Edited by

Krishna C. Majumdar and

Shital K. Chattopadhyay

Heterocycles in Natural Product Synthesis

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Edited by Krishna C. Majumdar and Shital K. Chattopadhyay

Heterocycles in Natural Product Synthesis

The Editors

Prof. Krishna C. MajumdarUniversity of KalyaniDepartment of ChemistryKalyani, W.B. 741235Indien

Prof. Shital K. ChattopadhyayUniversity of KalyaniDepartment of ChemistryKalyani, W.B. 741235Indien

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V

Contents

Preface XV List of Contributors XVII

Part One Strained Heterocycles in the Synthesis of Natural Products 1

1 Aziridines in Natural Product Synthesis 3Candice Botuha, Fabrice Chemla, Franck Ferreira and Alejandro Pérez-Luna

1.1 Introduction 31.2 Synthesis of Natural Products Containing

Aziridine Units 31.2.1 Synthesis of Aziridine-2,3-Dicarboxylic Acid 31.2.2 Synthesis of (Z)-Dysidazirine 51.2.3 Syntheses of Mitomycins 51.2.4 Syntheses of FR-900482 and FR-66979 81.3 Synthesis of Natural Products Involving the Transformation of an

Aziridine Moiety 101.3.1 Nucleophilic Ring-Opening of Aziridines for Natural

Product Synthesis 101.3.1.1 Carbon-Centered Nucleophiles 111.3.1.2 Nitrogen-Centered Nucleophiles 151.3.1.3 Oxygen-Centered Nucleophiles 181.3.1.4 Halogen Nucleophiles 241.3.1.5 Reductions 251.3.2 Cycloaddition Reactions and Rearrangements 251.3.2.1 Aziridines in [3 + 2] Cycloadditions 261.3.2.2 Aziridines in [2,3]-Wittig Rearrangements 271.3.2.3 Aziridines in Iodide-Mediated Rearrangements 271.3.2.4 Aziridines in Miscellaneous Rearrangements 281.3.3 Synthesis of Natural Products Involving the Transformation of an

Aziridinium Moiety 31

VI Contents

1.4 Conclusion 32 References 33

2 Azetidine and Its Derivatives 41Hidemi Yoda, Masaki Takahashi and Tetsuya Sengoku

2.1 Introduction 412.2 Structural Description of Azetidines 412.3 Synthetic Methodologies for the Formation of Azetidine Rings 432.4 Synthesis of Mugineic Acids 442.5 Synthesis of Penaresidins 462.6 Structural Description of Azetidin-2-ones 502.7 Synthetic Methodologies for the Formation of Azetidin-2-ones 502.8 Synthesis of Penicillin 522.9 Synthesis of Cephalosporin 542.10 Conclusion 56 Acknowledgment 56 References 57

3 Epoxides and Oxetanes 63Biswanath Das and Kongara Damodar

3.1 Introduction 633.2 Epoxides in Natural Product Synthesis 633.2.1 Synthesis of Natural Products Possessing an Epoxide Moiety 683.2.1.1 Synthesis of (−)-Posticlure 683.2.1.2 Synthesis of Natural Polyethers 683.2.1.3 Synthesis of (+)-11,12-Epoxysarcophytol A 683.2.1.4 Synthesis of (−)-Scyphostatine 683.2.1.5 Synthesis of Arenastatin A 703.2.1.6 Synthesis of (+)-Ambuic Acid 703.2.1.7 Total Synthesis of Epocarbazolin A 713.2.1.8 Synthesis of Multiplolide A 713.2.2 Synthesis of Natural Products Involving the Transformation

of the Epoxide Moiety 713.2.2.1 Synthesis of Dodoneine 713.2.2.2 Synthesis of (−)-Pericosin B 733.2.2.3 Synthesis of (−)-Peucedanol 733.2.2.4 Synthesis of (+)-Bourgeanic Acid 743.2.2.5 Synthesis of (6S)-5,6-Dihydro-6([2R]-2-Hydroxy-6-Phenylhexyl)-2H-

Pyran-2-one 743.2.2.6 Synthesis of Verbalactone 743.2.2.7 Synthesis of (2S, 3S)-(+)-Aziridine-2,3-Dicarboxylic Acid 753.2.2.8 Synthesis of d-erythro-Sphingosine 753.2.2.9 Synthesis of (+)-L-733,060 763.2.2.10 Synthesis of (+)-Chelidonine 763.2.2.11 Synthesis of (−)-Pironetin 76

Contents VII

3.2.2.12 Synthesis of (−)-Codonopsinine 773.2.2.13 Synthesis of Sesamin and Dihydrosesamin 773.2.2.14 Synthesis of (9S, 12R, 13S)-Pinellic Acid 783.2.2.15 Synthesis of (Z)-Nonenolide 783.2.2.16 Synthesis of (−)-Cubebol 793.2.2.17 Synthesis of (+)-Schweinfurthins B and E 793.2.2.18 Synthesis of (−)-Cleistenolide 803.2.2.19 Synthesis of Decarestricine J 803.2.2.20 Synthesis of (−)-Gloeosporone 823.2.2.21 Synthesis of (S)-Dihydrokavain 823.2.2.22 Synthesis of (−)-Phorocantholide-J 833.3 Oxetane in Natural Product Synthesis 853.3.1 Synthesis of Natural Products Possessing an Oxetane Moiety 853.3.1.1 Synthesis of Epi-oxetin 853.3.1.2 Synthesis of Dioxatricyclic Segment of Dictyoxetane 863.3.1.3 Synthesis of (−)-Merrilactone A 863.3.1.4 Total Synthesis of (+)-(Z)-Laureatin 873.3.1.5 Synthesis of Taxol 873.3.2 Synthesis of Natural Products Involving Transformation

of the Oxetane Moiety 883.3.2.1 Synthesis of Erogorgiaene 883.3.2.2 Synthesis of trans-Whiskey Lactone 883.3.2.3 Synthesis of (±)-Sarracenin 893.4 Conclusion 89 Acknowledgment 90 References 90

Part Two Common Ring Heterocycles in Natural Product Synthesis 97

4 Furan and Its Derivatives 99Alicia Boto and Laura Alvarez

4.1 Introduction 994.2 Natural Products Containing the Furan Ring 1004.2.1 Occurrence of Furan Rings in Natural Products 1004.2.2 Synthesis of Furans in Natural Products 1044.3 Furan Derivatives as Reagents in the Synthesis

of Natural Products 1064.3.1 Metallation 1074.3.2 Reduction and Oxidation 1114.3.3 Furan Derivatives as Electrophiles and Nucleophiles 1184.3.4 Furan in Cycloadditions 1244.3.4.1 [2 + 1], [2 + 2] and [3 + 2] Cycloadditions 1244.3.4.2 Diels–Alder ([4 + 2] Cycloadditions) 127

VIII Contents

4.3.4.3 [4 + 3], [6 + 4], [8 + 2] and [5 + 2] Cycloadditions 1334.3.5 Furan in Other Reactions 1364.3.6 Other Uses of Furan in Synthesis 1384.4 Summary 139 References 140

5 Pyran and Its Derivatives 153Hideto Miyabe, Okiko Miyata and Takeaki Naito

5.1 Introduction 1535.2 Application of Pyran Moieties in the Synthesis

of Natural Products 1585.2.1 2,6-Disubstituted Pyran Natural Products 1585.2.2 2,6-Cyclic Pyran Compounds 1615.2.3 Complex Pyran Natural Products 1655.2.4 Fused Pyran Compounds with Aromatic Rings 1685.2.5 Fused Pyran Compounds with Aliphatic Rings 1715.3 Conclusion 176 References 176

6 Pyrrole and Its Derivatives 187Dipakranjan Mal, Brateen Shome and Bidyut Kumar Dinda

6.1 Introduction 1876.2 Synthesis of Pyrrole Natural Products 1936.2.1 Monopyrrolic Natural Products 1936.2.2 Dipyrrolic Natural Products 2036.2.3 Tripyrrolic Natural Products: Prodigiosins 2056.3 Synthesis of Non-pyrrole Natural Products from

Pyrrole Derivatives 2096.4 Conclusion 214 Acknowledgments 214 References 215

7 Indoles and Indolizidines 221Sarah M. Bronner, G.-Yoon J. Im and Neil K. Garg

7.1 Introduction 2217.2 Applications of Indoles and Indolizidines in the Synthesis

of Natural Products 2227.2.1 Indoles and Oxindoles 2227.2.1.1 Total Synthesis of Actinophyllic Acid (Overman) 2227.2.1.2 Total Synthesis of Dragmacidin F (Stoltz) 2267.2.1.3 Total Synthesis of Penitrem D (Smith) 2307.2.1.4 Total Synthesis of Welwitindolinone A Isonitrile (Baran, Wood) 2327.2.2 Indolines 2377.2.2.1 Total Synthesis of 11,11′-Dideoxyverticillin A

(Movassaghi) 237

Contents IX

7.2.2.2 Total Synthesis of Minfi ensine (Overman, Qin, MacMillan) 2407.2.2.3 Total Synthesis of Norfl uorocurarine (Vanderwal) 2457.2.2.4 Total Synthesis of Psychotrimine (Baran) 2477.2.3 Indolizidines 2497.2.3.1 Total Synthesis of Myrmicarins 215A, 215B and 217

(Movassaghi) 2497.2.3.2 Total Synthesis of Serratezomine A (Johnston) 2527.3 Conclusion 254 Acknowledgment 254 References 254

8 Pyridine and Its Derivatives 267Paula Kiuru and Jari Yli-Kauhaluoma

8.1 Introduction 2678.2 Application of the Pyridine Moiety in the Synthesis

of Natural Products 2688.2.1 Pyridines 2688.2.1.1 Synthesis of Noranabasamine Enantiomers 2688.2.1.2 Synthesis of Quaterpyridine Nemertelline 2688.2.1.3 Synthesis of Caerulomycin C 2768.2.1.4 Synthesis of the Spongidine Isomer 2778.2.2 2-Alkylpyridines 2788.2.2.1 Synthesis of Montipyridine 2788.2.2.2 Synthesis of Piericidin A1 2788.2.3 3-Alkylpyridine, 3-Alkylpyridinium and 3-Alkyltetrahydropyridine

Compounds 2818.2.3.1 Synthesis of Xestamines 2818.2.3.2 Synthesis of Pyrinadine A 2828.2.3.3 Synthesis of Pyrinodemin A 2828.2.3.4 Synthesis of Haliclamine A 2848.2.4 Piperidines 2858.2.4.1 Synthesis of Coniine and Pipecoline 2858.2.4.2 Synthesis of Stenusine 2868.2.5 Pyridones 2878.2.5.1 Synthesis of (±)-Cytisine 2878.2.5.2 Synthesis of Iromycin A 2888.3 Conclusion 289 Acknowledgment 289 References 290

9 Quinolines and Isoquinolines 299Antonio Garrido Montalban

9.1 Introduction 2999.2 Application of Quinolines and Isoquinolines

in the Synthesis of Natural Products 300

X Contents

9.2.1 Quinoline-Containing Natural Products 3089.2.1.1 Quinine 3089.2.1.2 Sandramycin 3119.2.1.3 Lavendamycin 3139.2.2 Isoquinoline-Containing Natural Products 3179.2.2.1 Morphine 3179.2.2.2 Emetine 3209.2.2.3 Protoberberines 3269.2.2.4 Nitidine 3319.3 Conclusion 332 References 332

10 Carbazoles and Acridines 341Konstanze K. Gruner and Hans-Joachim Knölker

10.1 Introduction to Carbazoles 34110.2 Total Synthesis of Carbazole Alkaloids 34110.2.1 Palladium-Catalyzed Synthesis of Carbazoles 35010.2.1.1 Total Synthesis of Pityriazole 35010.2.1.2 Total Synthesis of Euchrestifoline and Girinimbine 35110.2.2 Iron-Mediated Synthesis of Carbazoles 35310.2.2.1 Total Syntheses of the Antiostatins 35310.2.2.2 Total Synthesis of R-(–)-Neocarazostatin B and Carquinostatin A 35510.2.3 Total Syntheses of Ellipticine and Staurosporinone 35610.2.3.1 Synthesis of Ellipticine 35610.2.3.2 Synthesis of Staurosporinone 35710.3 Introduction to Acridines 35810.4 Synthesis of Acridines and Acridones 36110.4.1 Total Synthesis of Acronycine 36110.4.2 Synthesis of Amsacrine 36210.4.3 Total Syntheses of Amphimedine 362 References 364

11 Thiophene and Other Sulfur Heterocycles 377Krishna C. Majumdar and Shovan Mondal

11.1 Introduction 37711.2 Synthesis of Natural Products Containing Thiophene 37811.2.1 Synthesis of Natural Products from

Thiophene-Based Substrates 37811.2.2 Synthesis of Natural Products by Construction

of the Thiophene Nucleus 38611.3 Synthesis of Natural Products Containing Other

Sulfur Heterocycles 39311.4 Conclusion 395 Acknowledgments 396 References 397

Contents XI

12 Oxazole and Its Derivatives 403David W. Knight

12.1 Introduction 40312.2 Mono-Oxazoles 40412.2.1 Pimprinin 40412.2.2 Texamine and Relatives 40512.2.3 Synthesis of Sulfomycin Fragments 40612.2.4 Ajudazol A and B 40812.2.5 Rhizoxin 40912.2.6 The Calyculins 41012.2.7 Leucascandrolide A, B and Neopeltolide 41312.2.8 Chivosazole 41612.2.9 Madumycin II 41612.2.10 14,15-Anhydropristinamycin IIB 41812.2.11 Griseoviridin 41812.2.12 Thiangazole 41912.3 Unconnected Bis- and Tris-Oxazoles 42012.3.1 Disorazole C1 42012.3.2 Phorboxazoles 42112.3.3 Leucamide A 42412.3.4 Promothiocin A 42512.3.5 Berninamycin A 42512.4 Cyclic Polyheterocyclic Metabolites Containing Single

Oxazole Residues 42612.4.1 Dendroamide A 42612.4.2 Nostocyclamide 42712.4.3 Bistratamides 42812.4.4 Tenuecyclamides A–D 42812.4.5 Dolastatin I 42912.5 Conjugated Bis-Oxazoles 42912.5.1 (−)-Hennoxazole A 42912.5.2 Muscoride A 43212.5.3 Diazonamide A 43312.5.4 Bengazole A 43712.5.5 Siphonazole 43912.6 Tris- and Poly-Oxazoles 44012.6.1 Ulapualide A 44012.6.2 (R)-Telomestatin 44312.6.3 IB-01211 44512.6.4 YM-216391 445 References 446

13 Thiazoline and Thiazole and Their Derivatives 459Zhengshuang Xu and Tao Ye

13.1 Introduction 459

XII Contents

13.2 General Methods for the Synthesis of Thiazoline and Thiazole Derivatives 460

13.2.1 Methods for the Preparation of Thiazolines 46013.2.1.1 Using Vicinal Amino Thiols as Starting Materials 46113.2.1.2 From Vicinal Amino Alcohol 46813.2.1.3 Miscellaneous 47313.2.2 Methods for Preparation of Thiazoles 47413.2.2.1 Dehydrogenation of Thiazolines or Thiazolidines 47413.2.2.2 The Hantzsch Method and Its Modifi cations 47913.2.2.3 Alkylation of Thiazole or Thiazole Derivatives 48313.2.2.4 Miscellaneous 48313.3 Thiazole and Thiazoline-Containing Natural

Products 48513.3.1 Thiazoline and Thiazole Embedded in Polyketides 48513.3.2 Thiazoline and Thiazole Embedded in Peptides 49113.4 Conclusions 494 References 494

14 Pyrimidine and Imidazole 507Vipan Kumar and Mohinder P. Mahajan

14.1 General Introduction 50714.2 Pyrimidine-Based Natural Products 50714.2.1 Introduction 50714.2.2 Synthesis of Pyrimidine-Based Natural Products 50814.3 Imidazole-Based Natural Products 51814.3.1 Introduction 51814.3.2 Synthesis of Imidazole-Based Natural Products 52014.4 Conclusion 527 Acknowledgment 528 References 529

Part Three Natural Products Containing Medium and Large Ring-Sized Heterocyclic Systems 535

15 Oxepines and Azepines 537Darren L. Riley and Willem A.L. van Otterlo

15.1 Introduction 53715.2 Synthesis of the Heterocyclic Core of Selected Natural Products

Containing Oxepines 53815.3 Synthesis of the Heterocyclic Core of Selected Natural Products

Containing Azepines 54915.4 Synthesis of the Heterocyclic Core of Selected Natural Products

Containing Oxazapines 55915.5 Conclusion 561

Contents XIII

Acknowledgments 562 References 562

16 Bioactive Macrocyclic Natural Products 569Siti Mariam Mohd Nor, Zhengshuang Xu and Tao Ye

16.1 General 56916.2 Natural Products Containing Azoles 56916.2.1 Apratoxin A 56916.2.2 Halipeptins A and D 57216.2.3 Largazole 57316.2.4 Bistratamide H and Didmolamide A 57516.2.5 IB-01211 57616.2.6 (R)-Telomestatin 57816.3 Pyridine- and Piperidine-Containing Natural Products 58116.3.1 Micrococcin P1 58116.3.2 GE2270s 58416.4 Indole- and Imidazole-Containing Natural Products 58716.4.1 Celogentin C 58716.4.2 Complestatin (Chloropeptin II) 58916.5 Pyran- and Furan-Containing Natural Products 59016.5.1 Phorboxazole B 59016.5.2 Sorangicin A 59216.5.3 Kendomycin 59416.5.4 Bryostatin 16 59716.5.5 IKD-8344 59816.5.6 Deoxypukalide 59916.5.7 Norhalichondrin B 60116.6 Piperazic Acid-Containing Natural Products 60516.6.1 Piperazimycin A 60516.6.2 Azinothricin and Kettapeptin 60716.7 Mixed Heterocyclic Systems 60816.7.1 (−)-Nakadomarin A 60816.8 Conclusions 610 References 611

Index 621

XV

Preface

Heterocycles are signifi cant because of their biological activity and their applica-tions in diverse fi elds, refl ected by the fact that heterocycles constitute more than half of known organic compounds. Heterocyclic moieties are ubiquitous in impor-tant classes of naturally occuring compounds, for example, alkaloids, vitamins, hormones, and antibiotics. They are also widely prevalent in pharmaceuticals, herbicides, dyes and many other application - oriented materials.

Many natural products possess heterocyclic moieties, and many of them are important in terms of their biological activities and application in different fi elds; for example, “ taxol ” isolated from the yew tree is an anticancer drug.

To the best of our knowledge, there is currently no comprehensive publication which deals with systematic survey of literature on the heterocycles for the syn-thesis of natural products in the form of a ready reference. The present book is an attempt to bridge this gap. Emphasis has been given to the current literature while including the earlier literature as references. Different heterocycles are clas-sifi ed according to their ring size under different sections and subsections. Sources, synthetic aspects, relevant biological activities and important physical properties and applications of the natural products are described. Unfortunately not all the important heterocycles, such as coumarins and fl avones, could be included due to the restricted size of the book. However, available literature in these areas has already been adequately reviewed. This may be the subject of a future edition on the basis of the feedback of this edition received from the users.

We are grateful to our contributors for their valuable contributions which have made this project successful. We are also grateful to the members of our research groups for their untiring assistance during the course of this project. Finally we do hope that this will be a valuable secondary source book for the concerned readers.

K.C. Majumdar S.K. Chattopadhyay

XVII

List of Contributors

Laura Alvarez Universidad Aut ó noma del Estado de Morelos Centro de Investigaciones Qu í micas Avenida Universidad 1001 Col. Chamilpa 62209 Cuernavaca, Morelos Mexico

Alicia Boto Instituto de Productos Naturales y Agrobiolog í a CSIC Avda. Astrofi sico Fco. S á nchez, 3 38206 La Laguna, Tenerife Spain

Candice Botuha IPCM – UPMC Univ Paris 6 Case Courrier 183 4 place Jussieu 75252 Paris Cedex 05 France

Sarah M. Bronner University of California Department of Chemistry and Biochemistry 607 Charles Young Drive East, Box 951569 Los Angeles, CA 90095 - 1569 USA

Fabrice Chemla IPCM – UPMC Univ Paris 6 Case Courrier 183 4 place Jussieu 75252 Paris Cedex 05 France

Kongara Damodar Indian Institute of Chemical Technology Organic Chemistry Division - I Uppal Road Hyderabad 500007 India

Biswanath Das Indian Institute of Chemical Technology Organic Chemistry Division - I Uppal Road Hyderabad 500007 India

Bidyut Kumar Dinda Indian Institute of Technology Department of Chemistry Kharagpur W.B. 721302 India

XVIII List of Contributors

Franck Ferreira IPCM – UPMC Univ Paris 6 Case Courrier 183 4 place Jussieu 75252 Paris Cedex 05 France

Neil K. Garg University of California Department of Chemistry and Biochemistry 607 Charles Young Drive East, Box 951569 Los Angeles, CA 90095 - 1569 USA

Antonio Garrido Montalban Arena Pharmaceuticals, Inc. 6166 Nancy Ridge Drive San Diego, CA 92121 USA

Konstanze K. Gruner Technische Universit ä t Dresden Department Chemie Bergstr. 66 01069 Dresden Germany

G. - Yoon J. Im University of California Department of Chemistry and Biochemistry 607 Charles Young Drive East, Box 951569 Los Angeles, CA 90095 - 1569 USA

Paula Kiuru University of Helsinki Faculty of Pharmacy, Division of Pharmaceutical Chemistry PO Box 56 (Viikinkaari 5 E) FI - 00014 Helsinki Finland

David W. Knight Cardiff University School of Chemistry, Main College Park Place Cardiff CF10 3AT UK

Hans - Joachim Kn ö lker Technische Universit ä t Dresden Department Chemie Bergstr. 66 01069 Dresden Germany

Vipan Kumar Guru Nanak Dev University Department of Applied Chemistry Amritsar 143005 India

Mohinder P. Mahajan Guru Nanak Dev University Department of Applied Chemistry Amritsar 143005 India

Krishna C. Majumdar University of Kalyani Department of Chemistry Kalyani, W.B. 741235 India

Dipakranjan Mal Indian Institute of Technology Department of Chemistry Kharagpur W.B. 721302 India

Hideto Miyabe Hyogo University of Health Sciences School of Pharmacy Minatojima Kobe 650 - 8530 Japan

List of Contributors XIX

Okiko Miyata Kobe Pharmaceutical University 4 - 19 - 1 Motoyamakita, Higashinada Kobe 658 - 8558 Japan

Siti Mariam Mohd Nor Universiti Putra Malaysia Department of Chemistry Faculty of Science 43400 UPM Serdang Selangor Malaysia

Shovan Mondal University of Kalyani Department of Chemistry Kalyani, W.B. 741235 India

Takeaki Naito Kobe Pharmaceutical University 4 - 19 - 1 Motoyamakita, Higashinada Kobe 658 - 8558 Japan

Willem A.L. van Otterlo University of the Witwatersrand Molecular Sciences Institute School of Chemistry PO Wits 2050 Johannesburg South Africa

Alejandro P é rez - Luna IPCM – UPMC Univ Paris 6 Case Courrier 183 4 place Jussieu 75252 Paris Cedex 05 France

Darren L. Riley University of the Witwatersrand Molecular Sciences Institute School of Chemistry PO Wits 2050 Johannesburg South Africa

Tetsuya Sengoku Shizuoka University Department of Materials Science, Faculty of Engineering 3 - 5 - 1 Johoku Naka - ku Hamamatsu Shizuoka 432 - 8561 Japan

Brateen Shome Indian Institute of Technology Department of Chemistry Kharagpur W.B. 721302 India

Masaki Takahashi Shizuoka University Department of Materials Science, Faculty of Engineering 3 - 5 - 1 Johoku Naka - ku Hamamatsu Shizuoka 432 - 8561 Japan

XX List of Contributors

Zhengshuang Xu Peking University Shenzhen Graduate School School of Chemical Biology and Biotechnology University Town of Shenzhen Xili, Nanshan District Shenzhen 518055 China and The Hong Kong Polytechnic University Department of Applied Biology and Chemical Technology Hung Hom, Kowloon, Hong Kong China

Tao Ye Peking University Shenzhen Graduate School School of Chemical Biology and Biotechnology University Town of Shenzhen Xili, Nanshan District Shenzhen 518055 China and The Hong Kong PolytechnicUniversity Department of Applied Biology andChemical Technology Hung Hom, Kowloon, Hong Kong China

Jari Yli - Kauhaluoma University of Helsinki Faculty of Pharmacy, Division of Pharmaceutical Chemistry PO Box 56 (Viikinkaari 5 E) FI - 00014 Helsinki Finland

Hidemi Yoda Shizuoka University Department of Materials Science, Faculty of Engineering 3 - 5 - 1 Johoku Naka - ku Hamamatsu Shizuoka 432 - 8561 Japan

1

Part One Strained Heterocycles in the Synthesis of Natural Products

3

1

Heterocycles in Natural Product Synthesis, First Edition. Edited by Krishna C. Majumdar and Shital K. Chattopadhyay.© 2011 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2011 by Wiley-VCH Verlag GmbH & Co. KGaA.

Aziridines in Natural Product Synthesis Candice Botuha , Fabrice Chemla , Franck Ferreira and Alejandro P é rez - Luna

1.1 Introduction

The aziridinyl ring has attracted considerable attention over the last 20 years. A number of reviews dedicated to the synthesis of aziridines has appeared, dealing mainly with the preparation of this small heterocycle [1] and its reactions [2] . Very few have focused on natural product synthesis using aziridines.

This review is devoted to the occurrence of the aziridine moiety in the total synthesis of natural products (Table 1.1 ). Aziridines can be present in the natural product itself, or can serve as intermediates in the course of the natural product synthesis. Only the synthesis of truly natural products will be discussed here, and the synthesis of analogs or non - natural products will not be developed [3] . This review covers the literature from 1986, and follows the previous review [4] focused on aziridines in natural product synthesis.

1.2 Synthesis of Natural Products Containing Aziridine Units

The ability of aziridines to undergo highly stereo - and regioselective ring - opening reactions has been exploited in nature. A number of natural products possessing an aziridine ring have been shown to possess potent biological activity, which is closely associated with the reactivity of the strained heterocycle.

1.2.1 Synthesis of Aziridine - 2,3 - Dicarboxylic Acid

Among natural products containing aziridines, C 2 - symmetric aziridine - 2,3 - dicarboxylic acid 4 , a metabolite of Streptomyces MD 398 - A1 [5a] was prepared in enantiopure form in few steps from l - ( + ) - diethyl tartrate [5b] . An optimized synthetic pathway to aziridine - 2,3 - dicarboxylate precursor 3 of naturally - occurring aziridine 4 was published later, removing the epimerization tendency

4

1 Aziridines in N

atural Product Synthesis

Table 1.1 Aziridine - based natural products.

Serial No. Trivial name Structure Source Isolation [Ref]

Biological activity Synthesis [Ref]

1 Aziridine - 2,3 - dicarboxylic acid

HN

HO2CCO2H

Streptomyces MD 398 - A1

[5a] Antibacterial activity

[5b, 6]

2 ( Z ) - Dysidazirine

N

CO2Me

Dysidea fragilis

[7a] Cytotoxicity, antifungal activity

[7b, 8]

3 FR - 900482

OH

OHC NO

OH

OCONH2

NH

Streptomyces sandaensis

[9a] Antibacterial, anticancer activity

[10 – 15]

4 FR - 66979

OH

NO

OH

OCONH2

NHHO

Streptomyces sandaensis

[9b] Antibacterial, anticancer activity

[15, 16]

5 Mitomycin A

O

OMeO

Me N

OMe

OCONH2

NH

Streptomyces cuesipitasus

[17b] Antibacterial, anticancer activity

[18, 19]

6 Mitomycin C

O

OH2N

Me N

OMe

OCONH2

NH

Streptomyces cuesipitasus

[17a] Antibacterial, anticancer activity

[19, 20]

7 Mitomycin K

OMeO

MeO

N

O

OMe

N

Streptomyces verticillatus

[17c] Antibacterial, anticancer activity

[21, 22]

1.2 Synthesis of Natural Products Containing Aziridine Units 5

of synthetic intermediates by using anti - 3 - azido - 2 - hydroxy - succinate 2 (Scheme 1.1 ) [6] .

1.2.2 Synthesis of ( Z ) - Dysidazirine

While the fi rst enantioselective synthesis of antifungal active ( Z ) - dysidazirine 7 isolated from the marine sponge Dysidea fragilis [7a] was achieved by a Darzens - type synthesis of cis - N - sulfi nylaziridine carboxylic acid [7b] , a very recent synthesis includes the transformation of tosylated imine 5 into azirine carboxylate 6 as a key step (Scheme 1.2 ) [8] .

1.2.3 Syntheses of Mitomycins

In the fi eld of total synthesis of natural products containing an aziridine ring, most efforts of synthetic organic chemists have been dedicated to mitomycins, a class of very potent antibacterial and anticancer compounds isolated [17] from extracts of genus Streptomyces , a fi lamentous gram - positive soil bacterium. The most abun-dant mitomycins in nature are represented in Scheme 1.3 . Mitomycin C [17a] , besides mitomycin A [17b] and K [17c] , has become the most effective drug of the series against non - small - cell lung carcinoma and other soft and solid tumors [23] . Despite signifi cant medicinal features, syntheses of this class of compounds (fur-thermore in racemic form) have been reported only four times over the past 30 years [24] .

Since the fi rst synthesis of a mitomycin by Kishi [18] , only few organic chemists have succeeded to achieve a total synthesis of a mitomycin since serious diffi culties occurred during the construction of both reactive quinone and aziridine rings with the elimination of methanol from the 9a position (Scheme 1.3 ). Mitomycins A and

Scheme 1.1 Aziridine - 2,3 - carboxylic acid.

HN

EtO2C

CO2Et

EtO2C

OO

CO2Et

S

O

1 3EtO2C

N3HO

CO2Et2

70Š80%

NaN3/DMF

70Š75%

PPh3, DMFHN

HO2C

CO2H

4

Scheme 1.2 ( Z ) - Dysidazirine.

11

N O

OMe

TsOquinidine

84% 11

NH2, Lindlar's cat.

quinolinehexanes

°C

°C N

CO2Me

5 6

752% (Z)-Dysidazirine

CO2Me

6 1 Aziridines in Natural Product Synthesis

C were successfully synthesized by Fukuyama and co - workers in 18 steps from a readily available chalcone [19] . An intramolecular azide - olefi n cycloaddition on 8 gave exclusively tetracyclic aziridine 9 . Isomitomycin intermediate 10 was then obtained in few steps providing mitomycin A by a subsequent reaction with Al( i - OPr) 3 . A fi nal ammonolysis step gave mitomycin C (Scheme 1.4 ).

Subsequent improvement for the total synthesis of mitomycin C was reported later by the same authors using highly reactive bridgehead iminium species in the key steps [20] . The required C - 9a methoxy group was introduced under mild acidic conditions to give 13 in 60% yield via highly strained iminium ion 12 which was obtained from compound 11 through acidic treatment. Transformation of the aromatic ring of 13 using hydrogenolysis followed by oxidation with DDQ afforded the desired quinone ring of isomitomycin A in 77% yield. Isomitomycin A was then converted to ( ± ) - mitomycin C via isomitomycin C 15 in 85% yield by treat-ment with NH 3 in methanol (Scheme 1.5 ).

Danishefsky and colleagues have designed a short total synthesis of the densely functionalized mitomycin K from parent mitomycins A and C by elimination of the carbamate at position 10 [21] . Introduction of N - methyl aziridine from an olefi n was achieved in only 3 steps by 1,3 - dipolar cycloaddition. Reaction of meth-

Scheme 1.3 General mitomycins.

OX

MeO

N

O

OMe

N Y

O

OX

Me N

OMe

OCONH2

N Y

Mitomycin A Mitomycin C Mitomycin F Porfiromycin

X Y

OMeNH2OMeNH2

HHMeMe

O

OX

Me N

OH

OCONH2

N Me

Mitomycin B : X = OMe Mitomycin D : X = NH2

Mitomycin G Mitomycin HMitomycin K

X Y

OMeOMe

MeHMe

NH2

10

9a9

Scheme 1.4 Mitomycin A and C.

OBzMeO

MeOMe

N3

O

Ph

OO

SEtOBz

MeO

MeOMe

O

Ph

N

OO

SEttoluene

ºC

OBzMeO

MeOMe

CH2OCONH2

N

NHOMe

10-isomitomycin A

MeOH, RT

Al(OiPr)3 Mitomycin ANH3, MeOH

8 993%

91%

RTMitomycin C

1.2 Synthesis of Natural Products Containing Aziridine Units 7

ylthiophenyl azide with imide 16 provided triazoline 17 which was then trans-formed to 18 in two steps. N - methylaziridine 19 , an advanced intermediate to mitomycin K, was obtained by irradiation at 254 nm (Scheme 1.6 ).

A facile method was set up for the transformation of azidomitosenes 20 into mitomycins (introduction of the C9a methoxy group) by using an oxidation reac-tion of the C9 - 9a double bond with MoO 5 · hexamethylphosphoramide ( HMPA ). Specifi cally, oxidation of 20 afforded in 46% 21 from which the fused N - methylaziridine ring could be constructed. 22 led to the mitomycin K in two steps. (Scheme 1.7 ) [22] .

Scheme 1.5 Mitomycin C.

OBn

MeO

MeOMe

CH2OCONH2

N

NHOH

CSA

MeOH, RT

OBn

MeO

MeOMe

CH2OCONH2

N

N +H

OMe60%

OBn

MeO

Me

OMe

CH2OCONH2

N

NHOMe

1. H2, 10% Pd/CEtOH2. DDQ, acetone, H2O

°C

O

MeO

MeO

CH2OCONH2

N

NHOMe

77%14-isomitomycin A

NH3

MeOH, RT

O

H2N

MeO

CH2OCONH2

N

NHOMe

15-isomitomycin C

Mitomycin C85%

11 12 13

Scheme 1.6 Mitomycin K.

OMe

MeO

Me

OMe

N

O

O

OMe

PhSCH2N3

90%

OMeMeO

MeOMe

N

O

O

OMe

NN

NSPh

2. L-selectride°C

77%

S

ImImDMAP, CH2Cl2

66%

1.

1.

2. Bu3SnH, AIBN, PhH

52 %

OMe

MeO

Me

OMe

N

O

OMe

NN

NSPh

1. hν, 254 nm48%

OMe

MeO

Me

OMe

N

O

O

OMe

N Me2. Raney Ni

70%

O

MeO

Me

O

N

O

OMe

N Me

Mitomycin K

16 17

1819

°C

°C

8 1 Aziridines in Natural Product Synthesis

1.2.4 Syntheses of FR - 900482 and FR - 66979

Antitumor antibiotic natural products FR - 900482 and FR - 66979 (Scheme 1.8 ) isolated from Streptomyces sandaensis [9] are structurally related to mitomycin C and possess similar biological activities. They have proven to be less toxic than mitomycins in clinical cancer chemotherapeutics. In addition of the biomedical potential, the uncommon structure and the synthetic problem related to the con-struction of both aziridine ring and the hemiacetal functionality of FR - 900482 and FR - 66979 have attracted the attention of a number of synthetic chemists. Although several approaches have been explored to construct these highly functionalized structures, only six total syntheses have been accomplished and two formal syn-theses [10, 25] have been reported to date.

The fi rst total synthesis of ( ± ) - FR - 900482 was realized in 41 steps from readily available N - benzylamine [11] . In this strategy, the authors introduced the aziridine ring at the end of the synthesis to prevent any lability of the three - membered ring under acidic condition. Azide 24 was prepared by ring opening of epoxide 23 with NaN 3 followed by the transformation of the resulting alcohol to a mesylate. Upon oxidative treatment of 24 to exchange the PMB - protecting group on the aromatic ring for a dimethyl acetal, reduction of azide 25 by PPh 3 in the presence of a base furnished aziridine 26 which was then advanced to the target compound (Scheme 1.9 ). An enantioselective total synthesis of ( + ) - FR - 900482 was reported later on by the same group with a slight modifi cation of the initial route [12] .

Scheme 1.7 Mitomycin K.

O

MeO

Me

O

N

O

OMe

N MeMitomycin K

OTBS

Me

MeO

OTBS

N

N3

OMs

MoO5/HMPA

°C

OTBS

Me

MeO

OTBS

N

N3

OMs

OMeO PPh3, NEt3

THF, H2O, RT

46%

70%

2. CH3OTf, pyr.CH2Cl2 °C 78%

1. OTBS

Me

MeO

OTBS

N

OMeO

N CH3

20 21 22

Scheme 1.8 FR - 66979 and FR - 900482.

FR-66979, R = CH2OHFR-900482, R = CHO

OH

R NO

OH

OCONH2

NH

9

10

7