/soquinoline Alkaloids Research 1972-1977

/soquinoline Alkaloids Research 1972-1977

Maurice Shamma and Jerome L. Moniot The Pennsylvania State University University Park, Pennsylvania

Plenwn Press· New York and London

Library of Congress Cataloging in Publication Data

Shamma, Maurice, 1926-Isoquinoline alkaloids research, 1972-1977.

Includes bibliographical references and index. 1. Alkaloids. 2. Isoquinoline. I. Moniot, Jerome L., joint author. II. Title.

QD421.S543 547.72 77-26929

ISBN-13: 978-1-4615-8821-4 DOl: 10.1007/978-1-4615-8819-1

©1978 Plenum Press, New York

e-ISBN-13: 978-1-4615-8819-1

Softcover reprint of the hardcover 1 st edition 1978

A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. 10011

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher

The authors who set out to say something that no one has said before are to be regarded with mistrust.

Max J. Friedlander

PREFACE

Substantial advances in the realm of isoquinoline alkaloids have occurred since The Isoquinoline Alkaloids, Chemistry and Pharmacology, was published in 1972. The present volume represents an effort to describe important developments since that time.

The organization of the present book is essentially the same as in The Isoquinoline Alkaloids. Each chapter begins with a discussion of structural elucidation and synthesis, a description of typical reactions then follows, and the chapter ends with coverage of biogenesis, pharmacology, and spectroscopy. New chapters have had to be added to describe the completely new alkaloidal types discovered since 1972. These include baluchistanamine (an isoquinolone­benzylisoquinoline dimer), the aporphine-pavine dimers, the 4,5-dioxoapor­phines, the secoberbines, the 3-arylisoquinolines, eupolauridine, and very recently imerubrine. Another new chapter discusses the chemistry of the aristolo­chic acids and aristolactams, a group of substituted phenanthrenes, obviously of isoquinoline derivation in spite of the fact that they do not incorporate a basic nitrogen function. The aristolochic acids and aristolactams were not in­cluded in The Isoquinoline Alkaloids even though they were known at the time that book was written.

On the other hand, one group of alkaloids which was included in The Isoquinoline Alkaloids and nevertheless was deemed not to belong properly in the present work is the naphthalenoisoquinolines, which include ancistro­cladine and its relatives. These bases do not originate biogenetically· from tyrosine, and beside incorporating tetrahydroisoquinoline moieties show no clear structural relationship to the more orthodox isoquinoline alkaloids.

As with The Isoquinoline Alkaloids, not all known or new isoquinoline alkaloids have been presented. Rather, selected examples have been discussed to illustrate specific principles or methods. For a complete listing of the iso­quinoline alkaloids, the reader is referred to T. Kametani's The Chemistry of the Isoquinoline Alkaloids, Vol. 2, * and also to the annual reviews on isoquinoline alkaloids and the aporphinoids included in Specialist Periodical Reports, The A lkalo ids. t

* The Sendai Institute of Heterocyclic Chemistry, Sendai, Japan (1974). t The Chemical Society, London.

vii

viii PREFACE

Percentage reaction yields are given in parentheses under the proper struc­tures. Infrared absorptions are quoted both in terms of wavelength and fre­quency. Ultraviolet log € values are given in brackets following the Amax values. The literature up to about mid-1977 has been covered. All nuclear magnetic resonance data are given in I) values, and were obtained in deuteriochloroform solution unless stated otherwise. A special effort was made to include C-13 nuclear magnetic resonance values where available. The term "tetrahydroiso­quinoline" refers to the 1 ,2,3,4-tetrahydro system, and the prefix" nor" relates solely to the N-nor series.

The authors would like to thank Drs. A. Patra and A. S. Rothenberg, as well as Mr. P. Chinnasamy, for commenting on the completed manuscript. A special debt is due senior editor, Mr. Ellis Rosenberg, and assistant managing editor, Ms. Betty Bruhns, for a dedicated effort in facilitating our work.

Maurice Shamma Jerome L. Moniot

CONTENTS

Chapter 1. The Simple Isoquinolines 1.1. Introduction 1 1.2. Synthesis 2

1.2.1. Pictet-Spengier Cyclization 2 1.2.2. Bischler-Napieralski Cyclization 4 1.2.3. Pomeranz-Fritsch Cyclization 6 1.2.4. Photocyclization of N-Chloroacetylbenzylamines 7 1.2.5. Amination of Benzopyrylium Salts 7 1.2.6. A New Isoquinoline Synthesis via Ortho-Substituted

Benzylamines 8 1.2.7. Cyclization of Aralkenyl-Substituted Quaternary Ammonium

Salts . 8 1.3. Some Reactions of Simple Isoquinolines . 8

1.3.1. Oxidation . 8 1.3.2. Alkylation and Acylation 10 1.3.3. Fluorophore-Forming Reactions 14 1.3.4. Electrolytic Oxidation . 15 1.3.5. Rearrangements of 1,2-Dihydroisoquinolines 17

1.4. Biogenesis . 18 1.5. Pharmacology 20 1.6. CMR Spectroscopy 22

References and Notes 23

Chapter 2. The Benzylisoquinolines 27 2.1. Introduction 27 2.2. Synthesis 28

2.2.1. The Use of Reissert Compounds 28 2.2.2. Friedel-Crafts Alkylation and Acylation 29 2.2.3. Pictet-Spengler Condensation 31 2.2.4. The Pomeranz-Fritsch/Reissert Approach 32 2.2.5. Cyclization of N-Sulfonylphenethylamines 33

2.3. Reactions of Benzylisoquinolines . 34 2.3.1. Oxidation . 34 2.3.2. Reduction and the Chemistry of the Reduction Products. 34 2.3.3. Photolysis . 36 2.3.4. Acetonylation at C-6' . 38 2.3.5. Fission of Ring B 38 2.3.6. Rearrangement of 1,2-Dihydroisoquinolines 40 2.3.7. Transformation of a-Ketobenzylisoquinolines. 41

ix

x

2.3.8. Electrolytic Oxidation . 2.3.9. Oxidative Dimerization

2.4. Conversion of Benzylisoquinolines to Morphine 2.5. Cryptopleurospermine, an Unusual Natural a-Dione 2.6. Biogenesis . 2.7. Pharmacology 2.8. NMR Spectroscopy 2.9. UV Spectroscopy.

References and Notes

CONTENTS

42 43 44 46 47 49 51 52 52

Chapter 3. The Isoquinolones 3.1. Introduction

57 57 57 58 60

3.2. Siamine 3.3. Synthesis and Reactions of Isoquinolones

References .

Chapter 4. The Pavines and Isopavines . 4.1. Synthesis

4.1.1. Pavines 4.1.2. Isopavines

4.2. Biogenesis . 4.3. Pharmacology 4.4. Spectroscopy and Crystallography .

References and Notes .

Chapter 5. The Bisbenzylisoquinolines 5.1. Introduction 5.2. Stepinonine, an Unusual Bisbenzylisoquinoline 5.3. Synthesis

5.3.1. The Cava Modification of the Ullmann Reaction 5.3.2. The Inubushi Synthesis of Obaberine and Trilobine 5.3.3. The Use of Reissert Compounds .

5.4. Controlled Oxidation 5.5. Some General Methods for Functional Group Modification of

61 61 61 64 68 68 68 69

71 71 81 84 84 85 88 89

Isoquinoline Alkaloids. 91 5.5.1. Selective Removal of an Aromatic Methyleliedioxy Group 91 5.5.2. Deoxygenation of a Phenol . 91 5.5.3. N-Demethylation of Tertiary Amines 91 5.5.4. N-Demethylation and N-Debenzylation of Quaternary

Ammonium Salts 92 5.5.5. O-Demethylation and O-Debenzylation of Aromatic Ethers 92 5.5.6. Methylenation of Catechols . 93 5.5.7. O-Methylation and Protection of Phenols 93 5.5.8. Aromatic Hydroxylation or Methoxylation 93

5.6. Biogenesis . 93 5.7. Pharmacology 97

CONTENTS

5.8. Spectral Measurements and CD Curves 5.9. X-Ray Diffraction

References and Notes .

Chapter 6. Baluchistanamine: An Isoquinolone-Benzylisoquinoline

Dimer. 6.1. Structure Elucidation and Synthesis 6.2. PMR Spectroscopy 6.3. UY Spectroscopy and Circular Dichroism

References .

xi

97 99

100

103 103 105 105 105

Chapter 7. The Cularines lO7 7.1. Synthesis 107 7.2. Absolute Configuration. 109 7.3. An Approach to the Synthesis of Cancentrine . 110 7.4. CMR Spectroscopy 111

References . 111

Chapter 8. The Dibenzopyrrocolines 113 8.1. Synthesis 113

8.1.1. Benzyne Intermediates. 113 8.1.2. Enzymic Processes 115 References . 116

Chapter 9. The Proaporphines 117 9.1. Introduction 117 9.2. Revision of Stereochemistry of the Reduced Proaporphines 117 9.3. Synthesis 118 9.4. Pharmacology 119 9.5. Spectral Studies 119

References and Notes 120

Chapter 10. The Aporphines . 123 10.1. Introduction 123 10.2. Synthesis . 123

10.2.1. Photolysis 123 10.2.2. The Use of YOCI3 126 10.2.3. The Use of YOF3-TFA 126 10.2.4. Electrolytic Oxidation 135 10.2.5. Oxidation with Cuprous Chloride and Oxygen 136 10.2.6. The Use of Lead Tetraacetate; Hydroxylation at C-4 . 137 10.2.7. Benzyne Intermediates 138 10.2.8. Enzymic Oxidative Coupling . 139 10.2.9. Reissert Intermediates 139 10.2.10. Improved Pschorr CycIizations 140 10.2.11. Coupling with Thallium Tristrifluoroacetate 140

xii CONTENTS

10.3. Reactions of Aporphines 141 10.3.1. Oxidation and Formation of Dehydroaporphines and

Oxoaporphines 141 10.3.2. Selective Cleavage of the Methylenedioxy Substituent. 142 10.3.3. Dimerization. 144 10.304. Hofmann and Emde Degradations 144 10.3.5. O-Acetylation i44 10.3.6. Hydroxylation 145 10.3.7. Selective O-Demethylation and N-Demethylation 145 10.3.8. Protonation and Formylation of Dehydroaporphines . 146

lOA. Absolute Configuration 146 10.5. Biogenesis. 147 10.6. Pharmacology 150 10.7. NMR Spectroscopy 152

References and Notes. 154

Chapter II. Pakistanamine: A Proaporphine-Benzylisoquinoline Dimer. 157

11.1. Synthesis . 157 References and Notes . 158

Chapter 12. The Aporphine-Benzylisoquinoline Dimers . 159

12.1. Introduction 160 12.2. Structural Elucidation. 160 12.3. Synthesis . 161 12.4. Reactions . 162 12.5. Biogenesis. 12.6. Pharmacology 12.7. PMR Spectroscopy

References and Notes .

Chapter 13. The Aporphine-Pavine Dimers 13.1. Introduction 13.2. Structural Elucidation. 13.3. UV and IR Spectroscopy

References.

Chapter 14. The Oxoaporphines

14.1. Introduction 14.2. Synthesis . 14.3. Pharmacology 14.4. Spectral Characteristics

References and Notes.

Chapter 15. The Phenanthrenes 15.1. Structural Elucidation and Synthesis 15.2. Pharmacology

163 164 165 165

167

167 167-170 171

173 173 173 175 175 176

179

179 180

CONTENTS

15.3. Mass Spectroscopy 15.4. PMR Spectroscopy 15.5. UV Spectroscopy

References and Notes .

Chapter 16. The 4,5-Dioxoaporphines 16.1. Introduction 16.2. A Revised Structure for Pontevedrine 16.3. Cepharadione-A and-B 16.4. Synthesis .

References.

Chapter 17. The Aristolochic Acids and Aristolactams 17.1. Introduction 17.2. Structural Elucidation. 17.3. Synthesis . 17.4. Biogenesis. 17.5. Pharmacology 17.6. PMR Spectroscopy 17.7. UV and IR Spectroscopy

References and Notes.

Chapter 18. The Dibenzazonines 18. I. Introduction 18.2. Structural Elucidation. 18.3. Synthesis .

18.3.1. Through a Benzyne Intermediate 18.3.2. By Photolysis . 18.3.3. Through Rearrangements .

18.4. Biogenesis . 18.5. PMR Spectroscopy 18.6. UV Spectroscopy

References.

Chapter 19. The Protoberberines and Retroprotoberberines 19.1. Introduction \9.2. Synthesis .

\9.2.1. Mannich Condensation 19.2.2. Variants of the Bischler-Napieralski Cyclization 19.2.3. Enamide Photocyclization 19.2.4. Thermolysis of Benzocyclobutenes 19.2.5. Pomeranz-Fritsch Cyclization \9.2.6. From Immonium Salts \9.2.7. From Protopines 19.2.8. From Spirobenzylisoquinolines 19.2.9. From Norphthalideisoquinolines 19.2.10. From Homophthalic Anhydrides

xiii

180 181 182 183

185 185 185 186 187 187

189 190 190 191 193 194 194 195 195

197 197 197 198 198 198 200 202 206 207 207

209 209 210 210 216 217 221 223 223 224 225 226 226

xiv CONTENTS

19.3. Reactions . 228 19.3.1. Carbon-Nitrogen Bond Cleavage 228 19.3.2. Rearrangements 233 19.3.3. O-Demethylation of Berberinium Salts 233 19.3.4. Oxidation 233 19.3.5. The Chemistry of Oxybisberberine . 235 19.3.6. Reactions with Alkylating and Acylating Agents 240 19.3.7. Transformations of Dehydroprotoberberines 242 19.3.8. Smiles Rearrangement 243 19.3.9. C-Acylation, a New Reaction of Benzylic N-Oxides 243

19.4. Biogenesis. 244 19.5. Pharmacology 249 19.6. Mass Spectroscopy 251 19.7. NMR Spectroscopy 252 19.8. IR, UV, and Fluorescence Spectroscopy 253 19.9. SoIidaIine, a Modified Protoberberine Alkaloid 254

References and Notes. 255

Chapter 20. The Secoberbines 261 20.1. Structural Elucidation and Synthesis 261

20.1.1. Canadaline, Aobamine, and Corydalisol 261 20.1.2. Hypecorine 263 20.1.3. Hypecorinine . 264 20.1.4. Peshawarine 264

20.2. Absolute Configuration 267 20.3. Biogenesis . 268 20.4. Mass Spectroscopy 268 20.5. PMR Spectroscopy 269 20.6. UV Spectroscopy 270

References. 270

Chapter 21. The Benzophenanthridines 271 21.1. Introduction 27J 21.2. Arnottianamide and Isoarnottianamide . 272 21.3. Synthesis . 273

21.3.1. Photocyclization 273 21.3.2. Benzyne Intermediates 278 21.3.3. From Protopines and Protoberberines 279 21.3.4. Mannich Cyclization 282 21.3.5. Friedel-Crafts Alkylation Using an Immonium Salt 283 21.3.6. Condensation of an Imine with a Homophthalic Ester 284

21.4. Conversion of Isoquinolinium Salts into Pseudobases 284 21.5. Biogenesis. 285 21.6. Pharmacology 287 21.7. Spectral Characteristics 288 21.8. X-Ray Crystallography 290

References and Notes . 290

CONTENTS xv

Chapter 22. The 3-Arylisoquinolines 293 22.1. Introduction 293 22.2. Structural Elucidation and Synthesis 293

22.2.1. Corydalic Acid Methyl Ester 293 22.2.2. Corydamine and N-FormyJcorydamine 294

22.3. Biogenesis . 295 22.4. Pharmacology 296 22.5. Mass Spectroscopy 296 22.6. PMR Spectroscopy 297 22.7. UV Spectroscopy 298

References and Note 298

Chapter 23. The Protopines 299 23.1. Syntheses and Interconversions 299

23.1.1. The Transformation of a 13-0xoprotoberberinium N-Metho Salt to a Protopine Analog. 299

23.1.2. The Conversion of an Aporhoeadane to AIIocryptopine 300 23.2. Reactions . 301 23.3. Biogenesis . 302 23.4. Pharmacology 303 23.5. Spectral Studies . 303

References and Notes. 305

Chapter 24. The Phthalideisoquinolines . 307 24.1. Introduction 307 24.2. Synthesis . 308

24.2.1. From a Substituted 2-Phenyl-l,3-indandione 308 24.2.2. By Condensation of an Immonium Salt with an

a-Diazotoluene 309 24.2.3. From Papaverine 310 24.2.4. From a Benzindenoazepine 311 24.2.5. An Improvement of the Haworth-Pinder Synthesis 312 24.2.6. From Protoberberinium Salts 313

24.3. Chemistry of (- )-a-Narcotine and Related Compounds. 314 24.4. Interconversions Among Lactonic Phthalideisoquinolines 317 24.5. Pharmacology 318 24.6. PMR and CMR Spectra of Phthalideisoquinolines; Conformational

Analysis 319 References and Notes . 322

Chapter 25. The Spirobenzylisoquinolines 325 25.1. Introduction 325 25.2. Synthesis . 325

25.2.1. Modified 1,2-Indandione and 1,2,3-Indantrione Approaches. 325 25.2.2. From Substituted 2-Phenyl-l,3-indandiones. 327 25.2.3. By Conversion of a l-Indanone to a 1,3-Indandione 328

xvi

25.2.4. By Thermolysis of Benzocyc!obutenes 25.2.5. Photolytic Proto berberine -7 Spirobenzylisoquinoline

Rearrangements 25.2.6. From Phthalideisoquinolines 25.2.7. From Tetrahydroprotoberberinium Salts

CONTENTS

329

330 331 333

25.3. Reductive Rearrangement of Spirobenzylisoquinolines to Dibenzocyc!opentazepines 334

334 334 335

25.4. Biogenesis . 25.5. Mass Spectroscopy

References and Notes.

Chapter 26. The Rhoeadines . 337 26.1. Introduction 337 26.2. Synthesis . 337

26.2.1. From Phthalideisoquinolines 337 26.2.2. From Spirobenzylisoquinolines and Dibenzocyc!opentazepines 338 26.2.3. By Ring Expansion of a Pseudo base . 342 26.2.4. From a Tetrahydroprotoberberine 343

26.3. Benzazepine Preparations of Potential Use in Rhoeadine Synthesis 344 26.4. Reactions . 347 26.5. Stereochemistry and Absolute Configuration . 349 26.6. Biogenesis . 349 26.7. CMR Spectroscopy 352

References and Notes. 352

Chapter 27. Emetine and Related Bases. 355 27.1. Introduction 355 27.2. Structural Elucidation and Synthesis 355

27.2.1. Ankorine 355 27.2.2. Alangiside 359 27.2.3. Emetine. 360

27.3. Pharmacology 362 27.4. CMR Spectroscopy 362

References and Notes . 363

Chapter 28. The Phenethylisoquinolines. 365 28.1. Synthesis and Chemistry 365 28.2. Pharmacology 368 28.3. Yolantinine, a New Dimeric Phenethylisoquinoline Alkaloid 369

References and Note . 370

Chapter 29. The Homoaporphines and Homoproaporphines 371 29.1. Introduction 371

29.1.1. The Structural Elucidation of Kesselringine. 372 29.2. Synthesis . 374

29.2.1. Direct Cyc!ization of a Tetrahydrophenethylisoquinoline 374

CONTENTS

29.2.2. Through the Intermediacy of Dienones 29.2.3. Phenolic Oxidative Coupling

29.3. Racemization of Homoproaporphines References and Notes.

Chapter 30. The I-Phenylisoquinolines 30. I. Introduction 30.2. Synthesis . 30.3. Stereochemistry 30.4. Biogenesis . 30.5. Pharmacology

References and Note

Chapter 31. The N-Benzyltetrahydroisoquinolines . References .

Chapter 32. Cherylline, a 4-Arylisoquinoline . References.

Chapter 33. The Azafluoranthenes and Tropoloisoquinolines . References.

Chapter 34. Eupolauridine: A 1,6-Diazafluoranthene References.

Author Index Subject Index

xvii

375 377 378 379

381 381 381 383 383 385 385

387 387

389 390

391 392

393 394

395 407