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CatalytiC CasCade ReaCtions


Edited by

Peng-Fei XuState Key Laboratory of Applied Organic ChemistryCollege of Chemistry and Chemical EngineeringLanzhou UniversityLanzhou PR China

Wei WangDepartment of Chemistry and Chemical BiologyUniversity of New MexicoAlbuquerque New Mexico

Copyright copy 2014 by John Wiley amp Sons Inc All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data

Catalytic cascade reactions edited by Dr Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Dr Wei Wang Department of Chemistry and Chemical Biology University of New Mexico pages cm Includes bibliographical references and index ISBN 978-1-118-01602-2 (hardback) 1 Organic reaction mechanisms 2 Catalysis 3 Chemical reactions 4 Organic compoundsndashSynthesis I Xu Peng-Fei 1964ndash editor of compilation II Wang Wei (Associate professor of chemistry) editor of compilation QD5025C38 2013 547prime215ndashdc23

2013011112

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

v

Contents

Contributors xi

Preface xiii

1 amine-Catalyzed Cascade Reactions 1Aiguo Song and Wei Wang

11 Introduction 212 Enamine-Activated Cascade Reactions 3

121 EnaminendashEnamine Cascades 31211 Design of EnaminendashEnamine Cascades 31212 Examples of EnaminendashEnamine and EnaminendashEnamine

Cyclization Cascades 31213 EnaminendashEnamine in Three-Component Cascades 61214 Enamine-Activated Double α-Functionalization 71215 Robinson Annulations 7

122 EnaminendashIminium Cascades 81221 Design of EnaminendashIminium Cascades 81222 Examples of [4 + 2] Reactions with Enamine-Activated

Dienes 81223 Inverse-Electron-Demand [4 + 2] Reactions with

Enamine-Activated Dienophiles 131224 EnaminendashIminiumndashEnamine Cascades 16

123 Enamine Catalysis Cyclization 191231 Design of Enamine-Cyclization Cascade Reactions 191232 Enamine-Intermolecular Addition Cascades 19

vi CONTENTS

1233 Enamine-Intramolecular Addition Cascades 201234 Enamine-Intramolecular Aldol Cascades 21

13 Iminium-Initiated Cascade Reactions 21131 Design of IminiumndashEnamine Cascade Reactions 21132 Iminium-Activated DielsndashAlder Reactions 22133 Iminium-Activated Sequential [4 + 2] Reactions 24134 Iminium-Activated [3 + 2] Reactions 25135 Iminium-Activated Sequential [3 + 2] Reactions 27136 Iminium-Activated [2 + 1] Reactions 30

1361 Iminium-Activated Cyclopropanations 301362 Iminium-Activated Epoxidations 321363 Iminium-Activated Aziridinations 34

137 Iminium-Activated Multicomponent Reactions 35138 Iminium-Activated [3 + 3] Reactions 37

1381 Iminium-Activated All-Carbon-Centered [3 + 3] Reactions 37

1382 Iminium-Activated Hetero-[3 + 3] Reactions 40139 Other Iminium-Activated Cascade Reactions 42

14 Cycle-Specific Catalysis Cascades 4215 Other Strategies 4516 Summary and Outlook 46References 46

2 Broslashnsted acidndashCatalyzed Cascade Reactions 53Jun Jiang and Liu-Zhu Gong

21 Introduction 5422 Protonic AcidndashCatalyzed Cascade Reactions 55

221 Mannich Reaction 55222 PictectndashSpengler Reaction 56223 Biginelli Reaction 58224 Povarov Reaction 59225 Reduction Reaction 60226 13-Dipolar Cycloaddition 61227 Darzen Reaction 65228 Acyclic Aminal and Hemiaminal Synthesis 66229 Rearrangement Reaction 672210 αb-Unsaturated Imine-Involved Cyclization Reaction 692211 Alkylation Reaction 692212 Desymmetrization Reaction 702213 Halocyclization 712214 Redox Reaction 722215 Isocyanide-Involved Multicomponent Reaction 732216 Other Protonic AcidndashCatalyzed Cascade

Reactions 7523 Chiral Thiourea (Urea)ndashCatalyzed Cascade Reactions 75

231 Neutral Activation 76

CONTENTS vii

2311 Halolactonization 762312 Mannich Reaction 772313 MichaelndashAldol Reaction 782314 Michael-Alkylation Reaction 792315 Cyano-Involved Michael-Cyclization Reaction 822316 Michael-Hemiketalization (Hemiacetalization)

Reaction 842317 MichaelndashHenry Reaction 872318 MichaelndashMichael Reaction 902319 Petasis Reaction 9423110 Sulfur YlidendashInvolved Michael-Cyclization Reaction 9523111 α-Isothiocyanato ImidendashInvolved Cascade Reaction 9623112 α-IsocyanidendashInvolved Cascade Reaction 98

232 Anion-Binding Catalysis 992321 PictetndashSpengler Reaction 992322 Other Iminium IonndashInvolved Cascade Reaction 1012323 Oxocarbenium IonndashInvolved Cascade Reaction 103

24 Broslashnsted Acid and Transition Metal Cooperatively Catalyzed Cascade Reactions 104241 Dual Catalysis 105242 Cascade Catalysis 108

2421 Pd(0)Broslashnsted Acid System 1092422 RutheniumBroslashnsted Acid System 1092423 Au(I)Broslashnsted Acid System 1132424 Other Binary Catalytic Systems 114

25 Conclusions 116References 117

3 application of organocatalytic Cascade Reactions in natural Product synthesis and drug discovery 123Yao Wang and Peng-Fei Xu

31 Introduction 12332 Amine-Catalyzed Cascade Reactions in Natural Product Synthesis 125

321 Iminium-Ion-Catalyzed Cascade Reactions in Natural Product Synthesis 125

322 Cycle-Specific Cascade Catalysis in Natural Product Synthesis 1293221 IminiumndashEnamine Cycle-Specific Cascade Catalysis 1303222 Enamine (Dienamine)ndashIminium Cycle-Specific

Cascade Catalysis 1323223 More Complex Cycle-Specific Cascade Catalysis 134

33 Broslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 137

34 Bifunctional BaseBroslashnsted AcidndashCatalyzed Cascade Reactions in Natural Product Synthesis 139

35 Summary and Outlook 140References 142

viii CONTENTS

4 gold-Catalyzed Cascade Reactions 145Yanzhao Wang and Liming Zhang

41 Introduction 14542 Cascade Reactions of Alkynes 147

421 Cascade Reactions of Enynes 1474211 Cascade Reactions of 16-Enynes 1474212 Cascade Reactions of 15-Enynes 1494213 Cascade Reactions of 14-Enynes 1514214 Cascade Reactions of 13-Enynes 1524215 Cascade Reactions of 1n-Enynes (n gt 6) 154

422 Cascade Reactions of Propargyl Carboxylates 156423 Cascade Reactions of ortho-Substituted Arylalkynes 161424 Cascade Reactions of Other Alkynes 165

43 Cascade Reactions of Allenes 17044 Cascade Reactions of Alkenes and Cyclopropenes 17345 Closing Remarks 174References 174

5 Cascade Reactions Catalyzed by Ruthenium iron iridium Rhodium and Copper 179Yanguang Wang and Ping Lu

51 Introduction 17952 Ruthenium-Catalyzed Transformations 18053 Iron-Catalyzed Transformations 18554 Iridium-Catalyzed Transformations 19155 Rhodium-Catalyzed Transformations 19456 Copper-Catalyzed Transformations 20257 Miscellaneous Catalytic Reactions 21558 Summary 219References 219

6 Palladium-Catalyzed Cascade Reactions of alkenes alkynes and allenes 225Hongyin Gao and Junliang Zhang

61 Introduction 22662 Cascade Reactions Involving Alkenes 226

621 Double MizorokindashHeck Reaction Cascade 226622 Cascade Heck ReactionC-H Activation 227623 Cascade Heck ReactionReductionCyclization 230624 Cascade Heck ReactionCarbonylation 231625 Cascade Heck ReactionSuzuki Coupling 232626 Cascade Amino-OxopalladationCarbopalladation Reaction 234

63 Cascade Reactions Involving Alkynes 237631 Cascade Heck Reactions 238

CONTENTS ix

632 Cascade HeckSuzuki Coupling 238633 Cationic Palladium(II)-Catalyzed Cascade Reactions 239634 Cascade Heck ReactionStille Coupling 241635 Cascade HeckSonogashira Coupling 243636 Cascade Sonogashira CouplingndashCyclization 244637 Cascade Heck and C-H Bond Functionalization 247638 Cascade Reactions Initiated by Oxopalladation 253639 Cascade Reactions Initiated by Aminopalladation 2566310 Cascade Reactions Initiated by Halopalladation or

Acetoxypalladation 2596311 Cascade Reactions of 2-(1-Alkynyl)-alk-2-en-1-ones 2636312 Cascade Reactions of Propargylic Derivatives 263

64 Cascade Reactions Involving Allenes 264641 Cascade Reactions of Monoallenes 264642 Cross-Coupling Cyclization of Two Different Allenes 274

65 Summary and Outlook 276Acknowledgments 277References 277

7 use of transition MetalndashCatalyzed Cascade Reactions in natural Product synthesis and drug discovery 283Peng-Fei Xu and Hao Wei

71 Introduction 28372 Palladium-Catalyzed Cascade Reactions in Total Synthesis 284

721 Cross-Coupling Reactions 2847211 Heck Reaction 2847212 Stille Reaction 2917213 Suzuki Coupling Reaction 297

722 TsujindashTrost Reaction 301723 Other Palladium-Catalyzed Cascade Reactions in Total

Synthesis 30373 Ruthenium-Catalyzed Cascade Reactions in Total Synthesis 30574 Gold- and Platinum-Catalyzed Cascade Reactions in Organic

Reactions 31875 Copper- and Rhodium-Catalyzed Cascade Reactions in Organic

Synthesis 32276 Summary 326References 326

8 engineering Mono- and Multifunctional nanocatalysts for Cascade Reactions 333Hexing Li and Fang Zhang

81 Introduction 33482 Heterogeneous Monofunctional Nanocatalysts 335

x CONTENTS

821 Metal-Based Monofunctional Nanocatalysts 335822 Metal OxidendashBased Monofunctional Nanocatalysts 340823 Orgamometallic-Based Monofunctional Nanocatalysts 340824 Graphene OxidendashBased Monofunctional Nanocatalysts 343

83 Heterogeneous Multifunctional Nanocatalysts 344831 AcidndashBase Combined Multifunctional Nanocatalysts 344832 MetalndashBase Combined Multifunctional Nanocatalysts 349833 OrganometallicndashBase Combined Multifunctional Nanocatalysts 349834 Binary OrganometallicndashBased Multifunctional Nanocatalysts 350835 Binary MetalndashBased Multifunctional Nanocatalysts 352836 MetalndashMetal Oxide Combined Multifunctional Nanocatalysts 353837 OrganocatalystndashAcid Combined Multifunctional Nanocatalysts 353838 AcidndashBasendashMetal Combined Multifunctional Nanocatalyst 356839 Triple EnzymendashBased Multifunctional Nanocatalysts 356

84 Conclusions and Perspectives 359References 360

9 Multiple-Catalyst-Promoted Cascade Reactions 363Peng-Fei Xu and Jun-Bing Ling

91 Introduction 36392 Multiple Metal CatalystndashPromoted Cascade Reactions 364

921 Catalytic Systems Involving Palladium 365922 Catalytic Systems Involving Other Metals 368

93 Multiple OrganocatalystndashPromoted Cascade Reactions 370931 Catalytic Systems Combining Multiple Amine Catalysts 371932 Catalytic Systems Combining Amine Catalysts and Nucleophilic

Carbenes 380933 Catalytic Systems Combining Amine and Hydrogen-Bonding

Donor Catalysts 385934 Catalytic Systems Involving Other Organocatalysts 390

94 MetalOrganic Binary Catalytic SystemndashPromoted Cascade Reactions 394941 Catalytic Systems Combining Secondary Amine and Metal

Catalysts 394942 Catalytic Systems Combining Broslashnsted Acid and Metal

Catalysts 404943 Catalytic Systems Combining Hydrogen-Bonding Donor

and Metal Catalysts 411944 Catalytic Systems Combining Other Organo- and Metal

Catalysts 41395 Summary and Outlook 415References 415

index 419

xi

ContRiButoRs

Hongyin gao Shanghai Key Laboratory of Green Chemistry and Chemical Processes and Department of Chemistry East China Normal University Shanghai PR China

liu-Zhu gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China

Jun Jiang Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry University of Science and Technology of China Hefei PR China

Hexing li Department of Chemistry Shanghai Normal University Shanghai PR China

Jun-Bing ling State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China

Ping lu Department of Chemistry Zhejiang University Hangzhou PR China

aiguo song Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico

yanguang Wang Department of Chemistry Zhejiang University Hangzhou PR China

yanzhao Wang Department of Chemistry and Biochemistry University of California Santa Barbara California

Wei Wang Department of Chemistry and Chemical Biology University of New Mexico Albuquerque New Mexico School of Pharmacy East China University of Science and Technology Shanghai PR China

xii CONTRIBUTORS

yao Wang State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China

Hao Wei State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China

Peng-Fei Xu State Key Laboratory of Applied Organic Chemistry College of Chemistry and Chemical Engineering Lanzhou University Lanzhou PR China

Fang Zhang Department of Chemistry Shanghai Normal University Shanghai PR China

Junliang Zhang Shanghai Key Laboratory of Green Chemistry and Chemical Processes Department of Chemistry East China Normal University Shanghai PR China

liming Zhang Department of Chemistry and Biochemistry University of California Santa Barbara California

xiii

PReFaCe

The state of the art of synthetic organic chemistry is such that given sufficient labor materials and financial resources it is possible to construct almost any isolated and designed organic molecule In light of increasing concerns related to chemical hazards pollution and sustainability the development of new synthetic strategies and concepts that can substantially improve resource efficiency avoid the use of toxic reagents and reduce waste and hazardous by-products has become essential in the practice of chemical synthesis Cascade processes that incorporate multiple bond-forming events carried out in one pot have come into play By definition during a cascade process only a single reaction solvent workup procedure and purification step is required thus increasing synthetic efficiency significantly This strategy has been the subject of intensive study as evidenced by the appearance of numerous reviews and books Two excellent books Domino Reactions in Organic Synthesis (L F Tietze G Brasche and K M Gericke Wiley-VCH Weinheim Germany 2006) and Metal Catalyzed Cascade Reactions (T J J Muumlller Springer New York 2006) have been written to summarize this dynamic field In the recent past we have also witnessed significant progress in developing new cascade reactions particularly catalytic versions Catalytic cascade reactions have become one of the most active research areas in modern organic syn-thesis New catalytic systems such as organo- and gold and platinum catalysis have emerged and been employed in cascade processes In addition new and impressive achievements have been reported in organometallic-catalyzed cascade reactions This book is a natural outcome of those developments

The first three chapters focus on organocatalytic cascade reactions including amines and Broslashnsted acids and the use of organocatalytic cascade reactions in natural product synthesis and drug discovery Subsequent chapters introduce new develop-ments and progress in transition metal cascade catalysis Gold- and platinum-catalyzed

xiv PREFACE

cascade reactions are discussed in depth and the progress in other transition metalndashcatalyzed cascade reactions (eg ruthenium iron iridium rhodium palladium copper) has been updated extensively A full chapter is devoted to the application of transition metalndashcatalyzed cascade reactions in natural product synthesis and drug discovery Finally an emerging field exploratory multiple-catalyst-promoted cascade reactions has been introduced

The book consists of contributions from a group of outstanding expert scientists who have made significantly original contributions in their fields We are grateful to all contributors for giving generously of their time and effort We would also like to acknowledge the support of many funding agencies worldwide as well as the debt to our families research groups and students We also thank the many chemists in this field who have developed the excellent science that constitutes the content of this book

Lanzhou PR China Peng-Fei Xu

Albuquerque New Mexico Wei Wang

Catalytic Cascade Reactions First Edition Edited by Peng-Fei Xu Wei Wang copy 2014 John Wiley amp Sons Inc Published 2014 by John Wiley amp Sons Inc

1

aMine-CatalyZed CasCade ReaCtions

Aiguo Song and Wei Wang

1

11 Introduction 2

12 Enamine-activated cascade reactions 3121 Enaminendashenamine cascades 3

1211 Design of enaminendashenamine cascades 31212 Examples of enaminendashenamine and enaminendashenamine

cyclization cascades 31213 Enaminendashenamine in three-component cascades 61214 Enamine-activated double α-functionalization 71215 Robinson annulations 7

122 Enaminendashiminium cascades 81221 Design of enaminendashiminium cascades 81222 Examples of [4 + 2] reactions with enaminendashactivated dienes 81223 Inverse-electron-demand [4 + 2] reactions with

enamine-activated dienophiles 131224 Enaminendashiminiumndashenamine cascades 16

123 Enamine catalysis cyclization 191231 Design of enamine-cyclization cascade reactions 191232 Enamine-intermolecular addition cascades 191233 Enamine-intramolecular addition cascades 201234 Enamine-intramolecular aldol cascades 21

13 Iminium-initiated cascade reactions 21131 Design of iminiumndashenamine cascade reactions 21132 Iminium-activated DielsndashAlder reactions 22133 Iminium-activated sequential [4 + 2] reactions 24134 Iminium-activated [3 + 2] reactions 25135 Iminium-activated sequential [3 + 2] reactions 27136 Iminium-activated [2 + 1] reactions 30

2 AMINE-CATALYZED CASCADE REACTIONS

11 intRoduCtion

Chiral amine-mediated organocatalytic cascade reactions have become a benchmark in contemporary organic synthesis as witnessed by a number of cascade processes devel-oped in the past decade [1] The great success is attributed to two unique interconvertible activation modes enamine [2] and iminium activations [3] Enamine catalysis has been widely applied to the α-functionalizations of aldehydes and ketones Mechanistically dehydration between a chiral amine and the carbonyl of an aldehyde or ketone generates an intermediate 2 which undergoes an enantioselective α-substitution or nucleophilic addition reaction to produce respective iminium intermediate 3 or 5 (Scheme 11) Hydrolysis affords the products and meanwhile releases the chiral amine catalyst

sCHeMe 11 Enamine-catalyzed nucleophilic substitution (a) and addition (b) reactions

(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2

1361 Iminium-activated cyclopropanations 301362 Iminium-activated epoxidations 321363 Iminium-activated aziridinations 34

137 Iminium-activated multicomponent reactions 35138 Iminium-activated [3 + 3] reactions 37

1381 Iminium-activated all-carbon-centered [3 + 3] reactions 371382 Iminium-activated hetero-[3 + 3] reactions 40

139 Other iminium-activated cascade reactions 42

14 Cycle-specific catalysis cascades 42

15 Other strategies 45

16 Summary and outlook 46

References 46

ENAMINE-ACTIVATED CASCADE REACTIONS 3

Correspondingly iminium catalysis involves nucleophilic addition to the b-position of an iminium species 8 derived from an αb-unsaturated aldehyde or ketone 7 with an amine catalyst (Scheme 12)

12 enaMine-aCtivated CasCade ReaCtions

We define the cascade reactions initiated by enamine catalysis in the initial step as an enamine-activated mode although an iminium mode might be involved in the following steps In this regard several catalytic cascade sequences including enaminendashenamine enaminendashiminium and enamine cyclization are discussed here

121 enaminendashenamine Cascades

1211 Design of EnaminendashEnamine Cascades Three possible active sites (eg carbonyl group nucleophilic α- and Y-positions) of enamine catalysis product 4 or 6 (Figure 11) can be further functionalized via a second enamine process in a cascade manner Taking advantage of the electrophilic carbonyl in 4 and 6 intermolecular enaminendashenamine (Scheme 13a) and enaminendashenamine cyclization (Scheme 13b) cascades could be possible In addition the α-position of the same (Scheme 13c) or different (Scheme 13d eg Robinson annulation) carbonyl group can be subjected to a second enamine process

1212 Examples of EnaminendashEnamine and EnaminendashEnamine Cyclization Cascades Inspired by a 2-deoxyribose-5-phosphate aldolase (DERA)ndashcatalyzed double-aldol sequence using only acetaldehyde to afford cyclized trimer 23

H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1

sCHeMe 12 Iminium catalysis

R

O

R1

X

4

Electrophilicattacked by

enamine Nucleophilicformation of

enamine

R

O

R1

X

6



enamine

YH

Nucleophilic

FiguRe 11 Possible sites of enamine catalysis products for a second enamine-activated process


sCHeMe 13 Design of enaminendashenamine cascade catalysis

(a) Intermolecular enaminendashenamine catalysis

H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4

(b) Intermolecular enaminendashenamine catalysis and cyclization

H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH

(c) Double-enamine catalysis at the same site

H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E

(d) Robinson annulation

R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2


(Scheme 14) [4] Coacutedova et al conducted l-proline-catalyzed direct asymmetric self-aldolization of acetaldehyde furnishing a triketide 24 instead of trimer 23 with 90 ee and 10 yield for the first time [5]

The mechanism proposed suggested that an enamine was involved in an Re-facial attack of the carbonyl group of acetaldehyde (Scheme 15) After the carbonndashcarbon bond-forming step the resulting reactive iminium ion instead of being hydrolyzed underwent a Mannich type of condensation [6] to give 24

Although the formation of hemiacetal 23 from acetaldehyde did not result from the use of l-proline trimeric aldol product 25 was obtained in 12 isolated yield with propionaldehyde [7] Slow addition of propionaldehyde to the reaction produced 25 in a significantly improved yield (53) as a 1 8 mixture of diastereomers (Scheme 16) Subsequent oxidation of the product enabled the synthesis of lactone 26 with modest enantioselectivity (47 ee)

Reactions involving nonequivalent aldehydes were also examined When 2 equiv of propionaldehyde was added slowly over 24 h to acceptor aldehydes such as isobu-tyraldehyde or isovaleraldehyde lactones were formed as single diastereomers in moderate yields (20 to 30) and poor ee (12) Improved ee (25) was observed when the reaction was conducted in an ionic liquid [8]

It was problematic to obtain high enantioselectivity when these consecutive aldol reactions were conducted within a single catalytic system Two-step synthesis of

H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24

10 yield90 eeTHF 0 degC

5 h

sCHeMe 14 Aldolase- and proline-catalyzed self-aldolization of acetaldehyde

H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24

Mannich-type condensation

sCHeMe 15 Mechanism proposed for proline-catalyzed self-aldolization of acetaldehyde


similar products was developed In 2004 Northrup and MacMillan reported an elegant synthesis of hexoses based on a proline-catalyzed dimerization of protected α-oxyaldehydes followed by a tandem Mukaiyama aldol cyclization catalyzed by a Lewis acid (Scheme 17) [9] The products were obtained in modest to good yields with high diastereoselectivity (10 1 to 19 1) and enantioselectivity (95 to 99)

To improve the efficiency and selectivity of the tandem aldol process Coacuterdovarsquos group also isolated the b-hydroxyaldol intermediate from the first aldol transformation prior to the second aldol reaction The pure intermediate was subjected to the second aldol reaction with a different catalyst (Scheme 18) The two-step synthetic protocol made it possible to investigate both (l)- and (d)-catalysts in stereocontrol The synthesis of hexoses proceeded with excellent chemo- diastereo- and enantioselectivity In all cases except one the corresponding hexoses were isolated as single diastereomers with gt99 ee [10]

1213 EnaminendashEnamine in Three-Component Cascades As part of a continuing effort Chowdari et al reported l-proline-catalyzed direct asymmetric assembly reactions involving three different componentsndashaldehydes ketones and azodicarbox-ylic acid estersmdashto provide optically active functionalized b-amino alcohols in an enzyme-like fashion These are the first examples of using both aldehydes and ketones as donors in one pot (Scheme 19) [11]

L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO

TiCl4 CH2 Cl2ndash40 to ndash20 degC

O

TIPSO OAcOH

OH

28

TIPSO68ndash96 yieldabout 19 1 dr

95ndash99 ee

sCHeMe 17 Two-step synthesis of hexoses with organo- and Lewis acid catalysis

R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30

L-proline(or D-proline)

DMF

D-proline(or L-proline)

propionaldehydeDMF

15ndash42 yieldsingle diastereomer

gt 99 ee

sCHeMe 18 Two-step direct proline-catalyzed enantioselective synthesis of hexoses

H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h

sCHeMe 16 Proline-catalyzed assembly of propionaldehyde and conversion to lactone


1214 Enamine-Activated Double a-Functionalization Enders et al reported an organocatalytic domino Michael additionalkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene 33 involving enaminendashenamine activation (Scheme 110) [12] This process is highly stereoselective and leads to the γ-nitro aldehydes which contain an all-carbon-substituted quaternary stereo-genic center

Moreover enamine catalytic in situ sequences of acetaldehyde with two electrophiles can be envisioned (Scheme 111) The first successful realization of this concept with a proline-catalyzed double Mannich reaction of acetaldehyde with N-Boc-imines 36 was developed to give pseudo-C

2-symmetric bbprime-diaminoaldehydes

37 with extremely high stereoselectivities (gt99 1 dr gt99 ee) [13] A similar approach with ketones was also realized [14]

1215 Robinson Annulations A silica gelndashabsorbed amino acid salt (39)ndash catalyzed asymmetric intramolecular Robinson annulation reaction with 38 was developed (Scheme 112) A tricyclic ring structure 40 was obtained in 84 yield and up to 97 ee [15] Intermolecular Robinson annulations with structurally diverse aldehydes and unsaturated ketones were also developed [16]

O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32

L-prolineCH3CNrt 72 h

80 yield56 44 antisynup to gt 99 ee

sCHeMe 19 Proline-catalyzed three-component reaction

H

O

R I NO2+

33

DMSO rt

34 PhCO2H

41ndash62 yieldup to 99 1 drup to 97 ee

NH

Ph

OTMSPh

3435

O2N

R

CHO

sCHeMe 110 Organocatalytic domino reaction of aldehydes and (E)-5-iodo- 1-nitropent-1-ene

H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37

L-prolineCH3CN 0 degC to rt

18ndash24 h

up to 90 yieldgt99 1 drgt99 ee

sCHeMe 111 Double Mannich reactions of acetaldehyde


122 enaminendashiminium Cascades

1221 Design of EnaminendashIminium Cascades Similar to an enaminendashenamine activation sequence a subsequent iminium process is possible on 6 and 41 (Figure 12)

A special but significant case of 6 is that of the αb-unsaturated ketones 41 (R is a vinyl group) An intramolecular attack on the αb-unsaturated carbonyl group of 41 by nucleophilic Y can be envisioned in an iminium activation process (Scheme 113a) The formation of 42 through an enaminendashiminium sequence can also be viewed as a DielsndashAlder reaction between intermediate 43 and the electrophile (Scheme 113b)

In principle simple intermediate 6 can undergo a similar intramolecular iminium process with an electrophilic carbonyl group However the resulting four-membered ring is too small to be formed from the attack of carbonyl by nucleophilic Y Prolongation of electrophile 44 is necessary (Scheme 114) Nucleophilic 12-addition to the iminium ion 45 resulting from the first enamine catalysis furnishes 46 which is then hydrolyzed to afford 47 (Scheme 114a) The overall reaction sequence can also be considered to be a [4 + 2] reaction between activated dienophiles 2 and 44 (Scheme 114b)

1222 Examples of [4 + 2] Reactions with Enamine-Activated Dienes It is well known that DielsndashAlder reactions can usually be regarded as double Michael

O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4

sCHeMe 112 Amino acid saltndashcatalyzed intramolecular Robinson annulation

R

O

R1

R1

R2X

6

Nucleophilichindered

YH

Nucleophilicattack

iminium ion

Electrophiliciminiumion for

12-addition

R = H aliphatic or aromatic groups

O

X

41

YH

Nucleophilicattack

iminium ion


14-addition


FiguRe 12 Design of enaminendashiminium cascade catalysis


reactions although concerted mechanisms are always proposed for these reactions Thus the enaminendashiminium activation sequence has been used in [4 + 2] cycloaddition reactions

In addition to the consecutive aldol reactions of aldehydes Barbasrsquos group also reported enamine-activated DielsndashAlder reactions (or double Michael reactions) between αb-unsaturated ketones and nitroolefin (Scheme 115) for the first time in 2002 [17] In contrast to MacMillanrsquos iminium catalysis for DielsndashAlder reactions wherein αb-unsaturated carbonyl compounds were activated as dienophiles in a LUMO-lowering strategy based on iminium formation [3] an alternative strategy involving the in situ generation of 2-amino-13-dienes from αb-unsaturated ketones

sCHeMe 113 Design of an enaminendashiminium cascade with enones

(a) Double-addition reactions via enaminendashiminium

O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y

(b) [4 + 2] Reactions with HOMO-raising dienes

R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y

sCHeMe 114 Design of an enaminendashiminium sequence based on 6 and 44

(a) Double-addition reactions via enaminendashiminium cascade

R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46

(b) [4 + 2] Reactions with activated dienophiles

acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44


was developed in a HOMO-raising fashion Either (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine or l-proline catalyzed the in situ formation of 2-amino-13-dienes 53 to provide cyclohexanone derivatives 51 and 52 in good yield (up to 87) in one step with modest enantioselectivity (up to 38 ee)

On another occasion Barbasrsquos group developed the first organocatalytic diastereospecific and enantioselective direct asymmetric domino Knoevenagel DielsndashAlder reactions that produce highly substituted spiro[55]undecane-159- triones 57 from commercially available 54 aldehydes 55 and 22-dimethyl- 13-dioxane-46- dione 56 (Scheme 116) [18] Among the catalysts screened 55-dimethyl thiazolidinium-4-carboxylate (DMTC) proved to be the optimal catalyst with respect to yield and provided 57 in 88 yield and 86 ee Up to 93 yield and 99 ee were observed when the reaction was extended to other substrates It is noteworthy that the product 57 was accompanied by a trace amount of the unexpected symmetric spirocyclic ketone 58

O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee

sCHeMe 116 Amino acidndashcatalyzed asymmetric three-component DielsndashAlder reaction

R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline

up to 87 yieldup to 8 1 dr

38 ee

R2 NO2

R1R2

NO2

N

R1

N

53

sCHeMe 115 Enamine-activated dienes for DielsndashAlder reactions


The mechanism proposed is summarized in Scheme 117 Knoevenagel reaction between aldehyde 55 and 22-dimethyl-13-dioxane-46-dione 56 will provide the dienophile for subsequent DielsndashAlder reaction with the reactive diene produced from 54 Then the intermediate 60 was hydrolyzed to produce the product desired and to release the catalyst

The asymmetric domino three-component KnoevenagelDielsndashAlder addition reaction promoted by the primary amine catalyst 9-amino-9-deoxy-epi-quinine was also reported Various pharmacological multisubstituted spiro[55]undecane-159-triones were obtained in moderate to good yields (up to 81) with excellent diastereo- (gt99 1 dr) and enantioselectivities (up to 97 ee) [19] The enamine-mediated DielsndashAlder reactions of αb-unsaturated ketones were also extended to nitroalkenes [20] and 3-olefinic oxindoles [21]

Inspired by the unexpected formation of symmetric 58 Ramachary and Barbas extended the synthesis of polysubstituted spirotriones to more complex systems through an aldolKnoevenagelDielsndashAlder reaction sequence in one pot (Scheme 118) [22] The DielsndashAlder product desired was obtained as a single dia-stereomer in moderate yield accompanied by some by-products

O O

O O

Ar H

O

+

55

56

KnoevenagelreactionO

O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph

sCHeMe 117 Mechanism of a secondary amine-catalyzed asymmetric three-component DielsndashAlder reaction

OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58

sCHeMe 118 Pyrrolidine-catalyzed stereospecific multicomponent aldolKnoevenagelDielsndashAlder reaction


The formation of these by-products could be avoided by changing acetone to Wittig reagent 61 It was found that DielsndashAlder product 62 could be obtained in 99 yield as a single diastereomer (Scheme 119)

Use of proline-catalyzed five-component cascade olefinationDielsndashAlderepimerizationolefinationhydrogenation reactions of enones aryl aldehydes alkyl cyanoacetates and Hantzsch ester to furnish highly substituted 66 in a highly diaste-reoselective fashion (99 de) with excellent yields (70 to 75) was also reported (Scheme 120) [23]

The possible reaction mechanism for a cascade olefinationndashhydrogenation reaction is illustrated in Scheme 121 First the reaction of proline with cis-isomer 67 gener-ates the iminium cation 68 which reacts with electrophile 64 via a Mannich-type reaction to generate Mannich product 69 A retro-Mannich or base-induced elimina-tion reaction of amine 69 would furnish active olefin 70 The subsequent hydrogen-transfer reaction is dependent on the electronic nature of the in situndash generated conjugated system or more precisely the HOMOndashLUMO gap of reactants 65 and 70

The strategy was extended to a tandem o-nitroso aldolndashMichael reaction with cyclic αb-unsaturated ketones to produce enantiopure nitroso DielsndashAlder adducts 74 in moderate yields (Scheme 122) [24]

Similarly the first direct catalytic enantioselective aza-DielsndashAlder reaction was also accomplished with excellent stereoselectivity (94 to 99 ee) (Scheme 123) [25]

O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr

sCHeMe 119 WittigKnoevenagelDielsndashAlder reaction

O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1

sCHeMe 120 Cascade olefinationDielsndashAlderepimierizationolefinationhydrogenation reactions


1223 Inverse-Electron-Demand [4 + 2] Reactions with Enamine-Activated Dienophiles In contrast to the Barbas grouprsquos ingenious design of DielsndashAlder reactions using enamine-activated dienes Joslashrgensen envisioned that chiral enamines could act as electron-rich dienophiles and undergo an enantioselective inverse- electron-demand hetero-DielsndashAlder reaction (Scheme 124) [26]

NO

RO R

NH HN N

NN

74 73

73CH3CN

40 degC15 h50ndash64 yield

98ndash99 ee

O

R R

NO

71 72

+

sCHeMe 122 o-Nitroso aldolndashMichael reactions

(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +

sCHeMe 123 Amine-catalyzed direct enantioselective aza-DielsndashAlder reaction

L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64

sCHeMe 121 Mechanism proposed for proline-catalyzed olefinationndashhydrogenation reactions


The mechanism proposed involved in situ generation of a chiral enamine 81 from a chiral pyrrolidine 78 and the aldehyde 76 (Scheme 125) followed by a stereoselective hetero-DielsndashAlder reaction with enone 77 to give aminal 82 The presence of silica facilitates the hydrolysis step in the catalytic cycle

OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79

sCHeMe 125 Catalytic cycle for an organocatalytic hetero-DielsndashAlder reaction

O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC

62ndash93 yieldgt100 1 dr

up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3

sCHeMe 124 Organocatalytic hetero-DielsndashAlder reaction

Inverse-electron-demand hetero-DielsminusAlder reaction of enolizable aldehydes with αb-unsaturated ketophosphonates [27] o-quinones [28] α-keto-αb-unsaturated esters [29] αb-unsaturated trifluoromethyl ketones [30] and o- benzoquinone diimide [31] was also reported

Encouraged by Joslashrgensenrsquos inverse-electron-demand hetero-DielsndashAlder reaction of aldehydes and αb-unsaturated α-keto esters Han He and others envisaged that an unprecedented asymmetric aza-DielsndashAlder reaction of N-sulfonyl-1-aza-13-butadienes and aldehydes might be developed by employing a similar strategy They found that the process proceeded with a chiral secondary amine 34 (Scheme 126) [32] Excellent enantioselectivities (up to 99 ee) were observed for a broad spectrum of substrates under mild conditions

Inspired by dienamine catalysis in inverting the inherent reactivity of αb-unsaturated aldehydes which acted as nucleophiles for direct enantioselective γ-amination with



Edited by











2013011112


10 9 8 7 6 5 4 3 2 1

v

Contents

Contributors xi

Preface xiii









vi CONTENTS













CONTENTS vii















viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3













2013011112


10 9 8 7 6 5 4 3 2 1

v

Contents

Contributors xi

Preface xiii









vi CONTENTS













CONTENTS vii















viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





v

Contents

Contributors xi

Preface xiii









vi CONTENTS













CONTENTS vii















viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





vi CONTENTS













CONTENTS vii















viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





CONTENTS vii















viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





viii CONTENTS












CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





CONTENTS ix














x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





x CONTENTS















index 419

xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





xi

ContRiButoRs











xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





xii CONTRIBUTORS







xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





xiii

PReFaCe



xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





xiv PREFACE






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3






1



1

11 Introduction 2









11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3






11 intRoduCtion



(a)

H2OR

O

R1

1

R

O

X

4

NH

ndashH2O

R

N

R1

2

X Y

ndashY

R

N

R1 R1

X

3

(b)

H2OR

O

R1

1

R1

R

O

X

6

YH

R1

R

N

X

5

YNH

ndashH2O

X YR

N

R1

2








References 46








H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3












H2OR

O

7

R1 R

O

10

R1

NuNH

R

N Nu

8R1 R

N

9

Nu

R1


R

O

R1

X

4



enamine

R

O

R1

X

6



enamine

YH

Nucleophilic





H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3








H2O

R1 R1

R

N

XOR

14

R1R1

R

O

XOHR

15

R

N

R1 R1

R

O

X

2 4


H2O

R1R1R

OX

OHR

12

YHR1

R1

YX

HO

R

R OH

13

R1R1R

NX

OR

11

YH

R1 R1R

N

R

OX

2 6

YH


H2O

R1

R

O

18

E

E

R1

R

O

E

4 or 6

ndashH2O

NH

R1

R

N

E E

16

R1

R

N

17

E

E


R1

R

O

1R1

R4

R5

R

O

20

O

R1

R4

R5

O

R

22

R5

R4

O

19

then H2O

R1

R4

R5

R

O

21

N

ndashH2O

NH

ndashH2ONH

R1

R

N

2







H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3











H

O3

DERA O

OH

OH

H

O3

L-proline

H

OOH

23

24


5 h


H

O

+NH

O

OH

ndashH2O

N

O

OH

N

HO

HO

O

N

O

OOH24







L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3









L-proline

H

O

OTIPS27

H

O

OTIPS

OHOTIPS

OAc

H

Me3SiO


O

TIPSO OAcOH

OH

28


95ndash99 ee


R H

O+

H

O

R1

29

R1

R H

OOHO

OH

R1

R O H

30


DMF


propionaldehydeDMF


gt 99 ee


H

O3 MnO2

EtOAc rt48 h

O

OH

HO

25

O

OH

O

2653 yield

8 1 dr

L-proline

DMF 4 degC10 h








O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3











O

H

O

Me

N

N

Cbz

Cbz

+ +

31

O

NCbz

HNCbz

Me

OH

32




H

O

R I NO2+

33

DMSO rt

34 PhCO2H


NH

Ph

OTMSPh

3435

O2N

R

CHO


H

O N

RH

Boc

+

36

R R

CHO

NH HNBoc Boc

37


18ndash24 h









O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3











O

CHO

38

39

rt 5 d

84 yield97 ee

OH

40

NH2

O

O

39

Nn-Bu4


R

O

R1

R1

R2X

6


YH

Nucleophilicattack

iminium ion


12-addition


O

X

41

YH

Nucleophilicattack

iminium ion


14-addition








O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3










O

R1

X

YH

R

H2O R1

O

XR Y

42

NH

R1

N

X

YH

R

R1

N

XR Y


R1

O

R

H2O

O

X

R1

R Y

42

NH

R1

R1

N

R

X

Y

43

N

XR Y



R

O

R1

1

acid R1

R4

R3Z

OHR

47

NH

ndashH2O R1

R2 R3

R

N

2

Z

44

R1R2

R3

R

N

45

ZZ

NR1

R2

R3 R

46


acid R1R3

R2

Z

OHR

47

Z

NR1 R3

R2

R

46

R

N

R1

R3

R2

2

Z

44




O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3








O

Ph +

NO2

CHO

+

O O

O O

54 55 56

OO

OO

O

Ar

Ph

57

OO

OO

O

Ar

Ar

58

+

Ar = 4 - NO2 - Ph

(DMTC)

S

NH

CO2H

MeOHrt

88 yieldgt 100 1 dr

86 ee


R1 R1 R2R2

NO2 NO2

O O

51 52

+

NH

N

50

R2 NO2+

O

R148 49

NH

50 orL-proline


38 ee

R2 NO2

R1R2

NO2

N

R1

N

53






O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3









O O

O O

Ar H

O

+

55

56


O

O

OAr

O

NH

RR

NRR

Ph

N

Ph

Ar

RR

OO

O

O

O

Ph

Ar

OO

O

O

DielsndashAlder 57

54

60

59

Ph


OAr

O

H

ArO

H O

OO

O

+

NH

Ar = 4-NO2C6H4

O

ArO

Ar

Ar

O

O

O

O

O

Ar

OH

O Ar

O

O

O

O

+

+ +

58








O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3











O O

H

Ph

Ph

O

HO

OO

O

+

P

Ph

Ph

Ph

61 O

Ph

Ph

O

O

O

O62

L-proline

C6H6 MeOH65 degC

99 yieldgt100 1 dr


O

ArNC

O

NC

O

Ar H

O

NH

HH+

L-proline

DMSO70ndash75 yield

99 de

Ar

Ar

CN

NC

66

63

64 65

CO2EtEtO2C

R2O2C

CO2R1

OR2

OR1




NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3







NO

RO R

NH HN N

NN

74 73

73CH3CN


98ndash99 ee

O

R R

NO

71 72

+


(S)-proline

DMSO 50 degC24 h

82 yield99 ee

N

O

75 O

O NH2

H

O

H

O

+ +


L-proline

O

Ar Ar

CO2R1NC

67CO2R1

CO2R2

CO2H

Ar

NC

Ar

N

CN

69

Ar Ar

CO2R1

CO2R2

NC

NC

70

Ar Ar

CO2R1

CO2R2

NC

NC

66

CO2

Ar Ar

CO2R1

CO2R2

NC

NH

CNHndash L-proline

EtO2C

EtO2C

NHH

H

65

CO2R1

OR2CO2

Ar Ar

NC

N

CN

O

68

H

64




OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3







OO

Ph

76

silicaON

PhO

Ph

NH

N

HO

H2O

H2O

CO2Me

CO2Et

CO2Et

77

81

78

82

79


O

i-Pr

+

CO2MeO

Ph

76 77

78

Silica

CO2EtOHO

Pri

Ph

79

PCC


up to 94 ee

CO2EtOO

i-Pr

Ph

NH Ar

Ar

7880

Ar = 35-(CH3)2C6H3





9781118016022 · 2013-10-07 · 1.2.1.2 examples of enamine–enamine and enamine–enamine...

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