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/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
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