das, H. P. Husson, P. Potier, and A. Cave,

C . R. Hebd. Seances Acud. Sci., Ser. C 278, 525 (1974); A 80, 133673~ 1974).

107. E. teinegger, Pharm. Acta Helv. 48, 517 (1973); A 80,575052 (1974).

108. R. T.Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim.

109. R. T.Mirzamatov, K. L. Lutfullin, V. M. Malikov, and S. Yu. Yunusov, Khim.

110. R. T.Mirzamatov, K. L. Lutfullin , V. M. Malikov, an d S. Yu. Yunusov, Khim.

111. W. Loewe and K. H. Pook, Ann. 1476 (1973).

112. J. Singh, M. A. Potdar, C. K. Atal, and K. L. Dhar, Phytorhemistry 13,677 (1974);

113. S. McLean, P.L. Lau, S. K. Cheng, and D. G. Murray, Can. J. Chem. 49, 1976

114. S.McLean, M. L. Roy, H. J. Lin, and D. T. Chu, Can. J . Chem. 50, 1639 (1972).

115. M. F.Mackay, L. Satske, and A. M. Mathieson, Tetrahedron 31, 1295 (1975).

116. S. R. ohns, J. A. Lamberton, A. A. Sioumis, and H. Suares, Aust. J. Chem. 27,2025 (1974); A 81, 120833t (1974).

117. E.J. Corey and R . D. Balanson, J . Am. Chem. SOC. 6, 6516 (1974).

118. G. A,Moro, M. N. Graziano, and J. D. Coussio, Phytochemistry 14,827 (1975); A

119. K. Jewers, M. J. Nagler, K. A. Zirvi, F. Amir, and F. H. Cottee, Pahlavi Med. .J . 5 ,

120. J.Reisch, G. W. Mirhom, J. Korosi, K. Szendrei, and I. Novak, Phytochemistry 12,

121. K. zendrei, I.Novak, M. Petz, J. Reisch, H. E. Bailey, and V. L. Bailey, LZoydia

122. A. Morales Mendez, A. Gonzalez Gonzalez, and F. Diaz Rodriquex, Rev. Fac.

123. D. . Bhakuni, C. Gonzalez, P. G. Sammes, and M. Silva, Rev. Latinoam. Quim. 5 ,

124. A.Gonzalez Gonzalez, R. Estevez Reyes, and E. DiazChico,An.Quim.70,281(1974);

125. G. Wsterman, Biochem. Syst. 2, 153 (1973); A 80, 5650e (1974).

126. P. W. effs, T. Caps, D. B. Johnson, J. M. Karle, N. H. Martin, and B. Rauckman,

127. S. Logar, N. Mesicek, M. Pcrpar, and E. Seles, Farm. Vestn. (Ljubljana) 25, 21

128. A. Klasek, V. A, Mnatsakanyan, and F. Santavy, Collect. Czech. Chem. Commun.

129. R. I.Gaiduk, M. V. Telezhenetskaya, and S. Yu. Yunusov, Khim. Prir. Soedin 414

Med. Phytother. 8,51 (1974); A 81, 117054J (1974).

Pr ir. Soedin. 415 (1974); A 81, 152460k (1974).

Pr ir. Soedin. 416 (1974); A 81, 166359~ 1974).

Pr ir. Soedin. 540 (1974); A 82, 82957x (1975).

C A 81, 35577t (1974).

(1971).

83, 93851e (1975).

1 (1974); A 81, 230973. (1974).

2552 (1973); A 80,12480w (1974).

36, 333 (1973); A 80,12510f (1974).

Farm., Uniu. Los Andes 8,77 (1971); A 82, 121629~ 1975).

158 (1974); A 82,108803~ 1975).

C A 81,117048k (1974).

J . Org. Chem. 39, 2703 (1974).

(1974); A 82, 82916h (1975).

40, 2524 (1975): A 83, 175453r (1975).

(1974); A 82, 54167w (1975).



556 R. H. F. MANSKE

130. A. Gonzalez Gonzalez, G. De la Fuente , and M. Reina, An . Quim. 69, 1343 (1973);

131. C. G. Gordon-Gray, R. B. Wells, M. B. Hursthouse, S. Neidle, and T. P. Toube,

132. C. G. Gordon-Gray and R. B. Wells, J . Chem.. Soc., Perkin Trans. 1 1556 (1974).

133. S. Ghosal, Phytochemistry 14, 830 (1975); CA 83, 93854h (1975).

134. L. Y. Isaev and I. A. Bessanova, Khim. Pri r. Soedin. 815 (1974); C A 82, 1216 77~

135. T. E. Monakhova, 0. N. Tolkachev, V. 8. Kabanov, M. E. Perel’son, and N. F.

136. T. E. Monakhova, 0. N. Tolkachev, M. E. Perel’son, V. S. Kabanov, and N. F.

137. N. Paslarasu and A. Badauta-Tocan, Farmacia (Bucharest)21, 693 (1973); CA 81,

138. M. Onda, Y . Konda, G. Narimatsu, H. Tanaka, J. Awaya, and S. Omura, Chem.

139. J. Steineger and G. Reuter, Pharmazie 28, 682 (1973); CA 80, 1181 96~1974).

140. M. Hikichi and T. Furuya, Tet. Lett. 3657 (1974).

141. T. Kametani, H. Terasawa, M. Iha ra, and J. Iriarte, Phytochemistry 14, 1884 (1975);

142. J. Vaquette, M. 0. Cleriot, M. R. Paris, J. L. Pousset, A. Cave, and R. R. Paris,

143. A. C. Casey and A. Malhotra, Tet. Lett. 401 (1975).

144. J. Vaquette, J. L. Pousset, and A. Cave, Plant. Med. Phytother. 8, 72 (1974);CA 81,

145. J. R. Cannon, J. R. Williams, J. F. Blount, and A. Brossi, Tet. Lett. 1683 (1974).

146. D. M. Crosby and J. L. McLaughlin, Lloydia 36, 416 (1974); C A 80, 68385m

147. J. D. Phillipson, L. Tezcan, and P. J. Hylands, Planta Med. 25, 301 (1974);CA 81,

148. V. K. Wadhawan, S. K. Sikka, and L. B. Mulchandani, India,A.E.C., Bhabha

149. N. B. Mulchandani, S. S. Iyer, and L. P. Badheka, India, A.E.C. Bhabba At.

150. M. A. Wasanova, U. A. Abdulaev, M . V. Telezhenskaya, and S. Yu. Yunusov,

151. K. Jankowski, S. Godin, and N. E. Cundasawmy, Can. J. Chem. 52, 2064 (1974);

152. F. Fish, A. I. Gray, P. G. Waterman, and F. Donachie, Lloydia 38, 268 (1975);CA

153. H. Ishii, K. Hosoya, T. Ishikawa, E. Ueda, and J. Haginiwa, Yakugaku Zasshi 94,

154. N. Decaudain, N. Kunesch, and J. Poisson, Phytochembtry 13, 505 (1974); C A 81,

CA 80, 96194s (1974).

Tet. Lett. 707 (1972).

(1975).

Proskurnina, Khim. Pri r. Soedin. 472 (1974); CA 82, 541764. (1975).

Proskurnina, Khim. Prir . Soedin. 752 (1974); CA 82, 121666~1975).

87965n (1974).

Phurm. Bull. 23, 2463 (1975); CA 84, 5213r (1976).

C A 84, 2213e (1976).

Plant. Med. Phytother. 8, 57 (1974); CA 81, 60857s (1974).

6085911 (1974).

(1974).

117038g (1974).

At . Res. Cent. [Rep.]B.A.R.C.-764, 6 (1974); CA 82, 171258n (1975).

Res. Cent. [Rep. ]B.A.R.C.-764, 3 (1974); C A 82, 171257m (1975).

Khim. Prir . Soedin. 809 (1974);C A 82, 140349~1975).

CA 81, 63831q (1974).

83, 128689n (1975).

322 (1974); CA 81, 132753e (1974).

74879n (1974).



SUBJECT INDEX

A

Abresoline, 531

Acacia, 43

2-Acetyltrop-2-ene, 87

N-Acetyltryptamine, 543Acnistus, 62

Aconitum, 24, 58

Acronycine, 515

Actinidia argista, 440

Actinidia polygama, 440

Actin idine, 52, 433, 436, 441

Adaline, 5 11

Adiantifoline, 269, 297

Adenocarpus, 46Adina cordifolia, 54

Agastachys odorata, 153Agroclavine, 63Ailanthus giraldii, 42

Ajrnalicine, 54

Aknad icine, 394

Aknadilactam, 394, 422

Aknad inine, 394

Alatamine, 218, 238

Alatolin, 242

Alchornea fioribunda, 48Alchorneine, 48

Alchorneinone, 48

Alphonsea venfricosa, 512

Alstonia venenata, 448Amanita Muscaria, 22

Ambrosia, 5

Ammodendron conollyi, 13, 45

Anabasine, 17, 25, 51

Anabasis aphylla, 13, 25Anabasine, 529Anagerine, 549

Anagy rine, 540, 543

Ancistrodadine, 512Ancistrocladus hamatus, 5 12

Ancistrocladus heyneanus, 5 12

Ancistrocladus vahlii, 5 12Androcymbine, 67, 69

9-Angelylretronecine, 5 1

Anhalidine, 25

Anhalon idine, 25

Anhydronupharamine, 185, 187Aniba duckei, 512Anisocycla grandidieri, 270, 291, 309

Anisodarnine, 91

Anisodas, 61

Anisodine, 91

Ankorine, 513

Anon aine, 526, 536

Anthocercis, 61

Anthocercis littorea, 154

Anthocercis tasmanica, 154

Anthocercis viscosa, 154

Anthocleisra procera, 453

Anthocleista rhizophoroides, 473

Anthranilic Acid, 14

Antirrhinum, 10

Antirrhinum hispanicum, 5 13Anfirrhinum molie, 513

Antirrhinum mollissimum, 5 13

Apoatropine, 91, I04

Apparicine, 539

Aquilegia, 10Araliopsis tabouensis, 544

Arborinine, 544

Arecoline, 65

Argemone, 32, 38

Ariocarpus agavioides, 5 13

Aristolochia argenrina, 513

Arrnepavine, 51, 267, 323

Armepavine, 543Arornoline, 258Asimilobine, 536

Aspergillus, 22Aspidosperma, 54

Atalantia monophylla, 5 14Atalaphylline, 514

557



558 SUBJECT INDEX

Atisine, 58 C

Atropa, 10, 12, 61

Atropa belladona, 93, 139, 146, 154, 162

Cadalene, 524

Cad aver ine , 16Atropa martiana, 164Atrophine, 104Atropine, 89, 127, 162

Azureocercus ayacuchensis, 5 14

B

Bacillus subtilis, 309

Bakanko side, 450

Baluchistanamine, 307

Baptisia leucophia, 11Bathiorhamnus cryptophorus, 5 14Belarine, 257

Bellendena montana, 85, 153

Bellendine, 85

2a-Benzoyloxynortropan-3~-01,92

2a-Benzoyltropane, 86

2-Benzyltropanes, 86

Benzoin aestivale, 535

Berbamine, 41, 297, 309, 348Berbamu nine, 334

Berbenine, 297Berberis , 33

Berberis baluchistanica, 280, 307

Berberis laurina, 257, 272Berberis lycium, 297Berberis petiolaris, 297

Berberis vulgaris, 309

Bhesa archboldiana, 5 1Bisjatrorrhizine, 258

N,N -Bisnoraro mo line , 258

Boemeria cylindrica, 64

Boehmeria platyphylla, 64Boldine, 543Boschniakine, 443, 532

Boschniaka rossica, 444Boschniakinic Acid, 438

Brugmansia, 61

Bruguiera exaristata, 89, 153

Bruguiera sexangular, 89, 153

Bruguiera cylindrica, 5 15Brugine, 515, 89

Bufotenine, 18

Bulbocapnine, 31Burkea africana, 515

Buxenine-G, 60Buxus, 61

Cadia ellisiana, 515Calligonum, 25

Calpurnine, 5 15

Calycanthine, 51

Calycanthus, 53

Camptorrhiza, 69

Camprotheca acuminata, 55Candicine, 65 , 525

Camptothecine, 515, 536

Canadaline, 532

Cantlega corniculata, 447Cantleyine, 446Canc entr ine , 260

Cannabis sativa, 515Cannabisatar ine, 515

Capsicum, 62

Caro coccu line, 5 18

Casimiroa, 19

Cassam ine, 46

Cassine matabelica, 246

Cassinic Acid, 246

Cassinine, 246Cass nopsis ilic ifolia, 55

Castoram ine, 191

Catharan thine , 54

Catharanthus, 54

Catha edulis, 216, 218, 516Cathidine D, 217, 218, 220, 224, 516

Ca thol , 225Celabenzine, 537

Celacinnine, 219, 536

Celafurine, 537

Celullocinnine, 537

Celapagine, 218, 220

Celap anigin e, 218, 220

Celapanine, 218, 220

Celapanol, 22 1

Celastrus angulatus. 246

Celastrus orbiculaius, 246

Celastrus panicufatus, 216, 218

Centaurium pulchella, 473

Centaurium spicatum, 477

Cephaelis, 57Cephalotaxus harringtonia, 5 16

Cephalofoxine, 532

Cephaeamine, 394, 420Cepharanoline, 261



SUBJECT INDEX 559

Cepharanthine, 261, 345

Cestrum, 62

Chelerythrine, 41

Chelidimerine, 261

Chelidonium majus, 261

Chondodent, 296, 371

Chondodendron toxicoferum, 295

Chondrucurine, 25 I , 296

Chondrofoline, 252, 374

Cinchona, 57

Cis-endodihydroisobellendine, 5

Clausena heptaphylla, 5 17

Clausena indica, 517

Claviceps, 22, 62Clitogbe fascicutata, 5 17

Cocaine, 51, 162

a-Cocaine, 119, 147

p-Cocaine, 120, 147

Coccineline, 538

Cocculus, 33

Cocculus carolinus, 58

Cocculus laurifolius, 518

Coclaurine, 543

Cocsoline, 305

Cocsuline, 262, 270, 309Cocsulinine, 305

Cocculus leaeba, 282

Cocculus pendulus, 262, 282, 305

Codonocarpine, 519

Colchicine, 67

Colchicurn, 69

Colpidium colpoda, 309

Colubrina asiatica, 275

Conessine, 60

Coniine, 17

Conium, 17, 23Contarea, 57Convergine, 538

Convolvulus, 61

Cordifoline, 54

Corydalis, 33

Corypalline, 526

Couroupita guianensis, 519

Couroupitine A , 519

Coryphantha calipensis, 5 19

Cremastosperma polyphlebum, 308

Crenatine 17, 543Crepidamine, 524

Crepidine, 7 1 524

Cratalaria, 207, 237, 44

Crotalaria assamiea, 519

Crotalaria burhia, 520

Crotalaria ferruginea, 520Crotalaria leioloba, 520

Crotalaria rnadurensis, 520

Crotalaria tetragona, 520

Crotalarine, 520

Croton, 48

Croton diaco, 49

Croton gabouga, 49

Croton salutaris, 32

Croton turumiquirensis, 49

Crotonosine, 48

Cryptocarya bowiei, 32, 64Cryptospermine, 64

Cryogenine, 531

Cryptophorine, 514

Cryptophorinine, 5 14

Cularine, 33

Curine, 296

Cuscohygrine, 90, 153

Cuspidaline, 334

Cyclea barbata, 309

Cyclea peltata, 263, 209

Cycleacurine, 263Cycleadrine, 264

Cycleahomine, 265

Cycleanine, 297, 375

Cycleanorine, 266

C ycleapeltine, 267

Cyclea sp. (?), 297

Cyclobuxine-D, 60

Cynadum wilfordii, 241

Cynanchum, 56, 64

Cyphomandea betacea, 154

Cystine, 540, 549Cyphomandra, 61

Cytisine, 44, 547

D

Daphnandra micrantha, 271

Daphneteijasmanine, 5 21

Daphmigraciline, 521Daphniphylline, 50

Daphniphyllum gracile, 521

Daphniphyllum teijsmanii, 521Daphrigracine, 521

Darlingia darlingiana, 86, 153

Darlingia ferruginea, 86, 153



560 SUBJECT INDEX

Darlingine, 86Datura, 12, 61

Datura alba, 154Datura arborea, 154Datura bernhardii, 154, 164

Datura candida, 154

Datura ceratocaula, 90, 141, 154Datura cornigera, 142, 154

Datura discolor, 154Datura fastuos a, 154

Datura fer ox , 137, 154, 162

Da fura godronii, 154Datura inermis, 144

Datura innoxia, 90, 138, 154, 162Datura leichardtii, 154

Datura metel, 154

Datura meteloides, 140, 154

Datura myoporoides, 144Datura pruinosa, 154

Datura sanguinea, 91, 140, 154

Datura sframon ium, 93, 136, 140, 154, 162Dafura suaveolens, 89, 154

Da tura tatula, 144, 154

Dauricine, 320, 387

Dauricinoline, 267Dauricoline, 268

Daurinoline, 297, 3342-Deacetylevonine, 218, 237

Delavaine, 394, 408

Dehydrodeoxynupharidine, I85

Dehydroskytanthine, 440

Delphinium, 24, 58N,N-Demethyl-3,4-dimethoxy

3-O-Demethylhernandifoline, 94, 41 1

4'-O-Demethylmesembrenone, 544Dendrobates histrionieus, 522Dendrobates pumilio, 522

Dendrobium, 7 1

Dendrobium chrysanthum, 524

Dendrobium erepidatum, 524

Dendrobium nobile, 524

Dendrobine, 523

(* -trans-Dendrochrysine, 524Dendrocrepine, 524

4-Deoxyeu onym inol, 246

CD eoxye vonin e, 218, 230

Deoxyharr ingtonine, 203-Deox ymayto1 , 226

Deoxynupharidine, 181

Deoxyscopoline, 132

&m ethoxyphenethy lamine, 5 19

Dercetylcolchicinu, 5320-Desmethyladiantifoline, 269

N ' -Desmethyldauricine, 27012'-O-Desmethyltrilobine, 270Desmodium, 43

Desmodium cephalotes, 525

Diethoxythiobinupharidine, 200

Dicaine, 164Dicentra, 33

Dicentra canaden sis, 260

2,6-Dideacetylevonine, 218, 237Dihydroerysodine, 38

6,6*-Dihydroxythio-binupharidine,00

6,6'-Dihydroxythionuphlutine,200Diphasia klainiana, 544

0,O-Dimethylcur ine , 374

0,N-D imethy lmicran thine , 271

N,N-Dimethyltryptamine, 18

Dipidax, 69Dipsacus aureus, 448

3a,6P-DitigIoyloxytropan-7B-O 89

Dolichotele baumii, 525

Dolichotele longim amm a, 525

Dolichotele melaleuca, 525

Dolichotele sphaerica, 525Dolichotele surculosa, 525

Dolichotele uberiformis, 525

Doryanine, 526

Doryophora sassajias, 526

Dorypho rnine, 526

Dregamine, 539

Drimys, 72

Drupacine, 516

Dubam ine, 531

Duboisia, 61

Duboisia hopwoodii, 154

Duboisia myoporoides, 153, 163

Du ckeine , 5 12

Dunalia, 61

E

Ecgonine, 162

Eduline, 539Effirine, 262

Elymoclavine, 63

Em etin e, 56, 531Enicoflavine, 458

Enicostemma hyssopitfolia, 458Enicostemma littorale, 453Enonymine, 218. 239

Ephedra, IS



SUBJECT INDEX 561

Ephe dr ine , 15, 546

-Ephedrine, 546

7-Epideoxynu pharidine, 182, 199

Epinetrum villosum, 297

3-Epinuphamine, 185, 189, 1%

Epin upha rarnine, 194, 199, 21 1

Epioxodap hnigraciline, 521

Epipilosine, 541Epistephamiersine, 394, 403Epistephanine, 272, 297, 309

Equisetum, 20Ergine, 63

Erginine, 63

Erythraea centaurium, 456Erythrina, 23, 33, 48, 44Erythrophleum, 46

Erythrophleum chlorosthehys, 526, 527

Erythrophleum ivorense, 526Erythrophleum monogynum, 527

Erythroxylum coca, 153

Erythroxylum ellipticum, 93, 153

Erythroxylum monogynum, 92, 153

Eschscholtzia, 32

Eschscholtzidine, 527

Eschsch ol tz ine , 33Espinidine, 272Espinine, 273

Ethoxythiobinupharidine, 200

Euda lene, 221Euolalin, 241

Eu onin e, 218, 239

Euonymus Europaeits, 51Euonyminol, 225, 231

Euonymus aiatus, 218

Euonymus europaeus, 216, 218

Euonymus sieboldianus, 217, 218Euxylophora paraensis. 527

Evodia boiviniana, 548

Evonimine, 218

Evo nine, 216, 218, 231, 516

Evonine Acid, 216, 229, 231

Evonoline, 218, 229

Evo r ine , 218

Evo xanthin e , 544, 548Ev ozin e, 218, 237

FFagara xanthoxyloides, 15. 528SF ag arin e, 530, 546, 551

Fagaronine, 528Fagomine, 528

Fagopyrum esculentum, 528

Fagrea fragrans, 474

Fangchinoline, 309Farnesol, 524Ferrugine, 86

Ferruginine, 86Festuca, 66

Festucine , 65

Fetidine, 252

Ficus, 64Fontanesia phillyroides, 454

Fontaphill ine, 454

N-Forrnyltortuosamine, 544

Fritillaria, 6 9Funiferine, 274Funtumia, 6 0

G

Galanthamine, 67

Garrya, 58

Genista, 46Genista monosperma, 543

Gentiabetine, 463

Gentialutine, 448

Gentiana angustifolia, 474Gentiana asclepiadea, 449, 456

Gentiana axillaris, 474

Gentiana axillijlora, 474

Gentiana barbata, 474

Gentiana biebersteinii, 474

Gentiana bulgarica, 474Gentiana caucasia, 473

Gentiana clusii, 474

Gentiana cruciata, 458

Gentiana decumbens, 474

Gentiana dinaerica, 474Gentiana fetisowii, 474Gentiana freyniana, 474

Gentiana greacilipes, 474

Gentiana kaufmanniana, 473Gentiana lutea, 449

Gentiana macrophylla, 456Gentiana olgue, 456

Genriana olivieri, 456, 457, 464Genfiana pneumonanthe, 474

Gentiana punctata, 474

Gentiana purdomrii, 474Gentiana purpurea, 474

Gentiana scabra. 474Gentiana schistocaktx, 474Gentiana septenfidea. 474



562 SUBJECT INDEX

Gentiana sino-ornata, 474

Gentiana spp,, 529

Gentiana straminea, 474Gentiana tibetica, 463

Gentiana turkestanorum, 455, 457Ge ntiana wirilowi, 475

Gentiana vvendenskyi, 475

Gentiana wutaiensis, 475

Gentianadine, 455

Gentianamine, 457

Gentianidine, 456

Gentianaine, 459

Gentianine, 52, 432, 452

Gentiocrucine, 458Gentioflavine, 457

Germacrane, 524

Glaucine, 31, 512, 534

Gliotoxin, 22

Gloriosa, 69

Glycoperine, 530

Glymnocactus , 529

H

Haemanthamine, 67Halfordinine, 537

Haloxylon amm odendron, 529

Hamatine, 5 12

Haplamine, 529

Haploperine, 531Haplophydine, 530

Haplophyllum latifolium, 53

Haplophyllum kowalenskyi, 546

Haplophyl lum perforatum, 529, 530

Haplophyllum schelkovnikovii, 546

Haplophyl lum tenue, 546Haplophyllum villosun, 546

Haplopine, 530, 551

Harmalan. 515

Harman, 25, 515, 539

Hasubanonine, 394, 398, 422, 427

Hedera helix, 531

Heimia salicifolia, 531

Heliosupine, 19

Heptazolidine, 517Hernandifoline, 394, 410

Hernandine, 394, 412Hernandoline, 394

Hernandolinol, 394, 413Heteratisine, 58

Hippodamine, 531, 538

Hippomane mancinelia, 49

Histamine, 19

Histidine, 14Histrionicotoxin, 522

Holarrhena, 24, 60

Holophyllamine, 60

Homatropine, 162

Hornoaromoline, 309

Homoroia riparia. 49

Homostephanoline, 394

Hordenine, 14, 65, 525

Hydrastis canadensis, 532

19-Hydroxycassaine, 526

1I-Hydroxycephalotaxine, 5 164-Hydroxydendroxine, 524

4-Hydroxyhygrinic Acid, 49

Hydroxylunine, 543

13-Hydroxylupanine, 5 15

1-Hydroxyrutaecarpine, 527

a-Hydroxyscopolamine, 91

Hydroxyskytanthine I, 439

6 -H ydrox ythiobinupharidine, 200

6-Hydroxythionuphlutine B, 200

Hydroxywilfordic Acid, 217, 229

Hygrine, 16, 51, 71Hymenocaridia, 48

Hymenoxys , 5

Hym enoxys acaulis , 13

Hymenoxys ives iana, 13

Hymenoxys scaposa , 13

Hyoscyamine, 90, 136, 162

Hyoscine, 89, 162

Hyoscyamus , 12. 61

Hyoscyamus a lbus , 154

Hyoscyamus aureus , 154

Hyoscyamus n iger , 93, 145, 154

Hyo scyam us orientalis , 154

hyoscyamus p ius i l lus , 154

Hypaphorine, 546

I

Idotetrandrine, 264, 294, 297, 309, 341

Incarvillea olgae, 471

Indicaine, 532

Indicaxanthine, 27

Indizoline, 517

Integerrimine, 520

Integerrisine, 543Inula rogleana, 58

Zphigenia, 69

Ipomoca, 63



SUBJECT I N D E X 563

Iridomyrmex, 52Isobellendine, 85

Isochondodendrine, 297Isocorydine, 526

Isocromadurine, 520

Isoeuonyminol, 23 1

Isoevo nine, 218, 237Isoevo rine, 218, 237

Isofangchinoline, 309Isogentialutine, 448Isoharningtonine, 532

Isolaureline , 535Isoliensinine, 361

Isooncinotine, 538Isoplatydesmine, 539

Isotheb aine, 31

Isoremerine, 535Isotenuipine, 275Isothalicbe rine, 257Isotril obin e, 253, 262, 271

Zxanthus niscosus, 475

J

Jabob ine, 545

Jasm inine, 462Jasminum domatiigerum, 476

Jasminum frutican s, 486

Jasminum gracile, 476

Jasmium lineare, 476

Jasminum SPP, 446, 463Jaborosa, 62

Jatrorrhiza paim ata, 258

Julocroron, 48

K

Knightia deplanchei, 87, 153, 532Kokusagine, 537, 549

Kokusaginine, 539Kreisiginone, 532Kreys igia , 69

Kreysigia multiflora, 532

L

Ladenbergia , 57Lagerine, 534

Lagerstroemia indiea, 534

Lamprobine, 20, 44Lapanine, 540, 549Laurifine, 5 18

Laurifinine, 518Laurifoline, 55 1

Laurifonine, 518

Laurotetanine, 535

Latura, 61Lepis ta caespi tosa, 5 17

Lepistine, 517

Leptorhabdos parvijlora, 450, 535Leptorhabine, 450, 535Lespedeza, 43Liensinine, 361Limacine, 309Limacu sine, 267

Lindera bemzoiin, 535

Liparis, 71

Lirine, 535Liriodenine, 65, 526, 535, 536, 548Liriodendron tulipifera, 535Littorica, 69

Littorine, 104, 139

Lobelia, 17Lomatogonium rotatum, 475

Loline, 65Lolium, 66Lonicera, 53

Lophocerine, 26

Lophophora diffusa, 535Lunaria, 65Lupinine, 25, 44

Lupinus, 71

Lyadine, 539

Lyaline, 539

Lycopersicum esculentum, 142

Lysicamine, 535Lysine, 14

Lycocfonine, 58

Lycopers icon, 60

Lycopodine, 20Lycopodium, 20

Lyco nne , 67Lysicanine, 65

Lysichitum camtschatcense, 65Lythrine, 531

M

Maculine, 549

Magnocurine, 536

Magnoflorine, 41, 551

Magnolamine, 336Magnoline, 334Magnolia obovata, 536Mahonia aquifolia, 297Malaxis, 71



564 SUBJECT INDEX

Malkangunin, 221, 241

Malkanguniol, 222, 245

Malonetia. 60Mandragora, 61

Mandragora autumnalis, 154

Mandragora oficinarum, 94, 154

Mappiene, 536

Mappia foctida, 55, 536

Matrine, 20

Maytansine, 2 19

Maytenus arbutifolia, 218, 536

Maytenus buchanii, 2 19

Maytenus chuchuhuasha, 219

Maytenus ovaius, 215, 218Maytenus senegalense, 218

Maytenus serrata, 218

Maytine, 215, 218, 220, 225

Maytol, 227

Maytolidine, 218, 220, 227

Maytoline, 215, 218, 220, 225

Melicope barbigera, 539

Melicope perspicuinerva, 537

Melicopidine, 515

Melicopine, 518

A'-Membrenone, 544

Menisarine, 357

Menispermum canadense, 297

Menispermum dauricum, 267

Menyanthes trifoliata, 449, 458

Meperidine, 101, I50

Merendera, 69

Mescaline, 25, 549

Mesembrine, 26

Mesembryanthemum, 26

N-Methylisopelletierine, 16

N-Methylpyrrolidine, 16

N-Methyltyramine, 65

Methysticodendron, 6

Mesodine, 531

Meteloidine, 89, 141

Metaphanine, 394, 396, 424

6-Methoxyteeleanthine, 548

3a-(p-Methoxyphenylacetoxy)-Tropan-6po,

3-Methoxytyramine, 549

0-Methylancistrocladine, 5 12

6P(2-Methylbutanoyloxy) tropan-3a-o I ,

3(3-Methylcrotonyl)-cassaine, 526

0-Methyldauricine, 275N-Methyl-3,4-dimethoxy-fi-methoxy-

91

90

phenethylamine, 5 19

N-Methyl-3,4-dimethoxyphene-

thylamine, 519Methylhernandine, 394, 412

0-Methyllagerine, 534

0-Methylmieranthine, 276

4-Methyl-2,6-naphthyridine,5 13

0-Methyloxyacanthine, 292

0-Methylpellotine, 535

N-Methylplatydesminium, 544

0-Methylptelefolium, 543

0-Methylthalicberine, 297, 348

N-Methyltyramine, 539

0-Methyltyrophorinidine, 540Miersine, 394

Micranthine, 253

Monocrotaline, 519, 520

Monomethyltetrandinium, 307

Morphine, 32

Munitagine, 33

Multiflorine, 5 15

Multifloramine, 532

Murrayacinine, 537

Murray a Koenigii, 537

Muscarine, 22Mycobacterium smetmatis, 300, 309

Mycobacterium tuberculosis, 300

Myrrhina, 538

N

Namedi ne, 67

Neferine, 361

Nelumbo, 57

Nemuarine, 276

Nemuaron vieillardii, 276

Neoeuonymine, 218, 239

Neoevonine, 218, 237

Neogomesia agavioides, 5 13

Neooneinotine, 538

Neothiobinupharidine sulfoxide, 197, 200

Neosophoramine, 546

Nicandra, 61

Nicojiana, 6, 12, 17, 61

Nicotiana tabacum, I54

Nicotine, 20, 25Nigella damascena, 46

Nitidine, 551

Nohilomethylene, 524

4 Noractinidine, 446

Noradrenaline, 34



SUBJECT INDEX 565

Noratropine, 89

Norbelladine, 67

2-N-Norberbamine, 277Norboldine, 543

Norcocaine, 123

Norcycleanine, 297

Norerythrostachaldine, 526

Norglaucine, 512

Norhyoscine, 89

Norlaudanosine, 30

Normacromerine, 519

N-Normethylskytanthine, 445

2-N-Norobamegine, 278

Norpseudoephedrine, 217Norpsicaine, 134

Nortilliacorine-A, 278

Nortiliacorinine-A, 278 ,

Nortiliacorinine-B, 278

Novacaine, 164

Nuciferine, 65

Nudiflorine, 48

Nuphamine, 185, 188

Nuphar, 57, 72

Nupharamine, 183, 185, 211

Nupharidine, 181Nuphar japonicum, 188

Nuphar luteum, 186, 197

Nupharolidine, 191, 199

Nupharolutine, 192, 199

Nuphenine, 187, 199

Nuphleine, 198, 200

Nymphaea, 57, 72

0

Obaderine, 260, 357

Obovanine, 536Olea paniculaia, 462

Oliveridine, 463

Oliveramine, 465

Oncinotine, 538

Oncinoris nijida, 538

Ophelia diluta, 475

Opuntia clavata, 539

Opuntia jicus-indica, 27

Orientalinol, 34

Orientalinone, 31

Ormocastrine, 541Ormosanine, 549

Ormosia, 23, 44

Ormosia semicastrata, 541

Ornithine, 14

Oscine, 143

Oxaline, 540

6,7-Oxidodeoxynupharidine, 99Oxodaphnigraciline, 521

Oxodaphnigracine, 521

16-Oxodelavaine, 394, 409

Oxoepistephanine, 279

16-Oxohasubanonine, 394, 405

16-Oxoprometaphanine, 394, 405

Oxostephamiersine, 394, 403

Oxyacanthine, 348

P

Pachygone pubescens, 297Pachysandra, 60

Pakistanamine, 280

Pakistanine, 281

Palustrine, 20

Panamine, 549

Pandaca calcarea, 539

Pandaca debragi, 539

Pandine, 539

Pandoline, 539

Papaver, 6, 12, 38

Papaver orientale, 31Papaver somniferum, 30

Papaverine, 30

Parthenium, 5

Passijlora coerulea, 539

. Passiyora decaisneana, 539

Passijora edulis, 539

Passij7ora foetida, 539

Passijora incarnara, 539

Passijlora, subpeltata, 539

Passijlora subulata, 539

Passijlora warmingii, 539Pauridianiha hyaflii, 539Pauwoljia verticillata, 448

Pedicularidine, 467

Pedicularine, 467'Pedicularis dolichorrhiza, 47

Pedicularis ludwigi Regel, 471

Pedicularis olgae, 443, 466

Pedicularis rhinanthoides, 472

Pedicularis rhinanthoides, 438

Pediculidine, 461

Pediculine, 467Pediculinine, 466

Peganum, 23, 42

Pelea barbigera, 539

Pelecyphora aselliformis, 5 13



566 SUBJECT INDEX

Penduline, 282

Penicillium, 22

Penicillium islandicum, 6Penicillium oxalicum, 540

Pennsylpavine, 306

Pennsylpavoline, 306

Pennsylvanamine, 306

Pennsylvanine, 306

Pergularia pal l ida, 540

Peripentadenia m earsii , 49, 92, 153

Periphylline, 540

Peripterygia marginata, 540

Petter ia ramentac ca , 540

Phaeanthine, 341Phaeanthus ebracteolatus, 3I0

Phaseolus aureus, 46

PPhenethylamine, 525, 543, 546

Phelline, 51

Phellodendron, 41

Phenethylamine, 14

Phenylalanine, 14, 43

2-Phenylglyceric Acid, 91

Phlebicine, 308

Phyllanthus, 47, 49

Physalis. 61Physalis a lkak engi , 94, 154

Physalis bunyardii, 94

Physalis peruviana, 94, 141, 154

Physochlaina, 61

Physochlaina alaica, 91, 154, 541

Physochlaine, 91, 541

Physos t igma , 23, 49

Physosrigma vertenosum, 43

Physostigmine, 23

Physoperuvine, 94

Picrasma ailrnthoides, 42Pilocarpine, 19

Pilocarpus, 19

Pilocarpus microphyllus, 541

Pilosine, 541

Pinidine, 20

Piper trichostachyon, 541

Piptanthine, 549

Pipranrhus, 44Plantago albicans, 471

Plantago coronop us, 471

Plantago crassifolia, 47

Plantago crypsoides, 471

Plantago cylindrica, 471, 443

Plantago m ajor , 471

P antago nota ta , 471

Plantago ovata, 472

Plantago psyl l ium, 47

Plantago ram osa, 443Plantagonine, 443Platydesmine, 537

Pleurospermine, 37

Podopetaline, 541

Podopetu lum ormondii , 541

Popowia cyanocaupa, 275

Poranthera corymbo sa , 542

Poranthericine, 542

Porantheridine, 542

Porantherilidine, 542

Parantheriline, 542Porantherine, 542

Pretazettine, 67

Prometaphanine, 394

6PF’ropanoyloxy-3a-tigloyloxytropane, 0

Propyleine, 538

Prosopis nigra, 543

Prosopis spicigera, 543

Protostephabyssine, 394, 401

Protostephanine, 427

Przewalskia shebbearei, 154

Przewalskia tangiotica, 154Pseudoephedrine, 15

Pseudotropine, 51, 109

Pseudornonas putid a, 165

Psicaine, 107

Psilocybe, 22

Psilocybin, 18, 22

Psychotria, 57

Pielen trifoliata, 543

Pterocelastrus marginatus, 540

Pumiliotoxin C , 522

Putrescine, 16

Pycnamine, 283, 209

Pycnarrhena australiana, 277, 297

Pycnarrhena ozantha , 258, 278

R

Remij ia , 57

Repandine, 357

Retama monosperma , 543

Retamine, 543

Reianilla ephedra , 543

(+)-Reticuline, 30, 520, 526, 536, 419

Retronecine, 545

Retrorsine, 545

R h a z y a , 54



SUBJECT INDEX 567

Ricinine, 48

Ricinus, 48

Rivea, 63

Robustine, 551

Rodiasine, 274

Ruta bracteosa, 544

Ruta chalepensis, 544

Rutamine, 544

S

Salpichroa, 61

Salpichroa originifolia, 154

Salpiglossis, 61

Salsolidine, 525Salsoline, 25

Salutaridine, 32

Sanguidimerine, 304

Sanguinaria canadensis, 304

Sarcocca, 60

Sceletenone, 544

Sceletium namaquense, 544

Sceletium strictum, 544

Schoenocaulon, 69

Scopolia, 61

Scopolamine, 162Scopolia carniolica, 94, 154

Scopolia himalaiensis, 140, 154

Scopolia japanica, 155

Scopolia lurida, 94, 136, 145, 155

Scopolia parviyora, 155

Scopolia sinesis, 155

Scopalia stramonifolia, 145, 155Scopolia tangutica, 155

Scopoline, 131

Securinega, 47

Securinine, 47Sedamine, 17

Sedumo maximum, 545

Senecio barbellatus, 546

Senecio cineraria, 545

Senecio eraticus, 545

Senecio petasites, 545

Senecio swaziensis, 546

Senecionine, 19, 545

Seneciphylline, 545

Serotonin, 18

Sida cordifolia, 546Silene, 10

Sinicuichine, 531

Skimmiancine, 531, 537, 544, 546, 549, 551

Skytanthine, 433

Skythanthines, 434, 470

GSkythanthine, 435

Skytanthus acutus, 432Solandra, 61

Solandra grandijlora, 143, 155

Solandra guttata, 155

Solandra harrwegii, 155

Solandra hirsuta, 155

Solandra macrantha, I55

Solanidine, 60

Solanocapsine, 60

Solanurn, 60, 61

Sophocarpine, 543, 546

Sophora alopeouroides, 546Sophora prodanii, 547

Sophoramine, 546

Sophoridine, 546

Sphaerocarpine, 45

Sparteine, 44, 20, 543. 547

Spathiostemon javensis, 49

Spherophysine, 547

Spicigerine, 543

Spiraea japonica, 58

Stehisimine, 297, 309

Stemmadinine, 54Stephaboline, 394, 401

Stephamiersine, 394, 403 .Stephania abyssinica, 394

Stephania cepharantha, 261, 394

Stephania delavayi, 394

Stephania hernandifolia, 279, 297, 394

Stephania japonica, 283, 394

Stephania sasakii, 297, 394

Stepinonine, 283, 310, 347

Stephasunoline, 394, 403

Stephavanine, 394, 400Stephisoferuline, 394, 398

Stephuline, 399

Streptomyces, 22

Streptomyces N337, 547

Streptosolen, 61

Stropharia, 22

Strychnine, 54

Strychnos, 54

Strychnos vacacoua, 450

Swainsonia coronillaefolia, 547

Swainsonia galegifolia, 547Swazine, 546

Swentia connata, 475

Swentia gracipora, 475

Swertia gracij?ifolia, 476



568 SUBJECT INDEX

Swertia japon ica, 453, 456

Swertia marginata, 475

Swertia sibirica, 475

Syneilesis palrnata, 547

Syneilsine, 547

T

Tabersonine, 54

Talauma mexicana, 381, 548

Taxine, 20

Tazettine, 67

Teclea boiviniana, 548

Teclea grandifolia, 548

Teclea unifoliata, 549Teclea verdoerniana, 544

Tecleanone, 548

Tecleanthine, 548

Tecoma fu lv a , 440

Tecom a radicans, 440

Tecoma stuns, 435

Tecomaine, 435

Tecomine, 435

Tecostanine, 30, 435

Tecostidine, 437, 438

Telobine, 285Teloidine, 111

Teloidinone, 111

Ternbetarine, 551

Templetonia retusa, 549

Templetine, 548

Tetrahydroharman, 25, 515

Tetrandrine, 266, 297, 309, 341

Thalfine, 286

Thalfinine, 287

Thalfoefidine, 255

Thalibruinine, 308Thalicarpine, 289, 297, 382

Thalicberine, 297, 348

Thalictrogarnine, 287

Thalictropine, 288

Thalictrum dioicum , 289

Thalictrum f oetidum , 286

ThalictrumJlavum, 297

Thalictrum glaucum , 292

Thalictrum isopyroid es, 289

Thalictrum minus, 269, 290, 297

Thalictrum polygam um , 287, 297, 306

Thalictrum rochebrunianum, 308

Thalictrum rugosum , 292, 297

Thalidasine, 255, 293

Thalidazine, 297

Thalidoxine, 289

Thaligine, 294

Thalisopidine, 289Thalmelatidine, 290

Thalmineline, 291

Thalrugosarnine, 292

Thalrugosidine, 293

Thalrugosine, 294, 309

Thalsrninine, 297

Thiobinupharidine, 195

Thionupharodioline, 200

Thionupharoline, 198, 200

Thionuphlutine, 196

Tigloyidine, 1403a-Tigloyloxytropan-6p01, 89

6~-Tigloyjoxytropan-3a-7pdiol,89

Tiliacora dinklagei, 305

Tiliacora fun ifera , 274

Tiliacora race mo sa, 278

Tiliacora w arneckei, 274

Tiliacorine, 279, 359

Tiliacorinine, 279, 359

Tiliageine, 305

Toddalia, 41

Toxicoferine, 295Trewia, 48

Trichocereus pa chan oi, 549

Trichoderma viride, 22

Trichodesmine, 520

Triclisia gillettii, 262, 309

Triclisia pa ten s, 309

Triclis ia su bcord ata, 262, 296, 309

Tricordatine, 296

Tricrotonylteteamine, 546

Trigilletine, 262

Trilobine, 270, 297, 3543a-(3,4,5-Trimethoxybenzogloxy)-tropane,

Triptergine, 240

Tripterygium forrestii , 246

Tripterygium wilfordii, 217, 218, 536

Tropacine, 164

Tropcocaine, 92, 162

Tropan-3a, 6P-dio1, 86, 91, 93

Tropan-2& 3P-dio1, 116

Tropane, 109, 123

Tropan-3a-01, 121

Tropan-3P-01, 101

Tropan-6po1, 123

Tropan-3-one, 12 1

Tropan-3a, 6P, 7ptrio1, 93

93



SUBJECT INDEX 569

Tropanyl Ethers, 124Tropidine, 109, 133Tropine, 61, 109

Vasicinone, 546

Vavicinol, 546

35980975 the alkaloids chemistry and physiology volume 16 1977 isbn 0124695167

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