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THE ALKALOIDS Chemistry and Physiology

VOLUME XI

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Chemistry and Physiology Edited by

R. H. F. MANSKE UniRoyal Limited Research Laboratory Guelph, Ontario, Canada

VOLUME X I

1968

ACADEMIC PRESS

NEW YORK

*

LONDON

BY ACADEMIC PRESSINC. ALL RIGHTS RESERVED. NO PART OF THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS.

COPYRIGHT0 1968,

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

United Kingdom Edition published by ACADEMIC PRESS INC. (LONDON) LTD. Berkeley Square House, London W.1

LIBRARY OF CONGRESSCATALOGCARD NUMBER: 50-5522

PRINTED IN TEE UNITED STATES OF AMERICA

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

W. A. AYER,University of Alberta, Edmonton, Canada (459) A. R. BATTERSBY, The Robert Robinson Laboratories, University of Liverpool, Liverpool, England (1 89)

B. GILBFRT,Centro de Pesquisas de Produtos Naturais, Faculdade de Farmhcia e Bioquimica, Rio de Janeiro, Brazil (205)

T. E. HABGOOD, University of Alberta, Edmonton, Canada (459) H. F. HODSON,The Wellcome Research Laboratories, Beckenham, Kent, England (189)

H. J. MONTEIRO,Centro de Pesquisas de Produtos Naturais, Faculdade de Farmacia e Bioquimica, Rio de Janeiro, Brazil (145)

B. A. PURSEY, Iowa State University, Ames, Iowa (407)

V. SNIECKUS, Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada ( 1 ) W. I. TAYLOR, Research Department, CIBA Pharmaceutical Company, Division of CIBA Corporation, Summit, New Jersey (41, 73, 79, 99, 125)

w. c. WILDMAN,Iowa State University,.Ames, Iowa (307, 407)

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PREFACE There has been no discernible abatement in natural product chemistry in recent decades, and the search for new alkaloids and the elucidation of their structures have occupied the attention of an ever-increasing number of chemists. The modern methods of structural investigation, dependent as they are upon physical methods, have rendered such studies feasible with quantities that several decades ago would scarcely have served to determine their empirical formulas. Consequently, many alkaloids, known formerly by name or number only and many recently discovered, have had their secrets laid bare. The consequent proliferation of literature has induced the publisher, the editor, and the many devoted authors to make another effort to bring this important field of chemistry into review once more. We have abandoned all attempts at the orderly arrangement of chapters, either chemically or botanically. Each of the twehe chapters in this volume is designed to bring the named subjects up to date. I n order to keep the volume to reasonable dimensions repetition of material from previous volumes is limited to the minimum consistent with clarity. This volume and a projected Volume XI1 can therefore be regarded as periodical reviews. Volumes beyond XI1 are in prospect but the date of their maturation will depend, among other factors, upon the volume of alkaloid chemistry which will make its appearance in the next few years. Entries in the subject index are restricted to topics which are basic to the substances or groups under discussion; incidental mention does not necessarily merit inclusion. Literature references are listed in the order in which they appear, and the abbreviations used for journals are those found in Chemical Abstracts List of Periodicals. Once more the editor, on behalf of the publisher and himself, takes this opportunity to express his indebtedness to the conscientious and competent authors who have made the publication of this volume possible. R.H. F. MANSKE Guelph, Ontario March, 1968

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LISTOF CONTRIBUTORS................................................... PREFACE ............................................................... C ~ N ~ E N T ~ O F P R E V I O U S V.......................................... OLUMES

vii xiii

Chapter 1. The Distribution of Indole Alkaloids in Plants V . SNIECKUS I Introduction .................................................... I1. Indole Alkaloids of Plant Origin ..................................... References

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Chapter 2 . The Ajmaline-Sarpagine Alkaloids W. I . TAYLOR I The Ajmaline Group .............................................. I1 The Sarpagine Group ............................................. References ......................................................

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Chapter 3 . The 2.2 '.Indolylquinuclidine Alkaloids W . I . TAYLOR I. Cinchomamine .................................................. I1. Cinchophyllamine and Isocinchophyllamine .......................... References ...................................................... Chapter 4

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73 74 77

The Iboga and Voacanga Alkaloids W . I TAYLOR

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I. The Iboga Alkaloids .............................................. I1. The ~ o a c a n g aAlkaloids ........................................... References ......................................................

79 92 97

Chapter 5 . The Vinca Alkaloids W . I TAYLOR I The Alkaloids of Vinca ro8ea L ...................................... I1. The Alkaloids of Vinca minor L ...................................... I11 The Alkaloids of Other Vinca Species ................................ References ......................................................

102 108 110 121

Chapter 6. The Eburnamine-Vincamine Alkaloids W. I TAYLOR Canthine Derivatives ............................................. The Eburnamine-VincamineAlkaloids ............................... The Hunteria Alkaloids ............................................ The Alkaloids ofSchizozygia caffeoides (Boj.)Bail1...................... References ......................................................

126 128 134 137 142

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CONTENTS

Chapter 7

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Yohimbine and Related Alkaloids

H . J . MONTEIRO I. Introduction and Stereochemistry .................................. I1 The Yohimbane Group ............................................ I11. TheCorynaneGroup .............................................. IV . The Heteroyohimbane Group ...................................... V. The Oxindole Group .............................................. VI . Other Bases ..................................................... VII . Syntheses ....................................................... VIII . Addendum ...................................................... References ......................................................

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145 146 148 159 162 165 166 183 185

Chapter 8. Alkaloids of Calabash Curare and Strychnos Species

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and H . F HODSON A . R . BATTERSBY I Introduction .................................................... I1. TheCzoAlkaloids ................................................. I11. The Dimeric Alkaloids of Calabash Curare ............................ References ......................................................

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189 189 200 204

Chapter 9 . The Alkaloids of Aspidosperm. Ochrosia. Pleiocarpa. Melodinus. and Related Genera

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B GILBERT I. Introduction .................................................... I1. The Aspidospermine Group ........................................ I11. The Meloscine Group .............................................. IV . The Aspidofractinine Group ........................................ V . Cyclic Ethers and Lactones ........................................ VI . The Aspidospermtidine Group ...................................... VII . Alkaloids Lacking the Tryptamine Bridge ............................ VIII . Some Miscellaneous Alkaloids ...................................... I X . Double Alkaloids ................................................. References ......................................................

206 207 242 244 260 269 271 279 291 303

Chapter 10. The Amaryllidaceae Alkaloids W . C. WILDMAN I Introduction and Occurrence ....................................... I1. Lucorine-Type Alkaloids .......................................... I11 Lycorenine-Type Alkaloids ........................................ IV. Galanthamine-TypeAlkaloids ...................................... V . Crinine-Type Alkaloids ............................................ VI . Montanine. Coccinine, and Manthine ................................ VII Tazettine-Type Alkaloids .......................................... V I I I. Unclassified Alkaloids and Other Substances .......................... I X . Alkaloids of Undetermined Structure ................................ X . Biosynthesis ..................................................... References ......................................................

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308 321 334 348 352 375 378 382 387 387 400

CONTENTS

xi

Chapter 11 . Colchicine and Related Compounds

W . C . WILDMANand B . A . PURSEY .................................................... I1. Distribution in Nature ............................................ 111. Chemistry of Colchicine Alkaloids ................................... IV. Photoisomers .................................................... V . Minor Alkaloids .................................................. VI . Synthesis ....................................................... VII ..Biosynthesis ..................................................... References ......................................................

I. Introduction

407 414 414 426 431 436 448 455

Chapter 12. The Pyridine Alkaloids

W . A . AYERand T. E . HABGOOD I . Introduction .................................................... I1. The Pepper Alkaloids .............................................

460 460 461 462 473 477 483 486 487

111. The Alkaloids of Pomegranate Root ................................. IV. Lobelia and Sedutn Alkaloids ....................................... V. The Alkaloids of Hemlock .......................................... VI The Tobacco Alkaloids ............................................ VII . The Biogenesis o f Nicotine, Anabasine, and Ricinine ..................... VIII . Alkaloids of Withania somnijera Dunal ............................... I X Gentianine ...................................................... X . The Pinus Alkaloids .............................................. X I . Alkaloids of Tripterygiurn wilfordii Hook and Evonymus europaeus L ...... XI1. Alkaloids of Adenocarpus spp ....................................... XI11. Carpaine, Cassine, Prosopine, and Prosopinine ........................ XIV . The Alkaloids of Astrocasia phyllanthoides ............................ XV . Nudiflorine ...................................................... XVI . Homostachydrine ................................................ XVII . Anibine ......................................................... XVIII . Julocrotine ...................................................... XIX . Ha2fordiaAlkaloids ............................................... XX . Monoterpenoid Alkaloids Containing a Pyridine or Piperidine Ring ....... References ......................................................

489 490 490 493 495 495 496 496 498 499 503

AUTHORINDEX .......................................................... SUBJECTINDEX .........................................................

511 535

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CONTENTS OF PREVIOUS VOLUMES Contents of Volume I CHAPTER 1 Sources of Alkaloids and Their Isolation BY R H F MANSKE . . . . . . . 2. Alkaloids in the Plant BY W 0. JAMES 3 The Pyrrolidine Alkaloids BY LEOMARION 4 . Senecio Alkaloids BY NELSONJ. LEONARD 5 The Pyridine Alkaloids BY LEOMARION 6. The Chemistry of the Tropane Alkaloids BY H . L HOLMES 7 The Strychnos Alkaloids BY H L HOLMES . . . . . .

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8.1 The Morphine Alkaloids I BY H L HOLMES 8.11 . The Morphine Alkaloids11 BY H L .HOLMES AND (INPART) GILBERT STORE 9 Sinomenine BY H . L HOLMES 10 Colchicine BY J .W COOKAND J D LOUDON 11. Alkaloids of the Amaryllidaceae BY J W COOKAND J D LOUDON 12 Aoridine Alkaloids BY J R PRICE . . . . . . . . . . . 13 The Indole Alkaloids BY LEOMARION . . . . . . . . . . 14 The Erythrina Alkaloids BY LEOMARION . . . . . . . . . 15. The Strychnos Alkaloids Part I1 BY H . L . HOLMES

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161 219 261 331 353 369 499 513

Contents of Volume 111

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The Chemistry of the Cinchona Alkaloids BY RICHARD B . TURNER~ N D 1 R . B . WOODWARD. . . . . . . . . . . . . . . Quinoline Alkaloids. Other than Those of Cinchona BY H T OPENSEIAW 65 The Quinazoline Alkaloids BY N . T OPENSHAW . . . . . . . 101 119 Lupin Alkaloids BY NELSONJ. LEONARD The Imidazole Alkaloids BY A R . BATTERSBY AND H T OPENSHAW . 201 The Chemistry of Solanum and Veratrum Alkaloids BY V PRELOG AND 0 JEGER . . . . . . . . . . . . . . . . . . 247 fl-PhenethylaminesBY L .RETI . . . . . . . . . . . . 313 339 Ephreda Bases RY L . RETI T h e I p e c a o A l k d o i d s ~MAURICE-MARIE ~ JANOT . . . . . . . 363

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Contents of Volume I V 25 26 27 28 29

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The Biosynthesis of Isoquinolines BY R . H . F MANSKE Simple Isoquinoline Alkaloids BY L RETI . . . . . . . . . Cactus Alkaloids BY L RETI . . . . . . . . . . . . . The Benzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . The Protoberberine Alkaloids BY R H . F MANSKEAND WALTERR ASH-

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. . . . . . . . . . . . . . . . . . . 30. The Aporphine Alkaloids BY R . H . F. MANSKE. . . . . . . . 31. The Protopine Alkaloids BY R . H . F. MANSKE. . . . . . . . FORD

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CONTENTS O F PREVIOUS VOLUMES

CRAPTE :R 32 . Phthalideisoquinoline Alkaloids

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38 39 40. 41 . 4 2. 43 . 44 45 . 46 47 48

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BY JAROSLAV STANEKAND R H F MANSKE . . . . . . . . . . . . . . . . . . Bisbenzylisoquinoline Alkaloids BY MARSHALL KULKA . . . . . The Cularine Alkaloids BY R . H F MANSKE . . . . . . . . or-Naphthaphenanthridine Alkaloids BY R . H . F MANSKE . . . . The Erythrophleum Alkaloids BY G DALMA . . . . . . . . The Aconitum and Delphinium Alkaloids BY E . S. STERN . . . .

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167 199 249 253 265 275

Contents of Volume V

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Narcotics and Analgesics BY HUGO KRUEGER Cardioactive Alkaloids BY E L MCCAWLEY RespiratoryStimulants BY MARCELJ DALLEMAGNE Antimalarials BY L . H . SCHMIDT. . . . . . . . . Uterine Stimulants BY A . K . REYNOLDS Alkaloids as Local Anesthetics BY THOMAS P . CARNEY Pressor Alkaloids BY K . K CHEN Mydriatic Alkaloids BY H R ING . . . . . . . . Curare-like Effects BY L . E . CRAIG The Lycopodium Alkaloids BY R . H F. MANSKE Minor Alkaloids of Unknown Structure BY R . H F MANSKE

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1 79 109 141 163 211 229 243 265 295 301

1 31 35 123 145 179 219 247 289

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Alkaloids in the Plant BY K MOTHES The Pyrrolidine Alkaloids BY LEOMARION Senecio Alkaloids BY N E L S ~JN LEONARD The Pyridine Alkaloids BY LEOMARION The Tropane Alkaloids BY G . FODOR The Strychnos Alkaloids BY J B HENDRICESON The Morphine Alkaloids BY GILBERTSTORK Colchicine and Related Compounds BY W C WILDMAN Alkaloids of the Amaryllidaceae BY W C. WILDMAN

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Contents of Volume V I I

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1 The Indole Alkaloids BY J . E SAXTON 201 The Erythrina Alkaloids BY V . BOEKELHEIDE Quinoline Alkaloids Other than Those of Cinchona BY H T OPENSHAW229 247 The Quinazoline Alkaloids BY H T OPENSHAW Lupin Alkaloids BY NELSONJ . LEONARD 253 Steroid Alkaloids: The Holarrhena Group BY 0. JECER AND V PRELOG . 319 Steroid Alkaloids: The Solanum Group BY V PRELOG AND 0. JEGER . 343 Steroid Alkaloids: Veratrum Group BY 0 JEGER AND V PRELOG. . 363 419 The Ipecac Alkaloids BY R . H F MANSKE 423 Isoquinoline Alkaloids BY R . H . F MANSKE Phthalideisoquinoline Alkaloids BY JAROSLAV STANBK 433 Bisbenzylisoquinoline Alkaloids BY MARSHALL KULKA . . . . . 439 The Diterpenoid Alkaloids from Aconitum. Delphinium. and Garrya 473 Species B Y E s STERN The Lycopodium Alkaloids BY R H F. MANSKE . . . . . . . 505 Minor Alkaloids of Unknown Structure BY R H F MANSKE 509

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CONTENTS O F PREVIOUS VOLUMES

Contents of Volume V I I I CHAPTER 1 1 The Simple Bases BY J . E . SAXTON. . . . . . . . . . . 2 Alkaloids of the Calabar Bean BY E COXWORTH. . . . . . . 27 47 3. The Carboline Alkaloids BY R . H F MANSKE. . . . . . . . 4 The Quinazolinocarbolines BY R . H . F MANSKE . . . . . . . 55 59 5. Alkaloids of Mitragyna and Ourouparia Species BY J E SAXTON . . 93 6. Alkaloids of Gelsemium Species BY J E . SAXTON. . . . . . . 7 Alkaloids of Picralima nitida BY J . E SAXTON . . . . . . . 119 8 Alkaloids of Alstonia Species BY J E SAXTON . . . . . . . 159 9 The Iboga and Voacanga Alkaloids BY W . I TAYLOR . . . . . 203 10 The Chemistry of the 2.2 '.Indolylquinuclidine Alkaloids BY W I . TAYLOR 238 11 The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids 250 by W I TAYLOR 12. The Vinca Alkaloids BY W I . TAYLOR. . . . . . . . . . 272 13 RouwolJia Alkaloids with Special Reference t o the Chemistry of Reserpine BY E . SCHLITTLER . . . . . . . . . . . . . . . 287 14 The Alkaloids of Aspidosperma. Diplorrhyncus. Kopsia. Ochrosia. Pleiocarpa. and Related Genera BY B . GILBERT. . . . . . . 336 15 Alkaloids of Calabash Curare and Strychnos Species BY A . R BATTERSBY and H F . HODSON. . . . . . . . . . . . . . . 515 16 The Alkaloids of Calycanthaceae BY R H F MANSKE . . . . . . 581 17. Strychnos Alkaloids BY G F SMITH. . . . . . . . . . . 592 18 Alkaloids of Haplophyton cimicidum BY J E SAXTON . . . . . 673 19 The Alkaloids of Geissospermum Species BY R H F. MANSKEAND W ASHLEYHARRISON . . . . . . . . . . . . . . . 679 20 Alkaloids of Pseudocinchona and Yohimbe BY R .H .F MANSEE . . . 694 . . . . . . 726 21 The Ergot Alkaloids BY A . STOLLAND A HOFMANN 22 The Ajmaline-Sarpagine Alkaloids BY W I TAYLOR 789

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Contents of Volume I X

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The Aporphine A l k a l o i d s ~MAURICE ~ SHAMMA . . . . . . . 1 The Protoberberine Alkaloids BY P. W JEFFS 41 STANEK . . . . . 117 Phthalideisoquinoline Alkaloids BY JAROSLAV Bisbenzylisoquinoline and Related Alkaloids BY M. CURCUMELLIRODOSTAMO and MARSHALL KULKA . . . . . . . . . . 133 Lupine Alkaloids BY FERDINAND BOHLMANN and DIETERSCHUMANN. 175 Quinoline Alkaloids Other Than Those of Cinchona BY H T OPENSHAW223 The Tropane Alkaloids BY G FODOR . . . . . . . . . . 269 Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V . ~ E R N P a n d F. SORM. . . . . . . . . . . . . . . . . 305 The Steroid Alkaloids : The Salamandra Group BY GERHARD HABERMEHL 427 Nuphar Alkaloids BY J . T . WROBEL 441 The Mesembrine Alkaloids BY A . POPELAE and G LETTENBAUER. . 467 The Erythrina Alkaloids BY RICHARD K HILL . . . . . . . . 483 Tylophora Alkaloids BY T . R . GOVINDACHARI 517 The Galbulimima Alkaloids BY E . RITCHIEand W . C. TAYLOR 529 . . . . . . . . . 545 The Stemona Alkaloids BY 0. E . EDWARDS

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xvi

CONTENTS OF PREVIOUS VOLUMES

Contents of Volume X CHAPTER

1 . Steroid Alkaloids: The Solanum Group BY KLAUSSCHRIEBER . . . . 1 2 . The Steroid Alkaloids: The Veratrum Group BY S . MORRIS KUPCHAN AND ARNOLD W. BY . . . . . . . . . . . . . . . . . 193 3. Erythrophleum Alkaloids BY ROBERT B . MORIN . . . . . . . 287 4. The Lycopodium Alkaloids BY D . B . MACLEAN . . . . . . . . 306 5. Alkaloids of the Calabar Bean BY B ROBINSON . . . . . . . 383 6. The Benzylisoquinoline Alkaloids BY VENANCIO DEULOFEU, JORGE COMIN, AND MARCELO J . VERNENGO. . . . . . . . . . 402 7 . The Cularine Alkaloids BY R . H . F . MANSKE . . . . . . . . 463 8. Papaveraceae Alkaloids BY R . H. F. MANSKE . . . . . . . . 467 9 . a-NaphthaphenanthridineAlkaloids BY R . H . F . MANSKE . . . . 485 10. The Simple Indole Bases BY J . E . SAXTON. . . . . . . . . 491 11 . Alkaloids of Picralima Nitida BY J . E . SAXTON . . . . . . . 501 12. Alkaloids of Mitragyna and Ourouparia Species BY J . E . SAXTON . . 521 13. Alkaloids Unclassified and of Unknown Structure BY R . H . F. MANSKE 545 14. The Taxus Alkaloids BY B . LYTHGOE . . . . . . . . . . 597

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THE DISTRIBUTION OF INDOLE ALKALOIDS IN PLANTS V. SNIECKUS Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada

I. Introduction.. ...................................................... 11. Indole Alkaloids of Plant Origin.. ...................................... A. Occurrence and Structural Features. ................................. B. Coverage and Organization of Tables.. ...............................

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References

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I. Introduction The publication of Volume VIII of this treatise afforded a timely opportunity t o examine the advances in indole alkaloid chemistry a t a stage which was immediately preceded, in a short five years, by the most intense and productive investigations that the field had ever experienced. At that time, a cursory examination of that volume revealed that the newly discovered compounds invariably offered minor variations from the previously known indole alkaloids and that, in many cases, they lent themselves t o a formal categorization according t o several basic structural types. I n general, the recent developments in the field tend t o support this observation although some notable exceptions are recognized. The increasingly successful application of mass and X-ray spectroscopic methods has been invaluable not only in the structural elucidation of minor indole alkaloids which exhibit subtle differences in oxidation state or functional group but has also yielded considerable information on new, possibly biogenetically significant, variations of known skeletal types. These variations a t times have been intriguing in that they represented distinct intermediate stages in an overall biosynthetic scheme for the production of a particular structural type ( I ) .The above physical methods have also yielded important information in the advancement of our structural knowledge of the dimeric indole alkaloids. These mslecules are steadily accumulating and offer the opportunity for biogenetic speculation. This process a t times still leads to valuable 1

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V. SNIECKUS

insight into the biosynthetic pathways which may be available to these indole alkaloids. However, most of the dimeric indole alkaloids whose structuies are now fully elucidated clearly exhibit in their complex architecture the skeletal features of the well-known monomeric indole alkaloid types. Some of the above considerations led to the proposal" which has resulted in this compilation of plant species and the classification according to their contained indole alkaloid structural types. The key t o this classification is derived from the recent biosynthetic work of Arigoni (Z), Battersby ( 3 , 3 a ) Leete , (a),and Scott ( 5 ) ,and their respective co-workers which, in its infancy when Volume V I I I of this series was in publication, now presents conclusive evidence concerning the origin of the complex indole alkaloids in plants (5a). 11. Indole Alkaloids of Plant Origin

A.

OCCURRENCE AND STRUCTURAL FEATURES

Alkaloids are most widely distributed among flowering plants and rarely occur in animals, simple vascular plants, mosses, ferns, fungi, and algae. Indole alkaloids are no exception to this general observation. Since tryptophan is recognized as a main constituent of plant proteins and as a common biogenetic precursor of the complex indole alkaloids, the wide occurrence of tryptamine derivatives in the plant kingdom is not unexpected. The presently known cases of these simple indole alkaloids have been ones in which a tryptamine unit formally appears as a slightly modified structure (e.g., by oxidation or methylation), as a cyclized form or a dimeric variation thereof, or as a modification which incorporates short carbon chains (e.g., Cq, C2) or a simple aromatic structure (anthranilic acid) respectively. The great majority of the simple indole alkaloids are confined to the dicotyledon plants. It is reasonable then that the complex indole alkaloids also mainly inhabit the dicotyledones. Moreover, as has been pointed out by Le Men and Taylor (6) they occur most frequently in the Apocynacege, Loganiaceae, and Rubiaceae plant families. A few representatives of this remarkable group have also been found in phylogenetically more remote families such as Annonaceae, Euphorbiaceae, and Sapotaceae. The questionably related Alangiaceae and Icacinaceae families are the most recent additions to the list of plants which contain complex indole alkaloids. The structural features of this cIass are a tryptamine unit *The proposal was advanced by Professor A. R. Battersby in conjunction with suggestions by Dr. B. Gilbert.

1. THE

DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

3

which is usually unmodified and easily recognized and a versatile C9 or Clo unit which a t times resemblesnaturally occurring cyclic monoterpenes and which until recently offered perplexing problems in the definition of its biosynthetic origin (see below). These basic features are also evident in the dimeric complex indole alkaloids although their contained monomeric segments may be linked in a biosynthetically unpredictablefashion. Until such time when the biosynthetic pathways of the complex indole alkaloids have been completely defined their full taxonomic value cannot be appraised. However, a number of recent reviews ( 7 , 8 )indicate that chemotaxonomic considerations in this area have been aided by the rapid progress made in the chemistry and biosynthesis of the various indole alkaloids. Furthermore, the latter two disciplines have benefited from the former in the search for new alkaloids and in the elucidation of biosynthetic pathways. I n the future it is expected that many advances in indole alkaloid chemistry will often arise as a result of the convergence of biochemical and chemical research efforts (9).

B. COVERAGE AND ORGANIZATION OF TABLES The present compilation derives a great deal of its content from previous tabulations and reviews. Extensive use has been made of Volumes 11, 111, V, VII, and V I I I of this treatise, the comprehensive volume of Boit (IO),and the tables of Willaman and Schubert (11),Hesse ( 1 2 ) ,and Holubek and Strouf (1%). Hesse's useful publication covered the literature to the end of 1963. The present tables extend the coverage of known indole alkaloids through May, 1967 Chemical Abstracts with an inclusion of some references from more current major journals. I n the tables are given only recent references which directly pertain to alkaloid isolation and structural elucidation and which have not appeared in the above tabulations and reviews. The absence of reference number for particular alkaloid types implies that the original paper(s) may be found by searching the indexes of these works under the corresponding plant species which contain them. The presentation of the tables follows, first of all, a major division into simple and complex indole alkaloids (Tables I and 11, respectively). Each table then lists, in alphabetical order, the plant families and genera in which specific indole alkaloids are found. These, in'turn, have been coded by letter, sometimes somewhat arbitrarily, into different structural types : Fig. 1 corresponds to structural types found in Table I and Figs. 2 and 3 correspond to structural types found in Table 11.The appearance of question marks in the tables, either alone or after a letter, implies that

4

V. SNIECKUS

the presence of a particular type in the juxtaposed plant species is not certain or that its structural elucidation is not complete. The authorities of the recently investigated species have been checked against Index Kewensis. Those authorities which have been listed in the previous volumes of this treatise and other compilations (10-12a) have been accepted. A question mark after a particular genus indicates that it is absent in Index Kewensis or that the inaccessibility of original literature prevented its complete definition. 1. Table I Table I is a compilation of plant species which contain the simple indole alkaloid types of Fig. 1. As mentioned earlier, the main requirement for the inclusion of a certain simple indole alkaloid into Table I is that it contain a tryptarnine unit as a readily distinguishable feature in its structure. That tryptamine is a precursor in the biosynthesis of many of the b , c, d , and e type simple indole bases is yet to be shown although it is felt that future work will prove the correctness of such a view. Gramine, the simplest indole alkaloid, has been included in the tryptamine classification a because it is biosynthetically related to tryptophan ; cryptolepine has been likewise included therein although its structural relationship to tryptophan appears more obscure (Volume VIII, Chapter 1, pp. 4,19). The calycanthine type does not possess a tryptamine structure but it is included in the simple indole alkaloid b classification since most of its congeners are tryptamine derivatives and since it exhibits a close biogenetic relationship to this latter (chimonanthine) type (Volume VIII, Chapter 16). Type d is represented by the small number of the socalled canthin-6-one alkaloids (Volume VIII, pp. 250-252, 497-498). The most recent variation of the simple indole alkaloids is found in the Anacardiaceae family. Its indoloquinolizidinenucleus suggests inclusion with type d on the basis of structural and biogenetic similarity. Finally, simple indole alkaloid type e is composed of the well-defined evodiamine (rutaecarpine) structural form (Volume VIII, Chapter 4).

2. Table 11 Table I1tabulates the plant species which contain the complex indole alkaloids. The letters in this table correspond t o the various structural types as coded in Figs. 2 and 3. Types I, 11,and I11 are the major variations of the Cs-C, 0 unit which, in combination with tryptamine, formally elaborate the three significantly different groups of' complex indole alkaloids : Corynanthe, Iboga, and Aspidosperma. Such initial classification follows the outline set by Battersby (3, 3a) and others (2, 4,5 ) . The

1. TEE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

b

5

c

FIQ. 1. The simple indole alkaloids. Letters define these schematic representations in Table I.

6

V. SNIECKUS

? 0

Ia

Ib

Id

Ib, Corynanthe type

Ic

Ie

FIG.2. The complex indole alkaloids. Schematic representations of the structural type I unit. The Roman numeral-letter combinations serve to define these skeletal variations in Table 11.

1. THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

Ih

Ih

0y.J Ik

11, Ipecacwnha type

7

8

V. SNIECKUS

ubiquitous C9-Clo moiety is schematically shown by heavy lines in the structures of Figs. 2 and 3. Further division by letter is intended t o aid in distinguishing relatively minor skeletal variations within each type. Two similar skeletons are coded by the same letter if, in going from one to the other, there is observed one carbon-carbon or carbon-oxygen bond cleavage or formation or other slight modification (e.g., type IIIa, Fig. 3). Where convenient, such changes are represented by dotted lines in a single structure (e.g., type I I I b , Fig. 3).

Type 1 Corynenthe

Type I1 Iboge

Type I11 Aspidosperma

For reasons of brevity, some skeletal variations are not clearly defined in Figs. 2 and 3 and some have been omitted. I n particular, the picraline (Volume VIII, p. 147), the echitamine (Volume VIII, p. 174) (78), and the aspidodasycarpine (53) skeletons have been merged into type If. The new alstophylline type (39, 40) is somewhat hidden in the Id reprepresentation. Gelsemine (Volume VIII, p. 95) has been included in the oxindole type Ic. Type IIa (Iboga) includes several closely related rearranged alkaloids (Volume VIII, Chapter 9) which are not shown in Fig. 3. An unusually modified Aspidosperma structure (83) is related to type IIIb and is listed as such. The dimeric complex indole alkaloids are coded simply on the basis of the two monomeric types (Figs. 2 and 3) which are part of their architecture. I n this manner no complete structural definition as to their exact interactions is possible but at least their probable biogenetic origin may be readily recognized. That the complex indole alkaloids contain a tryptamine unit is a requirement which is not always met at first sight. For example, some alkaloids from the Cinchona. and Remijia species (Rubiaceae) (Volume VIII, Chapter 10; type Ij, Fig. 2) contain quinoline rings in their overall structures. Nevertheless, it has been shown that tryptophan is readily incorporated into these alkaloids and on this basis they are justly included in Table 11.Furthermore, there are a number of complex alkaloids belonging to some Aspidosperma species (Apocynaceae) which seem to have lost the ethylamine side chain of a tryptamine unit (type Ik,Fig. 2).

1.

THE DISTRIBUTION OF INDOLE ALKALOIDS IN PLANTS

TABLE I

PLANTS AND THEIRCONTAINED INDOLE ALKALOID TYPES: ALKALOIDS THE SIMPLEINDOLE Type" (Reference)b

Plant ~

Aceraceae Acer rubrum L. Acer saccharinum L. ( = Acer dasycarpum Ehrd.) Amanitaceae Amanita citrina Pers. Amanita mappa Batsch Amanita muscaria L. Amanita pantherina DC. Amanita porphyria? Amanita tomentella?

a a a (15) a a a a (15) n

Amaranthaceae Charpentiera obovata Gaudich. Anacardiaceae Dracontomelum mangiferum B1. Apocynaceae Aspidosperma polyneuron Muell. Arg. Qonioma kamassi E. Mey. Pleiocarpa mutica Benth. Pleiocarpa tubicina Stapf. [Pleiocarpapycantha (K. Schum) Stapf var. tubicina (Stapf) Pichon] Preston& amazonicu (Benth.) Macbride ( = Haemadictyon amazonicum Benth.)

a

Araceae Syrnplocarpus foetidus Nutt.

a

Aslepidaceae Cryptolepis sanguinolenta (Lindl.) Schlechter Cryptolepis triangularis N.E .Br.

a a

d

Bignoniaceae Newbouldia laevis Benth. et Hook. f. Bromeliaceae Ananas sativus Schult. Calycanthaceae Calycanthus Jloridus L. Calycanthus glaucus Willd. Calycanthus occidentalis Hook. et Am. Chimonanthusfragrans Lindle ( = Meretia praecox Rehd. et Wils.) Meratia praecoz Rehd. et Wils. (see Chirnonanthus fragrans Lindle)

a

b b b b

9

10

V. SNIECKUS

TABLE 1-ontinued Plant

Typea (Reference)"

Caricaceae Carica papaya L. Chenopodiaceae Arthrophytum leptocladum M. Pop. Girgensohnia diptera Bunge Hammada leptoclada (Popov) njin. ( = Anthrophytum leptocladum) Convolvulaceae Ipomoea violacea Linn. Coprinaceae Coprinus micaceus Bull. Panaeolus acuminatus (Schff. ex Fr.) Qu6let Panaeolus campanulatus (Fr.) Qudet Panaeolus foenesecii Pers. [ =Panaeolina foenesessi (Pers.) R. Mre.] Panaeolus fontinalis? Panaeolus gracilis? Panaeolus semiovatus Fr. [ =Anellaria semiowata (Sow.) Pears. et Denn.] Panaeolus solidipes? Panaeolus sphinctrinus? Panaeolus subalteatus Berk. et Br. Panaeolus texensis? Cyperaceae Carex brevicollis DC.

C

Dilleniaceae (Polygonaceae) Calligonium alatum? Caligonium caput-medusae Schrenk Calligonium eripodum Bunge Calligonium macrocarpum Borszcz. Calligonium minimum Lipski Elaeagnaceae Elaeagnus angustifolia L. Elaeagnus hortensis Bieb. ( =Elaeagnus angustifolia L.) Elaeagnus orientalis L. ( =Elaeagnus angustifolia L.) Elaeagnus spinosa L. ( =Elaeagnus angustifolia L.) Euphorbiaceae Hippomane mancinella L.

C

C C

C

1. THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS TABLE I-continued Plant

Type" (Reference)6 ~

Gramineae Arundo donax L. Hordeum vulgare L. Phalaris arundinacea L. Phalaris tuberosa L. Lauraceae Persia gratissimu Gaertn. Legumilosae Abrus precatorius L. Acacia acuminata Benth. Acacia cardiophylla A. Cunn. ex Benth. Acacia confusa Merrill Acacia cultiformis A. Cunn. ex G. Don Acaciafloribunda Willd. (=Acacia longifolia Willd.) Acacia Zongifolia Willd. (see Acacia floribunda Willd.) Acacia maidenii F. Muell. Acacia podalyriaefoliu A. Cunn. Acacia pruinosa A. Cunn. ex Benth. Acacia vestita Ker-Gawl. Desmodium pulchellum Benth. ex Baker Dioclea bicolor Benth. Dioclea lasiocarpa Benth. Dioclea macrocarpa Huber Dioclea reflexa Hook. f. Dioclea violacea Mart. ex Benth. Erythrina abyssinica Lam. Erythrina acanthocarpa E. Mey. Erythrina americana ( =Erythrina carnea Ait.) Erythrina berteroana Urb. Erythrina costaricensis M. Micheli Erythrina cristugnlli L. Erythrina dominguezii Hassler Erythrina excelsa Baker Erythrina falcata Benth. Erythrina Jlabelliformis Kearn. Erythrina folkersii Krukoff et Moldenke Erythrina jusca Lour. Erythrina glauca Willd. Erythrinu grisebachii Urb. Erythrina herbacea L. Erythfina hypuphorus Boerl. ex Koord. Erythrina macrophylla DC.

11

12

V. SNIECKUS TABLE 1 4 o n t i n u e d

Plant

Leguminosae-continued Erythrina orophila Ghesq. Erythrina pallida Britton et Rose Erythrina poeppigiana 0. F. Cook Erythrina rubrinerva H.B. et K. Erythrina sandwicensb Degner Erythrina senegalensis DC. Erythrina subumbrans Merrill (Hypaphorus subumbrans Hassk.) Erythrinu th.ollonkna Hua Erythrina variegata L . vm. orientalis ( = indica Lam.) Erythrina velutina Willd. Lens esculenta (Moench)Meth. Lespedeza bicolor Turcz. var. japonica Nakai Lupinus albus L . Lupinus angustijolius L. Lupinus luteus L. Lupinus polyphyllus Lindl. Mimosa hostilis Benth. Mucuna pruriens DC. Petalostylis labicheoides R. Br. Physostigmu cylindrospermum Holmes Physostigma venenosum Balf. Piptadenia colubrina Benth. Piptadenia excelca Lillo Piptadenia jalcata Benth. Piptadenia macrocarpa Benth. Piptadenia peregrina Benth. Prosopsis juliflora DC.

Typeu (Reference)b

a a

Loganiaceae Strychnos melinoniana Baill.

C

Malphighiaceae Banisteria caapi Spruce Banwteriopsis inebrians Morton Cabi paraensis Ducke

C

C C

Malvaceae Abelmoschus esculentus (Moench)Meth. Gossypium hirsutum L. ( =herbaceurn L.)

a

Musaceae M u s a paradisiaca L.(see M u s a sapientium L.) Musa sapientium L.

a

a (30a)

1.

13

THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

TABLE I-continued Plant Passifloraeae Passijora actinea Hook. Passijora alata Ait. Passijora alba Link et Otto Passijora bryonioides H .B.K Passijora capsularis L. Passijora edulis Sims. Passijora eichleriana Mast. Passijorafoetida L. Passijora incarnata L. Passijora quadrangularis L. Passijora ruberosa?

Type" (Reference)b

. a L:

c C

Polygalaceae Polygala tenuifolia Willd. ?

a

Rosaceae Prunus domestica L.

a

Rubiaceae Arariba rubra Mart. (see Sickingia mbra K. Schum.) Hodgkinsonia jrutescens F. Muell. Leptactina densijora Hook. f. S'ickingia rubra K. Schum (Arariba rubra Mart.) Rutaceae Citrus aurantium L. Ewodia alata F. Muell. Ewodia rutaecarpa Hook. f. et Thoms. Hortia arborea Engl. Hortia braziliana Vel. Pentaceras australis Hook. f. Zanthoxylum (Xanthoxylum)budmnga Well. (see Zanthozylum rhetsa A. DC.) Zanthoxylum oxyphyllum Edgew. Zanthozylum rhetsa A. DC. (Zanthoxylum budrunga Wall.) Zanthoxylum suberosum C . T. White Simarubaceae Dictyolama incanescens DC. ( =Dictyolama vandellianum A. Juss.) Picrasma ailanthoides Sieb et Zucc. Picrasma crenata (Vill.)Engl.

b C C

a

C

e e

a d d

14

V. SNIECKUS TABLE I-continued

Plant

Type" (Reference)b

Solanaceae Lycopersicum esculentum Mill. Solanum melongena L. Solanum nigrum L. Strophariaceae Psilocybe atrobrunnea? Psilocybe aztecorum Heim Psilocybe baeocystis Singer e t Smith Psilocybe coerulescens Murr. var. muzntecorum Heim Psilocybe caevulipes? Psilocybe cyanescens ? Psilocybe mexicana Heim Psilocybe semperviva Heim e t Cailleux Psiloc ybe st ricticeps ? Psilocybe zapotecorum Heim Stropharia cubensis Earle Symplocaceae Symplocos racemosa Roxb. Urticaceae Urtica dioica L.

C

a

2yogophyllaceae Peganum h a m a l a L. Zygophyllum fabago L. Zygophyllum elephantiasis?

Letters refer to the alkaloid types as coded in Fig. 1, p. 5 . References are given for those alkaloids whose isolation and/or structural elucidation has been recorded since the publication of previous major compilations and reviews (see references 10-12a, and Volumes 11,111, V, VII, and VIII in this treatise).

TABLE I1 PLANTS AND THEIRCONTAINEDINDOLE ALKALOID TYPES: THECOMPLEX INDOLE ALKALOIDS Typea (Reference)b Monomeric

I

Plant Alangiaceae Alangium lamarckii Thw. Alangium salviifolium Wangerin (Grewia salviifolia Linn. f.) Annonaceae Enantia pilosa Exell. Enantia polycarpa Engl. et Diels ( =X y b p i a polycarpa Oliver) Apocynacerte Alstonia actinophylla (Cunn.)K. Schum. f. Alstonia angwtiloba Mig. Alstonia congensis Engl. Alstonia constricta F. Muell. Alstonia gilletii De Wild. Alstonia mmrophylla Wall. Alstonia Alstonia Alstonia Alstonia Alstonia

neriifolia D. Don muelleriana Domin. scholaris R. Br. somersetensis F. M. Bailey spathulata Blume

I1

Dimeric I11

IGSC (373 ?

J’

(38)

J’ (38) ?

f f, h a , b, h

f c, d (39, 40)

Id-Ig (413, Id-Id (39)

Ig-?

f

8

TABLE 11-continued

Typea (Reference)b Monomeric

I

Plant Apocynaceae-continued Alstonia spectabilis R . Br. Alstonia venenata R. Br.

Alslomia verticilZosa F. Muell. Alstonia villosa Blume Amsonia angustifoZia Michx. Amsonia e l l i p h a Roem. et Schult. Amsonia tabernaemontana Walt Aspidosperma album Vahl. (R. Benth. ex M. Pichon) A. auriculatum. Mgf. A. australe Muell. Arg. A. carapanauba M. Pichon A. chakensk Spegazzhi A. comptinervium. Kuhlm. A. cylindrocarpon Muell. Arg. A. dasycarpon A. DC. A. discolor A. DC. A. dispersum Muell. Arg. A. duckei Hub. A. eburneum Fr. Allem. ex Sald. ? A. exalatum Monachino A. exce2surn Benth. A. fendleri Woods.

Dimsric

I1

I11

f a (43-46), b, c

b (44, 46, 47), c (44, 4 6 )

f Id-Ig ( 4 8 )

a (49) U

b k C

k h (52)

b c (52) b

d , f (53),k (14, 53a, 5 4 ) a, b (54a) ? (55a) c (56)

6, k (52, 53a) a (56b)

b b (56a) ? (57)

c

A . gomezianum A. DC. A . hihrianurn Muell. Arg. A . l i m e Woods. A . longipetiolatum Kuhlm. A . macrocarpon Mart. A . mrcgravianurn Woods. A. megalocarpon Muell. Arg. A. multijlorum A. DC. A . neblinae Monachino A . nigricans Handro A . nitidum Benth. ex Muell. Arg. A. oblongurn A. DC. A . obscurinervium Azambuja A. olivaceum Muell. Arg. A. parvifolium A. DC. A . peroba F. Allem. ex Sald. A . polyneuron Muell. Arg. A . populijolium A. DC. A. pyricollum Muell. Arg. A. pyrijoliurn Mart. A . quebrachoblanco Schlecht. A . p i r a n d y Hassl. A . rejractum Mart. A . rigidum ( A .luxiJZormmKuhlm) Rusby A . sandwithianurn Mgf. A . sessilijorurn F. Allem. A . spegazzinii Molf. ex Meyer Aspidosperm spp. A . spruceanurn Benth. A . subincanum Mart. ex A. DC. A . tornentosum Mart. A . tritemuturn Rojas Acosta

k ( 5 2 , 53a) d i (59) k

b

c (56)

b (59a)

b (59a) b

k (52, 53a)

c

c

b

k (52, 59a) b (59a) a (59b),b k k a

0

w

a, d i a (61),h (59a),k (61) a, e, i

b b b b

k i, k (59a)

TABLE II-continued Typea (Reference)* Monomeric

I

Plant Apocynaceae-continued A . ulei Mgf. A . verbascifolium Muell. Arg. Callichilia (Hedanthera) barteri (Hook. f.) Pichon Callichilia stenosepala Stapf Callichilia subsessilis Stapf Catharanthus lanceus Boj. ex A. DC. (see Vinca lancea K. Schum.) Catharanthus pusillus (Murr.) G . Don [ = Vinca pusilla Murr., = Lochnera pusilla (Murr.) K. Schum.] Catharanthus roseus (L.) G . Don (see Vinca rosea L.) Catharanthus tricholophyllus (Baker) Pichon Conopharyngia durissima Stapf ( =Plumeria durissima Hort.) Conopharyngia holstii Stapf G . Don ( =Tabernaemontana holstii) Conopharyngia jollyana Stapf G . Don ( =Tabernaemontana joUyanu Pierre ex Stapf) Diplorrhyncus condylocarpon (Muell. Arg.) Pichon ssp. mssambicensw (Benth.) Duvign. Ervatarnia coronaria Stapf (see Tabernaemntana coronaria Willd.)

I1

Dimeric

I11

k

d?

a, d, h, i

IIIb-IIIb (65) I I I b - I l I b (66)

c

Ervatamiu dichotma Roxh. Ervatamia divaricata Burkill Excavatia coccinea (T. e t B.) Gabunia eglandulosa Stapf Cabunia odoratissima Stapf Geissospermum laeve Baill. ( = Geissospermum vellossii Allem.) Geissospermum serkeum Benth. et Hook. f. Geissospermum vellosii Allem. ( =Tabernaemontam laevis Vell.) Gonioma kamussi E. Mey. Haplophyton cimicidum A. DC. Hunteria corymbosa Roxb. Hunteria eburnea Pichon

a , b, k ( 7 0 ) d

(74

? (71)

w

b

Ib-Ih b, d , h d ( l a ) ,g ( 1 8 )

f' a, b ( 7 4 , 75), c,

a ( 7 4 , 75), c ( 7 5 ) 0

f , 9 (761, h Hunteria umbellata (K. Schum.) Hall. f. (Carpodinus umbellatus K. Schum., Polyadoa umbellata Stapf, Picralimu umbellata Stapf) f (77, 7 8 ) Kopsia albijlora Boerl. ( =Kopsiajlavida Blume) Kopsia arborea Blume Kopsia $avida Blume (see Kopsia albijlora Boerl.) Kopsia fruticosa (Ker.) A. DC. (=Kopsia pruniformis Reichb. f..et Zoll. ex Bakh. f.) Kopsia longijlwa Merrill Kopsia pruniformis Reichb. f. et Zoll. ex Bakh. f. [see Kopsiu fruticosa (Ker.) A. DC.] Kopsia singapurensis Ridley Lochnera lancea Boj. ex A. DC. [see Vinca lancea Boj. (ex A. DC.) K. Schum.1 Lochnera pusilla (Murr.) K. Schum. [see Catharanthus p u ~ i l l u s(Murr.) G. Don] Lochnera rosea Reichb. (see V'inca rosea L.)

w

c

(79)

bw

C

c

(80, 8 1 )

C

C

cd

E

3

m

w

W

Is

TABLE 11-continued

0

Type" (Reference)b Monomeric Plant

I

Dimeric

I11

I1

Apocy naceae-continued Macoubea guianensis Aubl. Mclodinus australis F. Muell. Melodinus scandens Forst. Ochrosia elliptica Labill. Ochrosia glomerata Valeton Ochrosia moorei F. Muell. Ochrosia oppositifolin K. Schum. ( = Ccrberu oppositi,folinLam.) Ochrosia poweri Bailey Ochrosia sandwicensis A. DC. Peschiera a$& (Muell. Arg.) Miers (see Tabcrnaemontana a$& Muell. Arg.) Picraliina klaineana Pierre [see Picralima nitida (Stapf) Th. et H. Durand] Picralima nitida (Stapf) Th. et H. Durand (Picralima klaineanu Pierre)

Picralima umbellatu Stapf [see Hunteria umbellata (K. Schum.) Hall. f.] Pleiocarpa fivescens Stapf. Pleiocarpa mutica Benth. Pleiocarpa tubicina Stapf.

4

c

a, c (88-91) b (93, 96),c (961, d (97)

m a - I I I c (92)

Pleiocarpa pycnnnthn (K. Schum.) Stapf. var. tubicina (Stapf.) Pichon RnzcioolJia cifinis Muell. Arg. R. uinsoniciefolia A. DC. R. bnhiensis A. DC. R. beddomei Hook. f. R. boliviunu Mgf. R. cntffa Sand. ( = R. natalensis Sand., R. welwitschii Stapf) R. cnmbodiana Pierre ex Pitard R. canescens L.( = t e t m p h y l h ) R. chinensis Hemsl. R. cubana A. DC. R. cummunsii Stapf R. decurva Hook. f. R. degeneri Sherff R. densijlora Benth. ex Hook. f. R. discolor?

a, b a, b? a, b b, d a , b, e

+ Y

ti

s

u,

Y

a, b, e a, b a (981, b, d , e a , b, e a, b

eB

u

4

b, d b, e n, d , e b (991, e (99)

!3

0

!4

0

Lltr

(I,

R. fruticosa Burck. a , b, e R. grandijora Mart. ex A. DC. a, b ri, b, d , e R. heterophylla Roem. et Schult. ( = tetrophyllo) R. hirsuta Jacq. ( = R. cfiizescens L.) a , b, d R. indecora Woods. a , b, d, e R. inebrians K. Schurn. ( =crijj”ra?) a, b R. javaniea Koord. et Val. a, b, d R. lamarckii A. DC. ( = R. uzridis Roem. et Schult.) a, b R. Zigustrina Willd. ex Roem. et Schult. a, b, d, e R. littoralis Rusby ( R . mcicrocnrpa Stapf) 0,b U R. longeacuminutn de Wild. et Th. Dur. R. Zongifolia A. DC. [see ToiLduzia Zongifolia (A. DC.) Mgf.1

b ( 9 6 ) ,c (94-96), d (96)

h (96),i (96)

a (99)?

0 F M

kL R

El Ll w

F

2

u,

fs w

E3

TABLE II-continued

E3

Typea (Reference)* Monomeric Plant Apocynaceae-conti?aued R. mncrocnrpn Stapf (see R. littoralis Rusby) R. inacrophylln Stapf R. mannii Stapf R. mnttfeldinnn Mgf. R. mnuiensis Sherff R. micrnntk Hook. f. R. micranthn? R. mombasiana Stapf R. nnna E. A. Bruce R. natalensis Sond. (see R. caffra Sond.) R. nitida Jacq. R. obscura K. Schum. R. paraensis Ducke R. pentnphyllu Ducke R. pernkensis King et Gamble

R. rosen K. Schum. R. salicifolia Griseb. R. sandwicensis A. DC. R. sarapiquensis Woods. R . schueli Spegazzinii R. sellowii Muell. Arg. R. semperjorens Schlecht.

I

I1

Dimeric I11

Ib-Ib

a ( l o o ) ,b a, b, e a, b a, b a, b, d (101, 102), e (102) a, b a, b a, b, e a a, b, e a, b, e e?

c

R. serpentina (L.) Benth. ex Kurz R. sprucei Muell. Arg. R. sumatrana (Miq.) Jack R. ternijolia HBK. ( = Zigustrina) R. tetraphylla L. R. verticillata (Lour.) Baill. 1 R. viridis (Muell. Arg.) Guillaumin R. vomitork Afz.

R . welwitsehii Stapf ( = R . caffra Sond.) R. yunnaneneis? Rejoua aurantiaca Gaudich. Rhazya strictu Decaisne Schizozygia caffaeoides (Boj.) Baill. Stemmadenia donnell-smithii (Rose) Woods. Stemmadenia galeottiana (A. Rich.) Miers Stemmadenia pubescens Benth. (Stemmadenia obovata K. Schum.) Stemmadenia tomentosa Greenman var. palmeri Tabernaemontana afinis Muell. Arg. [Peschiera affhnis (Muell. Arg.) Miers] Tabernaemontana alba Mill. or Nickolson (Tabernaemontana citrifolia L.) Tabernaemontana arnygdalifolia Sieber ex A. DC. Tabernaemontana australis Muell. Arg. Tabernaemontana coronaria Willd. (Ervatamia coronuria Stapf) Tabernaemontana fuchsiaefolia A. DC. Tabernaemontana heyneana Wall. Tabernaemontana lnevis Vell. (see Geissospermum vellosii Allem.)

a, b, d, e a, b a, b, d, e a, b a, b, e a, b U

a (103, 104), b ( 1 0 5 ) , c (103, lo?'), d ( 1 0 6 ) , e ( 9 8 ) , f (107) e a ( 1 0 8 ) ,b ( 1 0 8 ) a (109,110)

h, i

U

IIIb-IIIb ( 1 0 9 , 1 1 0 ) a, b a (112) b

0 4

Id-IIa

U

b, h, i h, i

U U

b b

d (113, 113a) b b (114) Id-IIa d d (116)

a (115) a (69, 117)

TABLE 11-continued Typeo (Reference)b Monomeric

I

Plant Apocynaceae-continued Tabernaemontana laurifolia Blanco? Tabernaemontana mucronata Merrill Tabernaemonta,naoppositqolia Urb. Tabernaemontana pachysiphon Stapf var. curnminsii H. Huber Tabernaemontana pandacaqui Poir. Tabernaemontana psychotrifolia H.B. et K. Tabernaemontana rupicola Benth. Tabernanthe iboga Beill. Tonduzia longiifolia (A. DC.) Mgf. (Rauwol&~ Zongifolia A. DC.) Vallesia dichotoma Ruiz e t Pav.

Vallesia glabra (Cav.) Link Vinca diffomis Pouvr. Vinca erecta Rgl. et Schmalh.

Vinca herbacea Waldst e t Kit. var. libanotka (Zucc.) Pichon

Dimeric

I1

i11

a (118) a (115)

c

Id-IIa

U

:8 v1

d (119), k h (120)

a,

a a a a a

(119) (115, 121)

b (119) b (120)

Id-IIa (122) (123)

IIa-IIa

b, e

a ( 1 2 4 ) ,b (125), d ( 1 2 5 ) ,h ( 1 2 5 ) , i ( 1 2 5 ) ,k ( 1 2 5 ) d ( 1 2 6 ) ,e ( 1 2 7 ) b ( 1 2 8 ) ,c (129), d ( 1 2 8 ) ,e (130), f (1291, h ( 1 3 1 )

b (132, 133), c ( 1 3 3 )

b ( 1 2 5 ) ,c ( 1 2 5 )

b a, b a ( 1 2 9 ) ,c (129, 132)

(lzq

2

Vinca lanrea Boj. (ex A. DC.) K. Schum. (Lochnera lancea K. Schum., Catharanthus lanceus Boj. ex A. DC.) a ( 1 3 4 ) ,b ( 1 3 4 ) , c (135, 136) Vinca major L. b ( 1 3 7 ) ,c ( 1 3 8 ) , d ( 1 3 9 ) , e,f Vinca minor L. a (141) Vinca pubescens Urv. (see Vinca major L.) Vinca pusilla Murr. [see Catharanthus pusillus (Murr.) G. Don] Vinca rosea (L.) Reichb. [Catharanthusroseus (L.) G. Don, Lochnern rosen Reichb.] a , b ( 1 4 3 ) ,c, d ( 1 3 6 ) , f ,h Vinca rosea var. alba? a d Voacanga a~ricanaStapf ex 8 . Elliot

b a (140) a (141, 142), b

U

a

Voacanga bracteata Stapf

a (153, 154)

Voacanga chalotiana Pierre ex Stapf d (155) Voacanga dregei E . Mey. d Voacanga globosa Merrill (Tabernaemontana globosa)

U

a (156)

Euphorbiaceae Alchornea Joribunda Muell. Arg. Alchornea hirtella Benth.

U

a?

b (144, 145), d (146)

Id-IIb ( 1 4 7 ) IIa-IIIb (148-151) Id-IIa ( 1 5 2 ) , IIIb-IIIb ( 6 5 ) Id-IIa (154)? IIIb-IIIb?

a (110) a 1159)

I d - I I a (156, 157), another? Id-IIa ( l a ) , another? Id-IIa ( 1 1 0 ) Id-IIn ( 1 5 9 )

U

Id-&

Voacanga megacarpa Merrill Voacanga papuann (F. Muell.) K. Schum. Voacanga schweinfurthii Stapf Voacanga thousarsii Roem. et Schult. var. obtusa Pichon

IIa-IIIb ( 1 3 4 )

TABLE II-continued

Typen (Reference)b Monomeric

I

Plant Loganiaceae Calebassen-Curared Gelsemiurn elegans (Gardn.) Benth. Gelsemiurn sernpervirens Ait. Gelsemiurn rankinii Small Mostuea buchholzii Engl. Mostuea stimulans A. Chev. Strychnos aculeata Solered. Strychnos amazonica Kruk. Strychnos chlorantha Prog. Strychnos cinnarnornijolia Thw. Strychnos colubrim L. Strychnos diaboli Sandwith Strychnos divaricans Ducke Strychnos jroesii Ducke Strychnos gaultheriana Pierre ex C. B. Clarke (=Strychnos rnalaccensis Benth.) Strychnos guianensis Baill. Strychnos henningsii Gilg Strychnos holstii Gilg ex Engl. var. reticulata f. condensata Strychnos icaja Baill. Stryehnos ignatii Berg. Strychnos kipapa Gilg

I1

Dimeric

I11

Ih-Ih (160)

Ih-Ih Ih-Ih h

h? h (163) h (164)

h (165) h (166) h

Strychnos KL 1929 Strychnos lanceolaris Miq. Strychnos ligustrina Blume Strychnos lucida R. Br. Strychnos macrophylla Barb. Rodr. Strychnos malaccensis Benth. (see Strychnos gaultheriana Pierre ex C. B. Clarke) Strychnos melinoniana Baill. Strychnos mitscherlichii R. Schomb. (Strychnos smilacina Benth.) Strychnos nux-vomica L. Strychnos psilosperma F. Muell. Strychnos quaqua Gilg Strychnos rheedei C. B. Clarke Strychnos rubiginosa A. DC. Strychnos smilacina Benth. (see Strychnos mitscherlichii R . Schomb.) Strychnos solimoesana Kruk. Strychnos splendens Gilg Strychnos subcordata Spruce Strychnos ticut4 Lesch. Strychnos tomentosa Benth. Strychnos toxijera R. Schomb. Strychnos trinerwis (Vell.)Mart.

Ih-Ih

U

z

0

r

Ih-Ih

Ih-Ih Ih-Ih Ih-Ih

Icacinaceae Cassinopsis ilicifolia Kuntze Rubiaceae Adina cordifolia Hook. Adina rubrostipulata K. Schum. (see Mitragyna rubrostipulacea Havil.) Antirrhea putaminosa (F.v. Meull.) Baill.

11-Sc (170) C

b (170a)

E3

T A B L E 11-continued Type" (Reference)* Monomeric Plant Rubiaceae-continued Cinchona calkaya W e d d . Cinchona caloptera Miq. Cinchona carabayensis W e d d . Cinchona conduminea Humb. e t Bonpl. (=Cinchona o f l i n a l i s L.) Cinchona cordifolia Mutis (Cinchona pubescens Vahl.) Cinchona corymbosa Karst. (Cinchona pitayensis Wedd.) Cinchona erythranthu Pav. Cinchona eqthroderma W e d d . Cinchona hasskarliana Miq. Cinchona hnceohta Ruiz e t Pav. (=Cinchona o f i i n a l i s L.) Cinchona lancifolia Mutis Cinchona ledgeriana Moens Cinchona lucumefolia Pav. (=Cinchona macrocalyx Pav.) Cinchona macrocalyx Pav. (see Cinchona lucumaefolia Pav.) Cinchona micraniha Ruiz e t Pav. Cinchona nit& Ruiz e t Pav.

I

I1

Dimeric I11

rj-sc

(171)

Cinchona oblongifolia Mutis ( = Cascarilla oblongif olia Wedd .) Cinchona o f i i n a l i s L. Cinchona ovata Ruiz et Pav. Cinchona pafiundiana Howard Cinchona pelletieriana Wedd. (=Cinchona pubescens Vahl.) Cinchona pitayensis Wedd. (see Cinchona corymbosa Karst.) Cinchona pubescens Vahl. (see Cinchona pelletieriana Wedd.) Cinchona robusta Howard Cinchona rosulenta Howard Cinchona scrobiculata Humb. et Bonpl. Cinchona succirubra Pav. Cinchona tucujensis Karst. Corynanthe lnacroceras (K. Schum.) Pierre (Pausinystalia lnacroceras Pierre ex Beille) Corynanthe paniculata Welw. Corynanthe yohimbe K. Schum. [ =Pausinystalia yohimba (K. Schum.) Pierre] Coutarea latiflora Sess6 et Mop ex DC. Mitragyna africana Korth. M . ciliata Aubr6v et Pellegr. M . diversifolia Hook. f. [see M . rotundi;folia (Roxb.) 0. Kuntze] M . hirsuta Havil. M . inermis 0. Kuntze M . javanim (Koord.) Korth. ( =Stephugine parvifolia) M . lnacrophylkz Hiern ( M . s t i p l o s a 0. Kuntze)

Y

b

j j j j(172) j

0 crl

U U

kw

a, b

j C C

b (173) C

b (173) c E3 (0

Cmynanthe yohimbe K. Schum.) Pausinystalia yohimba (K. Schum.) Pierre (see Pausinystalia trillesii Beille a Corynanthe macroceras (K. Schum.) Pierre Pausinystalia macroceras Pierre ex Beille (see Unearia rhynehophylla Miq.) Ourouparia rhynchophylla Matsumura (see DC.) Ourouparia guianensis Aubl. (see Uncaria tmentosa Roxb.) Ourouparia gambir Baill. (see Uncaria gambier (Nauclea fomnosana Metsumura) C Ourouparia formosana Matsumura et Hayata Ourouparia africana B a a . c (179) M . stipulosa 0. Kuntze (see M . nacrophylla Hiern) c (177, 178) M . speciosa Korth. b (176, I 7 7 ) , K. Schum.) C M . rubrostipulucea H a d . ( =Adina rubrostipulata Hook. f.) c (175) M . rotundifolia (Roxb.) 0. Kuntze ( M . diversifolia M . parwifolia Korth. c (174) Rubiaceae-continued

Plant

c

I

I1

I11

Monomeric

Dimeric

Typea (Reference)b ~

TABLE II--continued

~~

~~

~

0 W

u

d d

a-SI

1. THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

U

31

32

V. SNIECKUS

IIa, Ihoga type

a@ .--- ---

IIIa

IIIa

I

------

IIIb, Aspidosperma type

IIIb

IIIC

IIIC

IIIC

IIId

FIG. 3. The complex indole alkaloids. Schematic representations of the structural type I1 and type I11 units. The Roman numeral-lettercombinationsserve to define these skeletal variations in Table 11.

1. THE DISTRIBUTION OF INDOLE ALKALOIDS I N PLANTS

33

Although no incorporation experiments have been carried out on this group it has been reasonably suggested (13,14)that such a degradation might be likely a t some biosynthetic stage. Hence they are also included in Table 11. On the other hand, the tryptamine unit is easily recognized in the ergot alkaloid group (Volume VIII, Chapter 21) ( I d a ) and labeling experiments have shown tryptophan to be a precursor. However, this group has not been included in Table I1 since, up to a short time ago, most of its members were of fungal origin (Claviceps genus). The recent discoveries of ergot derivatives in Aspergillus and Rhizopus as well as in several species of the Convolvulaceae family indicate that they may be more widely distributed in flowering plants than originally envisaged. This indication together with the fact that tryptophan and mevalonic acid have been shown t o be precursors in both Claviceps and Convolvulaceae species point t o the future necessity of accepting the ergot group as representing yet another complex indole alkaloid type ( 8 ) . Finally, there will be found under the families Alangiaceae, Icacinaceae, and Rubiaceae in Table I1 three unusual dimeric alkaloids embodying a tryptamine residue in combination with a skeleton which in the past has been the structural characteristic of the Ipecacuanha alkaloid group (Volume VII, Chapter 18; type 11, Fig. 2). The biosynthesis of the latter group has been shown (3a) to proceed also via monoterpenoid involvement, a hint a t possible convergence of different biosynthetic pathways. The inclusion of these dimeric alkaloids in Table I1 is presupposed in that they exhibit tryptamine units. Therefore, it remains to be stressed that such variations in which there appear unexpected combinations of skeletons (previously found only in unrelated plant species) may be of considerable value in unraveling the biosynthetic avenues which are traveled not only by the indole alkaloids but by other classes of natural products as well.

REFERENCES 1. For a recent example, see A. R. Battersby, B. Gregory, H. Spencer, J. C. Turner, M.-M. Janot, P. Potier, P. Francois, and J. Levisalles, Chem. Commun. 219 (1967);

cf. also reference 171. 2. H. Goeggel and D. Arigoni, Chem. Commun. 538 (1966); P. Loew, H. Geoggel, and D. Arigoni, ibid. 347. 3. A. R. Battersby, R. T. Brown, R. S. Kapil, A. 0. Plunkett, and J. B. Taylor, Chem. Commun. 46 (1966); A. R. Battersby, R. T. Brown, J. A. Knight, J. A. Martin, and A. 0. Plunkett, ibid. 346; A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Knight, J. A. Martin, and A. 0. Plunkett, ibid. 888; A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Martin, and A. 0. Plunkett, ibid. 890.

34

V. SNIECKUS

3a. A. R. Battersby, R. Binks, W. Lawrie, G. V. Parry, and B. R. Webster,J. Chem. SOC.7459 (1965). 4. E. Leete and S. Ueda, Tetrahedron Letters 4915 (1966). 5. T. Money, I. G. Wright, F. McCarpa, and A. I. Scott, Chem. Commun. 537 (1966); E. S. Hall, F. McCarpa, T. Money, K. Fukumoto, J. R. Hanson, B. S. Mootoo, G. T. Phillips, and A. I. Scott, ibid. 348; T. Money, I. G . Wright, F. McCarpa, and A. I. Scott, Proc. Nut. Acud. Sci. U.S. 53, 901 (1965). 5a. For a recent review, see W. I. Taylor, Science 153, 954 (1965). 6. J. Le Men and W. I. Taylor, Experientia 21, 508 (1965). 7. See, for example, R. Hegnauer i n “Chemical Plant Taxonomy” (T. Swain, ed.), p. 389 ff. Academic Press, New York (1963);also i n “Comparative Phytochemistry” (T. Swain, ed.), p. 211 ff. Academic Press, New York (1966). 8. K. Mothes, Lloydia 29, 156 (1966). 9. J. D. Bu’Lock, “The Biosynthesis of Natural Products.” McGraw-Hill, New York, 1965. 10. H. G. Boit, “Ergebnisse der Alkaloid-Chemie bis 1960.” Akademie-Verlag, Berlin, 1961. 11. J. J. Willaman and B. G. Schubert, U.S. Dept. Aqr., Tech. Bull. 1234 (1961). 12. M. Hesse, “Indolalkaloide in Tabellen.” Springer, Berlin, 1964. 12a. J. Holubek and 0. Strouf, “Spectral Data and Physical Constants of Alkaloids,” Vols. 1 and 2. Heyden, London, 1965. 13. E. Wenkert, J. Am. Chem. SOC.84, 98 (1962). 14. J. A. Joule, H. Monteiro, L. J. Durham, B. Gilbert, and C. Djerassi, J . Chem. SOC. SOC.4773 (1965). 14a. The Ergot alkaloids are more recently reviewed by D. Groeger, Fortschr. Chem. Porsch. 6, 159 (1066). 15. V. E. Tyler, Jr. and D. Groeger, Plunta Med. 12, 397 (1964). 16. P. J. Scheuer and T. R. Pattabhiraman, Lloydia 28, 95 (1965). 17. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Australian J . Chem. 19, 1951 (1966); Chem. Commun. 421 (1966). 18. R. Kaschmitz and G. Spiteller, Monatsh. 96, 909 (1965). 19. H. Achenbach and K. Biemann, J . Am. Chem. SOC.87, 4177 (1965); M. A. Ferreira, A. C. Alves, and L. N. Prista, Qurcia 0rtu 11, 477 (1963); CA 62, 4323a (1965). 20. I. K. Orazkuliev, 0. S. Otroshchenko, and A. S. Sadykov, Zh. Prikl. Khim. 37, 1394 (1964); C A 61, 11014b (1964). 21. E. J. Staba and P. Laursen, J . Pharm. Sci.55, 1099 (1966). 22. V. E. Tyler, Jr. and D. Groeger, J . Pharm, Sci. 53,462 (1964); cf. also C A 61, 2181h (1964). 23. B. Abdusalamov, A. S. Sadykov, and Kh. A. Aslanov, Nauchn. T r . Tashkentsk. Qbs. Univ. 263, 3 (1964); CA 63, 3314b (1965). 24. C. C. J. Culvenor, R. D. Bon, and L. W. Smith, Australian J. Chem. 17, 1301 (1964). 24a. V. Lou, W.-Y. Koo, and E. Ramstad, Lloydiu 28, 207 (1965). 25. S. Ghosal and B. Mukherjee, Chem. & Znd. (London) 793 (1965). 26. H. Morimoto and N. Matsumoto, Ann. 692, 194 (1966); H. Morimoto and H. Oshio, ibid. 682, 212 (1965). 27. F. Sparatore, Ann. Chim. (Rome) 54, 246 (1964). 28. S. R. Johns, J. A. Lamberton and A. A. Sioumis, Austrulian J . Chem. 19, 893 (1966). 29. B. Robinson, J. Chem. SOC.1503 (1964). 30. G. A. Iacobucci and E. A. Ruveda, Phytochemistry 3,465 (1964). 30a. G. Rangaswami and M. Balasubramanian, Indian Phytopathol. 17, 234 (1965).

1. THE DISTRIBUTION

O F INDOLE ALKALOIDS I N PLANTS

35

31. S. R. Johns and J. A. Lamberton, AustralianJ. Chem. 19, 895 (1966). 32. M.-T. Li and H.-I. Huang, Yao Hsueh Hsueh Pao 13, 265 (1966); C A 65, 3922c (1966). 33. A. Chatterjee and K. S. Mukherjee, J . Indian Chem. Soc. 41, 857 (1964). 34. J. K. Wakhloo, Planta 65, 301 (1965). 35. A. Y. Leung, A. H. Smith, and H. G. Paul, J . Pharm. Sci. 54,1576 (1965). 36. V. Ivanov, N. Nikolov, and Iv. Tonev, Parrnatsiya (Sofia) 15, 164 (1965); C A 63, 16127b (1965). 36a. A. T. Awad, J. L. Beal, S. K. Talapatra, and M. P. Cava, J. Pharm. Sci.56, 279 (1967). 37. S. C. Pakrashi and P. P. Ghosh-Oastidar, IndianJ. Chem. 2, 379 (1964); S. Siddiqui, M. Amjad Ali, and U. U. Ahmad, Pakistan J . Sci. I d . Res. 7, 144 (1964); CA 62, 6720g (1965); N. H. Khan and M. S. Ali, PakistanJ. Biol. Agr. Sci. 8, 211 (1965); C A 64, 97826 (1966); J. D. Albright, J. C. Van Meta, and L. Goldman, Lloydia 28, 212 (1965); A. Popelak, E. Haack, and H. Springler, Tetrahedron Letters 1081 and 5077 (1966);A. R. Batteraby, R. S. Kapil, D. S. Bhakuni, S. P. Popli, J. R. Merchant, and S. 8. Salgar, ibid. 4965; S. S. Salgar and J. R. Merchant, Current Sci. (India)35, 281 (1966); CA 65, 76240 (1966). 38. A. Buzas and C. Egnell, Ann. Pharm. Franc. 23, 351 (1965). 39. T. Kishi, M. Hesse, W. Vetter, C. W. Gemenden, W. I. Taylor, and H. Schmid, Helw. Chim. Acta 49, 946 (1966). 40. T. Kishi, M. Hesse, C. W. Gemenden, W. I. Taylor, and H. Schmid, Heh. Chim. Acta 48, 1349 (1965). 41. M. Hesse, H. Hurzeler, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, Helv. Chim. Acta 48, 689 (1965);M. Hesse, F. Bodmer, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, ibid. 49, 1173 (1966); S. K. Talapatra and A. Chatterjee,Sci. Cult. (Calcutta) 31, 368 (1965); C A 64, 11268e (1966). 42. A. Chatterjee, B. Mukherjee, and A. B. Ray, Tetrahedron Letters 3633 (1965). 43. A. B. Ray and A. Chatterjee, J. Indian Chem. 41, 638 (1964). 44. B. Das, K. Biemann, A. Chatterjee, A. B. Ray, and P. L. Majumber, Tetrahedron Letters 2239 (1965). 45. A. Chatterjee, P. L. Majumber, and A. B. Ray, Tetrahedron Letters 159 (1965). 46. T. R. Govindachari, B. R. Pai, and T. S. Savitri, Tetrahedron 21, 2951 (1965). 47. B. Das, K. Biemann, A. Chatterjee, and A. B. Ray, Tetrahedron Letters 2483 (1966). 48. C. E. Nordman and S. K. Kumra, J . Am. Chem. Soc. 87, 2059 (1965). 49. H. Tomczyk, Dissertationes Pharm. 16, 297 (1964); C A 62, 9457a (1965). 50. E. S. Zabolotnaya, A. S. Belikov, S. P. Ivashchenko, and M. M. Molodozhnikov, Med. Prom. SSSR 18, 28 (1964); CA 61, 9774e (1964). 51. C. Ferrari and L. Marion, Can. J. Chem. 42, 2705 (1964). 52. B. Gilbert, A. P. Duarte, Y. Nakagawa, J. A. Joule, S. E. Flores, J.Aguayo Brissolese, J. Campello, E. P. Carrazzoni, R. J. Owellen, E. C. Blossey, K. S. Brown, Jr., and C. Djerassi, Tetrahedron 21, 1141 (1965). 53. M. Ohashi, J. A. Joule, and C. Djerassi, Tetrahedron Letters 3899 (1964). 53a. M. Ohashi, J. A. Joule, B. Gilbert, and C. Djerassi, Ezperientia 20, 363 (1964). 54. J. A. Joule, M. Ohashi, B. Gilbert, and C. Djerassi, Tetrahedron 21, 1717 (1965). 54a. N. J. Dastoor, A. A. Gorman, and H. Schmid, Helw. Chim. Acta 50, 213 (1967). 55. J. M. Ferreira, B. Gilbert, R. J. Owellen, and C. Djerassi, Ezperientia 19, 585 (1963). 55a. L. D. Antonaccio, B. Gilbert, and L. A. Paes Leme, unpublished results (1966). 56. J. M. Ferreira Filho, B. Gilbert, M. Kitagawa, L. A. Paes Leme, and L. J. Durham, J . Chem Soc., C, Org. 1260 (1966).

36

V. SNIECKUS

56a. K. S. Brown, Jr., W. E. Sanchez L., A. de A. Figueiredo, and J. M. Ferreira Filho, J . Am. Chem. Soc. 88, 4984 (1966). 56b. P. R. Benoin, R. H. Burnell, and J. D. Medina, Can.J. Chem. 45, 725 (1967). 57. P. Relyveld, Pharm. Weekblad 100, 614 (1965); C A 63, 7254c (1965). 58. R. H. Burnell, J. D. Medina, and W. A. Ayer, Chew. & Ind. (London) 33 (1964); Can. J . Chem. 44, 28 (1966). 59. M. Pinar, B. W. Bycroft, J. Seibl, and K. Schmid, Helv. Chim. Acta 48, 822 (1965); J. M. Pinar and H. Schmid, ibid. 50, 89 (1967). 59a. R. R. Arndt, S. H. Brown, N. C. Ling, P. Roller, C. Djerassi, J. M. Ferreira, F. B. Gilbert, E. C. Miranda, S. E. Flores, A. P. Duarte, and E. P. Carrazzoni, in publication. 59b. K. H. Palmer, Can.J. Chem. 42, 1760 (1964). 60. K. S. Brown, Jr. and C. Djerassi, J . Am. Chem. Soc. 86, 2451 (1964). 61. R. R. Arndt and C. Djerassi, Experientia 21, 566 (1965). 62. L. D. Antonaccio, C. Djerassi, and B. Gilbert, Anais. Assoc. BrasilQuim. 21, Numero Espec. 31 (1962); C A 61, 696a (1964). 63. S. Markey, K. Biemann, and B. Witkop, Tetrahedron Letters 157 (1966). 64. 0 . 0 .Orazi, R. A. Corral, and M. E. Stoichevich, Can. J . Chem. 44, 1523 (1966). 65. A. A. Gorman, V. Agwada, M. Hesse, U. Renner, and H. Schmid, Helv. Chim. Acta 49, 2072 (1966). 66. J. Poisson, M. Plat, H. Budzikiewicz, and C. Djerassi, Tetrahedron 22, 1075 (1966). 67. W. M. Fylypiw, N. R. Farnsworth, R. N. Blomster, J. P. Buckley, and D, J. Abraham, Lloydia 28, 354 (1965). 68. C. Hootele, J. Pecher, R. H. Martin, G. Spiteller, and M. Spiteller-Friedmann, Bull. Soc. Chim. Belges 7 3 , 634 (1964). 69. S. M. Kupchan, J. M. Cassady, and S. A. Telang, Tetrahedron Letters 1251 (1966). 70. J. W. Loder, AustralianJ. Chem. 19, 1947 (1966). 71. M. P. Cava, S. K. Talepatra, J. A. Weisbach, B. Douglas, R. F. Raffauf, and J. L. Beal, Tetrahedron Letters 931 (1965). 72. M. P. Cava, S. K. Talapatra, P. Yates, M. Rosenberger, A. G. Szabo, B. Douglas, R. F. Raffauf, E. C. Shoop, and J. A. Weisbach, Chem. & Ind. (London) 1875 (1963). 73. M. P. Cava, K. Nomura, and S. K. Talapatra, Tetrahedron 20, 581 (1964). 74. W. I. Taylor, M. F. Bartlett, L. Olivier, J. Levy, and J. Le Men, BuZl.Soc. Chim. Prance 392 (1964). 75. M. F. Bartlett, R . Sklar, A. F. Smith, and W. I. Taylor, J . Org. Chem. 28, 2197 (1963). 76. M. Hesse, W. von Philipsborn, D. Schumann, G. Spiteller, M. Spiteller-Friedmann, W. I. Taylor, H. Schmid, and P. Karrer, Helw. Chim. Acta 47, 878 (1964). 77. C. W. L. Bevan, M. B. Patel, A. H. Rees, D. R. Harris, M. L. Marshak, and H. H. Mills, Chem. & Ind. (London) 603 (1965). 78. B. W. Bycroft, M. Hesse, and H. Schmid, Helw. Chim. Acta 48, 1598 (1965). 79. A, Chatterjee and A. Deb, Summer School Org. Chem. Shillom, India 169 (1961); C A 64, 3622c (1965). 80. T. R. Govindachari, B. R. Pai, S. Rajappa, N. Viswanathen, W. G. Kump, K. Nagarejan, and H. Schmid, Helv. Chim. Acta 4 6 , ~ 5 7 2(1963); A. Guggisberg, T. R. Govindachari, K. Nagarajan, and H. Schmid, ibid. 679. 81. A. R. Battersby, J. C. Byrne, H. Gregory, and S. P. Popli, Chem. C m m u n . 786 (1966). 82. H. H. A. Linde, Helw. Chim.Acta 48, 1822 (1965). 82a. K. Bernauer, G. Englert, and W. Vetter, in publication.

1.

THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

37

83. K. Bernauer, G. Englert, and W. Vetter, Experientia 21, 374 (1965). 84. W. Jordan and P. J. Scheuer, Tetrahedron 21, 3731 (1965). 85. L. Olivier, J. Levy, J. Le Men, M.-M. Janot, H. Budzikiewicz, and C. Djerassi, Bull. SOC. Chim. France 868 (1965). 86. J. Levy, G. Ledouble, J. Le Men, and M.-M. Janot, Bull. SOC.Chim. France 1917 (1964). 87. G. Ledouble, L. Olivier, J. Levy, J. Le Men, and M.-M. Janot, Ann. Pharm. Franc. 22, 463 (1964). 88. Z. M. Khan, M. Hesse, and H. Schmid, Helv. Chim. Acta 48, 1957 (1965). 89. H. Achenbach and K. Biemann, J . A m . Chem. SOC.87, 4944 (1965). 90. H. Achenbach and K. Biemann, Tetrahedron Letters 3239 (1965). 91. D. W. Thomas, H. Achenbach, and K. Biemann, J . Am. Chem. SOC. 88,3423 (1966). 92. M. Hesse, F. Bodmer, and H. Schmid, Helv. Chim. Acta 49, 964 (1966). 93, B. W. Bycroft, D. Schurnann, M. B. Patel, and H. Schmid, Helv. Chim. Acta 47,1147 (1964). 94. M. B. Patel and J. M. Rowson, Planta Med. 12, 149 (1964). 95. C. Kump, J. Seibl, and H. Schmid, Helv. Chim. Acta 48, 1002 (1965). 96. W. G. Kump, M. B. Patel, J. M. Rowson, and H. Schmid, Helv. Chim. Acta 47, 1497 (1964). 97. C. Kump, J. Seibl, and H. Schmid, Helv. Chim. Acta 47, 358 (1964). 98. M. Shamma and R. J. Shine, Tetrahedron Letters 2277 (1964). 99. G. Combes, L. Fonzes, and F. Winternitz, Phytochemistry 5, 1065 (1966). 100. E. Smith, R. S. Jaret, M. Shamma, and R. J. Shine, Lloydia 27, 440 (1964);J. Am. Chem. SOC.86, 2083 (1964). 101. A. K. Kiang, H. Lee, J. Goh, and A. S. C. Wan, Lloydia 27,320 (1964). 102. A. K. Kiang, S. K. Loh, M. Demanczyk, C. W. Gemenden, G. J. Papariello, and W. I. Taylor, Tetrahedron 22, 3293 (1966). 103. M. B. Patel, J. Poisson, J. L. Pousset, and J. M. Rowson, J . Pharm. Phamnacol. 16, Suppl., 163 (1964). 104. J. L. Pousset and J. Poisson, Compt. Rend. 259, 597 (1964). Chim. 105. J. Poisson, R. Bergoing, N. Charean, M. Shamma, and R. Goutarel, Bull. SOC. France 2853 (1964). 106. J. Poisson, R. R. Ulshafer, L. E. Paszek, and W. I. Taylor, Bull. SOC.Chim. France 2683 (1964). 107. J. L. Pousset and J. Poisson, Ann. Pharm. Franc. 23, 733 (1965). 108. C. H. Wei, Yao Hsueh Hsueh P a o 12, 429 (1965); C A 63, 167792(1965). 109. G. B. Guise, E. Ritchie, and W. C. Taylor, AustralianJ. Chem. 18, 1279 (1965). 110. G. B. Guise, M. Rasmussen, E. Ritchie, and W. C. Taylor, Australian J . Chem. 18, 927 (1965). 111. H. K. Schnoes and K. Biemann, J. Org. Chem. 31, 1641 (1966). 112. U. Renner, Lloydia 27, 406 (1964);U. Renner and H. Fritz, Helv. Chim. Acta 48, 308 (1965). 113. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, R. F. Raffauf, and 0. Ribeiro, Chem. & Ind. (London) 1193 (1964). 113a. J. A. Weisbach, R. F. Raffauf, 0. Ribeiro, E. Macko, and B. Douglas, J. Pharm. Sci. 52, 350 (1963). 114. H. Achenbach, Tetrahedron Letters 5027 (1966); 1793 (1967). 115. A. Santos, G. Aguilar-Santos, and L. L. Tibayan, Anales Real. Acad Farm. 31, 3 (1965); C A 63, 7252d (1965). 116. H. Achenbach, Tetrahedron Letters 4405 (1966).

38

V. SNIECKUS

117. N. Ramiah and J. Mohandas, I n d i a n J . Chem. 4,99 (1966); E. J. Verkey, P. P. Pillay, A. K. Bose, andK. G. Das, ibid. 332;T. R. Govindachari, B. S. Joshi, A. K. Saksena, S. S. Sathe, and N. Viswanathan, Chem. Commun. 97 (1966); Tetrahedron Letters 3873 (1965). 118. M. P. Cava, S. K. Mowdood, and J. L. Beal, Chem. & Ind. (London) 2064 (1965). 119. M. B. Pate1 and J. Poisson, Bull. SOC. Chim. France 427 (1966). 120. P. Lathwilliere, L. Olivier, J. Levy, and J. Le Men, Ann. Pharm. Franc. 24, 547 (1966). 121. G. Aguilar-Santos, A. C. Santos, end C. M. Joson, J. Philippine P h a m . Assoc. 50, 821 (1964); C A 63, 3312e (1965). 122. C. Niemann and J. W. Kessel, Jr., J . Org. Chem. 31, 2265 (1966). 123. W. I. Taylor, J . Org. Chem. 30, 309 (1965). 124. C. Djerassi, H. J. Monteiro, A. Walser, and L. J. Durham, J . Ann. Chem. SOC.88, 1792 (1966). 125. A. Walser and C. Djerassi, Helv. Chim. Acta 47, 2072 (1964); ibid. 48, 391 (1965). 126. M. Falco, J. Gamier-Gosset, E. Fellion, and J. Le Men, Ann. Pharm. Franc. 22,455 (1964); B. C. Das, J. Gamier-Gosset, J. Le Men, and M.-M. Janot, Bull. SOC. Chim. France 1903 (1965). 127. J. Gamier-Gosset, J. Le Men, and M.-M. Janot, Bull. SOC. Chim. France 676 (1965). 128. V. M. Malikov, P. Kh. Yuldashev, and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk Uz. SSR 2, 338 (1966); C A 66, 6568431 (1967). 129. Sh. 2. Kasymov, P. Kh. Yuldashev, and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk U z . S S R 2, 260 (1966); C A 66, 2673r (1967). 130. P. Kh. Yuldashev and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk Uz. S S R 1, 10 (1965); C A 63, 8428a (1965). 131. M. A. Kuchenkova, P. Kh. Yuldashev, and S. Yu. Yunusov, Izw. Akad. Nauk SSSR, Ser. Khim. 2152 (1965); C A 64, 11269b (1966); Dokl. Akad. N a u k Uz. SSR 21, 42 (1964); C A 63, 4353f (1965). 132. I. Ognyanov, P. Dalev, H. Putschevska, and N. Mollov, Compt. Rend. Acad. Bulgare Sci. 17, 153 (1964); CA 61, 9547e (1964); Sh. Z. Kasymov, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. N a u k S S S R 162, 102 (1965); C A 63, 570411 (1965); I. Ognyanov and B. Pyuskyulev, Ber. 99, 1008 (1966). 133. I. Ognyanov, Ber. 99, 2052 (1966). 134. W. D. Loub, N. R. Farnsworth, R. N. Blomster, and W. W. Brown, Lloydia 27,470 (1964). 135. D. J. Abraham, N. R. Farnsworth, R. N. Blomster, and A. G. Sharkey, Jr., Tetrahedron Letters 317 (1965). 136. N. R. Farnsworth, W. D. Loub, R. N. Blomster, and M. Gorman, J . Pharm. Sci. 53, 1558 (1964). 137. P. Potier, R. Bengelmans, J. Le Men, and M.-M. Janot, Ann. Pharm. Franc. 23, 61 (1965). 138. N. Abduvakhimova, P. Kh. Yuldashev, and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk Uz. SSR 1, 224 (1965); CA 63, 16396g (1965). 139. J. K. Kaul, J. TrojBnek, and A. K. Bose, Chem. & Ind. (London)853 (1966). 140. W. Doepke and H. Meisel, Pharmazie 21, 444 (1966). 141. P. N. Lyapunova, Izuch. i Ispol’z Lekarstv. Rastit. Resurov SSSR Sb, 255 (1964); C A 63, 922g (1965). 142. J. Trojanek, 0. Btrouf, K. BlBha, L. Dolejk, and V. Hanuk, Collection Czech. Chem. Commun. 29, 1904 (1964);J. Mokry, I. Kompis, M. Shamma, and R. J. Shine, Chem. & Ind. (London)1988 (1964).

1.

THE DISTRIBUTION O F INDOLE ALKALOIDS I N PLANTS

39

143. J. P. Kutney and R. T. Brown, Tetrahedron 22, 321 (1966). 144. D. Groeger and K. Stolle, Naturwiss. 51, 637 (1964). 145. B. K. Moza, J. Trojanek, A. K. Bose, K. G. Das, and P. Funke, Tetrahedron Letters 2561 (1964); B. K. Moza and J. TrojBnek, Chem. & Ind. (London) 1260 (1964). 146. C. Djerassi, M. Cereghetti, H. Budzikiewicz, M.-M. Janot, M. Plat and J. Le Men, Helv. Chim. Acta 47, 827 (1964) 147. M. Gorman and J. Sweeney, Tetrahedron Letters 3105 (1964). 148. G. H. Svoboda, M. Gorman, and H. Tust, Lloydia 27, 203 and 214 (1964). 149. G. H. Svoboda and A. J. Barnes, J. Pharm. Sci.53,1227 (1964). 150. J. W. Moncrief and W. N. Lipscomb, J . Am. Chem. Soc. 87, 4963 (1965). 151. N. Neuss, L. L. Huckstep, and N. J. Cone, Tetrahedron Letters 811 (1967). 152. F. Phisieux, J.-P.Devissaguet, C. Miet, and J. Poisson, Bull. SOC.Chim. France 251 (1967). 153. F. Puisieux, J. M. Rowson, and J. Poisson, Ann. Pharm. Franc. 23, 33 (1965). 154. J. Poisson, F. Puisieux, C. Miet, and M. B. Patel, Bull.Soc. Chim. France 3549 (1965). 155. M. Denayer-Tournay, R. H. Martin, M. Friedmann-Spiteller, and G. Spiteller, Bull. SOC.Chim. Belges 74, 170 (1965); G. Lhoest, R. de Neys, N. Defay, J. Seibl, J. Pecher, and R. H. Martin, ibid. 534 and 3549. 156. M. Quirin, F. Quirin, and J. Le. Men, Ann. Pharm. Franc. 22, 361 (1964). 157. A. C. Santos and G . Aguilar-Santos, Anales Real. Acad. Farm. 30, 173 (1964); C A 62, 397g (1965). 158. F. S. Maguo, G. Aguilar-Santos, and A. C. Santos, Philippine J. Sci. 93, 597 (1964); C A 63, 12003b (1965). 159. F. Fish and F. Newcombe, J. Pharm. Pharmacol. 16, 832 (1964). 160. A. T. McPhail and G. A. Sim, J. Chem. Soc. 1663 (1965). 161. A. R. Battersby and D. A. Yeowell, J. Chem. SOC.4419 (1964). 162. H. Muller, M. Hesse, P. Waser, H. Schmid, and P. Karrer, Helv. Chim. Acta 48, 320 (1965). 163. J. S. Grossert, J. M. Hugo, M. E. von Klemperer, and F. L. Warren, J. Chem SOC. 2812 and 2814 (1965). 164. N. G. Bisset, Chem. & Ind. (London) 1036 (1965); J. L. Occolowitz, K. Biemann, and J. Bosley, Farmuco, Ed. Sci. 20, 751 (1965); C A 64, 6706h (1966). 165. N. Bisset, Compt. Rend. 261, 5237 (1965). 166. N. G. Bisset, C. G. Casinovi, C. Galeffi, and G. B. Marini-Belloto, Ric. Sci. Rend. Sez. B6, 273 (1965); C A 64, 12747d (1966). 167. A. Guggisberg, M. Hesse, H. Schmid, and P. Karrer, Helv. Chim. Acta 49, 1 (1966). 168. F. A. L. Anet, C a n . J . Chem. 41, 883 (1963). 169. M. Koch, M. Plat, B. C. Das, and J. Le Men, Tetrahedron Letters 2353 (1966). 170. P. Brauchli, V. Deulofeu, H. Budzikiewicz, and C. Djerassi, J . A m . Chem. SOC.86, 1895 (1964); H. Monteiro, H. Budzikiewicz, C. Djerassi, R. R. Arndt, and W. H. Baarschers, Chem. Commun. 317 (1965). 170a. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Chem. Commun. 229 (1967). 171. P. Potier, C. Kan, J. Le Men, M.-M. Janot, H. Budzikiewicz, and C. Djerassi, Bull. Soc. Chim. France 2309 (1966); J. Le Men, C. Kan, P. Potier, and M.-M. Janot, Ann. Pharm. Franc. 23, 691 (1965). 172. M. Quadrat-i-Khuda, K. A. Khaleque, M. Aminuddin, and S. Azim-ul-Mulk, Sci. Res. (Dacca, Pakistan) 2, 1 (1965); C A 63, 12004g (1965). 173. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillips, and C. M. Lee, J . Pharm. Pharmacol. 18, 553 (1966). 174. E. J. Shellard and J. D. Phillipson, Planta Med. 12, 160 (1964).

40

V. SNIECKUS

175. E. J. Shellard and J. D. Phillipson, Planta Med. 12, 27 (1964). 176. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, Planta Med. 14, 277 (1966). 177. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, J. Pharm. Pharmacol. 13, 753 (1965). 178. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, Planta Med. 14, 266 ( 1966). 179. Raymond-Hamet, Compc. Rend. 259, 3872 (1964). 180. S. R. Johns and J. A. Lamberton, Tetrahedron Letters 4883 (1966). 181. N. K. Hart, S. R. Johns, and J. A. Lamberton, Chem. Commun. 87 (1967). 182. L. Merlini, R. Mendelli, G. Nasini, and M. Hesse, Tetrahedron Letters 1571 (1967). 183. K. C. Chan, F. Morsingh, and G. B. Yeoh, J. Chem. Soc., C , Org. 2245 (1966); G. B. Yeoh, K. C. Chan, and F. Morsingh, Tetrahedron Letters 931 (1966).

--CHAPTER

2-

THE AJMALINE-SARPAGINE ALKALOIDS W. I. TAYLOR Research Department, CIBA Phamaceutical Company, Division of C I B A Corporation, Summit, New Jersey

I. The Ajmaline Group.. ................................................ A. Congeners of Ajmaline ............................................. B. The 16-MethoxycarbonyltetraphyllicineSubgroup. .................... C. The Mass Spectra of Ajmaline Derivatives.. .......................... D. A Synthetic Approach to Ajmaline.. ................................ 11. The Sarpagine Group.. ............................................... A. Congeners of SEtrpagine............................................ B. Minor Alkaloids of Voacanga chalotiana Pierre e t Stapf. . . . . . . . . . . . . . . . . . C. 3,4-Seco-lO-deoxysarpagine Subgroup. . . . . . . . ........2 . . . . . . . . . . . . . . . D. 4,2l-Seco-lO-deoxysarpagine Subgroup. .............................. References ..........................................................

41 45 46 48 50 51 51 56 61 67 70

I. The Ajmaline Group Several new structural modifications of the ajmaline-sarpagine group of alkaloids have been noted (Tables I, 11, and 111) and their chemistry explored since the last review. The principal new carbon-nitrogen networks belong t o the sarpagine subgroup (Chart I),the important ones being the 3,4- and 4,21-seco-l0-deoxysarpagineskeletons, which are also found as components of the voacanga and alstonia dimeric alkaloids, respectively. There are analogous 3,4-seco-(2-acylindole) compounds among other type I ( 1 )systems, e.g., burnamicine, picraphylline (Table IV). The 3,4-secosarpagines are often found along with their sarpagine equivalents ; a t our present level of understanding of biosynthesis it is not known if such 2-acylindoles are intermediates in the formation of, or are derived from, their ring-closed equivalents (2). A formal total synthesis of ajmaline has been accomplished. Most of the alkaloids can be interconverted with the exception of a general method for preparing 2-acylindoles from their ring-closed equivalents. Some progress has been made toward this goal ( 3 ) ,dihydroburnamicine being the synthetic closest t o a natural product. 41

TABLE I AJMALINE ALKALOLDS~

'OH

bH

I

I1

Tetraphyllicine

Ajmaline

Constantsb

Name Vincamajoreine ( 10-methoxytetraphyllicine) Majoridine ( 17-0-acetyl-10-methoxytetraphyllicine) Vincamajine (2-epi-16-methoxycarbonyltetraphyllicine) Vincarine (17(?)-epivincamajine) 17-O-Acetyl-d1-l-demethyltetraphyllicine [RP 7 (19)]nitrate Ajmaline Sandwicine (1"iepiajmaline) Isosandwicine (17,20,21 -triepiajmaline)

Melting point ("C)

222-223 263-264 235-237

[t(ID (solvent)

SourcecVd (structuree)

Table covers isolations and structures not given in Volume VIII, p. 787. Constants given for new alkaloids. Bracketed numbers refer to reference list. Plant key: a, Ervatamia coronaria Stapf (Tabernaemontana coronaria Br.); b, Gabunia odoratissima Stapf; c, Hunteria eburnea Pichon; d, Ochrosiapoweri Bailey; e, Peschiera affhis (Muel.-Arg.)Miers; f, Picralima nitida Stapf; g, Rauwolfia perakensis King et Gamble; h, Vinca Zancea Boj. (ex. A. DC.) K. Schum. [Catharanthus lanceus (Boj. ex A. DC.) Pich.]; i, V . rosea L. Reichb.; j, Voacanga africana Stapf; k, V . chulotiana Pierre ex Stapf; 1, Voacanga dregei E. Mey; m, V . bracteata Stapf var. bracteata [ V . zenkeri Stapf; V . obanensis Wernh.]; n, V . globosa (Blanco) Merr.; 0, V . papuana ( F . Muell.) Schum; p, Vinca difformis Pourr.; q, V . major L.;r, Aspidosperma dasycarpon A. DC.; s, A . peroba F . Allem ex Sald; t , V . Zancea Boj. (ex A. DC.) K. Schum.; u, Strychnos tozifera R. Schomb.; v, Pleiocurpa mutica Benth; w, Rauwolfia vomitoria Afzel.; x, R. manii Stapf; y, Vinca erecta Rgl. e t Schmahl; z, Aspidosperma spegazzinii Molf. exMayer; A, Tabernae montana fuchsiaefolia. 'Parenthetical numbers refer to reference list; reference not given to structure indicates well-known alkaloids.

E3

ez M

118

Peraksine

3,4-Seco-10-deoxysarpagine

Voacaline

Perakine

Ajmaline

10-Deoxysarpagine

Macroline

Alstophylline (4,21 -Seco-lO-deoxysarpctgine)

CHART I. Variation in the ring systems among the ajmaline-sarpaginealkaloids.

2. THE AJMALINE-SARPAGINE ALKALOIDS

45

Ajmaline, because of its availability and facile transformations, remains the compound of choice as a convenient material for partial synthetic work. The continuing study of its biosynthesis is beginning t o bear fruit and it is now certain that the hydroaromatic moiety of this type I base ( 1 )is derived from a terpenoid percursor (4). A. CONGENERS OF AJMALINE When crude ajmaline from RauwolJia vomitoria is purified by crystallization, there remains a n amorphous residue which yields a crystalline hydroclJoride. Investigation of this material revealed it t o be a mixture of ajmaline, isoajmaline, sandwicine, and isosandwicine, which were very difficult t o separate (5).The method of isolation adopted was t o crystallize fractionally the crude hydrochlorides from acetone. The analytical methods of choice were ( a ) vapor phase chromatography of the bistrimethyl silyl ethers ; ( b )NMR-spectroscopy which can detect the differing environments of the (3-17 proton in the normal and 17-epi series ( 6 ) . Thus in R. vomitoria all the peripheral diastereoisomers of ajmaline have been isolated except the C-2 epimers which have so far been confined to Vinea species. Ajmaline has been recognized for the first time outside the genus RauwolJia in Aspidosperma spegazzinii (7) along with sarpagine methochloride (named unnecessarily as spegatrine chloride) and akuammidine methochloride (presumably macusine C but differing from it slightly; see Table I).The morphology (8)of A. spegazzinii is said to have some peculiarities which distinguish it from other Aspidosperma species and hence account for the ajmaline content. The remaining two sarpagine bases, apart from their quaternary nature, are not unknown among Aspidosperma plants ( 9 ) . Some evidence concerning the steric effect of the 21-hydroxyl on the quinuclidine nitrogen of ajmaline has resulted from a study of rate of alkylation of derivatives and epimers. The conclusions reached were in accord with the accepted structure ( 6 ) .Whereas the reaction with methyl iodide was too fast to measure, the rate of ethiodide formation (Table 11) showed distinct differences (21)as can be seen from the results obtained from runs with pairs of isomers. I n all cases there was greater hindrance t o ethiodide formation for the jso derivative. As can be seen from models, the quinuclidine system is slightly skewed and the C-21 substituent in the isoajmalines (IV; partial formula) offers greater hindrance to the incoming ethyl group than its epimer (111;partial formula). When the 21-oxygen function is removed in the 21-deoxy (iso) ajmalines the rate of ethiodide formation increases by almost three orders of magnitude and the rates become almost identical.

46

W. I. TAYLOR

TABLE I1 PSEUDO-FIRST-ORDER RATESOF ETHIODIDE FORMATION FOR SOME AJMALINE DERIVATIVES

Compound

Pseudo-first-orderrate ( x 104 sec-1) 117.6 60.7

Ajmrtline Isoajmrtline Ajmaline-17-0-acetate Isoajmaline- 17 - 0 -acetate

53.8 27.9

Ajmaline-21-0-acetate Isoajmaline- 2 1- 0-acetate

12.9 3.2 6.1 1.5

2 1 -Deoxyajmaline 21 -Deoxyisoajmaline

111

694 648

IV

Many derivatives of ajmaline have been made in an attempt to produce a useful pharmaceutical (in particular a good antifibrillatory agent) but none have been realized ( 2 2 ) .

B. THE 16-METHOXYCARBONYLTETRAPHYLLICINE SUBGROUP From a combination of UV-spectra, NMR-, and mass spectrometric measurements majoridine (13) was shown t o be 10-methoxytetraphyllicine-17-0-acetate (12).A close over-all correspondence (mass spectrometric shift technique was observed between the following pairs : majoridine/tetraphyllicine- 17-0-acetate; deacetylmajoridine/tetraphyl-

2. THE AJMALINE-SARPALQINEALKALOIDS

47

licine, and dihydrodeacetylmajoridinel2 l-deoxyajmaline. This parallelism, especially the two strong peaks a t m/e 182 and 183 which are characteristic of ajmaline systems with a normal C-2 stereochemistry, i.e., the C-2 hydrogen cis to the C-7-C-17 bond (23)eliminates the 2-epi configurational possibility which was, until this work, a characteristic of ajmaline-type bases from Vinca species. This was confirmed by comparing the optical rotatory dispersion curves for majoridine and tetraphyllicine, both bases showed a positive Cotton effect a t about 260 nm. If the stereochemistry at C-2 had been different from tetraphyllicine the sign of bhe Cotton effect would have been negative ( 6 ) . The chemical shifts for the 17-0-acetate methyl and the (3-17 hydrogen and its coupling to the C-16 hydrogen were analogous with those recorded for 2l-deoxyajmaline-l7-0-acetate( 6 ) . I n view of the similarity between their physical data, deacetylmajoridine is believed t o be identical with vincamajoreine (10)which was already considered to be an isomer of 10-methoxytetraphyllicine (11). Vincarine is stated ( 1 7 , 1 8 )to have a formula and mass spectrum identical with quebrachidine [2-epi-17-methoxycarbonyl- 1-deme$hyltetraphyllicine (mp 276"-278"; [a]=+54" in CHC13) (24).It does belong to the ajmaIine class because lead tetra-acetate oxidation furnished an aldehyde which after reduction yielded polyneuridine. This experiment established uneqaivocally the complete stereochemistry of vincarine with the exception of C-2 and C-17. If the mass spectrum of vincarine is really closely similar t o t h a t of quebrachidine, as stated above, then the stereochemistry a t C-2 has been established because C-2 epimers of the ajmaline system have unique spectra clearly distinguishable from all the other isomers (C-17, C-20, C-21) which are very much alike (23).Vincarine must therefore be quebrachidine or its C-17 epimer. This, however, was not the conclusion of the Russian authors, who from some IRdata suggested that vincarine might be the C-16 epimer of quebrachidine (18). RP-7 from RauzcolJia perakensis, King e t Gamble (19),was guessed to be A~-demethyltetraphyllicine-17-0-acetate from an examination of the

Quebrechidine

48

W. I. TAYLOR

physical data and its conversion to vellosimine with base (20).This assumption was verified by its partial synthesis from tetraphyllicine17-0-acetate via oxidation with excess lead tetraacetate (20) [see the partial synthesis of dihydrovomilenine from ajmaline- 17-0-acetate (25)].

Tetraphyllicine-17-0-acetate

RP-7

C. THE MASSSPECTRA OF AJMALINE DERIVATIVES The mass spectra of ajmaline derivatives fall into three general types, namely, those that are similar to ajmaline itself, those that possess a (3-17 carbonyl function, and finally those differing in the stereochemistry a t C-2 ( 2 3 ) .This fundamental exploration into the fragmentation properties of epimeric complex systems was greatly aided by the application of a machine which measured the ion masses very accurately. Ajmaline showed the loss of 15 and 18 mass units attributable to the loss of a methyl group and water. The apparent loss of 29 mass units, however, was for the most part made up of CHO and only little loss of CzH5 which was formerly thought to be exclusively responsible for the peak a t m/e 297 (26).This at first sight surprising loss of CHO is probably due to the presence in the gas phase of chanoajmaline (the open chain aldehyde form), however, 21-deoxyajmaline also has a peak a t M-29 which is about equally attributed to loss of CzH5 and loss of CHO. The elimination of the latter must represent a rearrangement involving C- 1 7 which then enables a loss of CHO. If has been suggested (23) that the C-2 hydrogen which is cis to the C- 17 bridge migrates t o C-17 under electron impact-induced cleavage generating a sarpagine-like skeleton (path A, Chart 11) which would then give rise to peaks the same as those derived from sarpagine itself, e.g., the intense peaks at m/e 182 and 183. As would be expected these peaks were absent from the spectra of 2-epi compounds. Actually the peak a t mass 182 turned out to be more complicated when determined with a double focusing mass spectrometer, in addition to the

49

2. THE AJMALINE-SARPAGINE ALKALOIDS

/I-carboline ion, C12HloN2, there were species C13H12N and CloHlaNOz. Mass 183 is, however, due only to C12H11N2, the /I-carbolinium ion, aside from a minor contribution from 13C analogs of the species m/e 182. The origin of mass C13H12N is thought to derive from a species C13H14N0, m/e 200, of relatively low abundance (path B, Chart 11). The third unit of the 182-triplet, C10H16NO2, is a small contribution by a process (path C, Chart 11) which is a major pathway for the 2-epi series.

OB

1" J

H

1

'

\

\

Path C

PathA(Q)

r-

7"

OH

O T J N Me

L

1

m/e 182 (CIZHIONZ) (183 if protoneted)

CHART11. Some fragmentation parts for ajmaline.

50

W. I. TAYLOR

When the stereochemistry a t C-2 is reversed (e.g., 2-epi-21-deoxyajmaline) the C-2 hydrogen is now trans t o the C-17 bridge atom so that path A (Chart 11)leading to a sarpagine unit is not favored. Instead the C-2-C-3 bond is properly placed so that path C (Chart 11) assumes

OTQ

path D

path B

Me

0 0 Ajmalidine

CHART111. Two paths for the fragmentation of ajmalidine.

importance. This type of fragmentation was first observed with queN-diacetate, and vincamedine (l-methylquebrachidinebrachidine, its 0, 17-0-acetate) (24). I n the case of ajmalidine (a C-17 ketone) path B (Chart 111)is followed as well as one (path D) in which the carbonyl group is extruded, which leads t o ion m/e 144, the base peak (23).

D. A SYNTHETIC APPROACH TO AJMALINE system has A route (Chart IV) t o the 4,21-seco-l0-deoxysarpagine been revealed (26a).Full details are not available a t the time of writing, but it would seem that the concepts used in an earlier approach t o strychnine (266) have been used t o construct a 4,21-seco-l0-deoxysarpagine system. An appropriate derivative of the latter has been converted t o ajmaline, but it should be noted that in the critical conversion of the indole t o the dihydroindole the principal product [see 21-deoxyajmalal-A+21-deoxyajn~aline (26c)l has the desired C-2 configuration. Full details of this work, especially with respect t o stereoselectivity of a number of the steps, are t o be published.

2.

51

THE AJMALINE-SARPAOINE ALKALOIDS

COOMe

CHzOH

CHzOH

Me

1.

erythro

J

threo

I

0 9 0 4 , NaI04

a-$:Ho

to sarpagine group

CHzOH

C-15isomer

+

J

several atepa

15

QiiF$pQQ!& Me

Me H

CN

/

several steps

OH

Ajmaline CHART IV. A synthesis of ajmaline.

11. The Sarpagine Group

A. CONGENERSOF SARPAGINE The structures of the simple analogs of sarpagine shown in Table 111 were deduced as a natural consequence of a proper analysis of the spectral data routinely measured today. Even so, occasional problems are caused

ur

TABLE I11

f.3

SARPAGINE ALEALOIDS

% \

RI

Ra

3

2. Peraksine

1

4 Substituents on 1

Ri

Alkaloid 10-Deoxysarpagine &kine (deoxyajmalol-B) Vellosimine 10-Methoxyvellosimine [Alkaloid y (II)] Polyneuridine (or akuammidine) aldehyde Pericyclivine Sarpagine methochloridee 1-Methylsarpagine methochloridee Macusine-Be

Rz

Other

H

CHzOH

-

H H

CHzOH CHO

-

H

CHO

Melting point ("C)

[a]D

115-118 and 1 9 6 1 9 6

+19"

10-Me0

240

-128"

(COOMe, CHO) COOMe H H CHzOH

-

231-233 232 293

-

H H

1,4-diMe-lO-OH 4-Me

CHzOH CHzOH

1-Me

-

4-Me-10-OH

?

Constantsu

z (CHC13)

+5O

+37" (MeOH) +56" (as. MeOH)

(structured)

3

?!

Macusine-Ce

COOMe

CHzOH

4-Me

260-261

Voacarpine Voacoline Voamonine Peraksine (RP-5)

COOMe

CHzOH 3-OH I-Me (3) 3-OH (3) (2)

227-228 258 258 186-187

LI

Physical constants not recorded here for well-known alkaloids.

* For plant key see Table I.

Bracketed numbers refer to reference list. Parenthetical numbers refer to reference list; reference not given to structure indicates well-known alkaloids. Quaternary alkaloids. Voachalotine also isolated from this source.

ur

w

54

W. I. TAYLOR

by polymorphism (affinisine), lack of material [polyneuridine (or akuammidine) aldehyde], or a difference of opinion (macusine C). I n the case of peraksine [RP-5 (27)l it was shown t o have the formula ClsHzzNzO~,a fact not readily derived from combustion analysis since the free base crystallized from alcohol in a hydrated form (27). It has also been observed that this water of solvation could be displaced by chloroform (20).Peraksine has UV-absorption typical of a 2,3-disubstituted indole and reacted with benzoyl chloride t o form an 0-benzoyl derivative. The second oxygen was apparently present as a cyclic ether when it was found that although peraksine did not react with hydrazine derivatives, it was reducible with sodium borohydride t o furnish a diol (mp 290"-291"; [.ID +41" in P y ; diacetate, mp 103"-105"). This diol readily lost the elements of water upon acid treatment t o afford a new ether, deoxyperaksine, 230" change in crystalline form (mp 255"257"). Because of these properties peraksine was considered t o possess a cyclic hemiacetal moiety. The mass spectrum of peraksine shows peaks m/e 182, 169, 168, and 156 characteristic of tetrahydro-/3-carbolines. These peaks as well as an intense peak a t m/e 309 (M-1) suggested a sarpagine-like structure. The NMR-spectrum of peraksine showed that there were no olefinic bonds t o which protons were attached and no ethyl group could be detected; instead there seemed t o be a terminal methyl (doublet cent. .d a t 1.28 ppm) of the type CHB-CHX( X = O or N) and a multiplet IO.0 ppm) thought to be due to -CHzO-. Of the several structures which were considered upon biogenetic grounds, one (Chart V) was found to be correct as the result of an X-ray crystallographic analysis carried out using peraksine methiodide. The drawings assume the same absolute stereochemistry as other type I alkaloids (2). Peraksine is thus closely related t o the hypothetical proximal precursors of vomilenine and its isomerization produrt, perakine. The relative stereochemistry of the 19,20-vicinal substituents in perakine has not been determined but because of the possibilities for equilibration they would be assumed t o have taken up the least hindered orientation, i.e., trans t o each other. The trans orientation isosteric with isoajmaline, the base-catalyzed isomerization product of ajmaline, is favoured and a partial confirmation of this opinion was realized as follows (20). Brief treatment of perakine with base gave a dialdehyde [see closely related ring openings of indolenines t o deoxyajmalal-B ( S ) ] , which was reduced t o a diol (mp 190"-192"; ["ID +68" in Py) which unlike dihydroperaksine did not yield an ether under acidic conditions. The same '

Peraksine

Dihydroperaksine

t s

Deoxyperaksine

HBQ)py;l \ % 4

"CHO

19

l2.. oNaBHa Ho

'TH~OH

CHzOH

18

tH@

OAc

OAc

Vomilenine

Perakine

no reaction

OH

% H

OH

H

3 b-

4

zEl?g !

R

3

Lw L U

'

I

rJl

OH

Ajmaline Isoajmaline CHART V. Some properties of peraksine, vomilenine, perakine, ajmaline, and isoajmaline.

ur

01

56

W. I. TAYLOR

diol was also formed when perakine was first reduced to dihydroperakine (mp 250"-253"; [mID +12" in CHC13; CHO-tCH2OH) before base treatment. Although these reactions provide chemical evidence for the configuration of the aldehyde function in perakine, the orientation of the C-19 methyl remains circumstantial. The chemistry of voachalotine has been further examined. Methane sulfoiiyl chloride, thionyl chloride, and p-toluenesulfonyl chloride react with voachalotine (V) to give in each case the same hexacyclic compound 2-hydroxy-16-methoxycarbony117-deoxytetraphy11icine (VI) (mp 178"179";[aID -61' in MeOH) (38).The course of the reaction finds a parallel in the similar behavior of desoxyajmalol-A toward p-toluenesulfonyl chloride (26c). During the course of this study it was noted that if 10deoxysarpagine was treated with sulfonyl chlorides at an elevated temperature (1lSo), 17-chloro-10,17-deoxysarpagine (mp 225"-226" ; [aID +lo" in CHC13) was the sole product; a t room temperature the expected 0-sulfonates were obtained.

R'SOaCl

V

VI

Voechalotine

B. MINORALKALOIDSOF Voacanga chalotiana PIERRE ET STAPF Voacoline (VII), pK', 5.70, a minor component of V . chalotiana, is a sarpagine derivative which contains a hemiketal moiety (37). This functionality accounts for the ease with which voacoline forms 0-methyl (mp 211"-212") and 0-ethyl (mp 215"-216") derivatives (VIII) (see analogous properties of pseudostrychnine and eburnamine). The structure of voacaline has not been proved unequivocally, but all the available evidence is in its favor. The methyl functions were identified by NMRspectroscopy;ind-N-Me(3.6ppm), COOMe (3.0ppm, partially shielded), LC-Me (4.3 ppm; three proton singlet). There was also a -CH2-0/ (3.7ppm; singlet two protons) and four aromatic protons. Measurement of the NMR-spectrum of a compound in dimethylsulfoxide permits the coupling between the hydroxyl proton and the protons on the carbon to

57

2. THE AJMALINE-SARPAOINEALKALOIDS

which it is affixed to be determined (39).Under these conditions voacoline exhibited a singlet peak at 5.6 ppm which disappeared upon addition of deuterium oxide. Pyrolytic data (37, 40) and the mass spectra (37), particularly the M-1 peak and the strong peaks a t m/e 182 and 183, strongly indicated a sarpagine system. A correlation of voacoline with voacarpine was carried out on a small scale, with thin-layer chromatography an important tool for following the reactions. Voacoline was refluxed in benzene with potassium tertiary butylate to yield a complex mixture containing I X (positive iodoform reaction) which was esterified and subjected to a Wolf-Kishner reaction. From the products of this reaction a- and p-dihydrodehydroxymethylvoachalotine (X ; C-20 epimers) were recognized by thin-layer chromatography. It is of interest to note that voacoline is almost exactly a folded-up ajmalicine. MeOOC

COOMe

VIII

VII Voacoline KOBut

COMe

IX

Et

X

Voacarpine (XI) and voamonine appear from their UV-spectra measured in neutral, acidic (0.1 N HCI), or basic (0.1 N KOH) media to be ring A unsubstituted tetrahydro-/3-carbolines. However, upon acetylation or tosylation 0,N-bis derivatives are formed which have 2-acylindole chromophores (36). The structures assigned to these compounds use arguments similar to those developed for the 3,4-seco-10deoxysarpagine group (Section 11, C). Voacarpine and voamonine are different in that they prefer to remain ring-closed, possibly for steric reasons. This may be due to the bis-substitution of the (2-16bridge carbon. The known 2-acylindole alkaloids (Table IV) all have C-16 equatorial

TABLE I V 2-ACYLINDOLE ALKALOIDS

H

B

A

Alkaloid 3,4-Secosarpagine derivatives of known structure Perivine [Perosine ( 4 6 ) ] Vobasine Dregamine Tabernaemontanine Ochropamine Ochropine

Melting point ("C)

180-181 111-113

-121" -158"

A A

COOMe COOMe

H H

H Me

-

106-109 186-205 205-210 217-219 134

-93"

A

COOMe

H

Me

MeCH:=P-Et

i [a71 ( 4 9 ) b [28l,e [501, j [ 4 l , 421 (43) a [ 5 1 ] , 1 [ 5 2 ] pB3)

-57"

A

COOMe

H

Me

MeCH:=a-Et

a [ 5 3 ](43)

A

COOMe

H

Me

1-Me

d [541 ( 5 4 )

A

COOMe

H

Me

1-Me-11-Me0

d [ 5 4 ] (54)

146

-158" (acetone) -229" (acetone)

-

Periline

265 (dec.) 130-13 1

Periformyline Voacafrine

206-209 135-137

Voacafricine

196-198

Vincadiffine Voacarpine

230 227-228

Affinine

Other 2-acylindole alkaloids Voamonine, CzlH24Nz05 Perividine, CzoHzzNz04 Burnamicine, CzoHz6r\TzOz Picraphylline, CzzHz6Xz04

-106" (B.HC1 in MeOH) -121" (EtOH)

-

For plant key see Table I.

Parenthetical numbers refer to reference list.

A A A

Me

-

e [50] (55)

(CHzOH, H)

Me

-

g [271(56)

CHO Me -

t [571 (58) j [591 ( 5 6 )

Me

-

j [591 (56)

Me H

-

P [29l (60) k [361(36)

H

-

A

-1210

A B B A A A

3 -Hydroxyvoacaline k r361(37) Related t o perivine (?) i [61] 3,4-Secogeissoschizol c [621 ( 4 6 ) 4-Methyl-3,4-secotetrahydroalstonine f 1631 ( 6 4 )

+44" (MeOH)

* Bracketed numbers refer to reference list.

CHzOH

COOMe H (COOMe, CHzOH) (COOMe, CHzOH) COOMe CHzOH COOMe CHzOH

-107" (B.HC1 in MeOH)

258 230-260 198-200 255

A

-281" -37O

60

W. I. TAYLOR

substituents. Perhaps the additional axial substituent tips the balance in favor of the pentacyclic tautomer (e.g., XIa-XIb) where the same substituent is subject to fewer interactions ( 2 ) on the resultant, slightly skewed quinuclidine residue. It should be pointed out here that neither 0,N-diacetylvoacarpine (mp 212"; [.ID -22" in MeOH), 0,N-ditosylvoacarpine (mp 193"-194"; [.ID -70" in MeOH), nor acetylated voamonine (amorphous) have been reconverted into their parent alkaloids.

XI&

YOOMe

Voaoarpine

XIb

4 MeOOC

OH

O'/ XIIb

XIIa Isovoacarpine (7)

If voacarpine is refluxed for a prolonged period with 11N hydrochloric acid isovoacarpine (nip 227"-228"; mol. wt. 368) is formed. Its UVspectrum indicated indole and 2-acylindole chromophores. Upon acetylation N-acetylisovoacarpine (amorphous)was formed whose UV-spectrum now showed only the presence of the 2-acylindole. Structure XIIa is put forward for isovoacarpine because the derivative is known to lack the ethylidene group and has one active hydrogen less than voacarpine itself (36). Apparently in isovoacarpine the steric effects allow the presence of some 2-acylindole.

2.

THE

AJMALINE-SARPAOINE ALKALOIDS

61

c. 3,4-sECO-10-DEOXYSARPAGINE SUBGROUP Vobasine (XIII) was the first of the 2-acylindoles t o be examined thoroughly (41-43) and its structure and properties have become the foundation upon which is based all the later work in this area. Part of the work which led t o the structure of vobasine is summarized in Charts V I and VII along with the interrelationships established with other 2-acylindoles whose sources are listed in Table IV. Vobasine, either by the action of strong base or hydrolysis followed by reesterification, gave isovobasine (Chart VI). Vobasine methiodide, subjected to a Hofmann degradation under mild conditions, furnished vobasine methine (UV-spectrum = 3-vinyl-2-acylindole). From isovobasine an analogous methine was obtained. Both methines, upon treatment with sodium methoxide formed the same pair of optically inactive dl-vobasine methines (Chart VII). The course of the methine formation from the 16 epimeric vobasine methiodides is directed by stereochemical factors which govern the potential for a 1,a-transcoplanar relationship between N-4 and the (2-16 proton. It has been suggested that the isomethine racemizes via the anion XIV (Chart VII) (44). Vobasine methine methiodide subjected t o a second Hofmann degradation (KOBut) yielded trimethylamine and deazanorvobasine which retained the 3-vinyl-2-acylindole moiety and had in addition an isolated 1,3-diene function. If sodium methoxide was used as the base, the conjugated diene was not formed; instead there was an allylic displacement of trimethylamine by methoxide ion to form two racemates (XV+XVI ; partial formula). This conclusion was supported by the NMR-spectra of the methoxymethines.

I

OMe

xv

XVI

I n agreement with the derived structure hexahydrodeazanorvobasine, upon oxidation with chromic acid, formed a-methylbutyric acid in addition t o acetic and propionic acids. Also in complete harmony with the chosen structure was the formation of trideuterio- 16-epivobasine by a base-catalyzed deuteration (MeOD/MeONa) of vobasine followed by reprotonation of the indole nitrogen. Apart from the UV-spectrum, the two physical methods which played a supporting role in arriving a t the structure of vobasine now play an

62

+

.A

W. I. TAYLOR

-

A _\\___

Q @ H

Et

0 Perivine

Dregamine

Tabernaemontanine

1

1

NaOMe

-

NaOMe

NaOMe

unchanged

% \

Pericyclivine

Q-Jq 0

COOMe

Et

16-Epitabernaemontanie

3Me Dehydroxymethylakuammidine

CHARTVI. Interrelationshipsbetween some 3,4-secosarpaginederivatives.

Q)

W

64

3

3

0

W. I. TAYLOR

-

\ /

8

a,

r n

65

2. THE AJMALINE-SARPAQINE ALKALOIDS

important role in the recognition and characterization of 2-acylindole alkaloids. The first of these is NMR-spectroscopy which defines the gross proton topography of the molecule, the functionality of particular diagnostic value being the chemical shift for the highly shielded ester methyl ( 4 5 ) . The chemical shifts for methyl groups in 2-acylindole alkaloids are given in Table V and are compared whenever possible with TABLE V CHEMICAL SHIFTSFOR METHYLGROUPSI N 2-ACYLINDOLE ALKALOIDS AND SOMEDERIVATIVES

Compound

COOCH3

Perivine 16-Epiperivine Vobasine 16-Epivobasine Vobasinol 16-Epivobasinol Periformyline

2.45 3.88 2.61 3.50 2.35 3.40 2.55= 2.65= 2.57 2.68 2.58 3.1b

Vincadiffine Ochropine Ochropamine Voacarpine ~

N-4-CH3

Chemical shifto N-1-CH3 11-OCH3

2.57 2.56 2.58

-

-

3.97 4.05

3.86

-

-

-

Reference

30 54 54 36

~

ppm in deuteriochloroform relative to tetramethylsilane. Measured in trifluoroacetic acid. Indicative of the presence of a t least two conformations; 4-acetylperivine shows a similar effect.

their corresponding 16-epimers. The second method of great value is to interpret the mass spectrum. The value of this method is demonstrated by the elucidation of the structure of burnamicine (Table IV) which was available in minute quantity ( 4 6 ) .The principal fragmentation peaks for vobasine are sketched in Chart VIII. The fragmentation path is sensitive to the sterochemistry a t C-16, especially in the formation of mass m/e 180 which is more pronounced in 16-epivobasine because the C-16 hydrogen and the carbonyl group are nearer each other (43). An attempt was made to settle the structure and absolute stereochemistry of vobasine by a transformation into a sarpagine derivative, for example, by internal quaternization of vobasinol. However, under

66

W. I. TAYLOR

ordinary conditions the conformation of the molecule either did not allow C-3 to be within bonding distance of N-4 or the reaction could not go to completion under the chosen conditions. The first concept has received support from the normal frequency of the carbonyl group in the IR-spectrum [no transannular effect of N-4; see cryptopine and its congeners (65, SS)] as well as from the three-dimensional form of vobasine methiodide deduced from X-ray diffraction data ( 6 7 ) . Whether or not the method used to convert picraphylline into tetrahydroalstonine [pyrolysis of the picraphyllinol methochlorides (64)l would work with vobasine is not known. When N-4 lacks a methyl substituent as in perivine (Chart VI) cyclization of the equivalent alcohol, COOMe

COOMe

P

m/e 180

NMe

I-

4

L

m/e 158

XI11 Vobasine mle 194

O y J -

y

m/e 122 CHARTVIII. Some fragmentation products of vobasine.

2.

THE AJMALINE-SARPACTINE ALKALOIDS

67

perivinol to pericyclivine, a sarpagine derivative occurs under mild acidic conditions (32a, 49). Since perivine has been converted into vobasine, and pericyclivine into dehydromethylakuammidine of known absolute stereochemistry, the detailed structures of all the 2-acylindoles illustrated in Chart V I have been established in an elegantly simple fashion. Vincadiffine is believed to be 3-oxo-4-methyl-3,4-secoakuammidine (60). If the current interpretation (56) on the data for voacafrine and voacafricine is correct (Table IV), then one of these aklaloids should turn out to be identical with vincadiffine. Chenlical degradations of ochropamine and ochropine supported the structures deduced by physical methods (54).Digestion of ochropamine with hot caustic potash afforded 1,%dimethylindole and 2-acetyl-l,3dimethylindole and catalytic dehydrogenation of ochropine with 10 yo palladium on charcoal furnished 3-ethylpyridine and 2-acetyl-6methoxy- 1,2-dimethylindole.

SUBGROUP D. 4,2 1-SECO-10-DEOXYSARPAGINE Only two members of this group are known, both from Alstonia species. They are alkaloid C (XVII) from A. muelleriana Domin ( A . villosa Benth.) whose structure was determined by X-ray methods (68) and alstophylline (XVIII) from A. macrophylla Wall. whose structure was deduced largely from mass spectral data (69). Alstophylline is also

XVII Alkaloid C

XVIII Alstophylline

formed in the fission of macralstonine with perchloric acid or 2 N hydrochloric acid (7'0)and is also a close relative of macroline (XIX), a fission product of villalstonine (7'1). Alstophylline showed an UV-spectrum consistent with isolated 7-methoxyindole and p-methoxy-a,P unsaturated ketonic chromophores. The NMR-spectrum was informative and identified the methoxyl, the two N-methyls in different environments, the terminal methyl, the

68

W. I. TAYLOR

XIX Macroline

Me

1.37 ppm

2.30 ppm a

b

xx

olefinic proton, and the l12,4-arrangement of the aromatic protons in ring A in XVIII. The ketonic group was reduced with sodium borohydride to yield alstophyllinol (mp 170"-174"). Alstophylline refluxed in 2 N hydrochloric acid gave formic acid and the ketonic product, XX (mp 165"-167"; [aID - 59" in MeOH). This compound behavesindeuteriochloroform as if it were a mixture of ketonic and hemiketal forms XXa and b. The structures of alstophylline and its derivatives were determined

111111

OCOPh

OCOPh

IIIII~

Me

Me

1

2 1 0- Benzoylajmaline ~

1. Me1 2. NaOH

POClZ

collidine

XXI

2.

THE AJMALINE-SARPAOINE ALKALOIDS

69

by mass spectroscopy using the now extensive background data available on sarpagine-like compounds, especially the ajmaline derivative XXI (mp 176'-178'; [ c ~ ] ~ - 2 3 0 " in CHC13) which was prepared from 21-0benzoylajmaline in five steps (70). The principal peaks in the electron impact induced fragmentation of alstophylline are thought to proceed as indicated in Chart IX. The

m/e 200

J

m/e 366 Alstophylline

Me

m/e 297

m/e 211

A 31

m/e 212

CHART IX. Important fragmentation products of alstophylline.

absolute and relative stereochemistry remains to be elucidated but is probably the same as its ajmaline-derived equivalent.

70

W. I. TAYLOR

REFERENCES J. Le Men and W. I. Taylor, Ezperrentia 21, 508 (1965). W. I. Taylor, Lloydia 27, 368 (1964). L. J. Dolby and S. I. Sakai, J . Am. Chem. SOC.86, 1890 and 5362 (1964). A. R. Battersby, R. T. Brown, J. A. Knight, J. A. Martin, and A. 0. Plunkett, Chem. Commun. 346 (1966); P. Loew, H. Goeggel, and D. Arigoni, Ibid. 347; E. S. Hall, F. McCapra, T. Money, K. Fukumoto, J. R. Hanson, B. S. Mootoo, G. T. Phillips, and A. I. Scott, ibid. 348. 5 . P. R. Ulshafer, L. Paszek, M. E. Hunt, and W. I. Taylor, in press. 6. M. F. Bartlett, R. Sklar, W. I. Taylor, E. Schlittler, R. L. S. Amai, P. Beak, N. V. Bringi, and E. Wenkert, J . Am. Chem. SOC.84, 622 (1962). 7. 0 . 0. Orazi, R. A. Corral, and M. E. Stoichewich, Can. J . Chem. 44, 1523 (1966). 8. N. Guillen-Escalante and M. N. Marco, Bol. SOC.Botan. Arg. 10, 129 (1963). 9. L. D. Antonaccio, N. A. Pereira, B. Gilbert, H. Vorbrueggen, H. Budzikiewicz, J. M. Wilson, L. J. Durham, and C. Djerassi, J . Am. Chem. SOC.84, 2161 (1962). 10. M.-M. Janot and J. Le Men, Ann. Pharm. Franc. 13, 325 (1955). 11. M. Plat, R. Lemay, J. Le Men, M.-M. Janot, C. Djerassi, and H. Budzikiewicz, Bull. Soc. Chim. France 2497 (1965). 12. J. L. Kaul, J. Trojanek, and A. K. Bose, Chem. & Ind. (London)853 (1966). 13. J. L. Kaul and J. Trojanek, Lloydia 29, 26 (1966). 14. M. B. Patel, J. Poisson, J. L. Pousset, and J. M. Rowson, J . Pharm. Pharmacol. 17, 323 (1965). 15. M. A. Kuchenkova, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. N a u i Uz. S S R 21, No. 11, 42 (1964). 16. P. Kh. Yuldashev and S. Yu. Yunusov, Dokl. Akad. NaukSSSR 154, No. 6, 1412 (1964). 17. P. Kh. Yuldashev and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk Uz. SSRNo. 2, 110 (1965). 18. P. Kh. Yuldashev and S. Yu. Yunusov, Dokl. Akad. Nauk SSR 163 No. 1, 123 (1965). 19. A. K. Kiang, H. Lee, J. Goh, and A. S. C. Wan, Lloydia 27, 220 (1964). 20. A. K. Kiang, S. K. Loh, M. Demanczyk, C . W. Gemenden, G. J. Papariello, and W. I. Taylor, Tetrahedron 22, 3293 (1966). 21. M. Shamma and E. F. Walker, Jr., Ezperzentia 19, 460 (1963). 22. E. Bombardelli and A. Bonati, Boll. Chim. Farm. 102, 703 (1963); Farmnco ( P a m a ) , Ed. Sci. 18, 851 (1963); Fitoterapia 34, 66 (1963); P. Bite, L. Pongracz-Sterk, and E. Diszler, Magy. Kem. Folyoirat 69, 84 (1963); Aeta Chim. Acad. Sci. Hung. 38, 47 (1963);M. F. Bartlett and W. I. Taylor, U. S. Patent 3,169,968 (1965). 23. K. Biemann, P. Bommer, A. L. Burlingame, and W. J. McMurray, J . Am. Chem. SOC. 86, 4624 (1964); Tetrahedron Letters 1969 (1963). 24. M. Gorman, A. L. Burlingame, and K. Biemann, Tetrahedron Letters 39 (1963). 25. W. I. Taylor, A. J. Frey, and A. Hofmann, Helv. Chim. Acta 45, 611 (1962). 26. G. Spiteller and M. Spiteller-Friedmann, Tetrahedron Letters 147 (1963). 26a. S. Masamune, S. K. Ang, C. Egli, N. Nakatsuka, S. K. Sarkar and Y . Yasunari, J . Am. Chem. SOC.89, 2506 (1967). 26b. E. E . van Tamelen, L. J. Dolby, and R. G. Lawton, Tetrahedron Letters No, 19, 30 (1960). 26c. M. F. Bartlett, B. F. Lambert, H. M. Werblood, and W. I. Taylor, J . A m . Chem. SOC. 85, 475 (1963). 27. A. K. Kiang and A. S. C. Wan, J . Chem. SOC.1394 (1960). 1. 2. 3. 4.

2. THE AJMALINE-SARPAGINE ALKALOIDS

71

28. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, R. F. Raffauf, and J. L. Beal, Tetrahedron Letters 931 (1965). 29. H. Achenbach, Tetrnhedron Letters 4405 (1966). 30. M. Falco, J. Gamier-Gosset, E. Fellion, and J. Le Men, A n n . Pharm. Frnnc. 22, 455 (1964). 31. P. Potier, R. Beugelmans, J. Le Men, and M.-M. Janot, Ann. Pharm. Franc. 23, 61 (1965). 32. J. A. Joule, M. Ohashi, B. Gilbert, and C. Djerassl, Tetrahedron 21, 1717 (1965). 32a. N. R . Farnsworth, W. D. Loub, R. N. Blomster, and M. Gorman, J . Pharm. Sci. 53, 1558 (1964). 33. Z. M. Khan, M. Hesse, and H. Schmid, Helv. Chim. Acta 48, 1957 (1965). 34. F. Fish, M. Qaisuddin, and J. B. Stenlake, Chem. & Ind. (London) 319 (1964). 35. A. R. Battersby and D. A. Yeowell, J . Chem. SOC.4419 (1964). 36. M. Denayer-Tournay, J. Pecher, R. H. Martin, M. Friedmann-Spiteller, and G . Spiteller, Bull. SOC. Chim. Belges 74, 170 (1965). 37. G. Lhoest, R. de Neys, N. Defay, J. Seibl, J. Pecher, and R. H. Martin, Bull. SOC. Chim. Belges 74, 534 (1965). 38. J. C. Braekman, J. Dubois, M. Balikdjian, M. Kaisin, J. Pecher, and R. H. Martin, Bull. SOC.Chim. Belges 74, 253 (1965). 39. 0. L. Chapman and R. W. King, J. Am. Chern. SOC.86, 1256 (1964). 40. G. Van Binst, L. Denolin-Dewaersegger, and R. H. Martin, J . Chromatog. 16, 34 ( 1964). 41. U. Renner, Experientia 15, 185 (1959). 42. U. Renner and D. A. Prins, Chzmia (Aarau) 15, 321 (1961); Experientia 17, 209 (1961). 43. U. Renner, D. A. Prins, A. L. Burlingame, and K. Biemann, Helv. Chim. Acta 46, 2186 (1963). 44. M. E. Kuehne, see Renner et al. ( 4 3 , footnote 17). 45. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, and G. 0. Dudek, Tetrahedron Letters 53 (1963). 46. M. F. Bartlett and W. I. Taylor, J . Am. Chem. SOC.85, 1203 (1963). 47. G. H. Svoboda, J . Am. Pharm. Assoc. 47, 834 (1958). 48. M. Gorman and N. Neuss, Lloydia 27, 393 (1964). 49. M. Gorman and J. Sweeny, Tetrahedron Letters 3105 (1964). 50. J. A. Weisbach, R. F. Raffauf, 0. Ribeiro, E. Macko, and B. Douglas, J . Phnrm. Sci. 52, 350 (1963). 51. M. Gorman, N. Neuss, N. J. Cone, and J. A. Deyrup,J. Am. Chem.Soc. 82,1142 (1960). 52. N. Neuss and N. J. Cone, Experientia 15, 414 (1959). 53. A. N. Ratnagiriswaran and K. Venkatachalam, Quart. J . Pharm. Pharmacol. 12, 174 (1939). 54. B. Douglas, J. L. Kirkpatrick, B. P. Moore, and J. A. Weisbach, AustralianJ. Chem. 17, 246 (1964). 55. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, R . F. Raffauf, and 0. Ribeiro, Chem. & Znd. (London) 1193 (1964). 56. J. A. Weisbach and B. Douglas, Chem. & I n d . (London)623 (1965); ibid. 233 (1966). 67. W. D. Loub, N. R. Farnsworth, R. N. Blomster, and W. W. Brown, Lloydia 27, 470 (1964). 58. D. J. Abraham, N. R. Farnsworth, R. N. Blomster, and A. G. Sharkey, Jr., Tetrahedron Letters 317 (1965). 59. K. V. Rao, J . Org. Chem. 23, 1455 (1958).

72,

W. I. TAYLOR

60. B. C. Das, J. Gamier-Gosset, J. LeMen, andM.-M. Janot, BuZl.Soc. Chirn.France 1903 ( 1965). 61. G. H. Svoboda, Lloydia 26, 243 (1963). 62. M. F. Bartlett, R. Sklar, A. F. Smith, and W. I. Taylor, J. Org. Chem. 28, 2197 (1963). 63. G. Ledouble, L. Olivier, M. Quirk, J. LBvy, J. Le Men, and M.-M. Janot, Ann. Pharm. Frunc. 22, 463 (1964). 64. J. LBvy, G. Ledouble, J. Le Men, and M.-M. Janot, Bull. SOC.Chim. Prance 1917 (1964). 65. F. A. L. Anet, A. S. Bailey, and R . Robinson, Chem. & I d . (London) 944 (1953). 66. N. J. Leonard, M. Oki, and S. Chiavarelli, J.Am. Chern. SOC.77, 6234 (1955). 67. H. Jaggi and U. Renner, Chimia (Aarau)18, 173 (1964). 68. C. E. Nordman and K. Nakatsu, J. Am. Chem. SOC.85,353 (1963). 69. T. Kishi, M. Hesse, C. W. Gemenden, W. I. Taylor, and H. Schmid, Helw. Chirn. Acta 48, 1349 (1965). 70. T. Kishi, M. Hesse, W. Vetter, C. W. Gemenden, W. I. Taylor, and H. Schmid, Helw. Chim. Acta 49, 946 (1966). 71. M. Hesse, H. Hurzeler, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, Helv. Chim. Acta 48, 689 (1965);M. Hesse, F. Bodmer, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, zbid. 49, 1173 (1966).

-CHAPTER 3-

THE 2,2'-INDOLYLQUINUCLIDINE ALKALOIDS W. I. TAYLOR Research Department, C I B A Pharmaceutical Company, Division of C Z B A Corporation, Summit, New Jersey

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

73

11. Cinchophyllamine and Isocinchophyllamine..............................

74

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

77

I. Cinchonamine References

This group of bases still has a narrow distribution and only two members have been discovered in the last few years. In this article the accepted stereochemistry is used although an unequivocal proof is still 'required for C-3 in cinchonamine.

I. Cinchonamine The course of the acetylation of cinchonamine (I) (see Chart I) has been restudied using the parent base, dihydrocinchonamine and 0tritylcinchonamine (IV) ( 1 ) . Many of the compounds formed in this investigation were amorphous but were satisfactorily characterized via thin-layer chromatography and mass spectrometry along with UV- and IR-measurements. At low temperatures (dry ice-acetone) cinchonamine yielded O-acetylcinchonamine (11) (amorphous; hydrochloride, mp 201"-203" ; [.ID $8" in CHCl3) and 111(amorphous ; ["ID +39" in CHC13). Both compounds upon vigorous treatment with acetic anhydride afforded the known end product, O,N,-diacetylcinchonamone (V) (2). Compound I11 could be hydrolyzed to the corresponding amorphous diol ([a],,+60" in CHC13). Dihydrocinchonamine behaved analogously upon treatment with acetic anhydride although there were difficulties because of the amorphous nature of the products. Catalytic hydrogenation of O,N,-diacetylallodihydrocinchonamine afforded as expected I X (amorphous; [a]D +Oo in CHC13) identical with the hydrogenation product of O,N,diacetylallocinchonamine itself. 73

74

W. I. TAYLOR

0-Tritylcinchonamine upon acetylation a t a low temperature furnished crude V I I which after alkaline hydrolysis gave an amorphous alcohol (["ID -28" in CHC13).

+%*Ac

I Cinchonemine

I1

IV

V

I11

I

a-Jyi- Qpq& AeiO low temp.

0-trityl

1. OH@

NAo VII

VIII

IX

CHARTI. The acetylation of cinchonamine.

Analogies with the above reactions have been pointed out ( I ) ,namely, with the internal acylations of dihydrocorynantheine (3) and solanidan3-on-18-oic acid ( 4 ) . 11. Cinchophyllamineand Isocinchophyllamine A reinvestigation of the alkaloid content of the leaves of Cinchona legeriana Moens gave besides quinamine two new bases analyzing for C31H36N402; cinchophyllamine (mp 230" ; ["ID +23" in CHC13; pK', = 6.7 and 8.25) and isocinchophyllamine (mp 150"; ["ID +7" in CHC13;

3.

THE ~.~'-INDOLYLQUINUCLIDINE ALKALOIDS

75

pKL 6.3 and 8.1) ( 5 ,6 ) . Quinine, cinchonine, quinidine, and cinchonidine known alkaloids of the roots were not found in the leaf material. Cinchophyllamine contained two 5-methoxyindole nuclei with unsubstituted nitrogen atoms, a vinyl group, and of the two basic nitrogens one was tertiary and the other secondary. These conclusions were based on physical data ( 6 ) and the preparation of derivatives among which were the hydrochloride (mp 274"; ["ID +98" in MeOH); N-acetylcinchophyllamine (mp 204"; ["ID +147" in CHC13; methiodide (mp 242"; ["ID +146" in CHC13) ;dihydrocinchophyllamine (mp 238" decornp. ;[a]=$17" in CHCI,); N-acetyl- (mp 197"; ["ID +145" in CHCI,); N-acetylcinchophyllafnine (mp 204" ; ["ID +147" in CHC13) ; N-methylcinchophyllamine (mp 138"-140"; [a]= -8" in CHC13) (prepared by lithium aluminum hydride reduction of the amorphous N-formyl derivative). Dehydrogenation of cinchophyllamine (or isocinchophyllamine) with 5 yo palladium-charcoal a t 180"-200" afforded 7-methoxyharman ( 6 ) . Based on a combination of biogenetic considerations and the physical and chemical facts two structures, X a and XI, were considered as reasonable working hypotheses.

Xa; R = OMe, R1= vinyl Xb; R = H , RT=ethyl

XI

As a model X b was synthesized by a Pictet-Spengler type condensation of tryptamine with dihydrocorynantheal. I t s mass spectrum (allowing for the absence of the two methoxyl groups) did not resemble dihydrocinchophyllamine. Considerable support for X I as the structure of cinchophyllamine has been adduced from the mass spectrum and the presumed structures of the principal fragmentation products are shown in Chart 11." Given structure X I the stereochemistry still has t o be determined but probably is the same as cinchonamine a t ($15 and C-20.

* Upon electron-impact cinchonamine yields the following principal peaks; base peak m/e 156; peaks at m/e 187 (38%), 121 (26%), 121 (26%); 265 (la%),and 266 (15%).

76

W. I. TAYLOR

Isocinchophyllamine appears from its physical properties, especially the mass spectrum, t o be a stereoisomer of co-occurring cinchophyllamine ( 6 ) .Derivatives prepared were, dihydro- (mp 163"; [.In +21" in CHC13; pKi 7.0 and 8.3); N-acetyl- (mp 238"; [a]=+121 in CHC13).

MeoQy$ m/e 293

m/e 280

m/e 279

m/e 201

CHART11. Principal electron-impact fragmentation products of cinchophyllamine.

3. THE 2,2’-INDOLYLQUINUCLIDINlALKALOIDS

77

REFERENCES 1. R. Beugelmans, P. Potier, J. Le Men, and M.-M. Janot, Bull. Sac. Chim. France 2207 (1966). 2. R. Goutarel, M.-M. Janot, V. Prelog, and W. I. Taylor, Helv. Chim. Acta 33, 150 (1950). 3. L. J. Dolby and S. I. Sakai, J. Am. Chem. Sac. 86, 1890 (1964). 4. J. C. Sheehan, R. L. Young, and P. A. Cruickshank, J . Am. Chem.Sac. 8 2 ,6 1 4 7 (1960). 5. J. Le Men, C. Kan, P. Potier, and M.-M. Janot, Ann. Phurm. Franc. 23, 691 (1965). 6. P. Potier, C. Kan, J. Le Men, M.-M. Janot, H. Budzikiewicz, and C. Djerassi, Bull. Soc. Chim. France 2309 (1966).

This Page Intentionally Left Blank

--CHAPTER

4--

THE IBOGA AND VOACANGA ALKALOIDS W. I. TAYLOR Reseurch Department, C I B A Pharmaceutical Company, Division of C I B A Corporation, Summit, New Jersey

I. The Iboga Alkaloids .................................................. A. NewAlkaloids .................................................... B. Chemistry of the Iboga System.. .................................... C. A Synthesis of Ibogaine ............................................ D. Pharmacology ....................................................

89 92

11. The Voacangu Alkaloids. .............................................. A. The Structure of Voacamine ........................................ B. The Structures of Other Dimers ..................................... C. Vobtusine .........................................................

92 93 95 95

References

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

79 82 84

97

I. The Iboga Alkaloids Since the previous review several new peripherally substituted ibogamines have been isolated, the absolute stereochemistry of the pentacyclic system has been established, and a practical synthetic route t o the group as a whole has been published. The preparation and properties of the 16,21-seco bases" have been further explored. The success of all this work prepares the way for the eventual synthesis of vincaleukoblastine. It is now quite certain that the iboga alkaloids originate from tryptophan or its equivalent and two mevalonate residues ( 2 ) .The latter are linked head-to-tail since geraniol can also function as a precursor of the hydroaromatic portion ( 3 ) .These results along with incorporation of the same precursors in other indole alkaloids ( 4 )confirm the earlier hypothesis ( 5 )which was based solely on the classic method of recognizing similar units within apparently dissimilar natural products. I n Table I new isolations and alkaloids are recorded. It is unfortunate in view of the rapidity with which the structures of some of these com-

* The numbering system employed in the chapter assigns to the ring atoms the same numbers as their presumed equivalents in yohimbane ( 1 ) . 79

TABLE I IBOGA ALKALOIDS"

Alkaloid

R1

RE

B. Hydroxy ethyl side chain; Rz=OH Iboxygaine Me0 H

Ri

Rz

Sourceb*'

Alkaloid

h (12)

B. Hydroxy ethyl side chain; R3=OH Heyneanined H H Voacristine Me0 H (voacangarine) 19-Epivoacristined hovoecristined

Me0 H Me0

H

Sourcebrc

a (2Q P

k (16) k (16) h(I2)

W), b (22)

C. Oxidation and rearrangement products of parent bases

Iboluteine (ibogaine pseudoindoxyl) d (14) Voaluteined voacangine pseudoindoxyl d ( 1 4 ) r (14a) (rupicolined) Kisantine (ibogaline oxiudole) Montanined (voacangarine pseudoindoxyl?)

r (14a)

D. Some other bases isolated with the iboga alkaloids Affinine i (15) Stemmadenine f U I ) ,g (11)

Tabersonine Pachysiphine hydrochlorided

Ajmalicine

e ( U ) , f (W, g (ll), q (11) CZ~HZ~NZO i (~ 1 5. ) HC1 (mp 163O;[a]n -455' in MeOH) g (11) 0

Q

b-

Does not include sources in Volume VIII, p. 204. * Plant key: a, Conopharyngia jollyana Stapf; b, Ervatamia dichotolna (Roxb.) Blatter [Tabernaemontana dichotoma (Roxb.)]; c, Gabunia odoratissima Stapf; d, Rejoua aurantiaca Gaud (Tabernaemontana entartica Scheff); e, Stemmadenia donnell-smithii R. E. Woodson; f, S. tomentosa Greenman var. paleri; g, S.obovata K. Schum ;h, Tabernaemontana laurifolia Linn ;i, T . (Conopharyngia)pachysiphon var. cumminsi (Stapf)H. Huber; j. Tabernaemontana pandacaqui Poir.; k, Voacanga bracteata Stapf var. bracteata [ V .zenkeri Stapf]; 1, V . obanensis Wernh.; m, V . globosa (Blanco) Merr.; n, V . papuana (F.Muell.) K. Schum; 0,V . schweinfurthii Stapf; p, Tubernuemontuna heyneana Wall.; q,Tabernaemontana alba Miller; r, Tubernuemontuna rupicola Benth. Parenthetical numbers refer to reference list. New alkaloids.

82

W. I. TAYLOR

pounds were determined that trivial names should have been adopted. When only a few readily extractable alkaloids were known, a trivial name based on the plant source was useful but thiscustom has long since ceased to have any value except as a clue t o the plant of its first occurrence (see the distribution of coronaridine and voacangine listed in Table I). The true complexity of basic extracts and distribution of individual alkaloids began t o be recognized in the mid-fifties when alkaloid mixtures from apocynaceous plants were looked into very carefully. Where the effort has been intense an astonishing number of alkaloids have been separated,

14

19 18

16 17

Yohimbane

Iboga system (new numbering)

Iboga system (previous numbering)

e.g., in excess of 60 from Vinca rosea, and there is every reason t o believe that this is the rule rather than an exceptional case. Of the three major indole alkaloid classes ( 1 )the iboga system appears t o have the narrowest distribution ( 6 ) .

A. NEWALKALOIDS Kisantine was originally isolated in minute quantity from Tabernanthe iboga Baillon and it was not until its NMR and mass spectrum were measured that it was found to be ibogaline oxindole. Gabonine, on the other hand, was a dimer according to the mass spectrum, and on the basis of the other data, the given structure has been used as a working hypothesis. Both compounds are considered t o be artifacts formed from ibogaline during the isolation procedure (23).

4.

THE IBOGA AND VOUCU?ZgU ALKALOIDS

83

The structure of hyneanine (mp 105"-107", 160"-162"; ["ID -19" in CHC13) followed from its physical data and stepwise elimination of its two substituents t o form ibogamine (21,ZZ).Saponification of hyneaiiine followed by decarboxylation in hydrochloric acid furnished 19-hydroxyibogamine, C19H24N20* 0.5 MeOH (mp 158"-159", 223"-224"). The latter with p-toluenesulfonyl chloride in pyridine gave the quaternary salt which upon lithium aluminum hydride reduction afforded ibogamine.

afhNb

Me0 Me0

\

M e 0O \

H

H

Gabonine ?

I

Isovoacristine had a melting point of 104"-107" (dimethylsulfoxide solvate) ( [ a ] = -20" in CHCl,); picrate (mp 211"-213"); 0-benzoyl derivative (mp 190"-191"). Decarboxylation of isovoacristine b y warm hydrazine hydrate (or hydrolysis followed by heating with hydrochloric acid) afforded isoiboxygaine ( 11-methoxy-19-hydroxyibogamine) (mp 182"; [a]=-11" in CHC13). Tosylation yielded the quaternary tosylate (mp 240"-241") lithium aluminum hydride reduction of which gave tabernanthine (1.2) 19-Epivoacristine (19-epivoacangarine)(mp 115"; [.In -55" in CHC13) had spectrophotometric properties almost indistinguishable from voacristine (16).The only important difference was in the chemical shift, a doublet centered a t 1.28 pprn (-CHOH CH3) and found a t 1.11 ppm in voacristine. This epi compound had previously been prepared by the potassium borohydride reduction of voacryptine ( 2 4 ) . A conclusion as to the absolute configuration of the 19-hydroxyl was reached by using molecular rotation differences. The structure of voaluteine (rupicoline, voacangine pseudoindoxyl) was deduced from physical measurements. Of diagnostic value was the shielded methyl of the methoxyl 3.30 ppm (see voacangine 3.73 ppm). Attempts t o prove the structure by chemical degradation were not successful ( 1 4 ) .Preliminary attempts t o hydrolyze voaluteine with acid or base were not encouraging. Hydrolysis was slow and was accompanied by general decomposition. The crude amino acid fractions upon remethylation with diazomethane yielded only traces of voaluteine (14). Because ibogaine upon aerial oxidation followed by treatment with alkali gives low yields of iboluteine (25),a similar oxidation of voacangine

-

84

W. I. TAYLOR

was attempted. Oxidation proceeded rapidly in chloroform and darkened rapidly and after 2 days only traces of voacangine remained but no voaluteine could be detected after base or acid treatment (14). Upon catalytic oxidation of voacangine one group confirmed an earlier study (26) and only voacangine lactam could be isolated (14). Another group, however, was able to isolate a trace of the desired pseudoindoxyl but did not detect the lactam (14a). Photosensitized oxidation of voacangine with rose bengal in methanol furnished 10 yo voacangine lactam and 5 yo 7-hydroxy-7H-voacangine (mp 136O). This compound underwent very little fragmentation under electron impact conditions showing mainly the molecular ion m/e 367 ( 1 4 ) .Warming of the hydroxy compound with concentrated hydrochloric acid gave a quantitative yield of voaluteine. The best yield of the 7-hydroxy-7H-voacangine (35 yo)was realized by reacting voacangine with ethereal ethyl magnesium bromide followed by oxygen at 0". The method also worked well with ibogaine and 2,3-dimethylindole ( 1 4 ) . The structure of montanine .(voacangarine pseudoindoxyl ?) rests for the present entirely on plausible physical evidence (14a). Whether these pseudoindoxyls are natural products or artifacts is still to be determined. Conversion of the parent alkaloid could take place either after collection and drying and/or during the workup. The latter point has been studied and voacangine has survived the extraction conditions which were used to isolate rupicoline (14a).

B. CHEMISTRYOF

THE

IBOGA SYSTEM

A full paper amplifying previous notes has appeared concerning the chemistry of catharanthine (27). I n addition to previously discussed material it seems that when dihydrocatharanthine is refluxed in acetic acid no decarboxylation occurs ; instead, a mixture of starting material and coronaridine is obtained. Upon prolonged reflux ( > 3 days) i t was found that up to 95 yoof the dihydrocatharanthine was converted into coronaridine. When coronaridine was similarly refluxed in gla6ial acetic acid dihydrocatharanthine could be detected in the reaction mixture by use of thin-layer chromatography. These reactions require the intermediacy of the 16,21-secoiminiumsalt I1 (Chart I). An analogous intermediate must also be invoked to explain the formation of coronaridine, dihydrocatharanthine, and the vincadifformine-like base (111) upon mercuric acetate oxidation of methoxycarbonyldihydrocleavamine (28). I n the absence of the activating carbomethoxyl groups, i. e., dihydrocleavamine, oxidation gives rise solely to the aspido-

4. THE

QI-qq

IBOGA AND VOC&CangU ALKALOIDS

QrJ* = COOMe Dihydrocatharanthine

85

COOMe 16,21-Secoiminiumsalt

I1

il Coronaridine

CHARTI. Equilibration of dihydrocatharanthine and coronaridine.

sperma-like system (IV) (mp 128"-129" ; [ c L ] ~-105" in CHC13) (29) (see Chart 11). This structure was secured by X-ray crystallographic analysis (29). I n the course of these studies the absolute stereochemistry of cleavamine methiodide (V) was determined by X-ray methods ( 3 0 ) ; the consequences are used throughout this chapter. These results agree with those obtained by the X-ray crystallographic analysis of leurocristine methiodide (31)and are the mirror image of the absolute stereochemistry

I11

\

IV

CHART 11. Mercuric acetate oxidation of dihydrocleavamine and methoxycarbonyl dihydrocleavamine.

86

W. I. TAYLOR

inferred eight years ago from an optical rotatory dispersion curve of a degradation produck of ibogaine (25).

Cleavamine methiodide V

Dihydrocleavamine (mp 136"-138"; pKk 8.8; [aID -7" in CHC13) prepared by the catalytic hydrogenation of cleavamine has a /?-ethyl. I n the hydrogenation of methoxycarbonylcleavamine the hydrogen must come in from the opposite side since after decarboxylation epidihydrocleavamine (3a-ethyl) (mp 109"-111"; pKi 9.0; [aID $94" in CHC13) (27) is isolated. The effect of the 16-methoxycarbonyl group upon the,course of the hydrogenation finds a parallel in the behavior of catharanthine toward the same reagents (27). Another route to the 16,21-seco system, apart from the reductive cleavage of catharanthine derivatives (27),lies in the use of a fragmentation reaction originally applied in alkaloid chemistry to the sarpagine group (32). Voacanginol 0-tosylate (VIa) (mp 135"-140") decomposed r

1

VIa; R = H VIb: R=MeO

VIIIa; R = H VIIIb ; R = M e 0

VIIa; R = H VIIb : R = M e 0

CHART 111. Fragmentation of voacanginol 0-tosylate (R = H) and conopharyngol 0-tosylate (R = OMe).

4.

THE IBOQA AND Voacanga ALKALOIDS

87

upon warming in benzene containing triethylamine and yielded the 16,21-secodiene VIIa (mp 198"; UV = 2-vinylindole) whose assigned structure was in agreement with its chemical and physical properties (Chart 111).Catalytic reduction gave a tetrahydro derivative (mp 135") whereas sodium borohydride, as expected, afforded a dihydro compound VIIIa (mp 143"-145") (33).Conopharyngol behaved in exactly the same way, 0-tosylate (VIb) (mp 145"-148") ; fragmentation product (VIIb) (mp 180"-185") ; tetrahydro derivative (mp 97"-100") ; dihydro derivative VIIIb (mp 148"-151"). The success of the transformation (transcoplanarity of the centers) should be contrasted with the alternate mode of reaction of iboxygaine upon tosylation. This 1,3-aminoalcohol yields instead of a fission product an internally quaternized salt (34). r-

MeOOC

NC IX

Ibogaine

\

Bn

OC1

L

H

16-Cyanoibogaine

7-chloro-7H-ibogaine

X

CHART IV. Some transformation products of 7-chloro-7H-ibogaine.

88

W. I. TAYLOR

As a consequence of a study of the reactivity of the p-position of the indole moiety a route to the iboga ester alkaloids has been developed (35). Treatment of ibogaine with t-butyl hypochlorite yielded 7p-chloro7H-ibogaine (mp 90"-92"), lithium aluminum hydride reduction of which regenerated ibogaine. The chloroindolenine reacted slowly in aqueous

XI

methanolic potassium hydroxide to form 16-cyanoibogaine (mp 171"173"; [aID+28" in CHC13) which after hydrolysis and esterification with diazomethane afforded voacangine. The course of the rearrangement is another example of a general reaction of indolenines substituted at C-7 by a good leaving group (36). If the crude 7-chloroindolenine was refluxed in 1yohydrochloric acid in methanol 16-methoxyibogaine (mp 107"-108" ; ["ID +51" in CHC13) was produced which in turn upon hydrolysis in hot dilute aqueous TABLE I1 DISSOCIATION CONSTANTS A N D

RATESO F METHYLATIONOF

IBOGAMINE A N D ITS CONGENERS

Ibogamine

Substituent on ibogamine None 20-Epi10-Methoxy 11-Methoxy 10,ll-Dimethoxy 16-Methoxycarbonyl 16-Methoxycarbonyl-20-epi 1O-Methoxy-16-methoxycarbonyl 11-Methoxy-16-methoxycarbonyl 10,ll -Dimethoxy-16-methoxycarbonyl

PK: 8.1

-

8.1 7.85 7.66 6.1 6.4" 5.73" 5.65 5.61

Rate of methylation ( x 104 sec -1) 0.23 132.00 0.31 0.32

0.35 0.35 0.35

Value measured in 33% dimethylformamide. Other pK:s run in 80% methylcellosolve.

4. THE IBOGA

AND

Voacanga ALKALOIDS

89

hydrochloric acid furnished 16-hydroxyibogaine (mp 117"-119" ; [a],, + 4' in CHC13). Lithium aluminum hydride reduction of 16-methoxyibogaine gave ibogaine ; with lithium aluminum deuteride, 16-deuterioibogaine was the sole product. The displacement of the 7-chloro substituent by cyanide or methoxide ions is thought t o proceed via the mechanism sketched in Chart IV in which a nonclassic carbonium ion, X (see XXIII suggested by the same authors as an intermediate in the synthesis of ibogaine, Section 1,C) is suggested as the true intermediate rather than the more highly strained neutral possibility XI. An interesting transformation product IX (mp 78'430") was uncovered when the mother liquors from the preparation of the cyano compound were first digested with methanolic hydrogen chloride followed by methanolic hydroxide. The fragmentation step is analogous t o the fission of voacanginol-0-tosylate discussed above. Rates of methylation (Table 11) of iboga derivatives have been used to determine the configuration of the ethyl group (37).

C. A SYNTHESIS OF IBOGAINE An elegant and general route t o all the iboga alkaloids is summarized in Chart V (38). As examples ibogamine, ibogaine, and their respective C-20 epimers have been synthesized. This work along with the above work on the properties of 7-chloro-7H-ibogaine goes a long way toward the eventual synthesis of the important dimeric alkaloids represented by vincaleukoblastine. The synthesis can be broken into three parts, the construction of a suitable isoquinuclidine (XV), preparation of a tetracyclicindole intermediate (XVII),and its conversion to the iboga system. Reduction of N-benzyl-3-cyanopyridiniumbromide with sodium borohydride in aqueous solution containing sodium carbonate gave a mixture of the yellow 1,2-dihydropyridine and colorless 1,g-dihydropyridine which was condensed with methyl vinyl ketone without purification t o furnish the desired isoquinuclidine (XII) in 16 yo yield. Hydrolysis of the nitrile with cold concentrated hydrochloric acid afforded the amide identical with the adduct prepared by the reduction of 1-benzyl-3-carboxamidopyridinium chloride followed by condensation of the crude mixture of reduced pyridines with methyl vinyl ketone. Reduction of the ketoamide with sodium borohydride gave a mixture of epimeric alcohols (XIII) which with sodium hypochlorite in methanol yielded one of the tricyclic urethanes (XIV) in a readily crystallizable

90

W. I. TAYLOR

A

0

XI1

4-4 I3

jtjMei MeOOC .N H

0

xv

HzNOC

XIV

XI11

1.

R

Hm O

...--...--f-/-JR r -L.+

-

OAc

H OH

AcO

XVI

XVII

la H OH

XVIII

XIX

xx

0

XXI

CHARTV. Synthesis of (20-epi) ibogamine ( R = H ) a n d (20-epi) ibogaine (R=MeO). Reagents: 1, NaBH4; 2, methylvinyl ketone/BFs; 3, conc. HCI then NaBH4; 4, NaOCl/MeOH; 5, 6NHzS04 then AczO/Py; 6, Pd/HZ/HCl then tryptyl bromide; 7, p.MePh.SO2OH; 8, LiAlH4 then DMSO/DCC; 9, NaOMe; 10, Zn/HOAc; 11, WolffKishner.

4. THE

IBOGA AND

Vomungu ALKALOIDS

91

form. After some difficulties XIV was converted in quantitative yield to the ketone XV by hydrolysis with 6 N sulfuric acid followed by acetylation. The benzyl group was removed by catalytic hydrogenation and alkylation of the resulting secondary amine with tryptyl bromide produced the tertiary amine XVI. Cyclization by the action of ptoluenesulfonic acid in acetic acid solution furnished XVII which was converted in two steps into the pentacyclic ketone XVIII. Exposure of the ketone to a basic catalyst gave the unsaturated ketone. Compound XIX was converted into a mixture of 20-epimeric iboga ketones XX and hence to XXI. The synthesis of XVII was also accomplished in a number of steps starting with the addition of B-indolylacetyl chloride to XV (Bz = H). It is intereking to note that the first product (XXII) afijer hydrolysis and cyclim$ion with p-toluenesulfonic acid afforded the hexacyclic lactam XXXV, probably via the ion XXIII. Unlike 16-methoxyibogaine

XXII

I

XXIV

XXIII

(Chart IV) lithium aluminum hydride reduction of XXIV ceases after removal of the lactam carbonyl, the ether oxygen being unaffected. The original paper should be consulted for a detailed discussion of the many interesting reactions hinted at in Chart V. The full paper should also be compared with the preliminary communication. Other approaches to the total synthesis of iboga alkaloids have been published (39)one of which appears to have reached the stage of de-ethyl ibogamine (40)

92

W. I. TAYLOR

D. PHARMACOLOGY A review article on certain aspects of the pharmacological properties of most of the iboga alkaloids has appeared (41).Several compounds stimulated the central nervous system in a way which was not amphetamine-like and manifested itself in a number of cases as antagonism against the reserpine catalepsy. Many of the compounds caused hypotension and bradycardia in anesthetized cats. Under these conditions ibogaline was the most active alkaloid. Coronaridine is said to produce a significant diuresis (42) and catharanthine has some hypoglycemic activity ( 4 3 ) . 11. The Voacanga Alkaloids

Plants of the Voacanga genus have given rise t o four groups of bases apart from the iboga type represented by voacangine, voacristine, and TABLE I11 VOBASINE-IBOGA DIMERS

RzQy&19 R3

MeOOC

Vob=

R4

COOMe

3’

Substituents Name

Ri

Rz

R3

R4

Voacamine Voacamidine Voacorine 19-Epivoacorine Conoduramine Conodurine Gabunine (4’demethylconodurine)

H Vob H H H H

Me0 Me0 Me0 Me0 Vob

H H H

H

Vob H Vob Vob Me0 Me0

H

H

Me0

Vob

Other

H H Vob 4’-Demethyl c (9)

’I n addition to sources given in Volume VIII, p. 226. a

Plant key is given in Table I ; related 2-acylindoles are given in Chapter 2 of this volume. Bracketed numbers refer to reference list.

4. THE

IBOQA AND Voacanga ALKALOIDS

93

voacryptine ; these are the sarpagine, 2-acylindole seco-sarpagine derivatives [see Chapter 2 of this volume, callichiline (a methoxycarbonylmethyleneindoline)], and the dimer types. Since the last review the structures of all bisindoles as well as vobtusine and callichiline have been determined and total synthesis only awaits methods for preparing the appropriate 3,4-secosarpagine units. The structures and new sources of the dimers are given in Table 111.

A. STRUCTURE OF VOACAMINE Early work on voacamine established the presence in the molecule of one methoxyl, one N-methyl, and two methoxycarbonyl groups. Molecular weight determinations indicated a molecule containing twice as many atoms as the common indole alkaloids. Two of the four nitrogens were tertiary and basic (pKi 5.19 and 6.78) and 6he remaining two were part of indole nuclei. Alkaline treatment furnished a dicarboxylic acid salt which upon esterification with methanolic hydrochloric acid gave demethoxycarbonyl epivoacamine. Esterification with diazomethane yielded epivoacamine which could also be obtained directly from voacamine by sodium ethoxide catalyzed epimerization. This facile monodecarboxylation of the decarboxylic acid coupled with the production of 3-ethyl-5-methylpyridineby potash fusion of voacamine led t o the suggestion that voacangine might be a moiety of the dimer (26).It was found later that voacangine was a product of the acid-catalyzed cleavage of voacamine ( 4 4 ) . Cleavage of voacamine with 4 N hydrochloric acid in a mixture of deuterium oxide and methanol-0-d yielded after recrystallization from methanol, trideuteriovoacangine the NMR-spectrum of which indicated that only the aromatic protons had been exchanged ( 4 5 ) .This would seem t o exclude the hydroaromatic portion of voacangine as a point of attachment of the dimeric link, e.g., a Mannich base condensation product involving the basic nitrogen. This possibility was eliminated by taking dihydrovoacamine and oxidizing it with iodine t o the corresponding lactam (mp 242"-244" decomp.) which upon acid hydrolysis furnished voacangine lactam. The indolic nitrogens were excluded as points of attachment based on the recognition of signals in the NMR-spectra of a number of derivatives characteristic for two indole N-H groups (actually one of these a t 7.78 ppm was hydrogen bonded t o the 10-methoxyl). The NMR-spectrum of voacamine revealed only six aromatic protons and additional data which provided an important clue as t o the nature

94

W. I. TAYLOR

of the second half. There were signals characteristic of an ethylidene, an N-methyl, and a methoxycarbonyl(2.58 ppm) which moved t o 3.57 ppm in epivoacamine. Substantially identical chemical shifts for these functionalities are found in the spectra of vobasinol and 16-epivobasinol (46).The parallel behavior of voacamine and vobasine on base-catalyzed epimerization had already led t o the tentative proposal that the latter alkaloid was somehow related t o voacamine ( 4 7 ) . Other properties, especially the results obtained upon Hofmann degradation of voacamine monomethiodide, strengthened this view and in fact Ied t o XXV as a working hypothesis ( 4 5 ) . The initial mass spectra were not in agreement with this proposal but it turned out that what was being measured was the transmethylated pyrolytic product, voacamine methine (molecular ion m/e 722 5 4,calc. 7 18). Once the transmethylating methoxycarbonyl groups were removed the expected molecular ions were obtained. The full papers (45, 48) are worth reading for what they have t o teach concerning this difficulty.

voaciiine

xxv Voacamine

,

, I

I Vobaainol

XXVI Voacamidine

CHARTVI. Partial synthesis of voacamine and voacamidine.

4.

95

THE IBOGA AND VOUCUngU ALKALOIDS

A partial synthesis of voacamine (and voacamidine, XXVI) was carried out by condensing voacangine andvobasinol in refluxing 1.5yomethanolic hydrochloric acid (45, 49). This vinylogous Mannich type condensation (Chart V I ) has an analogy in the known dimerization of l-hydroxy1 2,3,4-tetrahydrocarbazole(45, 50). The absolute stereochemistry of voacamine was largely settled by the known configurations of the two halves and it remains only to settle the dimeric link c-ll-C-3'. The proton a t (2-3' is regarded as since in voacamine it absorbs a t 5.2ppm, while in epivoacamine the signal moves to 4.7 ppm. This implies that the methoxycarbonyl and the hydrogen atom must be in close proximity and the molecular model shows that XXV satisfies this structure. I n voacamidine (XXVI) the proton a t C-3' is felt t o be P-oriented based on expectation and also on the NMR-results. The restricted rotation of the C-3'-C-9 bond placed the C-3' hydrogen in the plane of the voacangine nucleus and it is magnetically deshielded by the ring current of the indole nucleus. Also the C-10 methoxyl (3.08 ppm) on the voacangine unit is situated above the indole ring of the vobasine fragment ( 4 9 ) . )

P

B. THE STRUCTURE OF OTHERDIMERS The partial synthesis and NMR-properties of voacamidine have been alluded to above. It has also been found that under acidic conditions stronger than used for the partial synthesis voacamidine is isomerized t o the more stable voacamine (49).Despite the apparent ease and reversibility of this reaction, these alkaloids do not seem to be artifacts of the isolation since the monomeric components when taken through a typical isolation procedure yield no trace of dimeric material (45,49). The structures of conodurine and conoduramine (see Table 111)follow from their spectroscopic properties and partial synthesis from isovoacangine and vobasinol (49). Epivoacorine (16)upon acid hydrolysis yielded 19-epivoacristine ( 19epivoacangarine). This coupled with its other physical properties led to the structure given in Table 111. Gabunine (N-demethylconodurine) mp 244"-246"; [a]= -105" in CHC13) was converted into conodurine by reductive methylation (formaldehyde-hydrogen-palladium charcoal) in 50 yo aqueous dioxane ( 9 ) . C. VOBTUSINE Vobtusine is different from the iboga-vobasine dimers in two ways; firstly, it cannot be split into monomeric units by acid treatment;

96

W. I. TAYLOR

oyp- i; /-p;T/c-c-)

COOMe

H

COOMe

L

(2 rings)

A

XXVII Vobtusine

secondly, it is made up of two type I11 (I)precursors. Physical measurements, especially high-resolution mass spectroscopy, on the various degradation products has led to the partial structure XXVII (51),which was refined by the Zurich group to XXVIII ( 5 2 ) .The latter workers’ investigation was assisted considerably by their recognition that the

I

Me0

XXIX

& XXVIII

\

H

i

COOMe

I I(-

’ ) gn i r

xxx

4. THE IBOGA AND Voacanga ALKALOIDS

97

structure of beninine was relevant to the vobtusine problem. Beninine (XXIX) is found along with vobtusine in Callichilia (Hederanthera), barteri (Hook. F.) Pichon. Very recently callichiline (XXX) has been recognized (53) t o be yet another member ( 5 4 )of this newly discovered bis-aspidosperma alkaloid complex. A base, alkaloid C, isolated from Voacanga globosa (Blanco) Merr. (Tabernaemontana globosa Blanco ; Voacanga cumingianaRolfe ;Orchipeda foetida F.) (mp 289" decomp.; [aID -318" in CHC13) is almost identical with vobtusine (mp 286" decomp.; [aID-321"). The UV- and I R (between.6 and 13 p ) spectra are practically superimposable upon those of vobtusine; the sole difference is the presence of a carbonyl band a t 1790 em-1 in alkaloid C. REFERENCES 1. J. Le Men and W. I. Taylor, Experientia 21, 508 (1965); W. I. Taylor "The Indole Alkaloids," Pergamon Press, Oxford, 1966. 2. A. R. Battersby, R. T. Brown, R. S. Kapil, A. 0. Plunkett, and J. B. Taylor, Chem. Commun. 46 (1966); M. Yamasaki and E. Leete, Tetrahedron Letters 1499 (1964). 3. A. R. Battersby, R. T. Brown, J. A. Knight, J. A. Martin, and A. 0. Plunkett, Chem. Commun. 346 (1966). 4. H. Goeggel and D. Arigoni, Chem. Commun. 538 (1965); P. Loew, H. Goeggel, and D. Arigoni, ibid. 347 (1966);F. McCapra, T. Money, A. I. Scott, and I. G. Wright, ibid. 537 (1965); E. S. Hall, F. McCapra, T. Money, K. Fukumoto, J. R. Hanson, B. S. Mootoo, G. T. Phillips, and A. I. Scott, ibid. 348 (1966). 5. R. Thomas, Tetrahedron Letters 544 (1961). 6. M. Hesse, "Indolalkaloide in Tabellen." Springer, Berlin, 1964. 7. C. HootelB, J. Pecher, R. H. Martin, G. Spiteller, and M. Spiteller-Friedmann, Bull. Soc. Chim. Belges 73, 634 (1964). 8. S. M. Kupchan, A. Bright, and E. Macko, J . Fharm. Sci. 52, 598 (1963). 9. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, R. F. Raffauf, and J. L. Beal, Tetrahedron Letters 931 (1965). 10. N. Ramiah and J. Mohandas, Indian J . Chem. 4, 99 (1966). 11. 0. Collera, F. Walls, A. Sandoval, F. Garcia, J. Herran, and M. C. Pereazmador, Bol. Inst. Quirn. Univ. Nacl. Auton. Mex. 14, 3 (1962). 12. M. P. Cava, S. K . Mowdood, and J. L. Beal, Chem. & Ind. (London)2064 (1965). 13. G. Aguilar-Santos, A. C. Santos, and L. M. Joson, J . Philippine Phrrrm. Assoc. 50, 321 and 333 (1964). 14. G. B. Guise, M. Rasmussen, E. Ritchie, and W. C. Taylor, Australian J. Chern. 18, 927 (1965). 14a. C. Niemann and J. W. Kessel, J . Org. Chem. 31, 2265 (1966). 15. M. B. Patel and J. Poisson, Bull. SOC. Chim. France 427 (1966). 16. F. Puisieux, M. B. Patel, J. M. Rowson, and J. Poisson, A n n . Pharm. Franc. 23, 33 (1965); J. Poisson, F. Puisieux, C. Miet, and M. B. Patel, Bull. Soc. Chim. France 3549 (1965). 17. M. Quirin, F. Quirin, and J. Le Men, Ann. Pharm. Franc. 22, 361 (1964). 18. F. Fish and F. Newcombe, J . Pharm. Pharmncol. 16, 832 (1964). 19. J. Thomas and G. A. Starmer, J . Pharm. Pharmacol. 15, 487 (1963).

98

W. I. TAYLOR

20. C. HootelB, A. McCormick, J. Pecher, and R. H. Martin, Intern. Symp. Chem. Stereochem. Steroid Indolalkaloide, Smolenice, Czechoslovakia, 1965 Abstracts p. 10. 21. T. R. Govindachari, B. S. Joshi, A. K. Saksena, S. S. Sathe, and N. Viswanathan, Tetrahedron Letters 3873 (1965); Chem. Commun. 97 (1966). 22. S. M. Kupchan, J. M. Cassady, and S. A. Telang, Tetrahedron Letters 1251 (1966). 23. W. I. Taylor, J . Org. Chem. 30,309 (1965). 24. U. Renner and D. A. Prins, Experienlia 17, 106 (1961). 25. M. F. Bartlett, D. F. Dickel, and W. I. Taylor, J . Am. Chem. SOC.80, 126 (1958). 26. F. Percheron, Ann. Chim. (Paris)[I31 4, 303 (1959). 27. M. Gorman, N. Neuss, a n d N . J. Cone, J. Am. Chem. SOC.87, 93 (1965). 28. J. P. Kutney, R. T. Brown, and E. Piers, J . Am. Chem. SOC.86,2286 and 2287 (1964); Lloydia 27, 447 (1964). 29. A. Camerman, N. Camerman. and J. Trotter, Acta Cyst. 19,314 (1965); J. P. Kutney and E. Piers, J. A m . Chem. SOC.86, 953 (1964). 30. J. P. Kutney, J. Trotter, T. Tabata, A. Kerigan, and N. Camerman, Chem. & I n d . (London)648 (1963); N. Camerman and J. Trotter, Acta Cryst. 17,384 (1964). 31. J. W. Moncrief and W. N. Lipscomb, J . Am. Chem. SOC. 87, 4963 (1965). 32. M. F. Bartlett, R. Sklar, W. I. Taylor, E. Schlittler, R. L. S. Amai, P. Beak, N. Y. Bringi, and E. Wenkert, J . Am. Chem. SOC.84, 622 (1962). 33. U. Renner, K. A. Jaeggi, and D. A. Prins, Tetrahedron Letters 3697 (1965). 34. R. Goutarel, F. Percheron, and M.-M. Janot, Compt. Rend. 246, 279 (1958). 35. G. Bdchi and R. E. Manning, J . Am. Chem. SOC.88, 2532 (1966). 36. W. I. Taylor, Proc. Chem. SOC.247 (1962). 37. M. Shamma and H. E. Soyster, Experientia 20, 36 (1964). 38. G. Bdchi, D. L. Coffen, K. Kocsis, P. E. Sonnet, and F. E. Ziegler, J . Am. Chem. SOC. 88, 3099 (1966); 87, 2073 (1965). 39. M. P. Cava and C. K. Wilkins, Jr., Chem. & I d . (London) 1422 (1964); G. I. Sallay, Tetrahedron Letters 2443 (1964). 40. J. W. Huffman, C. B. S. Rao, and T. Kamiya, J . Am. Chem. SOC.87, 2288 (1965). 41. G. Zetler, Arzneimittel-Forsch. 14, 1277 (1964). 42. M. Gorman, R. H. Tust, G. H. Svoboda, and J. Le Men, Lloydia 27, 214 (1964). 43. G. H. Svoboda, M. Gorman, and M. A. Root, Lloydia 27, 361 (1964). 44. W. Winkler, Naturwiss. 48, 694 (1961). 45. G. Buchi, R. E. Manning, and S. A. Monti, J . Am. Chem. SOC.86, 4631 (1964); 85, 1893 (1963). 46. M. P. Cava, S. K. Talapatra, J. A. Weisbach, B. Douglas, and G. 0. Dudek, Tetrahedron Letters 53 (1963). 47. U. Renner, Experientia 15, 185 (1959). 48. D. W. Thomas and K. Biemann, J . Am. Chem. SOC.87, 5447 (1965). 49. U. Renner and H. Fritz, Tetrahedron Letters 283 (1964). 50. S. G. P. Plant, R. Robinson, and M. Tomlinson, Nature 165, 928 (1950). 51. J. Poisson, M. Plat, H. Budzikiewicz, L. J. Durham, and C. Djerassi, Tetrahedron 22, 1075 (1966). 52. A. A. Gorman, V. Agwada, M. Hesse, U. Renner, and H. Schmid, Helv. Chim. Acta 49, 2072 (1966). 53. V. Agwada, A. A. Gorman, M. Hesse, and H. Schmid, Helv. Chim. Acta 50, 1967 (1967). 54. M. Plat, N. Kunesch, J. Poisson, C. Djerassi, and N.Budzikiewicz, Bull. SOC.Chim. France 2669 (1967).

-CHAPTER

5-

THE VINCA ALKALOIDS* W. I. TAYLOR Research Department, C I B A Pharmaceutical Company, Division of C I B A Corporation, Summit, New Jersey

I. The Alkaloids of Vinca roses L.. ....................................... A. Vincaleukoblastine ............................................... B. Modified Dimers ................................................. C. Other Alkaloids.. ................................................

102 102 105 106

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

108

111. The Alkaloids of Other Vinca Species. .................................. A. Vinca difformis Pourr. ............................................ B. VincamajorL.................................................... C. Vinca pubescens Urv. ............................................. D. Vinca erecta Rgl. e t Schmalh. ...................................... E. Vinca herbacea Waldst. e t Kit.. ..................................... F. Catharanthus Zanceus (Boj. ex A. DC.) Pich.. .......................... G. Catharanthus pusillus (Murr.) G. Don.. ..............................

110 110 110 113 113 116 119 120

11. The Alkaloids of Vinca minor L..

References

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

121

The synonyms for the genus Vinca are Lochnera, Pervinca, Catharanthus and Ammocallis; since the botany of the plants does not concern us here, the term Vinca is preferred (I),although this matter has been the subject of a recent discussion (2). The results now available show considerable diflerences between the alkaloids isolated from different species and this information ought to be of considerable value t o the systematic botanist. The most marked contrast is between the bases of V . major and V . pubescens, and other Vinca species (see tables in this chapter). The structural challenge created by the isolation of the aspidospermaiboga dimers has been solved by applying to the problem the most sophisticated physical methods but neither a purely chemical proof nor a synthetic route to these dimers has been realized.

* The numbering system used in this chapter assigns to the atoms in the various alkaloids the same numbers as their yohimbine equivalents. 99

w 0 0

TABLE I

THEALKALOIDS OF Vincu roseu

Name (isolation reference) Mitraphylline ( 1 3 ) Akuammicine ( 1 3 ) Deacetylvindoline ( 1 4 ) Vinosidine (13, 15) Lochnervine (13, 15) Leurosivined ( 1 3 , 1 5 )

Formula

Melting point ("C)

253-257 278-280 > 353

Maximum wavelength [a]=(CHC13)

pK: (33% DMF)

hl,,

6.80 None 4.80, 5.80

226, 254, 259, 300' 296, 329' 214,265,295,310

Cavincined (13, 15)

275-277

6.90

224,281,288

Ammocalline ( 1 3 )

> 335

7.30

218,288

Observations

Dimeric?

3 {IsZFne?

t-' b-

Pericalline ( 1 3 )

196-202

8.05

207,304

Ammorosine' ( 1 3 ) CavincidinedBG( 1 3 ) Maandrosined ( 1 3 )

221-225 236-239 160-173

7.30 7.85 6.90

227,280 222,281,289 204,244,290

Cathindined ( 1 3 )

239-245

-

224,282,289

Perividine ( 1 6 )

230-260

None

Vinaspine ( I 7) Vincathicined ( 1 7 ) Rovidined ( 1 7 )

235-238 > 320 > 320

7.85 5.10, 7.05 4.82, 6.95

240,286, 315 (shoulder) 225,281, 289 231, 264, 300' 214,265, 286

+4 F Tabernoschizine [S.cuffaeoides (21, 2211

0

Deacetylvin~aleukoblestine~ (17) Vinaphamine ( 17) Lochrovine (18) Perimivine (18)

320 229-235 258-263 292-293

Insoluble -99"

23Ck233 21 3-2 18 234-238 165-170

-32" -496' -345O -25'

-

5.40, 6.90 5.15, 7.0 None Insoluble

214, 266, 2 9 P 214, 262, 292 229,301,344 232, 302,340

6.1 5.60 4.50 5.45

244,300 226, 297, 328" 225, 298, 326" 244, 302

Also occurs in

V . lancea (23) Vincoline' (18) Lochrovidine (18) Lochrovicine ( 1 8 ) Vincolidine' (18) Demethoxyvindoline [vindorosine (19)]

Previously called vindolidine ( 2 4 ) ; also isolated from V. pusillus (24a) structure (25)

Deacet ylvindorosine [catharosine ( Z O ) ]

CzzH~eNz04

141-143

Provisional formula. a Suggestive of indole and indoline chromophores. 6-Anilinoacrylate chromophore.

252, 306

&OO

Isolated as the sulfate. 'Analytical data recorded but no interpretation. Believed to be related to vindolinine.

'

cn

3 8

b

F

F

stl m

102

W. I. TAYLOR

The full power of the thin-layer chromatographic method has been brought to bear to the analysis of these alkaloids and it is certain that the alkaloids in Table I do represent new entities in Ti. rosea even where insufficient material was available for complete physical examination. Several papers (3-5) are worth special attention for the effort which was put in; applications of this work can also be found ( 6 ) .

I. The Alkaloids of Vi'incarosea L.

A. VINCALEUKOBLASTINE The position of attachment of vindoline t o the iboga moiety in the indoline-indole dimer, vincaleukoblastine, has been solved as well as a revision of the structure of the iboga portion. High-resolution mass spectroscopy a t first indicated that the initially accepted formula C46H56N409 may have t o be revised t o C48H62N409, but this was traced to the production of methylation products of vincaleukoblastine [a similar problem arises when the mass spectrum of voacamine is run (7)l. If vincaIeukoblastine was spread out as a thin film on glass wool and vaporized directly a t the ion source and the resulting mass spectra measured as a function of time, the true molecular weight is m/e 8 10 42 19, i.e., C46&,8N409, was observed but after a brief period peaks a t m/e 824.4372 (M + CH2) and 828 * 4538 (M + 2CH2) predominate over M (810.4219). Subsequent measurements on deacetyl-l6'-demethoxycarbonylvincaleukoblastine monohydrazide (mp 210-214" ; +41° in CHC13), obtained by the prolonged treatment of vincaleukoblastine with hydrazine, proved t o be very useful since it lacked the transmethylating methoxycarbonyl groups. With a revised formula of (&HS8N4O9 vincaleukoblastine had two hydrogens more than had been previously accepted and therefore one ring less, a fact in agreement with the original cleavage experiments in which deacetylvindoline (pentacyclic) and velbanamine (tetracyclic) were produced. The necessity of explaining how a pentacyclic iboga system was converted into a 16,21seco equivalent was removed (8, 9). I n the fragmentation of the monohydrazide particularly informative was the ion m/e 592 which corresponded to the loss of C3HsN203, a combination that must contain the hydrazido group (H2N. N H .CO-) plus two oxygens and two carbons. This piece of evidence localized the hydrazido group on the vindoline moiety, i.e., in the C-16, C-17 bridge. It also showed that the methoxycarbonyl which was lost came from the velbanamine portion and that the dimeric link could not have been a t

5. THE Vinca ALKALOIDS

103

either C- 16 or C- 1 7 . Additional information regarding the attachment of the two parts of the dimer was deduced from the peak m/e 509, C32H35N303, which is in agreement with the structure in Chart I and

\ H Deaoetylvindoline

N

H COOMe

Velbanamine

Methylester

Vincaleucoblastine

Le m/e 154

m/e 609

CHARTI. Some properties of vincaleukoblastine.

requires, because of its high oxygen content, that the vindoline moiety (minus the hydrazido group) be intact. A fragment, of mass 154 (CgHleNO),most abundant in velbanamine, was also seen and is thought to represent the piperidine portion plus

104

W. I. TAYLOR

C-17' and C-5'. This makes the attachment of the vindoline portion to that region improbable and restricts it to either C-16' or C-6' To establish exactly the linkage between the monomeric units, vincaleukoblastine was cleaved in heavy water, deuterium chloride, stannous chloride, and tin, the resulting deuteriovelbanamine (M = 304) showed absence of deuterium in the piperidine ring because the prominent peak at m/e 154 was unchanged. Six deuterium atoms were located in a fragment m/e 247 corresponding t o m/e = 241 in velbanamine itself (Chart 11).Four of these deuteriums are in the aromatic ring (NMR-

Velbanamine

r

Me

1

+

m / e 241 C H S C H ~ C O m/e 57 CHART 11. Origin of the ion m/e 241 from velbanamine.

evidence) while the remaining two must be on C-16' or C-6', one of which had to be the terminus of the vindoline moiety. Of these possibilities C-6' was eliminated as follows. Cleavage of vincaleukoblastine in boiling 40% aqueous sulfuric acid gave an amino acid which was esterified to furnish the methyl ester (mp 129"-132"; [aID -65" in CHCI,; M= 354) (Chart 1).Treatment of this ester with deuterium chloride in heavy water containing stannous chloride and tin afforded deuteriovelbanamine with a mass spectrum identical with that of the sample prepared directly from vincaleukoblastine. Comparison of the NMR-spectrum of the methyl ester with methoxycarbonyldihydrocleavamine (mp 164"-166' ; [.ID +96" in CHC13) [prepared by refluxing catharanthine in acetic acid with zinc (I)] further supported its structure. The C-16' proton in the NMR-spectrum of methoxycarbonyldihydrocleavamineappeared as a multiplet centered at 4.0 ppm which was absent from the methyl ester.

5.

THE

Vinca ALKALOIDS

105

The formation of the ether from vincaleukoblastine suggests that the C-20' ethyl is a-oriented.

This deduction left to be decided the stereochemistry a t C-16, C-17, and C-16' as well as the absolute stereochemistry. The structure and absolute stereochemistry of leurocristine ( 1-formyl- 1-demethylvincaleukoblastine) methiodide has been deduced by X-ray crystallographic analysis (10). The found absolute stereochemistry was in complete agreement with that deduced for the vindoline [optical rotatory dispersion arguments (141 and velbanamine portions [X-ray structure of . the conformations of the nine cleavamine methiodide ( E ) ]However member rings are considerably different in leurocristine and cleavamine methiodides owing to the attachment of the bond (10-16') joining the two parts of the dimer molecule. The structures of two close relatives of vincaleukoblastine and leurocristine, leurosine, and leurosidine still await solution.

B. MODIFIED DIMERS Vinkaleukoblastine and leurocristine have shown significant differences in their clinical activity against human neoplasms (26).The carbon skeleton of these two alkaloids is quite similar to those of leurosine and leurosidine, two other co-occurring bases, but the peripheral differences were sufficient to cause a wide variation in activity. Since the acetyl group in vincaleukoblastine seems t o be important for activity, a t least in the animal screens: variations in this moiety have been made. From a series of 17-O-acyl analogs of 17-deacetylvincaleukoblastine, one, the dimethylamino acetyl derivative, was very good (27). Parenthetically, the ease of acylation and subsequent hydrolysis of the tertiary acylate at C-16 was noted in the course of this work. Because of the resemblance of voacangine t o the iboga portion of the dimeric F'inca alkaloids, perivinol has been coupled to vindoline in refluxing methanolic hydrogen chloride. A dimer, perivindoline (11) (sulfate, mp > 300") was obtained (28)but was found to be inactive against P-1534 leukemia, which is known t o be very sensitive to the oncolytic

106

W. I. TAYLOR

Vinca alkaloids. Up t o this date no perivinol type of dimeric alkaloid has been recognized in V . rosea although vindoline and perivine are major alkaloids of this plant. MeOOC

Me0

OAc

I1 Perivindoline

I11 Deacetyldihydrovindoline ether

The possibility of microbiological conversion of vindoline has been studied. A group of 437 microorganisms were screened. About 25 yoof a large group of Streptomyces spp. were found to effect some kind of conversion, many of them converting vindoline t o deacetylvindoline. One culture, identified as a strain of Streptomyces cinnamonensis, had the ability t o convert 0-acetylvindoline t o vindoline, vindoline t o deacetylvindoline, and deacetylvindoline t o deacetyldihydrovindoline ether (111).Crown gall cultures of V . rosea produce small amounts of alkaloids (yield about 0.1 mg/gm of dried tissue). The principal base identified was vindoline (29). C. OTHER ALKALOIDS Sitsirikine, reported earlier as its sulfate (30),was suggested to be a new yohimbine isomer but a more systematic examination (31)revealed it t o be a mixture of two closely related compounds, sitsirikine (mp 181"; [a]=-52" in MeOH) and dihydrositsirikine (mp 177"-179"; acetone solvate, mp 215', anhydrous; [.ID - 55" in MeOH) which have been shown t o be closely related t o corynantheine and its dihydroderivative which also coexist in nature. A correlation between dihydrocorynantheine and dihydrositsirikine was achieved by the following sequence of

5. THE ViTinCa ALKALOIDS

107

reactions. Mild acid hydrolysis converted dihydrocorynantheine into demethyldihydrocorynanthcine which upon reduction with sodium borohydride furnished dihydrositsirikine (Chart 111).

MeOOC*CHZOH

MeOOC ACHO

MeOOCACH

I

OMe Sitsirikine; R = a-vinyl Dihydrosi+,sirikine;R = a-ethyl Isoaitairikine; R =ethylidme

Dihydrocorynsntheine

CHART111. Relationships between the sitsirikines and corynantheine.

From the amorphous postperivine fractions from the chromatography of fraction B (30)a second batch of sitsirikine was isolated, reinvestigation of which showed that it was actually a new isomer of sitsirikine (31). Isositsirikine (amorphous; [a],, -20" in CHCl,; sulfate, mp 263.5'; picrate, mp 216@)was found to have an ethylidene group but otherwise to have the same functionalities as its congeners. Sitsirikine and/or isositsirikine have since been found in Aspidosperma oblongurn A. DC. (32) and dihydrositsirikine has been isolated from Pausinystalia yohimbe Pierre (33). Cavincine and cathindine (13) are also believed (22)to be relatives of sitsirikine. The structure of the 2-acylindole, perivine (see Chart VI), has been established (28) (see Chapter 2 of this .volume) and is one of the key compounds in this group. Perosine sulfate (13)appears to be a crystalline modification of perivine sulfate (22).Perividine (16)is a neutral substance empirical formula CzoHz~Nz04,with an UV-spectrum corresponding to the presence of a 2-acylindole. It has a methoxycarbonyl group and a n NMR-spectrum "very similar to that of perivine." Reduction with sodium borohydride furnishes a compound with an indole UV-spectrum but no further work has been carried out (22).

Lochnericine; R = H Lochnerinine; R = OMe

108

W. I. TAYLOR

On the basis of an analysis of the physical data (the most valuable being mass spectra) of lochnericine and its transformation products, it has been suggested that it is the Aspidosperma-type molecule illustrated below with the novel feature of a n epoxide moiety (33a). Lochnerinine was shown previously to be methoxylochnericine (19),later work placing it on C-11 (33a). 11. Alkaloids of Vinca minor L.

Almost all the alkaloids isolated from V . minor are derived from the type 111 moiety (41) belonging t o the vincamine, Aspidosperma, and quebrachamine subclasses. I n this sense there is more uniformity among the alkaloids of P.minor than the other V'inca species. The alkaloids are also unusual in that amongst the three subclasses are found racemic alkaloids, namely, dl-eburnamine (vincanorine), dl-N-methylquebracharnine ; dl-vincadifformine and its dl-1-methyl derivative (minovine) (see Table 11). From the physical and analytical data 16-epivincamine could have differed from vincamine in the position of the hydroxyl and/or methoxycarbonyl or was simply a stereoisomer. That the latter was true followed from its reduction t o a diol with lithium aluminum hydride oxidation of which furnished I-eburnaminone. Heating 16-epivincamine* in dry

16-Epivincamine

Apovincamine

I -Eburnamonine

* This number follows the convention suggested in reference 41. On the old numbering system this compound would be 14-epivincamine.

L4

5 . THE Vinca ALKALOIDS

a"

2 w^ 2

110

W. I. TAYLOR

methanol saturated with hydrogen chloride yielded apovincamine, also obtainable from vincamine. This last proof was not unequivocal since the hydroxyl group eliminated could have been on C-17. The stereochemistry of these bases is discussed in Chapter 6. The conformation of vincaminorine and its C- 16 epimer, vincaminoreine, represents an interesting problem in this particular azabicyclododecene system, the final structure being determined by a consideration of the NMR-spectra and rates of methiodide formation (35, 36). Of particular interest is the opinion that a peak a t 6.25 ppm in the NMRspectrum of vincaminorine representing one proton is due t o the C-16 proton being strongly deshielded by N-4, as indicated below (see also Chapter 9 of this volume). As a result of a mass spectrometric examination and other considerations the epimeric configuration at C-16 has been proposed (37). COOMe

2 Vincaminorine

111. The Alkaloids of Other Vinca Species

A. Vinca difformis POURR. Continuation of the French work on the alkaloids of V . difformis has led t o the isolation of vellosimine (["ID +56" in MeOH) which was identified by direct comparison and conversion t o 10-deoxysarpagine ( 4 2 ) . A second base, a 2-acyl indole, vincadiffine, obtained in a very small quantity (42),was assigned the structure, 3-oxo-4-methyl-3,4-secoakuammidine (IV), a deduction based on its NMR- and mass spectra (see Chart IV, and Chapter 2 of this volume). The configuration of C-16 substituents followed directly from the chemical shift of the ester-methyl 2.57 ppm (methyl-shielded by the aromatic group).

B. Vinca major L. Further examples of the ajmaline-sarpagine group of alkaloids have been isolated and studied (Table 111).It is interesting that vincamajor-

5. THE VinCU ALKALOIDS &i--H MeOOC l6

*

H

""B:l

111

H O

\ Vincadiff ine

m/e =352

r

COOMe ' ug%OOMe

/ @kMe

t

m/e= 180 I

CHART

I v . Principal fragmentation path for vincadiffine.

eine (10-methoxytetraphyllicine, V) and its 0-acetate should turn out t o have the opposite stereochemistry a t C-2 to vincamajine (VI) and its 0-acetate, also contituents of V . major and V . diflormis (49).Such isomerism has not yet been noticed among the many ajmaline-type bases of the Rauwol$a species. The occurrence of such C-2 epimers in the same plant could support the thesis that an indolenine is a n obligate intermediate in the biosynthesis. Majdine after treatment with acetic anhydride and hydrolysis gives isomajdine (mp 204"-206" ; -90" in MeOH). This transformation

Meo

% N \ /

OH V Vincemajoreine

HO VI Vincamejine

COOMe

TABLE I11 TEE ALEALOIDSOF Vinca difforrnis, V . major, AND V . pbescens"rb Formulac Name A. Oxindoles Majdine" Alkaloid V

Vinine B. Ajmaline-sarpagine group 10-Methoxyvellosimine (alkaloid Y) Vincamajoreine Majoridine Vellosimine Vincadiffine C. Other cQmpounds Pubescine 11-Methoxyvincamine (vincine) Majorine Majovine Vincanovine

Melting point ("C)

[.ID

186-188 Amorphous

-

(solvent)

-137" (MeOH)

Observations

Stereoisomer of carapanaubine Isomer of carapanaubine possibly identical with majdine (46) Identified as carapanaubine

224-226

-

22 2-223

-26" (CHCl3)

10-Methoxytetraphyllicine 10-Methoxy-17-0-acetyl tetraphyllicine

230

-121" (CHC13)

2-Acylindole; see Chapter 2 Identified as reserpinine

247-249 (decomp.) 227-229 M= 362 330 (decomp.)

-265" (CHC13) +133" (CHCl3) -20' (EtOH)

A,,

(E::,) 223 (2.94), 289 (3.10) Indolic chromophore A,, (E:tm)232 (2.62), 327 (2.20)

Key: Vinca difformis, d ; V . major, m; V . pubescens, p. Does not include alkaloids of known structure reported in Volume VIII, Table 111, p. 281. Physical data for previously characterized compounds not presented. Reference dealing with isolation of the alkaloids given in parentheses; those referring to structure appear in brackets. Described as majoroxine by J. L. Kaul and J. Trojknek, 25th Intern. Congr. Pharm. Sci., Prague, 1965.

Referenced

5. THE VinCU ALKALOIDS

113

parallels that for vineridine to ttinerine (Section 111,D) and is typical for yohimbinoid oxindoles (50). The identification of carapanaubine (isoreserpilineoxindole A) in V .pubescens (Section 111,C) along with the close relationship between these two species suggests that isomajdine might turn out to be carapanaubine. C. Vinca pubescens URV. Pubescine and vinine isolated some thirty years ago (51)are stated to be identical with reserpinine and carapanaubine respectively ( 4 4 ) .In all probability vinine will be found to be identical with majdine (see Table 111) and only further work will establish the relationship with carapanaubine (52).These new findings support the thesis that V . pubescens is V . major L. ( I ) ,a conclusion which had been challenged on morphological grounds (52a).

D. Vinca erecta RGL.ET SCHMALH. Continued work in Tashkent has resulted in the obtention of alkaloids of classes other than the type 111-eburnaminegroup in particular new examples of type I bases (41) of the strychnoid, oxindole, and ajmaline classes (see Table IV). The chemistry of the phenolic base vinervine (hydrochloride, mp 154"-155"; [ a ] -511" ~ in MeOH) parallels that of akuammicine. With sodium borohydride it yields a 2,l6-dihydro derivative (mp 268"-270"; [@ID -29" in MeOH), ozonolysis gives acetaldehyde, and in 15yohydrochloric acid a t 100" it furnishes demethoxycarbonylvinervine (mp 185"-187") (53). Vinervine forms an 0-methyl ether (mp 188"-189") with diazomethane and this product after treatment with 20 yohydrochloric acid in a sealed tube at 110" followed by sodium borohydride reduction (in aqueous methanolic hydrochloric acid) gave the same indoline (mp 240"-242") as that formed from vincanidine by an analogous procedure (54).The phenolic hydroxyl was placed at (3-11 since the UVspectrum of 2,16-dihydrovinervine was found to resemble closely model derivatives (54) and this was proved 11-hydroxytetrahydro-p-carboline by the oxidation of deformyl-0-methyldihydrovincanidine to 4-methoxyN-oxalylanthranilic acid (55).The over-all structure was finally established by conversion of 0-tosyltetrahydrovinervine (mp 262') into tetrahydroakuammicine by Raney nickel (54, 55). Vinerine and vineridine from a consideration of the analytical and physical data seem to be oxindoles isomeric with reserpinine oxindole

(a]),

TABLE IV THE ALKALOIDS OF Vinca erecta' Formula' Name A. Strychnoid bases Akuammicine (R=COOMe) 1 1-Hydroxyakuammicine (vinervine) Norfluorocurarine (vincanine; R,= CHO) 11-Hydroxynorfluorocurarine (vincanidine; R = CHO) B. Oxindole Vinerine Vineridine ( 7 -epivinerine) C. Other bases Vincine I-Vincadifformine (ervamine) Kopsinine Pseudokopsinine Ercine Vincarine

Melting point ("C)

nI.[

Observations

(solvent)

Reference

(54)

Chars 250-280 ClgHzaNzOz -849" (MeOH)

179-180 CzzHzsNzOs +23" (Py)

MeOOC Detected by paper chromatography

136-138 CzlHz6NzOz -30" (MeOH) 158-159 CzsHzsNzOa -121' (MeOH) 263-264 C Z ~ H Z ~ N +14' ~ O(MeOH) ~

Isolated as the nitrate Indoline W; COOMe UV=indole; COOMe Isomer of 16-methoxycarbonyl tetraphyllicine

(?I ~~

Table does not include alkaloids isolated previously and reported in Volume VIII, p. 282. Physical data for well-known alkaloids are not presented. References dealing with sources of the alkaloids appear in parentheses; those referring to structure appear in brackets.

(54)

5.

THE

Vinca ALKALOIDS

115

(56, 57). Both bases upon acetylation gave the same acetyl derivative (mp 158"-159"; [aID -100" in acetone) hydrolysis of which regenerated vinerine. Reserpinine oxindole (mp 200"-201") was prepared as follows. Treatment of reserpinine with lead tetraacetate gave 7-acetoxy-7Hreserpinine (mp 206"-207"; [a]=+125" in CHC13) which with acid gave the oxindole. Although the UV-spectrum of this oxindole was in good agreement with those of vinerine and vineridine, the respective IR-

VII

spectra were dissimilar. It is believed that the difference lies in the configuration at (3-19 and/or 6 2 0 . From the physical data and combustion figures, pseudokopsinine, another base isolated from aerial parts of V . erecta, could very well be the 16-epimer of kopsinine (VII) which is also obtained from the same plant (58). I n the same investigation vincanidine and vinervine were also identified by paper chromatography. From the mother liquors of the isolation of erectiiie (59) there was NIu ~ O-502" ~ in MeOH) obtained (60) an amorphous base C Z ~ H Z ~ ([.

A

COOMe

VIII Vincadiff ormine

X

I

NaRHdOHO

XI I-Quebrechamine CHARTV. Some properties of I-vincadifformine (ervamine).

116

W. I. TAYLOR

with a typical P-anilinoacrylate UV-spectrum. This base, called ervamine was characterized as its hydriodide (mp 198"-200"; tartrate, mp 128"129"; nitrate, mp 256"-258"; methiodide, mp 241"-242") (see Chart V). Analogous to vincadifformine (VIII)it was reduced by zinc in methanolic sulfuric acid to the 2,16-dihydro compound ([m]D +25" in MeOH). Upon heating in 20% hydrochloric acid in a sealed tube a t 115" it furnished the demethoxycarbonyl derivative which on reduction by sodium borohydride in alkaline solution gave I-quebrachamine (XI). I n acidic medium reduction gave the indoline (X) (mp 113°-114"; [mID -13" in acetone). These data are in good agreement with the idea that ervamine is 1-vincadifformine, a constituent of Vinca minor (61),a conclusion which was recognized in principle by the Russian authors. The final base to be considered is the indoline, vincarine (mp 263"264"; [a]=+14" in MeOH) (62),which was found (63, 6 4 ) to have a formula and mass spectrum identical with quebrachidine (mp 276"-278" ; [.ID +54" in CHC13) (65). Vincarine, upon oxidation with lead tetraacetate, gave an aldehyde which afcer reduction furnished polyneuridine (XIII). The latter experiment established unequivocally the complete stereochemistry of vincarine with the exception of the positions C-2 and C-17. If the mass spectrum of vincarine is really identical with that of quebrachidine (XU) the former alkaloid can only differ (66) from the latter a t C-17 ;this point is discussed further in Chapter 2 of this volume. The above was not the conclusion of the Russian authors, who argued that vincarine differed from quebrachidine by a change of configuration a t C-16 (64).

% \

HOCHa

OH XI1 Quebrachidine

COOMe COOMe

XI11 Polyneuridine

E. Vinca herbacea WALDST.ET KIT. From a variety collected in Moldavia several bases in addition t o herbaceine (Volume VIII, p. 282) have been isolated. Among the new

5 . THE Vi%CaALKALOIDS

117

bases were, reserpinine ; a compound, CzzH24Nz03 (perchlorate, mp 229"-231"); a compound (mp 232"-235"; [E]D -94" in P y ) ; and a base, Cz3Hz~NzO6(mp 208"-210"; ["ID -111" in Py) (72). More recently herbaline, C23H30N206 (mass spectrometric M = 430) (mp 276"-278" ; [.ID -147" in Py) has been found ( 7 3 ) . s 6.87

s 3.88 Me0

t /

s 3.97 H H : sM6.98 e O 8.03 R y % H \\\\\\ 3.70 -L* MeOOC

d 1.22 (J=7)

CH3

4

m 3.97

XI1 Herbaceine

3.87 d 1.16 ( J = 7 )

3.90

Herbeline

CHARTVI. NMR-data on herbaceine and herbaline (chemical shifts in ppm; J in cps; d-doublet; s=singlet; m=multiplet; sample in CDCla).

Vincaherbinine ( 7 4 ) , CzoHzlNzOz (OCH3)3 (mp 139"-140" decomp. ; [a]= -238" ; perchlorate, mp 205"-207" decomp.) has a UV-spectrum and is thought (75) t o be similar t o 1 l-methoxytetrahydro-/3-carboline identical with herbaceine (XII). Vincaherbine ( 7 4 ) , CzoHz4NzOz (OCH3)2(mp 129"-130" decomp. ; [E]D -253"; perchlorate, mp 202"-203") has a UV-spectrum which resembles 11 -methoxytetrahydro-/3-carbolines and is thought ( 7 5 ) t o be identical with herbaine (mp 126"-128"; [aID -217") ( 7 5 ) .

118

W. I. TAYLOR

I n contradistinction to the earlier report herbaceine has the formula C23H30N205 (mass spectrum M = 414.5) rather than C Z ~ H ~ Z Nthree ~O~, rather than four methoxy groups, and is inert t o hydrogenation in the presence of Adams' catalyst (75).Herbaceine has one active hydrogen, an ind-NH as judged by the infrared spectrum and a >CH-CHz according t o its NMR-spectrum. From the mass spectrum and the ultraviolet absorption spectrum herbaceine must be a 10,ll-dimethoxyindole [compare seredine (76)l. The mass spectral data are consistent with the (77) idea that herbaceine is a complex dimethoxytetrahydro-/3-carboline which is also consistent with its oxidation t o 3-dehydroherbaceine (A, 310, 334, and 400 nm) and reversion t o the starting alkaloid with sodium borohydride. The last experiment suggests that the CD ring is TABLE V PRINCIPAL FRAGMENTS" IN THE MASSSPECTRAOF SOME OXINDOLE ALKALOIDS Alkaloid Mitraphylline Carapanaubine Yohimbine oxindole B Herbaline

Principal peaks 130 190 130 190

144 204 144 204

145 205 145 205

146 206 146 206

159 219 159 219

208 208 207 210

223 223 225 225

353 413

415

368 428 370 430

mje.

transfused (i.e., C-3 proton axial and trans t o the lone pair orbital on N4), a conclusion supported by the presence of the Bohlmann bands in the IR-spectrum (2700-2900 cm-1) of herbaceine. Hydrolysis of herbaceine yields methanol and epiherbaceinic acid (hydrochloride, mp > 200" decomp.) which upon esterification with diazomethane forms epiherbaceine (mp 142"-150" ; [aID -19" in MeOH). The epi compound can also be produced by refluxing herbaceine in methanolic sodium methoxide for 15 hours. Herbaceine upon reduction with lithium aluminum hydride furnishes herbaceinol (perchlorate, mp 215"-217"). These experiments along with the inertness of herbaceine toward acylating agents led t o the suggestion that herbaceine has structure XI1 possibly with a cis DE ring junction; the relationship between the various asymmetric centers is now defined (76a).Based on a limited amount of data, mainly of a physical nature, herbaine is considered t o be 10-demethoxyherbaceine (75, 76b). Herbaline from its UV-spectrum and other data is suggested t o be the oxindole analog of herbaceine (73). However, no attempt appears t o

5 . THE

119

~ ~ ‘ W ALKALOIDS C 4

have been made to make a structure proof trivial by converting herbaceine into its oxindole equivalent [compare the conversion of reserpiline into carapanaubine (79)I.There is certainly a close resemblance between the NMR-data of herbaceine and herbaline; the principal peaks in the mass spectrum of herbaline are exactly those which would have been predicted. I n Table V the principal peaks obtained for herbaline and three other yohimbinoid oxindoles (80) are compared (78).As expected, the parallelism with yohimbine oxindole B is excellent. 11-Methoxysitsirikine (hervine) has been isolated from the crystallization hother liquors derived from herbaceine and herbaine (80a).

*

F. Catharanthus Zanceus (BoJ. EX A. DC.) PICH.

I n addition to yohimbine, ajmalicine, tetrahydroalstonine, and lanceine (Volume VIII, p. -282) nine additional alkaloids have been MeOOC

H

-

COOMe I

-e

IllUlS

spertroineter

O

+ACHo

XI11 Periformyline

T XIV Pericyclivine

Perivine

I

hare

MeOOC’

‘CHzdH

Akuammidine

COOMe

xv

CHARTVII. Some properties of pericyclivine and periformyline.

m/e = 194

120

W. I. TAYLOR

isolated from Catharanthus Zanceus ( V . lancea). Most of these bases had already been obtained from other Vinca species and their recognition in C. Zanceus was facilitated by the extensive use of paper and thin-layer chromatography. Bases which also occur in C. roseus are leurosine (81)) perivine (81),vindoline (82),pericalline [(23)also in Xchizozygia cafleoides ( 2 1 ) ] ,perimivine [(23) also in 8. rosea ( 8 3 ) ] ,and lochnerinine ( 8 4 ) . Minovincine [20-oxo-l-vincadifformine (61) ex. V . minor] was also recognized (23).An apparently new base is cathalanceine (mp 188"-190" ; pKb 4.50 (33 yo DME');its UV-spectrum is typical of a /3-anilinoacrylate and its chromatographic behavior is different from any of the known C. roseus alkaloids (23). Pericyclivine, C20H22N202 (mp 232"-233"; [aID +5" in CHCl,; pKO, 6.75 (33 %DMF) was recognized (85)t o be XIV, a known cyclization product of perivinol (28, 86). This was confirmed by its base-catalyzed conversion t o XV, a derivative of akuammidine. Pericyclivine has been found also in Gabundia odoratissima (87). Additional study of the alkaloidal fractions has given rise to a neutral component, periformyline (XIII) (mp 206"-209"; pKi < 4) whose physical properties, formula, UV-, IR-, and mass spectra were suggestive of its structure. The NMR-spectrum in particular showed the formyl hydrogen as a doublet a t 8.2 ppm. Its structure was established by the formylation of perivine with the mixed anhydride prepared from acetic anhydride and formic acid (84, 88) (Chart VII).

G. Catharanthus pusillus (MuRR.) G. DON This Catharanthus species, also known synonymously as Vinca pusilla Murr. or Lochnera pusilla (Murr.) K. Schum., is native to India. An examination of the alkaloids of this plant following a gradient p H procedure (89) has yielded ajmalicine, vindorosine [demethoxyvindoline (24a)],and vindoline [demonstrated by means of thin-layer chromatography (24a)l.None of these bases appears to resemble the previously reported amorphous and poorly characterized alkaloids, pusiline (mp 294"-295") and pusilinine (mp 250"-252") (73). A minute amount of N-benzoyl-Z-phenylalaninol(mp 171"-173" ; [XI,, -78" in Py), a neutral component, has been isolated from another sample. Mass spectrometry established the molecular formula C ~ ~ H ~ ~(Me N O255.1247 Z ; calc. 255,1259) and the base peak a t m/e was assigned t o PhCOe. Abundant 0

ions a t m/e 91 and 7 7 corresponded to PhCHz and C&j@, whereas those at m/e 237, 224, and 164 arose from loss of HzO, CH20H, and PhCHz, respectively, from the parent ion. The IR-spectrum showed bands a t

5.

THE

VinCa ALKALOIDS

121

Its 3360 cm-1 (bonded OH), 3310 cm-1, and 1640 cm-1 (-CONH-). UV-spectrum showed a maximum a t 229 mp and the NMR-spectrum (in CF,COOH) showed a doublet centered a t 6.8 ppm (2H; J = 7 cps), a singlet a t 4.7 ppm (2H), and two singlets corresponding each t o 5H in the region 7.0-8.0 ppm. The structural assignment was confirmed by the benzoylation of Z-phenylalaninol in an excess of alkali (90).The synthetic product was identical with the natural material. REFERENCES M. Pichon, Mem. Museum Natl. Hist. Nat. (Paris) 23(4), 439 (1951). J. D. Dwyer, Lloydia 27, 282 (1964). N. J. Cone, R. Miller, and N. Neuss, J . Pharm. Sci. 52, 688 (1963). N. R. Farnsworth, R. N. Blomster, D. Damratoski, W. A. Meer, and L. V. Cammarato, Lloydia 27, 302 (1964). 5. N. R. Farnsworth and I. M. Hilinski, J . Chromatog. 18, 184 (1965). 6. I. M. Jakovljevic, D. Seay, and R. W. Shaffer, J . Pharm. Sci. 53, 553 (1964); D. Groger and K. Stolle, Arch. Pharm. 298, 246 (1965); L. N. Prista, M. A. Ferreira, and A. S. Roque, Garcia Orta 12, 277 (1964). 7. G. Buchi,R. E. Manning, andS.A. Monti,J. Am. Chem. SOC. 86,4631 (1964); 85,1893 (1963). 8. P. Bommer, W. McMurray, and K. Biemann, J . Am. Chem. SOC.86, 1439 (1964). 9. N. Neuss, M. Gorman, W. Hargrove, N. J. Cone, K. Biemann, G . Buchi, and R. E. Manning,J. Am. Chem. Soc. 86, 1440 (1964). 10. J. W. Moncrief and W. N. Lipscomb, J. Am. Chem. SOC.87, 4963 (1965). 11. D. Schumann, B. W. Bycroft, and H. Schmid, Ezperientia 20, 202 (1964); W. Klyne, R. J. Swan, B. W. Bycroft, and H. Schmid, Helv. Chim. Acta 49, 833 (1966). 12. N. Camerman and J. Trotter, Acta Cryst. 17, 384 (1964). 13. G. H. Svoboda, A. T. Oliver, and D. R. Bedwell, Lloydia 26, 141 (1963). 14. D. Groger and K. Stolle, Naturwiss. 51, 637 (1964); D. Groger, K. Stolle, and C. P. Falshaw, ibid. 52, 132 (1965). 15. G. H. Svoboda, J . Pharm. Sci. 52,407 (1963). 16. G. H. Svoboda, Lloydia 26, 243 (1963). 17. G. H. Svoboda and A. J. Barnes, Jr., J. Pharm. Sci. 53, 1227 (1964). 18. G. H. Svoboda, M. Gorman, and R. H. Tust, Lloydia 27, 203 (1964). 19. B. K. Moza and J. TrojQnek, Collection Czech. Chem. Commun. 28, 1419 (1963). 20. B. K. Moza and J. TrojBnek, Chem. S I n d . (London) 1260 (1965). 21. U. Renner and P. Kernweisz, Ezperientza 19, 244 (1963). 22. M. Gorman and N. Neuss, Lloydia 27, 393 (1964). 23. R. N. Blomster, R. E. Martello, N. R. Farnsworth, and F. J. Draus, Lloydia 27, 480 (1964). 24. B. K. Moza and J. TrojBnek, Chem. & I d . (London) 1425 (1962). 24a. W.M.Fylypiw,N. R.Farnsworth, R.N.Blomster, J. P. Buckley,andD. J.Abraham, Lloydia 28, 354 (1965). 25. B. K. Moza and J. TrojBnek, Collection Czech. Chem. Commun. 28, 1427 (1963); B. K. Moza, J. T r o j h e k , V. H a n k , and L. Dolejg, ibid. 29, 1913 (1964). 26. I. S. Johnson, J. G. Armstrong, M. Gorman, and J. P. Burnett, Jr., Cancer Res. 23, 1390 (1963); E. Frei, 111, Lloydia 27, 364 (1964). 27. W. W. Hargrove, Lloydia 27, 340 (1964). 1. 2. 3. 4.

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28. M. Gorman and J. Sweeny, Tetrahedron Letters 3105 (1964). 29. G. B. Boder, M. Gorman, I. S. Johnson, a n d P . J. Simpson. Lloydia 27, 328 (1964). 30. G. H. Svoboda, M. Gorman, N. Neuss, and A. J. Barnes, Jr., J. Pharm. Sei. 5 0 , 409 (1961); G. H. Svoboda, I. S. Johnson, M. Gorman, and N. Neuss, ibid. 51, 707 (1962). 31. J. P. Kutney and R. T. Brown, Tetrahedron 22, 321 (1966); Tetrahedron Letters 1815 (1963). 32. G. Spiteller and M. Spiteller-Friedmann,Monatsh. 94, 779 (1963). 33. T. H. van der Meulen and G. J. M. van der Kerk, Rec. Traw. Chim. 83, 148 and 154 ( 1964). 33a. B. K. Moza, J. TrojBnek, A. K. Bose, K. G. Das, and P. Funke, Tetrahedron Letters 2561 (1964). 34. J. Mokrjr and I. KompiEi, Tetrahedron Letters 1917 (1963). 35. J. Mokrjr, I KompiH, M. Shamma, and R. J. Shine, Chem. & I n d . (London) 1988 (1964). 36. J. Mokr? and I. KompiS, Lloydia 27, 428 (1964). 37. J. Trojanek, 0. Strouf, K. Blitha, L. DolejB, and V. HanuEi, Collection Czech. Chem. C'ommun. 29, 1904 (1964). 38. J. Mokrj. and I. KompiS, Chem. Zwesti 17, 852 (1963). 39. D. Zachystalova, 0. Strouf, and J. Trojanek, Chem. & I n d . (London)610 (1963). 40. J. Mokrjr, L. Dhbrakova, and P. SefCoviE, Eqerientia 18,564 (1962). 41. J. Le Men and W. I. Taylor, Ezperientia 21, 508 (1965). 42. M. Falco, J. Gamier-Cosset, E. Fellion, and J. Le Men, A n n . Pharrn. Franc. 22, 455 (1964). 43. N. Abdurakhimova, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. S S R 21, No. 4, 33 (1964). 44. N. Abdurakhimova, P. Kh. Yuldashev, and S. Yu. Yunusov, Khim. Prirodn. Soedin., Akad. Nauk Uz. SSR NO. 3, 224 (1965). 45. M. Plat, R. Lemay, J. Le Men, and M.-M. Janot, Bull. SOC. Chim. France 2497 (1965); P. Potier, R. Beugelmans, J. Le Men, and M.-M. Janot, Ann. Pharm. Franc. 23, 61 (1965). 46. J. L. Kaul and J. Trojanek, Lloydia 29, 26 (1966). 47. J. L. Kaul, J. TrojBnek, and A. K . Bose, Chem. & Ind. (London)853 (1966). 48. B. C. Das, J. Gamier-Gosset, J. Le Men, and M.-M. Janot, Bull. SOC.Chim. France 1903 (1965). 49. M.-M. Janot, J. Le Men, J. Gosaet, and J. L6vy, Bull. Soc. Chim. France 1079 (1962); J. Gosset-Gamier, J. Le Men and M.-M. Janot, ibid. 676 (1965). 50. J. C. Seaton, M. D. Nair, 0. E. Edwards, and L. Marion, Can.J. Chem. 38,1035 (1960). 51. A. P. Orekhoff, H. Gurevich, S. Norkina, and N. Prein, Arch. Pharm. 272, 70 (1934). 52. B. Gilbert, J. A. Brissolese, N. Finch, W. I. Taylor, H. Budzikiewicz, J. M. Wilson, and C. Djerassi, J . Am. Chem. Soc. 85, 1523 (1963). 52a. E. G. Pobedimova, Izw. Akod. N a u k S S S R Moscow 19, 646 (1952). 53. M. A. Kuchenkova, P. Kh. Yuldashev, and S. Yu. Yunusov, Izv. Akad. NaukSSSR, Ser. Khim. 2152 (1965). 54. M. A. Kuchenkova, P. Kh. Yuldashev, and 6 . Yu. Yunusov, Dokl. Akad. Na;rk Uz. SSR 21, No. 11, 42 (1964). 55. P. Kh. Yuldashev, U. Ubaev, M. A. Kuchenkova, and S. Yu. Yunusov, Khim. Prarodn. Soedin., Akad. Nauk U z . S S R No. 12, 34 (1965). 56. Sh. Z. Kasymov, P. Kh. Yuldashev, and S. Yu. Yunusov. Dok2. Akad. Nauk SSSR 162, No. 1, 102 (1965). 57. Sh. Z. Kasymov, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk S S S R 163, No. 6, 1400 (1965).

5 . THE

VinGa ALKALOIDS

123

58. N. Abdurakhimova, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. S S R 21, No. 2, 29 (1964). 59. P. Kh. Yuldashev, V. M. Malikov, and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. SSR No. 1, 25 (1960). 60. V. M. Malikov, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. SSR 20, No. 4, 21 (1963). 61. M. Plat, J. Le Men, M.-M. Janot, H. Budzikiewicz, J. M. Wilson, L. Durham, and C. Djerassi, Bull. Soc. Chim. France 2237 (1962). 62. P. Kh. Yuldashev and S. Yu. Yunusov, Dokl. Akad. Nauk SSSR 154, No. 6, 1412 (1964). 63. P. Kh. Yuldashev and S. Yu. Yunusov, Khim. Prirod?z. Soedin., Akad. Nauk Uz. SSR No. 2, 110 (1965). 64. P. Kh. Yuldashev and S. Yu. Yunusov, Dokl. Akad. NaukSSSR 163, No. 1,123 (1965). 65. M. Gprman, A. L. Burlingame, and K. Biemann, Tetrahedron Letters 39 (1963). 66. K. Biemann, P. Bommer, A. L. Burlingame, and W. J. McMurray, J . Am. Chem. SOC. 86, 4624 (1964); Tetrahedron Letters 1969 (1963). 67. P. Kh. Yuldashev and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. S S R 3 , 28 (1960). 68. P, Kh. Yuldashev and S. Yu. Yunusov, Uzbeksk. Khim. Zh. 7 . 4 4 (1963); 8, 61 (1964). 69. Kh. Ubaev, P. Kh. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk Uz. SSR 21, No. 10, 34 (1964). 70. Kh. Ubaev, P. Kh. Yuldashev, and S. Yu. Yunusov, Izv. Akad. Nauk SSSR, Ser. Khzm. 1992 (1965). 71. N. I. Koretskaya and L. M. Utkin, Zh. Obshch. Khim. 33, 2065 (1963). 72. I. Ognyanov, P. Dalev, H. Dutschevska, and N. Mollov, Compt. Rend. Acad. Bulgare Sci.17, 153 (1964). 73. I. Ognyanov, Ber. 99, 2052 (1966). 74. E. 8 . Zabolotnaya and E. V. Bukreeva, Zh. Obshch. Khim. 33, 3780 (1963). 75. I. Ognyanov and B. Pyuskyulev, Ber. 94, 1008 (1966). 76. J . Poisson, N. Neuss, R. Goutarel, and M.-M. Janot, Bull. Soc. Chim. France 1195 (1958). 76a. I. Ognyanov, B. Byuskyulev, M. Shamma, J. A. Weiss, and R. J. Shine, Chem. Commun. 579 (1967). 76b. I. Ognyanov, B. Byuskyulev, and G. Spiteller, Monatsh. 97, 857 (1966). 77. H. Budzikiewicz, C. Djerassi, and D. H. Williams, “Structure Elucidation of Natural Products,” Vol. I. Alkaloids. Holden-Day, San Francisco, California, 1964. 78. D. N. Majumdar and B. Paul, IndianJ. Pharm. 21, 255 (1959). 79. N. Finch, C. W. Gemenden, I. H. Hsu, and W. LTeylor, J. Am. Chem. Soc. 85, 1520 (1963). 80. 33. Gilbert, J. A. Brissolese, N. Finch, W. I. Taylor, H. Budzikiewicz, J. M. Wilson, and C. Djerassi, J . A m . C’hem.Soc. 85, 1523 (1963). 80a. I. Ognyanov, B. Pyushyulev, B. Bozjanov, and M. Hesse, Helv. Chim. Acta 50,754 (1967). 81. N. R. Farnsworth, W. D. Loub, and R. N. Blomster, J . Plkarm. Sci. 52, 1114 (1963). 82. W. D. Loub, N. R. Farnsworth, R. N. Blomster, and W. W. Brown, Lloydia 27, 470 ( 1964). 83. M. Gorman, R. H. Tust, G. H. Svoboda, and J. Le Men, Lloydin 27, 214 (1964). 84. E. M. Maloney, N. R. Farnsworth, R. N. Blomster, D. J. Abraham, and A. G. Sharkey, Jr., J . Phamn. Sci. 54, 1166 (1965). 85. N. R. Farnsworth, W. D. Loub, R. N. Blomster, and M. Gorman, J . Pharm,. Sci. 53, 1558 (1964). 86. G. Buchi, Pure and Applied Chemistry, 9, No. 1, 21 (1964).

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87. M. P. Cave, S. K. Talapatra, J.,A. Weisbach, B. Douglas, R. F. Raffauf, and J. L. Bed, Tetrahedron Letters 931 (1965). 88. D. J. Abraham, N. R. Farnsworth, R. N. Blomster, end A. G. Sharkey, Jr., Tetrahedron Letters 317 (1965). 89. G . H. Svoboda, N. Neuss, and M. Gorman, J . Am. Pharm. Assoc. Sci. Ed. 48, 659 (1959). 90. A. R. Battersby and R. S. Kapil, Tetrahedron Letters 3529 (1965).

-CHAPTER

6-

THE EBURNAMINE-VINCAMINE ALKALOIDS W. I. TAYLOR Research Department, C I B A Pharmaceutical Company, Division of C I B A Corporation, Summit, New Jersey

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

126

11. The Eburnamine-Vincamine Alkaloids ................................ A. Pleiomutine ..................................................... 8.Eburnamonine .................................................. C. Vincamine ...................................................... D. OtherBases .....................................................

128 128 129 131 134

111. The Hunteria Alkaloids .............................................. A. Hunteria eburnea Pichon .......................................... B. Hunteria umbellata K.Schum. .....................................

134 134 136

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

137 142

I. Canthine Derivatives

IV. The alkaloids of Schizozygia cafjeoides (Boj.) Baill. References

Under this heading the recent chemistry of those alkaloids having the canthine, eburnamine, and schizozygia skeletons are considered.

Canthine group

Eburnamine (vincamine) group

Schizozygia group

The number system employed in the chapter assigns to the ring atoms of the complex alkaloids the same numbers as their presumed equivalents in yohimbane ( I ) . For convenience, those alkaloids related to the canthin-6-one group are considered here although their chemistry is different from the cooccurring hydroaromatic bases. Whether they are derived in a simple manner or are degradation products of the more complex bases is not known. It seems quite sure now that a t least the complex members of this group owe the origin of their hydroaromatic portions t o two mevalonate 125

126

W. I. TAYLOR

( 17')

19 18

18

18

17

Yohimbane

New numbering

21

Previous numbering

residues, and in fact geraniol has been shown t o be utilizable by the plants (2). It should be noted that when mevalonate residues are in-. corporated in these type I11 bases (I)the positions 17 and 17' a t some stage become equivalent. Also the occurrence of racemic as well as the optical antipodes can be most simply explained if C-16 and C-17 are substituted for C-18 and C-19 by a rotation of (3-20, i.e., in the absence of C-17' there is a possible equivalence of these two carbon units. This would mean that the atom numbering for optical antipodes would be different ; however in the absence of definitive experiments no such distinction will be made a t least for those compounds lacking C-17' (I).

I. Canthine Derivatives The new alkaloids of this group, all from Pleiocarpa species, are tuboflavine (I)from Pleiocarpa tubicina Stapf [P. pycnantlta. (K. Schum.) Stapf var. tubicina (Stapf)Pichon], the same alkaloid, isotuboflavine (11) (mp 263"-265") and norisotuboflavine (111) (mp 282"-284") from Pleiocarpa mutica Benth. 1-Methoxycarbonyl-P-carboline was also isolated along with the latter alkaloids ( 3 ) . The UV-spectra of all three yellow alkaloids were similar but did show distinct differences ; they were different from the canthin-6-one (IV), and exhibited a large bathochromic shift in acid or upon formation of the respective methiodides. Tuboflavine was reduced by lithium aluminum hydride to a mixture of two compounds, both of which had UV-absorption like N*-methyl-

6.

THE EBURNAMINE-VINCAMINE

127

ALKALOIDS

/

Tv

11; R=Me III;R=H 1

harman. Tuboflavine, upon treatment successively with dilute alkali and methanolic hydrochloric acid, furnished l-methoxycarbony1-/3carboline ( 4 ) . This behavior clearly distinguished it from canthin-6-one (5). Tuboflavine has been synthesized as follows (6);Condensation of dl-tryptophan with dl-ethylsuccinic acid gave a mixture of amides V and VI. Cyclization of V in a mixture of polyphosphoric acid, phosphorus oxychloride and vanadium pentoxide afforded the known 4-ethylcanthin6-one (VII) (7) along with a trace of 4-ethyl-4,5-dihydrocanthin-6-one. VI under the same cyclization condensation conditions yielded 5-ethyl4,5-dihydrocanthin-B-one (VIII) (mp 105"-107") after palladium charcoal hydrogenation of the crude product along with a larger amount of was reduced the 4-ethyl isomer. The 5-ethyl-4,5-dihydrocanthin-6-one with zinc dust in hydrochloric acid ;the only product upon oxidation with selenium dioxide in boiling toluene was tuboflavine (I)(mp 216"). The structures of isotuboflavine and nortuboflavine have been derived largely from physical data ( 3 ) in which mass spectroscopy played a

V

VI

1

1

P.Os/VnOs/POCla

1. PiOs/VnOs/POCla 2. Pd-C/Ha

/

VII

VIII

128

W. I. TAYLOR

decisive role in determining the position of the alkyl groups by a method other than elimination. I n the case of isotuboflavine the ethyl group had t o be in ring D because alkaline hydrolysis of the alkaloid followed by diazomethane on the resultant hydrochloride gave l-methoxycarbonylP-carboline. 11. The Eburnamine-Vincamine Alkaloids

As indicated below the absolute configuration of this group has been established by chemical methods. It still has not been possible to go directly from the eburnamine to the Aspidosperma class or vice versa, but a model study ( 8 )is interesting in this respect (Chart 111). A. PLEIOMUTINE The structure of pleiomutine, I X (mp 225") (9),a constituent of Pleiocarpa rnutica (lo),has been established largely on the basis of a detailed analysis of the mass spectra of derivatives, deuterium exchange,

OTQS

-

HO \\\\''

COOMe Eburnamine

Pleiocarpinine

IX Pleiomutine CHARTI. Some properties of pleiomutine.

-COOMe

6.

THE EBURNAMINE-VINCAMINE

129

ALKALOIDS

UV-, IR- and NMR-spectra, degradation to, and partial synthesis from pleiocarpinine and eburnamenine ( 9 , I I ) .This base joins thegrowing list of dimers formed by Mannich-type condensations of monomers (cf. vincaleukoblastine, voacanga dimers). When pleiomutine [lo-(16’eburnamyl)pleiocarpinine] was refluxed with dilute hydrochloric acid or phosphoric acid, pleiocarpinine was produced. I n order to isolate the eburnamine portion the dimer had to be refluxed in dilute hydrochloric acid containing powdered tin in order to reduce the first-formed eburnamenine to a n isolable derivative, dihydroeburnamenine (9). If eburnamenine is heated with acid under the conditions used to split pleiomutine, it is rapidly converted into an amorphous polymeric material (12). A partial synthesis of pleiomutine was accomplished by both groups of workers by the acid-catalyzed condensation of pleiocarpinine and eburnamine (Chart I). The pleiocarpinine moiety is considered to be equatorially substituted on the E’ ring and this was confirmed by NMR-measurements (9). B. EBURNAMONINE The full paper on the synthesis of eburnamonine starting with the condensation product X I of ethyl bromoacetate with X has appeared

I

xv Vincamine

XIV Eburnamonine CHART11. A synthesis of eburnamonine.

i

XI11

130

W. I. TAYLOR

(13).The immonium salt X I in buffered solution gave the lactam XIl, reduction of which by either chemical or hydrogenative means would be predicted t o lead stereoselectively t o the trans system XI11 since the angular ethyl group in this nearly planar substance would be expected t o have a strong effect (Chart 11).Hydrogenation, as well as sodium borohydride reduction of XI1 gave a single product, dl-epieburnamonine, XIII. Hydrogenation or sodium borohydride reduction of X I yielded a mixture of eburnamoninic and epieburnamoninic esters, alkaline treatment of which led to dl-eburnamonine (XIV), and dl-epieburnamonine

1. oso4

1. BFa-EtsO 2. LiAlHd

/ dl-Ehurnamine

dl- 16-Methyaspidospermidine

CHART111. A route to eburnamine and 16-methylaspidospermidinegroup from a common intermediate.

(XIII). While sodium borohydride afforded a 1 : 1 mixture of products, hydrogenation yielded predominantly dl-eburnamonine [vincanorine ( 1 4 ) ] .Complete support for these conclusions has come from an examination of vincamine, XV (see below). The ability t o rearrange substituted tetrahydro-/3-carbolines into indolenines under appropriate acidic conditions has led to a synthesis of 16-methylaspidospermidine from an intermediate in another total synthesis of the eburnamine-type alkaloids (Chart 111).This route to dl-eburnamine is an interesting variant of an earlier synthesis of eburnamonine (7). The boron trifluoride-etherate rearrangement and ring closure of the tetracyclic intermediate appeared to have given an entirely homogeneous product and the subsequent lithium aluminum hydride

6.

THE EBURNAMINE-VINCAMINE

ALKALOIDS

131

reduction was also stereospecific. These results compare well with the results obtained in the total synthesis of aspidospermine where the stereospecificity, the reasons for it, and the consequences were noted (l4a). Eburnamine has been recognized in Gonioma kamassi E. May (15) and the same compound, isoeburnamine, eburnamonine, the indoles, base A (mp 229"-230"), base B (mp 246"-247.5' decomp.), base V (mp 224"225" decomp.), and the dihydroindole, base G (mp 115°-116.50) have been obtained from Amsonia tabernaemontana Walt. (Amsonia salicifolia Pichon) (16).

C. VINCAMINE I n an earlier report (17) it was stated that lithium aluminum hydride reduction of vincamine gave ( - )-eburnamonine (optical antipode of , obtained eburnamonine). This was not confirmed by others ( 1 8 , 1 9 ) who the expected product, the glycol, vincaminol. It has now been shown that the odd result obtained by the first-mentioned workers was due t o the conditions of the work-up which involved heating the crude reduction product with acid (20). It was found that vincaminol, upon reflux in 2 N hydrochloric acid, is quantitatively converted into ( - )-eburnamonine. Although a cis fusion for the DE rings of vincamine (XV) follows from its conversion t o eburnamonine, independent physical evidence has been sought and a total synthesis has been realized. I n t h e IR-spectrum in the 3.4 p region there are no bands characteristic of a cis-fused quinolizidine system (rings CD) (21) and in the NMR-spectrum the peak for the C-3 proton is a t 3.92 ppm ( Z l ) , a position characteristic for C-3 hydrogens in analogous cis-fused quinolizidines such as the yohimbinoid bases (22). The pseudo-first-order rates of methiodide formation have also been measured and were in agreement with, but could not be used as a proof of configuration (21). 16-Epivincamine (mp 181'-185"; [a],, -36" in CHC13) has been found among the alkaloids of Vinca minor L. and it was very similar in its IR-and UV-spectra t o vincamine ( 2 3 ) .The mass spectrum with peaks a t M, M-15, M-18, M-29, M-47, M-59, M-70, and the intense peak a t M-102 were nearly identical with those of vincamine differing somewhat in the intensity of some peaks and mainly in the peak at mle 266 which in vincamine is found a t m/e 267. Reduction of the alkaloid gave 16epivincaminol which after oxidation with periodic acid furnished ( - )-eburnamonine. Another proof for the (3-16 isomerism was obtained

132

W. I. TAYLOR

by dehydrating the alkaloid.with methanolic hydrogen chloride which gave a product identical with apovincamine. The discovery of the epi alkaloid made possible a useful NMRcomparison of 16-substituted derivatives (Table I) in which the downfield resonance of the protons of the quasi-equatorial substituents can be seen and for which structural assignments have been made. Deoxyvincamine and deoxyepivincamine were produced by the hydrogenation of apovincamine in a ratio of about 1 : 9. Deoxyepivincamine after hydrolysis and reesterification was converted into deoxyvincamine ( 2 3 ) . TABLE I CHEMICAL

SHIFTS O F SOME C- 16-SUBSTITUTEDDIHYDROEBURNAMENINES Substituents

e-COOMe a-COOMe e-COOMe a-H e-H a-COOMe e-H a-H

Compound 3.82 3.70 3.89 4.68 5.00 3.82 6.00 5.48

Vincamine Epivincamine Deoxyvincamine Deoxyepivincamine Isoeburnamine Eburnemine

The absolute configuration of vincamine and hence the other eburnamine alkaloids has been accomplished by showing that the optical rotatory dispersion curve of ( - )-l,l-diethyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3a]quinolizine (XVI) (mp 105"-106") obtained by a Wolf-Kishner reaction on ( - )-eburnamonine was enantiomeric with ( + )-1,2,3,4-tetrahydroharman (XVII) ( 2 4 ) .The R-configuration has t o be ascribed t o the latter compound because it has been converted into N-carboxyethyl-D-alanine(XVIII) of known absolute configuration ( 2 4 ) .This work, with the exception of the Xchizozygia alkaloids, establishes the absolute configurations of the eburnamine alkaloids since they have all been interrelated.

\ XVI

XVII

XVIII

6. THE EBURNAMINE-VINCAMINE ALKALOIDS

133

Viiicamine has been synthesized by a route which makes its own contribution to the solution of the stereochemical problem and the results were in agreement with the above results (25). Acid-catalyzed condensation of tryptamine with the aldehydic ester XIX yielded a mixture of the tetracyclic lactams XX. Reduction of the lactam carbonyl was achieved through conversion to the bhiolactam esters with phosphorus pentasulfide and subsequent desulfurization with Raney nickel to give the amino esters XXIa and b. The stereochemistry of the amino esters could be decided on the basis of the ease of oxidation of

MeOOC

MeOOC XIX

XX

XXIb

XXII dlc -Vinoamine

CHART IV. A synthesis of vincamine.

XXIa by mercuric acetate; this was the isomer which was less rapidly eluted upon chromatography than XXIb, and had vc=o 1735 cm-1 (XXIb; v , = ~1725 cm-1). Mercuric acetate oxidation, followed by reduction of the resultant immonium salt with sodium borohydride, was a convenient method for the interconversion of XXIa and b. Oxidation of the methylene group adjacent to the methoxycarbonyl group could be accomplished in low yield by treatment of the amino ester XXIa with sodio-p-nitrosomethylaniline and excess triphenylmethyl sodium followed by acid hydrolysis. This procedure gave rise to dlvincamine XXII in low yield. Oxidation of isomer XXIb furnished products which could be differentiated from vincamine by thin-layer chromatography (see Chart IV).

134

W. I. TAYLOR

D. OTHER BASES

A full but delayed paper detailing the structural work on vincine (XXIII) has been published (26). Detailed physical evidence for the structures of vincaminine (XXIV; R = H ) and vincinine (XXIV; R = OMe) has been given which are in agreement with the earlier conclusions. The stereochemical assignments depend on the similarity of the NMR-spectra (identical topology except for the -COCH3 versus CHzCH3) and mass spectra (essentially identical if the extra weights of the Me0 and carbonyl oxygen are allowed for) (27).

Me0

HO

HO

xxm

xxrv

Vincaminine; R = H Vinoinine : R = OMe

Vincine

111. The Hunteria Alkaloids

A. Hunteria eburnea PICHON The full paper on the X-ray crystallographic analysis of hunterburnine P-methiodide has appeared (28). A new dimeric hypotensive alkaloid has been reported from Hunteria eburnea Pichon (29). Hunteriamine, C S ~ H ~ ~ fNCH2 ~ Owas Z amorphous and gave crystalline salts (perchlorate, mp 279"-281" decomp. ;,1I.[ 1 2 9 " in MeOH; pKA 6.50;hydrochloride, mp 310°-315" decomp.; [.In +27" in MeOH; pK2 6.56;hydroiodide, mp > 300"). The alkaloid has a and a bathochroUV-spectrum typical of a 2,3-dialkyl-5-hydroxyindole mic shift was observed in base. I n the IR-spectrum OH/NH bands were

Hunterburnine OL- and methochlorides

8-

xxv

6. THE EBURNAMINE-VINCAMINE

135

ALKALOIDS

seen, but evidence for the presence of carbonyl groups was lacking. Evidence for the dimeric nature of the alkaloid depended on the equivalent weight by potentiometric titration, one methylimide group, and a t least one C-ethyl. Hunterburnine a- and P-methochlorides and huntrabrine methochloride have been isolated from the closely related plank, Pleiocarpa mutica Benth. (30).The mass spectra of hunterburnine a- and p-methochlorides have been studied along with other quaternary salts (31).Both

3oJ$zoJ$ H o

MeOOC/)

H "0

MeOOC

MeOOC

OMe XXVII

XXVI

I '

OMe

OMe

CHO

XXVIII

I '

OH

Dihydroburnsmicine

XXIX

CHARTV. A synthesis of dihydroburnamicine.

spectra are almost the same and lack peaks characteristic of 8-carboline derivatives and it is thought that the quaternary salts decompose via the Hofmann base XXV. The base peak for both bases was m/e 255. Dihydroburnamicine has been synthesized (Chart V) but could not be compared (32)with the same derivative of the natural product because none of the latter remained from structural studies (33). The action of lead tetraacetate in benzene transformed dihydrocorynantheine into 7-acetoxy-7H-dihydrocorynantheine (XXVI; mp 180"-181") which was converted into its methiodide (mp 206" decomp.). Hydrolysis of the methiodide in refluxing aqueous acetic acid containing sodium acetate gave the 2-acylindole XXVII (my) 153"-155" or 208"-209") which gave the expected UV-spectrum in ether but in a more polar solvent (ethanol)

136

W. I. TAYLOR

isomerized into the polar species, XXVIII. The inertness of the 2acylindole toward sodium borohydride in aqueous methanol is in accord with this form. Saponification and acid-catalyzed hydrolysis of the XXVII was accompanied by decarboxylation t o afford the crude ketoaldehyde X X I X which was reduced with sodium borohydride t o dihydroburnamicine (mp 101"-103" in benzene solvate). I t s physical properties, particularly its mass spectrum, were in complete agreement with the assigned structure. The structure elucidation of pleiocarpamine, a yohimbinoid alkaloid of H . eburnea, and its relationship t o mavacurine (34)is discussed elsewhere in this volume.

B. Hunteria umbellata K. SCHUM. From the seeds of Hunteria umbellata (K. Schum.) Hall. f. (Curpodinus umbellutus K. Schum. ; Polyadoa umbellata Xtapf; Picralima umbellata Stapf) there has been reported the isolation of corymine X X X [first discovered in Hunteria corymbosa Roxb. ( 3 5 ) ] ,0-acetyl corymine, and a new base isocorymine, CzzHzsNz04 (mp 183"-115"; [a],, -243"; 0-acetate, mp 166") for which the structure X X X I was suggested (36). An investigation of the leaves yielded erinine, CzzH~4Nz04(XXXII ; mp 267"-269"; [.ID -186" in CHCl3; picrate, mp 195"-197" decornp.) as the principal base along with 19,20-&hydroerinine (erinicine, mp 216"218"; [a]= -149" in CHC13; no crystalline picrate); corymine, and an indoline, PUA-6, C Z Z H ~ ~ N ~ O(mp ~ - H140"; ~ O ["ID -164" in CHCI,; picrate, mp 173"-174" decomp.) (37). All these bases have UV-absorption characteristic of an indoline displaced toward longer wavelengths for which corymine [structure proved also by X-ray crystallographic analysis of its hydrobromide hydrate (36)]is the model. The first known member of this group was 21

xxx

Corymine

I

XXXI Isocorymine

19

6. THE

EBURNAMINE-VINCAMINE

XXXII Erinine

137

ALKALOIDS

XXXIII

I

I

HalPt

XXXV

XXXIV

echitamine chloride (XXXIII) some of whose degradation products, namely, a,/?-dihydroechitinolide (XXXIV),its N,-methyl, and O-acetylN,-methyl derivatives were used as reference compounds for the comparative physical measurements (particularly high-resolution mass spectroscopy and optical rotatory dispersion) with similar derivatives of 19,20-dihydroerininediol (XXXV; mp 211"-213"; -197" in MeOH),the lithium aluminum hydride reduction product of erinine ( 3 8 ) . Analysis of the results led to the depicted structures for erinine and XXXV in which the absolute stereochemistries a t C-2 and C-6 have been est,ablished.It will be interesting to see if the stereochemistry a t C-15 in erinine will turn out t o be equivalent t o C-15 of yohimbine (39). PUA-6 is possibly an isomerization product derived from one of the major bases during the isolation procedure (37).

IV. The Alkaloids of Schizozygia cafeoides (Boj.) Baill. Schizozygine (XXXIX) is the most abundant member of a new group of alkaloids found so far in a single plant source, Schizozygia caSfeoides confined to East Africa (40).The structures of seven of the bases have

138

W. I. TAYLOR

been elucidated apart from the absolute stereochemistry (41, 42) and their general properties are summarized in Table 11. Schizozygine is unique among indole bases in possessing a methylenedioxy group. This was readily detected and positioned on the aromatic nucleus via the NMR-spectrum. The methylenedioxy group had a pronounced bathochromic effect on the UV-spectrum of the N-acylindoline. The schizozygine group XXXVI is obviously related t o the eburnamonine group (XXXVII) on the one hand and t o the Aspidosperma class (XXXVIII) on the other, but whether it is derived along the biosynthetic pathway or from XXXVII or XXXVIII is yet t o be determined.

XXXVI

XXXVII

Eburnamonine group

Schizozygine group

XXXVIII Aspidospernza group

I n schizozygine the lactam was six-membered and unstrained according t o the IR-spectrum ( v , , ~1653 cm-1) and its facile reformation after hydrolysis. Upon lithium aluminum hydride reduction in tetrahydrofuran dihydrodesoxyschizozygine (mp 231"-133" ; [a]= +83" in CHC13 ; p K i 5.63) and deoxyschizozygine (an N-vinylindoline ; mp 184"-186" ; +606" in CHC1,; pKL 5.03) were formed (41). The presence of an isolated olefinic bond and its environment could be deduced from the NMR-spectrum of schizozygine. I n agreement with this conclusion, catalytic hydrogenation of the alkaloid gave dihydroschizozygine (mp 190"-191"; [a]= $29" in CHC1,; pKL-5.00) as well as the Emde product, tetrahydroschizozygine (mp 147"-148" ; ["ID +52" in CHC13; p K i 6.21). That the latter product possessed an n-propyl group was demonstrated by the formation of butyric acid in the Kuhn-Roth

TABLE II

THEALEALOIDS OF Schizozygia cuffeoides (BoJ.)BAILL.

H MeOOC

0

1

2

OH

P)

8M

3

M

Alkaloid

Melting point ("C)

w d

Observationsa

[aID(CHC13)

__

b

Schizozygine (1; R1, Rz = OCHzO) Schizophylline (3) Schizogaliine (1;R 1 = H ; Rz=MeO)

192-194 129-130 156-157

+16' -64' f29"

4.29 6.13 4.32

Isoschizogaline (7-epischizogaline)

110-112

-262"

4.56

Schizogamine ( 1; R1= Rz =MeO) Isoschizogamine (7-epischizogamine) a-Schizozygol (2) /3-Schizozygol Schizoluteine

123-125 184-185 210-611 247-250 2 10-2 12

-8' -239" +51°

4.35 4.58 4.80 4.47 2.5-3.0

Caffaeoschizine CzoHzoNz04 ( ? )

208-212

+26"

4.10

269 (3.99), 313 (3.97) 251 (3.89), 299 (3.61) 219 (4.32), 255 (3.97), 295 (3.86), 300 shl (3.85) 217 (4.47), 250 (4.02), 286 (3.67), 293 (3.67) 264 (4.09), 302 (4.0) 259 (4.12), 290 (3.87) 267 (4.01), 313 (3.97) 267 (4.00), 313 (3.96) 231 (4.24), 272 (3.89), 317 (3.95) 264 (3.96), 307 (3.83)

Tabenoschizineb ClsHzoNz

198-199

-138"

7.26

303 (4.26)

-

v,=o 5.87 p, 6.02 p

6.03 p ; no MeO, MeN or C(Me) No carbonyl, MeN, or C(Me); relative of uleine ( ?)

Isolation of the alkaloids given in Renner and Kernweisz ( 4 0 ) ; references referring to structures appear in brackets. I , Identical (40)with alkaloid E from Conophaqmgia durissima ( 4 3 ) also recognized in Conopharyngia hoklii (40) and is identical (44) with pericalline (45). a

E

w W (0

140

W. I. TAYLOR

oxidation (schizozygine, under the same conditions gave no volatile acid). The chromic acid in pyridine oxidation of dihydroschizozygine yielded products (Chart VI) important in the structural elucidation, namely, the alcohol (oxidation a t the benzyl carbon, C-7; mp 187"-188"; ["ID +3OoinCHC13;pK&4.96) andthe unsaturatedamide, XL (mp 315'-316"; [aID+40" in CHC13) ; long wavelength absorption maximum a t 380 nm (log E 4.17). An examination of the products formed in the Hofmann degradation of schizozygine methiodide also led to the conclusion that there was a proton attached to C-7 (Chart VI). Schizozygine methiodide (mp > 300"; [a]* $21" in Py) upon reflux in t-butanol with potassium t-butoxide afforded a mixture of the methine (mp 166"-168'; ["ID t 1 6 0 ' in CHC13; pK&4.18; UV-schizozygine) and the isomethine (mp 236"-237"; ["ID - 157" in CHC13; pK,' 4.47; UV shifted toward the visible with respect to schizozygine). Further reflux of the methine under the above Hofmann conditions converted it into the isomethine. That the original double bond of schizozygine played no part .in these reactions was proved by the obtention of the same N,N-dimethylhexahydroschizozygine(mp 141"142"; ["ID +129"; pKk 3.14) from the following reactions, namely, an Emde reaction on schizozygine methine methiodide (mp 200"-201") and executing a Hofmann degradation on N-methyltetrahydroschizozygine (mp 178"-179"; ["ID +71"; pKL 5.58) followed by catalytic hydrogenation ( 4 1 ) . These results along with a detailed analysis of the NMR-spectra led to the structures shown in Table I1 and Chart VI. I n contrast t o the eburnamonine group (XXXVII) the DE rings of schizozygine must be tra,ns-fused in order to have a strain-free system which allows the insertion of the ethylene bridge. Rings B and C must be cis-fused to account for the facile Hofmann degradation, that is, a proton /3 and trans-coplanar to the basic nitrogen. Only small amounts of the remaining alkaloids were available for examination so that physical methods (especially mass spectra and NMR-spectra) were indispensable in defining their structures,. Schizogamine (a 5,6-dimethoxy-N-acylindoline) and schizogaline (a 6-methoxyN-acylindoline) both have mass spectra essentially equivalent t o schizozygine if allowance is made for the difference in ring A substitution, and the NMR-spectra in the nonaromatic regions are identical (42). The structure of the ester alkaloid, schizophylline followed from its facile conversion (chromatography over activity I alumina) into isoschizogaline ( 4 2 ) .

*\

/

X

-

0

gj \ / 0

V

0

Xllllll

0

0

@ -

\ / 0 V 0

-

@ 0

\ / V

0

d

0

sg

HC

0

EBURNAMINE-VINCAMINE

t

d

pi

c

6. THE

@ 0

V

0

0

g@\ / 0

V

ALKALOIDS

N

-

0

141

gij \ / 0 V

0

\0V0/

-

0

@

142

W. I. TAYLOR

a-Schizozygol upon tosylation and elimination furnished schizozygine. From the NMR-spectrum the alcoholic function must be attached to a secondary carbon adjacent to a methylene group. I n the absence of any rearrangements during these reactions the structure for a-schizozygol is that given in Table I1 ( 4 2 ) . Isochizogamine (also isoschizogaline) distinguished itself from the other member of the group (Table 11) in possessing a high negative rotation, having the lactam carbonyl frequence (Y,.~ x 1690 cm-1) much higher than schizozygine, and the UV-absorption maxima a t shorter wavelength. The more strained situation of the lactam ring was also shown by the fact that after hydrolysis a methyl ester could be obtained by treatment with diazomethane. The lactam could be regenerated from the ester by acid treatment or chromatography over activity I alumina. Isoschizogamine methiodide (mp 238"-240" decornp. ; [aID -157" in HzO) underwent a normal Emde degradation (see schizozygine, Chart VI) t o furnish N-methyltetrahydroisoschizogamine (mp 131"-133" ; [.ID -9" in CHC1,; p K i 3.59) which upon chromic acid oxidation gave butyric acid ( 4 2 ) .The Hofmann degradation of the methiodide proceeded abnormally. The products were isoschizogamine alone with compound A (mp 198"-199"; p K i 3.45) which had no olefinic protons, an angular ,C-Me, and the same aromatic nucleus, and amorphous compound B &ch had no aromatic protons and appeared to be a substituted quinone. It was concluded that in this is0 compound there was no proton ,B to the quaternary nitrogen with the proper configuration for a Hofmann degradation. Taking all the evidence a t hand, including the mass spectra which were the same €or the is0 compounds but different for the normal series, the current working hypothesis is that they are isomeric t o schizozygine a t C-7 (see Table 11). REFERENCES 1. J. Le Men and W. I. Taylor, Experientia 21, 508 (1965); W. I. Taylor "The Indole Alkaloids," Pergamon Press, Oxford, 1966. 2. A. R. Battersby, R. T. Brown, R. S. Kapil, A. 0. Plunkott, and J. B. Taylor, Chem. Commun. 46 (1966); A. R. Battersby, R. T. Brown, J. A. Knight, J. A. Martin, and A. 0. Plunkett, ibid. 346; H. Goeggel and D. Arigoni, ibid. 538 (1965); P. Loew, H. Goeggel, and D. Arigoni, ibid. 347 (1966); F. McCapra, T. Money, A. I. Scott, and I. G. Wright, ibid, 537 (1965); E. S. Hall, F. McCapra, T. Money, K. Fukumoto, J. R. Hanson, B. S.Mootoo, G. T. Phillips, and A. I. Scott, ibid. 348 (1966). 3. H. Achenbach and K. Biemann, J . Am. Chem. SOC.87, 4177 (1965). 4. C. Kump, J. Seibl, and H. Schmid, Helw. Chim. Acta 46, 498 (1963). 5. H. F. Haynes, E. R. Nelson, and J. R. Price, AustraZianJ. Sci. Res. 5 , 387 (1952). 6. H. J. Rosenkranz, G. Botyos, and H. Schmid, Ann. 691, 159 (1966). 7. M. F. Bartlett and W. I. Taylor, J . Am. Chem. SOC.8 2 , 5941 (1960).

6. T H E EBURNAMINE-VINCAMINE ALKALOIDS

143

8. J. E. D. Barton and J. Harley-Mason, Chem. Commun. 298 (1965); J. E. D. Barton, J. Harley-Mason, and K. C. Yates, Tetrahedron Letters 3669 (1965). 9. D. W. Thomas, H. Achenbach, and K. Biemann, J . Am. Chem. SOC.88, 1537 (1966). 10. W. G. Kump and H. Schmid, Helv. Chim. Actn 44, 1503 (1961). 11. M. Hesse, F. Bodmer, and H. Schmid, Helv. Chim. Acta 49, 964 (1966). 12. W. I . Taylor, unpublished results (1962). 13. E. Wenkert and B. Wickberg, J . Am. Chem. Roc. 87, 1580 (1965). 14. J. MokrJi, I. Kompib, P. SefEoviE, and S. Bauer, Collection Czech. Chem. Commun. 28, 1309 (1963). 14a. G. Stork and J. E. Dolfini, J . A m . Chem. SOC.85, 2872 (1963). 15. R. Kaschnitz and G. Spiteller, Monatsh. 96, 909 (1965). 16. E. S. Sabolotnaya, A. S. Belikov, S. P. Ivashchenko, and M. M. Molodozhnikov, Med. Prom. SSSR 18, 28 (1964). 17. M. Plat, D. D. Manh, J. Le Men, M.-M. Janot, H. Budzikiewicz, J. N.Wilson, L. J. Durham, and C. Djerassi, Bull. SOC.Chim. France 1082 (1962). 18. R. T. Major and I. El Kholy, J . Org. Chem. 28, 591 (1963). 19. J. MokrJi, I. Kompib, and P. SefEovi6, Tetrahedron Letters 433 (1962). 20. M. Plat, R. Lemay, J. Le Men, M.-M. Janot, C. Djerassi, and H. Budzikiewicz, Bull. SOC.Chirn. France 2497 (1965). 21. J. Mokrjr, M. Shamma, and H. E. Soyster, Tetrahedron Letters 999 (1963). 22. E. Wenkert, B. Wickberg, and C. Leicht, Tetrahedron Letters 822 (1961). 23. J. Mokrjr and I. KompiF;, Lloydia 27, 428 (1964). 24. J. Trojitnek, Z. Kablicova, and K. Blitha, Chem. & I n d . (London) 1261 (1965). 25. M. E. Kuehne, J . Am. Chem. SOC.86, 2946 (1964); Lloydia 27,435 (1964). 26. 0. Strouf and J. Trojanek, Collection Czech. Chem. Commun. 29, 447 (1964). 27. J. Holubek, 0. Strouf, J. Trojhek, A. K. Bose, and E. R. Malinowski, Tetrahedron Letters 897 (1963). 28. J. D. M. Asher, J. M. Robertson, and G. A. Sim. J . Chem. SOC.6355 (1965). 29. U. Renner, 2. Physiol. Chem. 331, 105 (1963). 30. Z. M. Khan, M. Hesse, and H. Schmid, Helv. Chim. Acta 48, 1957 (1965). 31. M. Hesse, W. Vetter, and H. Schmid, Helv. Chim. Acta 48, 674 (1965). 32. L. J. Dolby and S.-I. Sakai, J . Am. Chem. SOC.86, 5362 (1964). 33. M. F. Bartlett and W. I. Taylor, J . Am. Chem. SOC.85, 1203 (1963). 34. M. Hesse, W. von Philipsborn, D. Schumann, G. Spiteller, M. Spiteller-Friedmann, W. I. Taylor, H. Schmid, and P. Karrer, Helv. Chim. Actn 47, 878 (1964). 35. A. K. Kiang and G. F. Smith, Proc. Chem. SOC.298 (1962). 36. C. W. L. Bevan, M. B. Patel, A. H. Rees, D. R. Harris, M. L. Marshak, and H. H. Mills, Chem. & Ind. (London)603 (1965). 37. C. Kump, M. B. Patel, J. M. Rowson, M. Hesse, and H. Schmid, Pharm. Acta Helv. 40, 586 (1965). 38. B. W. Bycroft, M. Hesse, and H. Schmid, Helv. Chim. Acta 48, 1598 (1965). 39. A. K. Bose, B. G. Chatterjee, and R. S. Iyer, I n d i m J . Phnrrn. 18, 185 (1956); E. Wenkert, W. E. Robb, and N. V. Bringi, J . Am. Chem. SOC. 79,6570 (1957). 40. U. Renner and P. Kernweisz, Ezperientin 19, 244 (1963). 41. U. Renner and H. Fritz, Helw. Chim. Actcr 48, 308 (1965); U. Renner, Angew. Chem. 75, 1126 (1963). 42. U. Renner, LZoydia 27, 406 (1964). 43. U. Renner, D. A. Prins, and W. G. Stoll, Helw. Chirn.Acta 42, 1572 (1959). 44. M. Gorman and N. Neuss, Lloydia 27, 393 (1964). 45. G. H. Svoboda, A. T. Oliver, and D. R. Bedw.el1, Lloydia 26, 141 (1963).

This Page Intentionally Left Blank

.CHAPTER

7-

YOHIMBINE AND RELATED ALKALOIDS H . J . MONTEIRO C'entro de Pesquisas de Produtos Naturais. Paculdade de Farmdcia e Bioquimica. Rio de Janeiro. Brazil

I . Introduction and Stereochemistry

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

.......

.

145

I1 The Yohimbane Group ............................................ A . Introduction .................................................. B . 19-Dehydroyohimbine ..........................................

146 146 147

I11. The Corynane Group .............................................. A. ntroduction .................................................. B . Sitsirikine. Dihydrositsirikine. Isositsirikine ....................... ................................................ C . chrosandwine . D . Vallesiachotamine ............................................. E . Aspexcine and Methoxygaissoschizine ............................. IV . The Heteroyohimbane Group ...................................... A . Introduction .................................................. B . Herbaceine and Herbaine .......................................

148 148 148 154 155 158 159 159 160

V . The Oxindole Group .............................................. A . Introduction .................................................. B . Herbaline ..................................................... C. Rauvoxine and Rauvoxinine .................................... D . AlkaloidV .................................................... E. Vinerine and Vineridine ......................................... F. Majdine .......................................................

162 162 162 163 164 165 165

t

VI . Other Bases

...................................................... VII . Syntheses ......................................................... A . The Yohimbane Group .......................................... B . The Corynane Group ........................................... C. Oxindoles and Pseudoindoxyls ................................... D . Other Synthetic Work .......................................... E . Modified Yohimbines ........................................... VIII . Addendum ...................................................... A . TheYohimbaneGroup .......................................... B . The CorynaneGroup ............................................ C . The Heteroyohimbane Group .................................... D . The Oxindole Group ............................................ E . Other Bases .................................................... References ..................................... ...............

165 166 166 172 177 180 182 183 183 183 184 184 185 185

.

I Introduction and Stereochemistry The main purpose of this chapter is to supplement the review by R . H . F. Manske in Volume V I I I on the alkaloids from Pseudocinchona 145

146

H. J. MONTEIRO

and Yohimbe. As the yohimbinoids, or alkaloids of related structural type, are of widespread occurrence, this review is not limited to those two genera but includes all those bases, not 'described in detail in other chapters, but which can be included in that large group. Table I lists the a aloids which have been isolated recently, their sources, and some of t eir physical properties. The stereochemistry of yohimbinoids and heteroyohimbinoids has been the subject of several recent papers. A detailed account of the determination of the absolute stereochemistry of yohimbine and reserpine has appeared ( 1 ) .Shamma and Richey (2) published the full paper on the stereochemistry of heteroyohimbines (see Volume VIII, p. 708). The configurations a t C-3 and C-20 of the last class of alkaloids can also be settled by ORD-studies. Compounds with the 3a,20a-configuration exhibit a negative Cotton effect a t about 235-255 mp while those with the 3~(,20/3-, 3/3,20a-, and 3/3,20/3-configurationdisplay a positive Cotton effect a t the same region. It was suggested that such behavior arises from different chiralities of hetefo ring E (3).ORD-studies were also used to settle the stereochemistry of several indolenine derivatives, precursors in the partial syntheses of oxindoles and pseudoindoxyls. X-ray analysis of 7-acetoxy-7H-yohimbine (as niethiodide) firmly established its structure and absolute stereochemistry as shown in I. Its ORD-curve was then used as reference in the determination of the stereochemistry of other 7-substituted indolenine derivatives ( 4 ) .

P

OH T

11. The Yohimbane Group

A. INTRODUCTION Several new alkaloids of this group have been recently described (see Table I, Part 1). Venenatine, isovenenatine ( 5 , 6 ) , and venoxidine (venenatine-N,-oxide) (7) from AZstonia venenata as well as oxygambir-

7.

147

YOHIMBINE AND RELATED ALKALOIDS

tannine, gambirtannine, 3,14-dihydrogambirtannine (d), and ouroparine (9) from Uncaria garnbier are all included in Table I for the sake of completeness. Their chemistry is discussed in the relevant chapters. A further new member of this group, 19-dehydroyohimbine, was isolated from Aspidosperma pyricolluna which also yielded yohimbine, p-yohimbine, uleine, apparicine, and demethylaspidospermine (10). A new source of yohimbine is Ladenbergia hexandra (Rubiaceae) ( 1 1 ) .

B. ~~-DEHYDROYOHIMBINE The spectral properties of this new alkaloid were very similar to those of yohimbine (10). The NMR-spectrum besides showing signals also present in the spectrum of yohimbine, further showed a signal for an olefinic proton a t 5.55 6, thus indicating the presence of a tri-substituted double bond. The mass spectrum of 19-dehydroyohimbine confirmed the empirical formula CzlHzzNz03 by showing a molecular ion a t m/e 352 and also suggested the probable position of the double bond as shown in 11, since the relative intensity of the ion peak a t m/e 184 was much smaller than that of the peak a t m/e 156, as would be expected from structure I1 on the basis of the proposed fragmentation mechanisms (Volume VIII, p. 486). The alkaloid gave an 0-acetyl derivative and could be hydrogenated to @-yohimbine. Although it was very sensitive to oxidizing

OH

OH

I1

111

0

IV

148

H. J . MONTEIRO

agents it could be oxidized to the unstable and completely enolic /3-keto ester (111)(IR-bands a t 1709 and 1658 cm-1, NMR-peaks a t 12.3 and 5.55 6). Acid treatment of I11 yielded the a,P-unsaturated ketone (IV) which was characterized by its mass- (Mi-292), IR- (band a t 1672 cm-I), and NMR- (two doublets centered at 5.92 and 6.65 6 ; J = 10 cps) spectra. 19-Dehydroyohimbine is thus closely related to the reserpinoids raujemidine (12) and deserpidine (13) which also exhibit unsaturation a t the 19,20-position. 111. The Corynane Group

A. INTRODUCTION New additions to this fast growing group of alkaloids are sitsirikine, , dihydrositsirikine, and isositsirikine, from Vinca rosea ( 1 4 , 1 5 ) Pausinystalia yohimbe (16),and possibly Aspidosperma oblongum ( 17 ); ochrosandwine, from Ochrosia sandwicensis (18); speciogynine and paynantheine from Mitragyna speciosa (19); and hirsutin, from M . hirsuta (19a),which are discussed in the relevant chapter in this volume. From Vallesia dichotoma vallesiachotamine, an interesting alkaloid with a modified corynane structure, has been isolated (20). Aspexine and methoxygeissoschizine have been isolated from Aspidosperma excelsum (2Oa). The X-ray analysis of hunterburnine /3-methiodide, another modified corynane derivative, has been published in detail (21). A new source for this alkaloid and the epimeric hunterburnine a-methochloride is Pleiocarpa mutica, which also yielded huntabrine methochloride ( 2 2 ) . Hunterburnine a-methochloride also occurs in 0. sandwicensis (18). Corynantheidine has been found in M . speciosa (19).

B. SITSIRIKINE,DIHYDROSITSIRIKINE, ISOSITSIRIKINE The name sitsirikine was originally applied to an alkaloid mixture (thought a t the time to be an homogeneous compound) isolated from Vinca rosea by workers a t the Eli Lilly Co. (14).Reinvestigation of the substance by Kutney and Brown (15) resulted in the isolation of three closely related bases, which were properly named sitsirikine, dihydrositsirikine, and isositsirikine. Separation of the bases was difficult t o achieve, but, sitsirikine, C Z I H Z ~ N Z(mp O ~206"-208O), contaminated with traces of dihydrositsirikine could be obtained after several fractional recrystallizations, while the isomeric isositsirikine was secured as an amorphous powder homogeneous on thin-layer chromatography. Pure

7.

YOHIMBINE AND RELATED ALKALOIDS

149

dihydrositsirikine, CzlHzsNz03 (mp 2 15') was readily available by catalytic hydrogenation of sitsirikine (15) or by chromatography of the alkaloidal extract from the barks of Pausinystalia yohimbe (16); because of the ease of obtaining it in pure form, most of the chemical degradations were performed on it. Dihydrositsirikine displayed, as did its two other companions, UV- and IR-spectra indicative of the presence of an unsubstituted indole chromophore and of carbonyl, N-H, and 0-H groups. The alkaloid contained a C-ethyl (modified Kuhn-Roth oxidation) and one methoxyl (Zeisel determination) group. Its NMR-spectrum showed the expected signals for an unsubstituted indole nucleus and confirmed the presence of the methoxyl group. Further, it exhibited a t 3.9 6 a multiplet integrating for two protons, which was attributed to the hydrogen atoms a t the carbon carrying the hydroxyl group, since in the spectrum of dihydrositsirikine monoacetate the same signal was shifted t o 4.4 6, a behavior typical of protons adjacent t o a primary alcoholic function. Upon reduction with lithium aluminum hydride dihydrositsirikine afforded a diol, C~oHzsN202,and the three oxygen atoms in the alkaloid molecule can thus be attributed to a methoxycarbonyl and primary alcoholic groups. Evidence concerning the relative positions of these two functions was provided by the following observations. Saponification and reesterification of dihydrositsirikine yielded, beside the starting material and an isomeric compound, an a,P-unsaturated ester (C21H2sN202)which could be hydrogenated to a mixture of two isomeric substances (C21HzsN202) with two C-methyl groups ( 1 6 ) .The same a,/?-unsaturated ester was also available by sodium methoxide treatment of dihydrositsirikine (15). These results suggested the presence of a P-hydroxyester moiety in the parent alkaloid, the unsaturated ester arising by loss of water from that moiety t o yield a terminal olefine. This suggestion was further strengthened by the observation that dihydrositsirikine diol readily afforded a crystalline acetonide on exposure t o acetone and p-toluenesulfonic acid. The NMR-spectrum of the acetonide was of great informative value in that it showed, in addition to the six-proton peak for the newly introduced gem-dimethyl group, a four-proton doublet a t 3.75 6 arising from the splitting of the two oxygen carrying methylene protons by a lone hydrogen atom. This fact was only compatible with a partial structure of the type :

I

VH2-CH-VHz I I

/"

\O C C H d 'CH3

TABLE I YOAIMBANE AND RELATED ALKALOIDS Name

nI.[

Melting point ("C)

(solvent)

Source

Ref.

Part 1. Alkaloids of the yohimbane group 19-Dehydroyohimbine, CziHz4Nz05 Venenatine, CzzHzsNz04 Isovenenatine =alstovenine, CzzHzsNz04 Venoxidine, CzzHzsNzOs Ouroparine, C Z ~ H ~ ~ N Z O Z Oxygambirtannine, C Z ~ H I ~ N Z O ~ 3, 14-DihydrogambirtannineI CziHzoNzOz Gambirtannine, CzlHlsNzOz

254 decomp. 123-125 (MeOH solvate) 169-170 decomp.

+106" (Py) -76.1"

Aspidosperma pyricollum M d l . -Arg. Alstonia venenata R.Br.

10

+9.42"

Alstonia venenata

5, 6

218-219

-58.2" (HzO)

-

7 9

-

-

Abtonia venenata Uncaria gambier (Roxb.) Baillon Uncaria gambier Uncaria gambier

8 8

0

-

-

Uncaria gambier

8

E l

228

5

Part 2. Alkaloids of the heteroyohimbane group Herbaine, CzzHzsNz04 Herbaceine, C Z ~ H ~ O N Z O S Picraphylline, CzzHzsNz04 Mitrajavine, CzzHz6Nz04-HzO

126-127 144 255 117

-217'

(Py)

-37" (CHC13) -37.6" (CHCla)

Vinca herbacea W.K. Vinca herbacea Picralima nitida Stapf M . javanica Koord et Valetone

24 24 25 19a

Part 3. Alkaloids of the corynane group Sitsirikine, C21H26N203 Isositsirikine, C Z ~ H Z ~ N Z O ~ Dihydrositsirikine, CzlHzsNz03

206-208

215

-58' (MeOH) . -20" (CHC13) -55' (MeOH)

Vinca rosea L. Vinca rosea Vinca rosea

14,15, 17 (?) 14, 15, 17 ( ? ) 14-1 6

w CI E

3

Ochrosandwine, CzzHzsN2OzCl Vallesiachotamine, Cz1HzzNz03 Aspexcine, C Z ~ H Z ~ N Z O ~ Methoxygeissoschizine, CzzH26Nz04 Speciogynine, C23H3oNzO4 Paynantheine, C23HzaNzOs Hirsutine, CzzHzsNz03

288-289 (capillary), + 8 5 O 261-262 (Kofler) 253 decornp. +160" (CHC13) 191 -64.5" (Py)

-

-

214 98 softens 101

+28.4' (CHC13) -28.9' (CHC13) +68.6" (CHC13)

Ochrosia sandwicensis A, Gray

18

Vallesia dichotoma Ruiz e t Pav. Aspidosperma excelsurn Benth. Aspidosperma excelsum Mitragyna speciosa Korth. Mitragyna speciosa Mitragyna hirsuta Havil

20 20a 20a 19 19 19u 4

0

Part 4. Oxindoles

217-219 209-21 1 210-21 1 201-202 276-278 -

183 186-188 180

-

Vinca erecta -102.5' (CHC13) Uncaria pteropoda - l l l . O o (CHC13) Uncaria pteropoda +98" (CHC13) Rautuol$a vomitoria Afzel. +64" or +68O (CHC13) Rauwolfia vomitoria -147" ( P y ) Vinca herbacea Vinca major +91.3' (CHC13) Mitragyna speciosa -137' (MeOH) Vinca mujor +77.4' (CHC13) Mitragyna javanica

29 33,33a 33,33a 28 28 32 31 19 30 19a

2 P 2 U

Et3

z kb M

U

sU

Part 5. Other alkaloids

Indolo[2,3-a]pyridocolline, CisHloNz Dihydroindolo[ 2,3-a]pyridocolline, C15H12N2 ( -)-1,2,3,4,6,7,12,12b-Octahydroindolo[2,3-a]quinolizine,C15HleN2

B

E

m

-

-

Gonioma karnassi E. Mey.

35

-

-

Goniomu kamassi

35

158-159

-12.5'

Dmcontomelum mungijerum B1.

36

(MeOH)

152

H. J. MONTEIRO

Mass spectrometric measurements and dehydrogenation experiments provided the desired evidence regarding the complete framework of dihydrositsirikine. The mass spectrum of the alkaloid confirmed its molecular formula (M+ 356) and also exhibited peaks arising by successive losses of fragments from the p-hydroxyester moiety. Of great diagnostic value was the presence of peaks a t m/e 355 (&I-1),184, 170, 169, and 156, characteristic of a tetrahydro-P-carboline moiety as in alkaloids of the yohimbine type. Selenium dehydrogenation of dihydrositsirikine yielded alstyrine (16)whereas use of lead tetraacetate or palladium on charcoaI afforded derivatives exhibiting UV-spectra of dehydroyohimbine or harmane type respectively (15).Dehydrogenation of the

ayJq&

QTJcH20H I

H \\\"

\\\\\

"%,

/

CH~OBC

M

V

Qy%o,////,Oyj?/// H \\\\'

HOHzC VII

'CH2

HOH&

VIII

hydrobromide of the base with palladium a t 280" gave, as a main product, a substance with UV-spectrum resembling that of 5,6-dihydroflavocoryline hydrochloride (5,6-dihydro-V). Further dehydrogenation with 2,3-dicliloro-5,6-dicyano-p-benzoquinone afforded flavocoryline hydrochloride (V) identified by its UV-absorption and paper chromatographic behavior. All this evidence pointed to a probable structure of type V I (no stereochemistry implied) for dihydrositsirikine. Attempted correlation of the alkaloid with demethoxydihydrocorynantheine alcohol (VII), obtained by Karrer and co-workers during his degradation studies on corynantheine, resulted in failure. Although lithium aluminum hydride reduction of the a,P-unsaturated ester cited above gave a mixture of products whichseemedto contain a small amount of the alcohol VII, the major substance formed on such reduction was a

7.

YOHIMBINE AND RELATED ALKALOIDS

153

compound (CzoHzGNzO) with melting point and rotation in close agreement with those reported for isodemethoxydihydrocorynantheine alcohol (VIII), also obtained by Karrer. However, direct comparison was precluded by lack of authentic VIII. Finally, confirmation of the structure and stereochemistry of dihydrositsirikine as depicted in VI was provided by its correlation with dihydrocorynantheine (IX),which after demethylation and borohydride reduction of the resulting demethyldihydrocorynantheine afforded dihydrositsirikine (VI) identical with the naturally occurring base. The chemistry of isositsirikine was very similar to that of dihydrositsirikine. The base contained one C-methyl and a j3-hydroxyester moiety, evidenced by Kuhn-Rothoxidation and lithium aluminum hydridere duction to a 1,3-diol, which readily afforded an acetonide. On dehydrogenation over palladium flavocoryline was also obtained. However, while

catalytic hydrogenation of sitsirikine generated dihydrositsirikine, that of isositsirikine yielded, as the main product, another isomer, dihydroisositsirikine ( C Z ~ H ~ ~ N Z Conclusive O~). proof that sitsirikine and isositsirikine differed from each other in the location of the easily reducible double bond was gathered from their NMR-spectra and from ozonolysis experiments. The NMR-spectrum of sitsirikine showed a multiplet centered a t 5.3 6 attributed to a terminal methylene, which integrated for only 1.8 protons on account of the impurity of the sample used (a 2 : 1 mixture of sitsirikine and dihydrositsirikine). On the other hand, signals a t 5.47 6 ( l H , quartet, J = 7 cps) and 1.4 6 (3H, doublet, J = 7 cps) were present in the spectrum of isositsirikine and readily assigned to an ethylidene grouping. Ozonolysis of sitsirikine and isositsirikine yielded formaldehyde and acetaldehyde, respectively, thus confirming the spectral evidence. These data permitted the assignment of structures X and X I to sitsirikine and isositsirikine, respectively, dihydroisositsirikine being represented by the expression XII. Spiteller and Spiteller-Friedmann (17) have isolated small amounts of some alkaloids from A . oblongurn and proposed structures identical

154

H. J. MONTEIRO

CH3OzC

X ; R = a-CH=CHz XI; R = CH-CH3 XII; R = B-CHzCH3

with those depicted in VI, X, and XI on the basis of their mass spectrometric fragmentations. Confirmation of these observations must await further studies.

C. OCHROSANDWINE The alkaloid, CzzH29NZOzCl (mp 288') has UV- and IR-spectra very similar to those of hunterburnine-a-methochloride. The 5-hydroxyindole chromophore was confirmed by the NMR-spectrum which showed the appropriate set of aromatic proton peaks a t 6.9 and 7.4 S and further suggested the presence of an ethyl (0.9 and 1.4S), a quaternaryN-methyl (2.6-2.9 S), and hydroxymethyl (3.7 6 ) groups. The mass spectrum of ochrosandwine was strongly reminiscent of that of corynantheol but a 16-mass unit shift was observed in the peaks arising from the tetrahydro/3-carboline moiety of the alkaloid due t o the phenolic oxygen atom. Further confirmation of two acylable hydroxyl groups was provided by the formation of an amorphous 0,O-diacetate. Selenium dehydrogenation of ochrosandwine gave, after purification, two main fractions. The first, less polar on thin-layer chromatography, was a mixture of two substances which could not be further separated and displayed an UV-spectrum resembling that of alstyrine. The more polar fraction exhibited maxima a t 232 and 356 mp in the UV-spectrum and suffered a bathochromic shift on addition of alkali. The broad band a t about 3330-3280 cm-1 in its IR-spectrum, coupled with the UV-data suggested

HoQyc+r; ,\\\\

HOHzC

XI11

15 //O//,,

H\\\\\\\ HOHzC

x IV

xo

7.

YOHIMBINE AND RELATED ALKALOIDS

155

a hydroxyalstyrine chromophore and thus must still contain the phenolic hydroxyl. Based on the above evidence the structure XI11 was proposed for ochrosandwine. Its possible correlation with huntabrine (XIV) was abortive on account of the tendency of the latter to suffer Emde degradation on catalytic hydrogenation. The stereochemistry of ochrosandwine as indicated in XI11 was based on the following facts : Its IR-spectrum showed bands for a trans-quinolizidine system and the quaternary N-methyl group presented absorption a t very high field in the NMRspectrum as expected for an axial orientation ; the stereochemistry a t C-15 follows from Wenkert's rule, whereas that a t C-20 was based on comparison of the rotation of the alkaloid with that of several closely related alkaloids of known stereochemistry. Similar arguments permitted the assignment of the stereochemistry shown in XIV to huntabrine (18).

D. VALLESIACHOTAMINE This unstable alkaloid, CzlHzzNz03 (mp 253") was isolated in small yields from Vallesia dichotoma (20).Its UV-spectrum presented maxima a t the wavelength expected for a 2,3-disubstituted indole cliromophore. However the peak a t about 290 mp had a very high extinction coefficient thus suggesting the presence of a second chromophore absorbing a t that region. The presence of N-H and/or 0-H, and a$-unsaturated carbony1 groups was evidenced by the IR-spectrum which showed bands typical of those groupings. The mass spectrum of vallesiachotamine presented a fragmentation pattern which did not allow an immediate classification of the alkaloid (23).It confirmed the molecular formula by showing a molecular ion peak a t mje 350 and further exhibited a series of peaks in the high mass range whose nature will be discussed later. The NMR-spectrum of the alkaloid was complicated by the presence of double signals probably arising from restricted rotation. However, the presence of formyl, methoxycarbonyl, and ethylidene groupings was clearly evident from an examination ofthe 100Mc spectrum of the base. Further, the unsubstituted nature of the indole chromophore was firmly established by the presence of a four-proton multiplet due to the aromatic hydrogen atoms and a pair of broad singlets a t about 8 . 6 6due to the indole N-H. A pair of singlets a t 7.67-7.7 6integrating for one proton was attributed to a highly deshielded olefinic hydrogen atom. Lithium aluminum hydride reduction of vallesiachotamine yielded an amorphous product which lacked any carbonyl absorption in the IR-spectrum, but displayed UV-absorption typical of a 2,3-disubstituted indole chromophore thus suggesting that one of the carbonyls was associated with the chromophore absorbing a t the longer wavelength in the UV-spectrum of the original

156

H. J . MONTEIRO

alkaloid. The NMR-spectrum of this amorphous product did not show any signal which could be attributed to an N-methyl and thus ruled out the possibility of an N-formyl group in vallesiachotamine. Of great informative value was the mass spectrum of this reductibn product. In addition to showing a molecular ion a t m/e 324 (CzoHz4NzOz)and strong M-1 peak, it exhibited peaks a t m/e 156,169,170 and 184, thus providing the first clue to the presence of a tetrahydro-P-carboline moiety in vallesiachotamine. Mild reduction of the alkaloid with sodiuM borohydride in alcoholic solution afforded a crystalline alcohol, dihydrovallesiachotamine (C21H24N203;M+ 352), which on catalytic hydrogenation was M+ O 354). ~ further reduced to tetrahydrovallesiachotamine ( C Z I H ~ ~ N; Z The NMR-spectrum of dihydrovallesiachotamine was very similar to that of the parent alkaloid except for the absence of the signal due to the formyl proton and the appearance of a new signal at 4.03 6 due to the newly formed =CCHzOgrouping. These transformations did not affect the chromophore responsible for the enhanced absorption a t about 290 mp as could be evidencedby the practically unchanged UV-spectra of these hydro derivatives. Evidence that this chromophoric system must incorporate the N b nitrogen, a double bond, and the methoxycatbonyl group in a vinylogous urethane moiety came from the observation that vallesiachotamine failed to form a methiodide. Also, the IR-spectra of the alkaloid and its dihydro derivative showed bands a t 1660 and 1600 cm-1 while their NMR-spectra displayed a signal for a strongly deshielded proton a t about 7.7 6 as would be expected for the presence of

xv

XVIII

XVI XVII; I9,20-Dihydro

XIX

7. YOHIMBINE AND RELATED ALKALOIDS

an >N,,-CH=C-C0&H3

157

moiety. These conclusions were further con-

I firmed by comparison with model compounds. The above data, coupled with biogenetic arguments, led t o XV as the probable structure for vallesiachotamine, the dihydro and tetrahydro derivatives being repredented by XVI and XVII respectively. Supporting evidence for these assignments came both from careful decoupling experiments conducted on the NMR-spectrum of dihydrovallesiachotamine which unambiguously confirmed the sequence >Nb-CH-CH2--CH-C=, compatible only

I

I

I

with structure XVI, and from accessory chemical degradations. Reduction of the double bond in the vinylogous urethane moiety could be effected by treatment of vallesiachotamine with sodium borohydride in glacial acetic acid. Thus two substances were obtained which showed the chemical and spectral properties expected for structures XVIII and XIX. The mass spectra of vallesiachotamine and its derivatives were in entire agreement with the proposed structures. The ions a t the high mass range were examined by high-resolution mass spectrometry and their empirical compositions ascertained. The strong peak a t m/e 279 (C17H15N202) observed in the spectra of the parent alkaloid (XV) and its dihydro derivative (XVI)was shifted t o m/e 281 (C17H17N202)in the spectrum of tetrahydrovallesiachotamine (XVII).The structures a and b were proposed for these ions. The ion a t m/e 322 (CZoH22N202) in the spectrum of vallesiachotamine arises from loss of carbon monoxide from the molecular ion; it must be associated with the aldehyde function, since no such ion was observed in the spectrum of dihydrovallesiachotamine. By further losing methoxyl it gave rise to ion c a t m/e 291

c ; m/e 291

d ; m/e 263

158

H. J. MONTEIRO

CH3OzC

CH30zC

xx

CHARTI

(C1gHIgNzO) as could be evidenced by the observation of a metastable peak a t m/e 263.1 (calcd. 263). Expulsion of methoxycarbonyl from the ion a t m/e 322 led to species d a t m/e 263 (CIgH19Nz). From the biogenetic aspect vallesiachotamine exhibits a very interesting structure. Several hypothetical ways in which it could arise in nature can be suggested but the most interesting seems t o be the path starting with geissoschizine (XX) or a related base (Chart I). Such a path would lead to a structure having the absolute configuration a t c-15 opposite to that of the commonly encountered indole alkaloids. Chemical proof of the stereochemistry a t C-3 and C-15 must await further experimental work (23).

E. ASPEXCINE AND METHOXYGEISSOSCHIZINE The structures XXI and XXII have been allocated to aspexcine and methoxygeissoschizine, respectively. The evidence for these assignments was provided mainly by UV- and mass-spectral determination ( 2 0 ~ ) .

CH30zC XXII

7.

YOHIMBINE AND RELATED ALKALOIDS

159

IV. The Heteroyohimbane Group

A. INTRODUCTION Novelties in this area are the alkaloids herbaceine and herbaine from Vinca herbacea (24,24a)as well as mitrajavine, from Mitragyna javanicu (19u),and the modified heteroyohimbine picraphylline from Picralima nitida (25)which are discussed in detail in another part of this volume. The close relationship between rauvanine and raumitorine, and the interconversion of reserpiline and isoreserpiline has been investigated (26).3-Epirauvanine (XXIII)prepared by dehydrogenation of rauvanine with mercuric acetate followed by treatment with zinc and perchloric acid has a large rate of methiodide formation (K = 2 x 10-2 s-1). It is the first member of the H group in the stereochemical classification of the heteroyohimbines given by Shamma and Richey ( 2 ) .

Rauvanine

4

XXIII

160

H. J . MONTEIRO

XXIV

CHnO.

A

xxv Mercuric acetate oxidation of both reserpiline (XXIV) and isoreserpiline (XXV) gave a common d3,4-dehydroheteroyohimbine(XXVI). Sodium borohydride reduction of XXVI gave back only isoreserpiline, whereas reduction with zinc and perchloric acid yielded a mixture of reserpiline and isoreserpiline. Neoreserpiline (Volume VIII, p. 708) is apparently identical with isoreserpiIine as indicated by their IR- and NMR-spectra (27).

B. HERBACEINE AND HERBAINE Herbaceine, C23H30N205 (mp 144'; [ c c ] ~-219"), is a very sensitive alkaloid which rapidly becomes yellow on exposure to air and light (24). One active hydrogen and three methoxyl groups are present in the alkaloid, as indicated by Zerewitinoff and Zeisel determinations. Its UV-

7.

YOHIMBINE AND RELATED ALKALOIDS

161

spectrum was in good agreement with a 5,6-dimethoxyindole chromophore and its IR-spectrum showed bands a t 1725, 1740, and 850 cm-1 due to unconjugated ester carbonyl and tetra-substituted benzene ring, respectively. The unsubstituted nature of the indolic nitrogen was indicated by a band a t 3477 cm-1 and by the reddish-brown color the alkaloid gave with ceric sulfate. Hydrolysis of herbaceine with ethanolic alkali yielded methanol and epiherbaceic acid LCzzHzsNz05) which on reaction with diazomethane afforded epiherbaceine (Cz3H30Nz05). Quantitative isomerization of herbaceine to epiherbaceine was better effected by refluxing the alkaloid with sodium methoxide in methanol. -18.8") displayed a double melting point (142"Epiherbaceine 150" and 220"-222") and had UV- and IR-spectra very similar t o that of herbaceine itself. Lithium aluminum hydride reduction of herbaceine afforded an amorphous alcohol, herbaceinol ( C Z Z H ~ O N which Z O ~ ) lacked absorption for carbonyl in the IR-spectrum but showed bands a t 3377 and 3475 cm-1 attributable t o associated 0-H and N-H groups. Evidence that herbaceine belonged to the heteroyohimbine class was provided by the following observations. I t s mass spectrum besides displaying the strong peaks a t m/e 414 (M+) and 413 (M-1) further exhibited peaks a t m/e 216,229,230, and 244 as expected for the presence of a tetrahydro-/3-carboline moiety bearing two aromatic methoxyl groups; the nature of the fifth oxygen atom was settled as ethereal on account of its chemical inertness. Finally, the NMR-spectrum in CDC13 showed signals a t 1.22 6 due to a secondary methyl group, two singlets at 3.70 and 3.88 6 attributed to the carbomethoxyl and one of the aromatic methoxyl groups, two singlets a t 6.87 and 6.98 6 due t o two isolated aromatic protons, and one broad peak a t 8.03 6 due t o theindolic proton. One multiplet a t 3.97 6 integrating for five protons was interpreted as arising from the unaccounted aromatic rnethoxyl and the methylene group adjacent t o the ethereal oxygen, since in deuteropyridine the multiplet was resolved into a three-proton singlet and a twoproton multiplet a t 3.88 and 3.97 6, respectively. These data led to the allocation of structure XXVII to herbaceine. The probable stereochemistry, 3a715a,20a,was proposed on the basis of the presence of Bohlmann bands in the IR-spectrum, dehydrogenation and reduction experiments, and inertness of the indolic N-H t o acetic anhydride under varied conditions. From the mother liquors of crude herbaceine a second alkaloid, herbaine, C Z Z H Z ~ N (mp Z O ~126"-127") could be isolated (24, 24a). I t s UV-spectrum was typical of a 6-methoxyindole and its IR-spectrum was very similar t o that of herbaceine, except for the differences in the aromatic absorption. NMR- and mass-spectral evidence (24a) showed

162

H. J. MONTEIRO

herbaine t o differ from herbaceine in the lack of one aromatic methoxyl group and thus the structure XXVIII was proposed for herbaine, the stereochemistry a t C-3 being based on the appearance of the Bohlmann bands in its IR-spectrum.

XXVII ; R = CH 3 0 XXVIII : R = H

Herbaine and herbaceine are identical with the two alkaloids vincaherbine and vincaherbinine (24a).

V. The Oxindole Group

A. INTRODUCTION New, naturally occurring representatives of this group are : rauvoxine and rauvoxinine from Rauwolfia vomitoria (28); vinerine and vineridine from V'inca erecta (29); majdine from V . pubescens (30); alkaloid V from V . major ( 3 1 ) ;and herbaline from V . herbacea (32). Four other new oxindoles pteropodine and isopteropodine isolated from Uncaria pteropoda (33, 33a), speciophylline from Mitragyna speciosa (1 9 ),and the base Pa7 from M . javanica (19a), are discussed in detail in the chapter dealing with the genus Uncaria in another part of this volume.

B. HERBALINE The oxindole structure (XXIX) of this alkaloid was established by consideration of a combination of spectral evidence. Thus, its mass spectrum confirmed the analytically found molecular formula of C23H30N206 by showing a molecular ion a t m/e 430. Further, it exhibited a strong peak a t m/e 225 due t o the fragment e , two mass units higher than the corresponding ion in the mass spectra of mitraphylline and carapanaubine which have a (2-16, (2-17 double bond. Other peaks in the spectrum are also shifted by the appropriate number of mass units expected for

7.

YOHIMBINE AND RELATED ALKALOIDS

163

struc,ilre XXIX. The NMR-spectrum showed the signals for one methoxycarbonyl, two isolated aromatic protons, one N-H, and one secondary methyl group. Two closely spaced peaks a t 3.87 and 3.90 8, the first integrating for five protons, accounted for the two aromatic methoxyls and the (3-17 methylene hydrogen atoms. Further support for the saturated nature of hetero ring E in herbaline was provided by its UVspectrum, which besides presenting maxima a t 273 and 305 mp, characteristic of a 5,6-dimethoxyoxindole chromophore, also exhibited a minimum a t about 245 mp, which is absent in heteroyohimbine oxindoles having the unsaturated ring E (32).

XXIX

m/e 225 e

C. RAUVOXINE AND RAUVOXININE The two alkaloids (Cz3HzsNzOs) are isomeric with carapanaubine, with which they occur in the leaves of RuuwolJu vomitoria. The partially synthesized bases were prepared, together with carapanaubine, by lead tetraacetate oxidation of reserpiline (XXIV),followed by acid rearrangement of the resulting 7-acetoxy-7H-reserpiline. Interconversion of the three bases sould be effected by refluxing either alkaloid with acetic acid, when an equilibrium mixture containing 80 %of carapanaubine and 10 yo each of rauvoxine and rauvoxinine resulted. Epimerization of rauvoxine or rauvoxinine by refluxing pyridine, afforded in each case identical equilibrium mixtures contairhg ca. 66 yo of the former base, approximately 33 % of rauvoxinine and only traces of carapanaubine. The last alkaloid remained unchanged when subjected to the above treatment. These results suggested that rauvoxine and rauvoxinine are a C-7 epimeric pair of oxindoles (A/B pair) having the C-3,9-configuration. The difference between the molecular rotation of the two alkaloids (rauvoxine - rauvoxinine = -145" in CHC13) further strengthened this suggestion. Also, the formation of a considerable amount of carapanaubine during acid equilibration of either alkaloid permitted the conclusion that epimerization a t C-7 was concomitantly accompanied

164

H. J. MONTEIRO

by epimerization a t C-3. This behavior is considered to be characteristic of indole bases of the all0 type, the equilibrium being favorable t o the 3aepimer. Consideration of these results and of the NMR-data led to the allocation of structures XXX and X X X I to rauvoxine and rauvoxinine, respectively (28). Preliminary results of X-ray analysis are in agreement with structure X X X I for rauvoxinine ( 3 4 ) . CH3

H

xxx

XXXI

D. ALKALOID V This amorphous base (C23HZsN206) was isolated in small amounts from the aerial parts of Vinca major. Its mass spectrum was superimposable upon that of carapanaubine and the UV-, IR-, and NMR-data agreed well with a structure of the type XXXIIa-c. The NMR-spectrum of the alkaloid further indicated a pair of o-hydrogen atoms in the aromatic ring. However, a decision could not be made among the three possible structures (31).

7.

YOHIMBINE AND RELATED ALKALOIDS

165

E. VINERINEAND VINERIDINE The structure X X I I I was proposed for these isomeric alkaloids based on several spectral data. Treatment of the bases with acetic anhydride N~O 158" G ; [a]:" -99.5). gave identical acetyl derivatives, C ~ ~ H Z ~ (mp Conversion of vinerine t o vineridine was effected by refluxing the former with pyridine for 5 hours, when change in the configuration apparently a t C-3 occurred. Neither of the alkaloids was identical with reserpinine oxindole although their UV- and IR-spectra were similar. The stereochemistry a t C-15 was assumed to be a in analogy with other heteroyohimbines but the configurations a t C-19 and C-20 remained unsettled (29).

n

XXXIII

F. MAJDINE This alkaloid (C23HzgN206) is isomeric with carapanaubine, as evidenced by NMR- and mass-spectral data. Treatment with hot acetic anhydride causes its conversion t o isomajdine (mp 200"-206"; [a]&8 -90"). The structure XXXIV has been proposed for this new base (30).

CH3

CH302C XXXIV

VI. Other Bases The two anhydronium bases XXXV and XXXVI were isolated in small amounts from Gonioma kamassi (35)and their structures established mainly on the basis of their mass and UV-spectra. The mass spectrum of the amorphous XXXV was very poor in fragments. Apart from the molecular ion peak a t m/e 218 (base peak), the only peaks of any significance appeared a t mje 109 (M++), 190, 191, and 192, the last three

166

H.J. MONTEIRO

arising from loss of HzCN, HCN, and CzHz, respectively. The picrate of XXXV showed a melting point (250"-255" decornp.) identical with that exhibited by the picrate of authentic material. The second anhydronium base (XXXVI) displayed, as does XXXV, a UV-spectrum resembling that of the sempervirine type of chromophore. Its mass spectrum showed a molecular ion a t m/e 220 and peaks a t m/e 219 (base peak), 110 (M++), and 109.5 (219++).Small peaks a t ni/e 191 and 192 (219-HzCNand 219HCN, respectively) were also present. Reduction with zinc powder and sulfuric acid yielded a mixture whose mass spectrum indicated it to be composed of products with 4-6 hydrogen atoms more than the starting

xxxv

XXXVI

XXXVII

material. Some of the peaks in the spectrum were characteristic for a tetrahydro-P-carboline moiety and were also present in the spectrum of the indolo[2,3-a]-quinolizineXXXVII . This latter substance [( - )-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine] has also been identified as the major alkaloid from Bracontomelum mangiferum (Anacardiaceae) (36).

VII. Syntheses A. THEYOHIMBANE GROUP A great deal of endeavor has been spent lately in the elaboration of new synthetic approaches to the yohimbane group of alkaloids, some interesting syntheses having been reported. Racemic yohimbine and P-yohimbine were elegantly synthesized through a simple new route (Chart 11). Condensation of dihydro-& carboline (XXXVIII) with either the vinyl ketone X X X I X or the

H

XXXVIII

XLI

0

1I

(EtO)zP--CHzR X L I I e ; R=COaCH.q XLIIb; R =CN V

R XLIVs;R=COzCHs XLIVb;R=CN

\

RCH X L I I I e ; R=COzCHs XLIIIb; R=CN

XVLIII

qH Lb

H"

H

CHARTI1

CHsOzC"''~ OH

La.

168

H. J. MONTEIRO

Mannich base XL provided the tetracyclic ketoester XLI. Construction of ring E was then initiated by reacting compound XLI with the phosphonic acid derivatives (XLIIa) or (XLIIb) t o yield the unsaturated diester XLIIIa or the nitrile XLIIIb which were subsequently hydrogenated t o XLIVa and XLIVb, respectively. Dieckmann condensation of XLIVa in homogeneous phase (NaH in dimethyl sulfoxide) effected its cyclization t o the pentacyclic derivative XLV which was mostly in the enolic form. Structural and stereochemical proof of XLV was provided by its hydrolysis and decarboxylation t o ( & ) -yohimbone (XLVI), further converted t o ( & )-yohimbane (XLVII) by Wolff-Kishner COz ‘Bu

dN(yJ +

H$ J (

0 LI

LII

/N

LIII

I

n

v LIV

LV HOAc CHaOH

LVII

LVI

CHARTI11

7. YOHIMBINE AND RELATED ALKALOIDS

169

reduction or reconverted t o the starting compound (XLV) by treatment with methyl magnesium carbonate. Cyclization of the diester in the desired direction could be effected by Dieckmann condensation in heterogeneous phase (NaOMe in benzene), when a 1 : 1 mixture of the nonenolizable keto ester XLVIII and its isomer XLV was obtained. Homogeneous Dieckmann condensation of the iiitrile XLIVb gave, however, good yields of the ketonitrile XLIX. Sodium borohydride reduction of the ketoester XLVIII t o a 3 : 1 mixture of ( T )-yohimbine (La) and ( f )-P-yohimbine (Lb) completed their total syntheses (37). Wenkert and co-workers (38) have devised an elegant synthesis of dl-epialloyohimbane (Chart 111).The glutaconimide L I upon reaction with POC13and catalytic hydrogenation afforded the tetrahydroisoquinoline L I I which was next converted to the t-butyl ester L I I I by consecutive hydrolysis, esterification to the methyl ester, and transesterification with potassium t-butoxide. Reaction of LIII with tryptophyl bromide afforded the quaternary salt LIV. The next two steps constitute the most attractive features in the synthetic scheme. The first was the conversion of the quaternary salt (LIV) to the octahydroisoquinoline derivative LV, which could be achieved by a controlled catalytic hydrogenation of the salt (LIV) under alkaline conditions (Pd/C in anhydrous methanol and triethylamine), advantage being taken of the stabilizing effect of a p-acyl substituent in the pyridine nucleus of (LIV) (cf. 39). The second step, which led t o the complete framework of the molecule, was aPictetSpengler cyclization of the octahydroisoquinoline derivative (LV). The utility of a t-butyl carboxylic ester as the /3-acyl substituent in the intermediate (LV) was then patent by the ease with which it could be converted t o the expected dl-epialloyohimbane (LVI), mere refluxing treatment of LV with dilute acetic acid sufficing t o effect the desired change. The racemic epialloyohimbane thus obtained was identical with an authentic specimen and was further characterized by conversion t o dl-alloyohimbane (LVII) through conventional oxidation and reduction experiments. The synthetic scheme used by Woodward in his famous reserpine synthesis has been adapted for a synthesis of racemic apoyohimbine (Chart IV). The aldehyde LIXa, precursor of rings D-E of apoyohimbine, was prepared together with its epimer (LIXb) by Os04/Ba(C103)2 oxidation of the key intermediate (LVIII) (cf. reserpine synthesis, Volume VIII, p. 316). Condensation of LIXa with tryptamine, followed by the conventional steps, yielded the racemic lactone LXIV, which u7as subsequently hydrolyzed and esterified to LXV, isomeric with corynanthine. Racemic apoyohimbine (LXVI) was then secured by tosylation of LXV followed by basic treatment of the 18-tosylate (39a).

170

H. J. MONTEIRO

I

1. TaCl

1. Hydrolysis 2. CHnNa

2. HOO/CHsOH

I

H

H"'

CHsOzC LXVI

Methylation

LXIII

-

ir

1.

2. Tryptamine 3. NaBHl

LXV

CHART I V

OH LXIV

7. YOHIMBINE AND RELATED ALKALOIDS

171

dl5(20)-Yohimbane (LXVIII) has been prepared very simply by with 3-bromoacetyl indole and reacting 5,6,7,8-tetrahydroisoquinoline reducing the resulting quaternary salt with lithium aluminum hydride in tetrahydrofurane (40).

LXVII

LiAlHl

LXVIII

Details of the neat total synthesis of alstoniline have been published (41, cf. Volume VIII, p. 173). Homosempervirine (non-naturally occurring) has also been synthesized through the same approach (42). Aromatic cyclodehydration has been used in the preparation of several indolo[2,3-a]acridiziiiium salts (43) (Chart V). Reaction of 1-formyl-Pcarboline (LXIX)with benzyl bromides in dimethyl formamide a t room temperature provided the quaternary salts (LXX ; R = H or OMe) which were smoothly converted t o the desired indolo-[2,3-a]acridizinium salts (LXXI) by action of polyphosphoric or concentrated hydrochloric acid (when R = OMe).

172

H. J. MONTEIELO

Qr-qQ!

+

R+R

H H/ C\o

R = H or CHsO CHzBr

LXIX \

J

V

R LXX PPA. 120"

conc. HC1,lOO"

R LXXI

B. THECORYNANEGROUP Several syntheses of corynane derivatives have been reported in the recent literature. dl-Corynantheine has been totally synthesized by van Tamelen's group (44) (Chart VI). The key intermediate, LXXIII, obtained by a biogenetic type of interaction of tryptamine, formaldehyde and the ketoester LXXII, was converted in four steps to an isomeric mixture (15,2.0-trans/cis-isomers)of the tetracyclic ketoester LXXIVa,b.

7.

173

YOHIMBINE AND RELATED ALKALOIDS

H CHsOzCfil

CHaO

1 I

t-BuOH

1. POCla

CHsOzC CHsOzC

LXXIII

4. Eeterlf.

\

LXXII

CHsOeC

0

II

1. NaC$s/CHaOICH

2. CHINS

LXXIVa R, a - C C H s

1

0

II

LXXIVb R, p-C--CHs

CHsOeC LXXVIII

NaC$al CH~OICH

LXXVII

LXXX

174

H. J . MONTEIRO

The major component of the mixture (ratio 61 : 39 by NMR-analysis) was shown t o be the desired trans-isomer LXXIVa by its conversion to the derivative LXXX, of known stereochemistry, through formation of the mixture of ethylene dithioketals, chromatographic separation, and reductive desulfurization. The tosyl hydrazone of the pure trans-keto ester LXXV, obtained directly from the isomeric mixture and chromatographic separation, was then submitted t o the Bamford-Stevens reaction, thus yielding LXXVI and the isomeric LXXVIII. Formylation of the olefinic ester LXXVI followed by methylation with diazomethane afforded dl-corynantheine (LXXVII) with an IR-spectrum identical with that of the naturally occurring base. Formylation of the ethylidene ester LXXVIII would be expected to afford the indole base geissoschizine (LXXIX), a scission product of the alkaloid geissospermine. However, the product secured from the formylation procedure was not identical with the expected base, the nonidentity of the two materials probably being due to different geometry of the ethylidene bond. An interesting synthesis of dl-corynantheidol illustrates the neat approach used by Wenkert and co-workers (38)for the total synthesis of simple indole alkaloids (Chart VII). Dihydrogentianine (LXXXV), obtained as shown in the scheme was used as a building block. Its reaction with tryptophyl bromide provided the pyridinium salt (LXXXVI), which was subsequently converted t o the tetrahydropyridine (LXXXVII) by controlled catalytic hydrogenation (Pd/C in anhydrous methanol and triethylamine). Mild acid treatment of LXXXVII effected its cyclization t o the lactone LXXXVIII. Removal of the undesirable lactone moiety in LXXXVIII was achieved by acid hydrolysis and dehydrogenation on refluxing with palladium in maleic acid solution, when the expected loss of carbon dioxide took place; subsequent treatment with sodium borohydride afforded dl-corynantheidol (LXXXIX), identical with authentic material. On the other hand, treatment of the tetrahydropyridine LXXXVII with alkali stereospecifically generated the C-3 epimeric alcohol, dl-isocorynantheidol (XC), this transformation probably taking the path shown. Treatment of XC with palladium in maleic acid solution, followed by sodium 50: ahydride reduction confirmed its stereochemical assignment, since the product obtained from the above series of reactions was the expected dl-corynantheidol (LXXXIX). dl-Dihydrocorynantheine and its C-20 epimer, dl-corynantheidine, were obtained by Weisbach and co-workers (45) in a total stereospecific synthesis (Chart VIII) starting with the tetracyclic ketone XCI, already available from other synthetic studies (45a). On reaction with trimethyl- or triethylphosphonoacetate it was converted t o the ester XCII

COzCHs

1

HO

LXXXVIII

I

1. Pd/C/maleic acid 2. NaBH,

4

1. Pd/C/maleic arid 2. NaBHr

HO'

CHARTVII

xc

176

€ J. I. MONTEIRO

xcv CHARTV I I I

7.

YOHIMBINE AND RELATED ALKALOIDS

177

which was further hydrogenated to the corresponding racemic saturated ester XCIII. The relative stereochemistry of XCIII was tentatively on the basis of melting point comparison and assigned as 3~r,15~(,2OP IR-spectral evidence. Formylation of XCIII followed by methylation under acetal-forming conditions provided the expected dl-dihydrocorynantheine (XCV),identical with the natural base. Attempted epimerization of XCII a t C-3 or C-20 produced the P,y-unsaturated ester XCVI which, however, failed t o undergo reduction t o the expected 15~r,20~r derivative (XCVIII). This difficulty was circumvented by oxidizing XCVI to the quaternary salt XCVII with iodine and sodium acetate, followed by catalytic reduction and transesterification (in the case where R = E t ) t o afford the desired XCVIII. Alternatively the quaternary salt XCVII was obtained by direct oxidation of XCII with mercuric acetate. Formylation and methylation of XCVIII then completed the synthesis of dl-corynantheidine (C), identical with authentic material.

C. OXINDOLESAND PSEUDOINDOXYLS Partial syntheses of oxindoles and pseudoindoxyls were already known a t the time of publication of Volume VIII. Exposure of yohimbines or heteroyohimbines to t-butyl hypochlorite (46)or lead-IV salts of strong carboxylic acids ( 4 ) afforded the corresponding indolenines (CI, X = C1 or RCOz ), which upon acid treatment rearranged to oxindoles, whereas base treatment led to pseudoindoxyls. The method has been used in the partial syntheses of mitraphylline and isomitraphylline (46).

CI

dl-Rhynchophyllol (CVII) has been obtained by an elegant, biogenetjcally patterned, total synthesis ( 4 7 ) (Chart IX). Lithium aluminum hydride reduction of the amide C I I provided the amine CIII which was protected and the double bond hydroxylated with OsO4 t o give the diol CIV. Oxidation of CIV with N-bromosuccinimide followed by catalytic hydrogenolysis afforded the oxindole CV, the amorphous hydrobromide of which was further oxidized t o the dialdehyde CVI and this cyclized with acid. Sodium borohydride reduction of the resulting nonacidic

178

H. J. MONTEIRO

si;

/

CIII

CII

I

1. $-CHzOzCCI

2. oso1,-7no 3. H a Y

QTDNH

1 . NRR 2. Pd/Ha

H HO o* cv

CIV

NaIOa HaO; 0"

CVI CHART IX

fraction yielded, after chromatographic separation, dl-rhynchophyllol (CVII), identical with authentic material obtained by degradation of rhynchophylline. The easy condensation of aldehydes with 3-monosubstituted oxindoles has been further exploited by Ban and co-workers, who synthesized several 3-spirooxindole derivatives (48).The approach was used in the stereospecific synthesis of racemic N-methylrhynchophyllaiie (Chart X). The trans-diethylcyclopentanone CVIIIa was subjected t o BaeyerVilliger oxidation t o yield the thrclo lactone CIX, which was converted t o the chloroaldehyde CXI, by successive reaction with phosphorus

7.

179

YOHIMBINE AND RELATED ALKALOIDS

p\ 0

CIX

CVIIIa

Q$lTl,,,,,L= room temp. 2 days

cx

CXI

+

CH3 CXIIIa

a CVIIIb

CH3

CXII

n

CXIIIb

CHART X

pentachloride, N-methylaniline, and lithium aluminum hydride. Condensation of the aldehyde CXI with 1-methyl-2-hydroxytryptamine ((2x11)then yielded a mixture of two isomeric products (oxindoles A and B), one of which was identical with authentic N-methylrhynchophyllaiie (CXIIIa) prepared by degradation and methylation of rhynchophylline. Repetition of the sequence starting with the alternate cis-diethylcyclopentanone CVIIIb again yielded a mixture of two isomeric (at C-7) allo-N-methylrhynchophyllanes(CXIIIb) (49). Reduction of oxindoles with limited amount of lithium aluminum hydride, followed by acid treatment has been used in the preparation of indoles (49a).

180

Q$Jo

H. J. MONTEIRO

>$::::

CHa

0-Q CHI

4-Indoxyls subjected to an analogous reaction sequence afford the interesting inverted indole alkaloids ( 4 ) . H

I

D. OTHERSYNTHETIC WORK I n this section are described the syntheses of some simple indolo[Z,S-ajquinolizine derivatives which bear a close relationship to the alkaloids of the yohimbane and corynane groups.

CXVII

-1

CXVI

cxv

7.

YOHIMBINE AND RELATED ALKALOIDS

181

Two further syntheses of flavopereirine (Volume VIII, p. 688) have been reported. The first is an application of the reductive cyclization approach. The quaternary salt CXIV (R = Et), obtained by exposure of 3-acetylindole to iodine and 3-ethyl pyridine, yielded upon reduction with lithium aluminum hydride in tetrahydrofurane the tetracyclic compound CXV (R = Et), which could be converted to flavopereirine (CXVI;R = E t ) by known methods. Use of ethyl ether as solvent in the reduction of CXIV led to the formation of the tetrahydropyridine CXVII (40). The second synthetic approach t o flavopereirine is based on a neat new method of preparation of octahydro-indolo[2,3-~]quinolizines (5052). Condensation of +unsaturated ketones with dihydroj3-carboline (CXVIII), itself prepared by cyclization of N-formyltryptamine with POC13, afforded CXIX in high yields. Wolff-Kishner reduction of CXIX (R = Et) followed by dehydrogenation gave flavopereirine (CXVI) (52). 0

+

II

CHB=C-C-CH~

I

R

I H

R = C H I or CzHs

CXVIII

"

I CXIX

I

0

1. W.K. reduction 2. Dehydrogenation

CXVI

182

H. J. MONTEIRO

The non-naturally occurring 10-methoxyflavopereirine has been prepared by Ban and Inoue (52a) using the same approach as for their synthesis of the unsubstituted alkaloid (see Volume VIII, p. 689). Application of Fischer indole synthesis to ketone CXXI or its open chain precursor CXX resulted in the formation of 12H-indolo[2,3-a]pyridocolinium salts substituted a t the 2-position (CXXII) (53). R I R I

cxx

CXXI

R =CH3 or CH30CHz

Fischer indole synthesis

Fischer indole synthesis

XQ

R CXXII

E. MODIFIEDYOHIMBINES Many modified yohimbines have been prepared for testing their pharmacological effects. Most of the synthetic work in this area constitutes the subject of patent literature t o which the reader should refer for details. 3-Substituted yohimbanes have been obtained by treatment of the appropriate 3-dehydroyohimbane with nucleophilic agents (CNG, Grignard reagents) ( 5 4 ) .Yohimbanone or alloyohimbanone have been subjected to base-catalyzed condensation with magnesium methyl carbonate, diethyl oxalate, or ethyl formate to afford the corresponding 18-substituted derivatives (55).

7.

183

YOHIMBINE AND RELATED ALKALOIDS

VIII. Addendum A. THEYOHIMBANE GROUP Full papers dealing with the chemistry of gambirtannine, oxygambirtannine, dihydrogambirtannine (56),deserpidine, and raujemidine (57')have appeared. A new base, excelsinine (1O-methoxycorynanthine, Cz6Hz6NzO4, mp 201") has been isolated from Aspidosperma excelsum (58).A new synthesis of ( )-yohimbane has been published ( 5 9 ) )and 7-benzyl-7H-yohimbanes have been prepared and their ORD curves examined (60).

B. THE CORYNANEGROUP Antirhine ( C ~ ~ H Z ~ mp N ~ 112-114", O, ["ID -2" (CHCls)), has been isolated from Antirrhea putaminosa (F.v. Muell.) Bail. and the structure CXXIII has been proposed for it (61). Vinca herbacea yielded hervine (C~3HzsNz04,mp 173-175", ["ID -93" (EtOH)) for which the structure CXXIV has been assigned ( 6 2 ) . From Uncaria gambier a further base could be obtained and the name gambirine (CzzHzsNz04, mp 163-165", +28.6" (CHCl3)) given to it; its structure is represented by CXXV (63).Conformational analysis coupled with physical measurements has been used to study the conformation and configuration of the corynantheidine-type alkaloids

I

H"U'

CH30QY%

*/

I

H#\

-$ H

HOHzC CXXIII

\

H,\\\* CH30zC CXXIV

CHzOH

184

H.J. MONTEIRO

(64-66). A partial synthesis of natural (3~!3,15S,20R)-corynantheine involving an interesting ring cleavage of yohimbone has been published (67). C. THE HETEROYOHIMBANE GROUP

A further alkaloid from V . erecta is ervine (CzlHz4Nz03, mp 222223") for which the structure CXXVI was deduced (68).Tetraphyllinine (CzzHzsN~05,mp 231-234') from a RauwoZJia species has the interesting structure CXXVII (69). The stereochemistry of herbaceine has been investigated (70).

OH

CXXVI

CXXVII

D. THEOXINDOLEGROUP The Cahn, Ingold, Prelog stereochemical nomenclature has been applied to the oxindole alkaloids (71). The stereochemistry of several pentacyclic oxindoles, among them rauvoxine and rauvoxinine, has been examined by equilibration experiments and NMR spectroscopy ( 7 2 ) . Circular dichroism (CD) has also been used as a tool for stereochemical assignments in this area. Thus based on CD studies the structure CXXVIII was assigned to corynoxine (73). The stereochemistry of herbaline has been examined ( 7 0 ) .A further paper on vinerine and vineridine has been published (74).

f

CXXVIII

7.

YOHIMBINE AND RELATED ALKALOIDS

185

E. OTHER BASES The full paper on the base XXXVII from Drncontomelum mnngiferum has appeared (75). From Adina cordifolin the interesting alkaloid cordifoline (CXXIX, C29H30N2012) has been isolated (76).

REFERENCES 1. Y. Ban and 0. Yomemitsu, Tetrahedron 20, 2877 (1964). 2. M. Shamma and J. M. Richey, J . Am. Chem. Soc. 85, 2507 (1963). 3. N. Finch, W. I. Taylor, T. R. Emerson, W. Klyne, and R. J. Swan, Tetrahedron 22, 1327 (1966). 4. N. Finch, C. W. Gemenden, I. Hsiu-Chu Hsu, A. Kerr, G. A. Sim, and W. I. Taylor, J . Am. Chem. SOC.87, 2229 (1965). 5. T. R. Govindachari, N. Viswanathan, B. R. Pai, and T. S. Savitri, Tetrahedron 21, 2951 (1965). 6. A. B. Ray and A. Chatterjee, J . Indian Chem. SOC. 41, 638 (1964). 7. A. Chatterjee, P. L. Majumder, and A. B. Ray, Tetrahedron Letters 159 (1965). 8. M. Hesse, L. Merlini, R. Mondelli, and G. Nasini, 4th I U P A C S y m p . Chem. flat. Prod. Stockholm, 1966. 9. W. I. Taylor and M. Raymond-Hamet, Compt. Rend. D262, 1141 (1966). 10. R. R. Arndt and C. Djerassi, Experientia 21, 566 (1965). 11. J. S. E. Holker, W. J . Ross, W. B. Whalley, and R. F. Raffauf, Phytochemistry 3, 361 (1964). 12. M. Shamma and R. J. Shine, Tetrahedron Letters 2277 (1964). 13. E. Smith, R. S. Jaret, M. Shamma, andR. J. Shine,J. Am. Ghem.Soc. 86,2083 (1964). 14. G. H. Svoboda, I. S. Johnson, M. Gorman, and N. Neuss, J. P h a m . Sci. 51, 707 (1962). 15. J. P. Kutney and R. T. Brown, Tetrahedron 22,321 (1966). 16. T. H. van der Meulen and G. J. M. van der Kerk, Rec. Trav. Chim. 83, 148-154 (1964). 17. G. Spiteller and M. Spiteller-Friedmann, Monatsh. 94, 779 (1963). 18. W. Jordan and P. J. Scheuer, Tetrahedron 21, 3731 (1965). 19. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, J. Pharm. Pharmacol. 17, 753 (1965). 19a. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, J . Pharm. Pharmacol. 18, 553 (1966). 20. A. Walser and C . Djerassi, Helv. Chim. Acta. 48, 391 (1965).

186

H. J. MONTEIRO

20a. P. Relyveld, Doctoral Thesis, Utrecht University (1966). 21. J. D. M. Asher, J. M. Robertson, and G. A. Sim, J . Chem. SOC.6355 (1965). 22. 2. M. Kahn, M. Hesse, and H. Schmid, Helw. Chim. Acta 48, 1957 (1965). 23. C. Djerassi, H. J. Monteiro, A. Walser, and L. J. Durham, J . Am. Chem. SOC.88, 1792 (1966). 24. I. Ognyanov and B. Pyuskyulev, Ber. 99, 1008 (1966). 24a. I. Ognyanov, B. Pyuskyulev, and G. Spiteller, Monatsh. 97, 857 (1966). 25. J. Levy, G. Ledouble, J. Le Men, and M.-M. Janot, Bull. SOC.Chim. France 1917 (1964). Chim. 26. J. Poisson, R. Bergoeing, N. Chaveau, M. Shamma, and R. Goutarel, Bull. SOC. France 2853 (1964). 27. Personal communication from Dr. L. J. Durham to Dr. Benjamin Gilbert (1966). 28. J. L. Pousset and J. Poisson, Compt. Rend. 259, 597 (1964). 29. S. 2. Kasymov, P. K. Yuldashev, and S. Y. Yunusov, Dokl. Akad. N a u k S S S R 163, 1400 (1965). 30. N. Abdurakhimova, P. K. Yuldashev, and S. Y . Yunusov, Khim. Prirod,n. Soedin., Akad. N a u k U z . S S R 224 (1965); C A 63,16396 (1965). 31. M. Plat, R. Lemay, J. Le Men, M.-M. Janot, C. Djerassi, and H. Budzikiewicz, Bull. Soc. Chim. Prance 2497 (1965). 32. I. Ognyanov, Ber. 99, 2052 (1966). 33. G. B. Yeoh, K. C. Chan, and F. Morsingh, Tetrahedrm Letters 931 (1966). 33a. K. C. Chan, F. Morsingh, and G. B. Yeoh, J . Chem. SOC.2245 (1966). 34. C. Pascard-Billy, Compt. Rend. C262, 197 (1966). 35. R. Kaschnitz andG. Spiteller, Mona,tsh. 96, 909 (1965). 36. S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Chem. Commun. 421 (1966). 37. Cs. Szantay, L. Toke, and K. Honti, Tetrahedron Letters 1665 (1965). 38. E. Wenkert, K. G. Dave, and F. Haglid, J . Am. Chem. SOC.87, 5461 (1965). 39. E. Wenkert and B. Wickberg, J . Am. Chem. SOC.87, 1580 (1965). 39a. I. Ernest and B. Kackac, Chem. & I n d . (London) 513 (1965); cf. Collection Czech. Chem. Commun. 31, 278 (1966). 40. K. T. Potts and P. R. Liljgren, J . Org. Chem. 28, 3066 (1963). 41. Y. Ban and M. Seo, Chem. & Pharm. Bull. (Tokyo) 12, 1296 (1964). 42. Y. Ban and M. Seo, Chem. & Pharm. Bull. (Tokyo) 12, 1378 (1964). 43. C. K. Bradshev and A. J. Umans, J . Org. Chem. 28, 3070 (1962). 44. E. E. van Tamelen and I. G. Wright, Tetrahedron Letters 295 (1964). 45. J. A. Weisbach, J. L. Kirkpatrick, K. R. Williams, E. L. Anderson, N. C. Yim, and B. Douglas, Tetrahedron Letters 3457 (1965). 45a. H. T. Openshaw and N. Whittaker, J . Chem. SOC.1449 (1963). 46. H. Zinnes and J. Shavel, Jr., J . Org. Chem. 31, 1765 (1966). 47. E. E. van Tamelen, J. P. Yardley, and M. Myiano, Tetrahedron Letters 1011 (1963). 48. Y. Ban and T. Oishi, Chem. & Phnrm. Bull. (Tokyo) 11,441 (1963). 49. Y. Ban and T. Oishi, Ciiem. & P h a r m Bull. (Tokyo) 11, 451 (1963). 49a. T. Oishi, S. Maeno, and Y. Ban, Chem. & Pharm. Bull. (Tokyo) 11, 1195 (1963). 50. Cs. Szantay and L. Toke, Tetrahedron Letters 251 (1963). 51. L. Szab6, L. Toke, K. Honti, and Cs. Szantay, Tetrahedron Letters 2975 (1966). 52. Cs. Szantay and L. Toke, Acta Chim. Acad. Sci. Hung. 39, 249 (1963). 5%. Y. Ban and I. Inoue, Chem. & Pharm. Bull. (Tokyo) 12, 1381 (1964). 53. G. A. Swan and P. R. Thomas, J . Chem. SOC.3440 (1963). 54. H. Zinnes, R. A. Comes, and J. Shavel, Jr., J . Org. Chem. 30, 105 (1965). 55. J. D. Albright, L. A. Mitscher, and L. Goldman, J . Org. Chem. 28, 38 (1963). 56. L. Merlini, R. Mondelli, G. Nasini, and M. Hesse, Tetrahedron 23, 3129 (1967).

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YOHIMBINE AND RELATED ALKALOIDS

187

E. Smith, R. S. Jaret, R. J. Shine, and M. Shamma,J. Am. Chem. Soc. 89,2469 (1967). P. R. Benoin, R. H. Burnell, and J. D. Medina, Can. J . Chem. 45, 725 (1967). G. C. Morrison, W. A. Cetenko, and J. Shavel, Jr., J . Org. C'hem. 31,2695 (1966). M. von Strandtmann, R. Eilertsen, and J. Shavel, Jr.,J. Org. Chem. 31,4202 (1966). S. R. Johns, J. A. Lamberton, and J. L. Occolowitz, Chem. Commun. 229 (1967); Australian J . Chem. 20, 1463 (1967). 62. I. Ognyanov, B. Pyuskyulev, B. Bozjanov, and M. Hesse, Helv. Chim. Acta 50, 754

57. 58. 59. 60. 61.

63. 64. 65. 66, 67. 68. 69. 70. 71. 72. 73. 74. 75. 76.

(1967). L. Merlini, R. Mondelli, G. Nasini, and M. Hesse, Tetrahedron Letters 1571 (1967). W. F. Trager, C. M. Lee, and A. H. Beckett, Tetrnhedron 23, 365 (1967). C. M. Lee, W. F. Trager, and A. H. Beckett, Tetrahedron 23, 375 (1967). W. F. Trager, C. M. Lee, J. D. Phillipson, and A. H. Beckett, Tetrahedron 23, 1043 (1967). R. L. Autrey and P. W. Scullard, Chem. Commun. 841 (1966). V. M. Malikov, P. K. Yuldashev, and S. Y. Yunusov, Khim. Prirodn. Soedin. A k a d , N a u k Uz. SSR 2, 338 (1966); CA 66, 6568411 (1967). G. Combes, L. Fonzes, and F. Winternitz, Phytochemistry 5 , 1065 (1967). I. Ognyanov, B. Pyuskyulev, M. Shamma, J. A. Weiss, and R. J. Shine, Chem. Commun. 579 (1967). J. Poisson and J. L. Pousset, Tetrahedron Letters 1919 (1967). M. Shamma, R. J. Shine, I. Kompis, T. Sticzay, F. Morsingh, J. Poisson, and J. L. Pousset,J. Am. Chem. Soc. 89, 1739 (1967). J. L. Pousset, J. Poisson, and M. Legrand, Tetrahedron Letters 6283 (1966). S. 2. Kasymov, P. K. Yuldashev, and S. Y. Yunusov, Khim. Prirodn. Soedin. A k a d . N a u k Uz. SSR 2, 260 (1966); CA 66,2673r (1967). S . R. Johns, J. A. Lamberton, and J. L. Occolowitz, Australian J . Chem. 19, 1951 (1966). R. T. Brown and L. R. Row, Chem. Commun. 453 (1967).

This Page Intentionally Left Blank

-CHAPTER

8-

ALKALOIDS OF CALABASH CURARE AND STRYCHNOS SPECIES A. R. BATTERSBY T h e Robert Robinson La,boratories, University of Liverpool, Liverpool, England

and

H. F. HODSON T h e Welleome Research Laboratories, Beckenham, K e n t , England

I. Introduction ........................................................ 11. The CzoAlkaloids .................................................. A. C-Mavacurine, C-Fluorocurine, C-Alkaloid Y, and Pleiocarpamine. ...... B. Alkaloids Related to the Wieland-Gumlich Aldehyde. ................. C. Norfluorocurarine ................................................

111. The Dimeric Alkaloids of Calabash Curare. .............................. A. C-Calebassine .................................................... B. Toxiferine-I, C-Dihydrotoxiferine-I, and Related Alkaloids. ............ C. C-CurarineandRelatives .......................................... References

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

189 189 189 194 199 200 200 200 202 204

I. Introduction During the nineteen-fifties and early sixties, there was intense interest and activity in the study of calabash curare alkaloids. These researches led t o structural solutions for all the major alkaloids and an impressive body of knowledge was gained concerning the chemistry of these fascinating and complex alkaloids. All this work was covered in Volume VIII. With the major problems solved, there has inevitably been less activity in the field; the following sections outline new work published over the past three or four years. 11. The Czo Alkaloids

A. C-MAVACURINE,C-FLUOROCURINE, C-ALKALOID Y, AND PLEIOCARPAMINE The small quantities available of C-mavacurine and C-fluorocurine had precluded any further structural investigations beyond those leading 189

190

A. R. BATTERSBY AND H. F. HODSON

to the structures given in Volume VIII, p. 526, as working hypotheses. However, an interesting development in the chemistry of these alkaloids came with the realization that pleiocarpaminol, a reduction product of the alkaloid pleiocarpamine, is isomeric with normavacurine and like the latter compound has an N-substituted indole chromophore. A detailed chromatographic and spectroscopic comparison of normavacurine and pleiocarpaminol, and of their respective methyl quaternary derivatives showed that these compounds are not identical although they are very similar in many respects ( I ) . The tertiary alkaloid pleiocarpamine, CzoHzzNzOz (mp 159'), was first isolated ( 2 )from the roots of Pleiocarpa mutica Renth. and subsequently ( 3 ) from the bark of Hunteria eburnea Pichon (both Apocynaceae). It possesses (2) an N-substituted indole chromophore and its IR-spectrum indicated the presence of a carbonyl group (1727 cm-1 in Nujol or KBr) ; OH and ;NH absorptions were absent. Analysis revealed the presence of one methoxyl and one C-methyl group and the absence of N-methyl groups. Reduction of pleiocarpamine with lithium aluminum hydride gave the crystalline base pleiocarpaminol, C19H22N20 (mp 187.'-189" ; [a]&1+144", C = 0.266 in methanol), also with an N-substituted indole chromophore but showing hydroxyl absorption (3584 cm-1) and no carbonyl absorption in the IR-spectrum. Pleiocarpamine was thus assumed to have a methoxycarbonyl group and pleiocarpaminol therefore contains a primary hydroxyl group (1). Pleiocarpamine ([cY];~+ 136" in methanol) was converted by treatment with strong base into the isomeric epipleiocarpamine ( +242" in methanol) which showed a UV-spectrum and carbonyl region of the IR-spectrum identical with those of pleiocarpamine. With potassium t-butoxide in deuteriomethanol, pIeiocarpamine gives a monodeuterioepipleiocarpamine, and the deduction that the formation of epipleiocarpamine involves epimerization a t a >CH-COOMe group was confirmed by the NMR- and mass-spectra of these compounds. Lithium aluminum hydride reduction of epipleiocarpamine gave an amorphous alcohol, epipleiocarpaminol, which showed the same R, values as normavacurine on thin-layer chromatography. The crystalline hydrochlorides had identical IR-spectra in Nujol ; furthermore, the methiodide of epipleiocarparninol was shown t o be identical with C-mavacuriae iodide (specific rotation, UV- and IR-spectra, and paper chromatography of the corresponding chlorides) (1). C-mavacurine therefore has a primary hydroxyl group and the earlier formula can be revised to the biogenetically acceptable I. (Evidence for the illustrated stereochemistry is given later.) It then followed from

8.

ALKALOIDS OF CALABASH CURARE AND

Strychnos

191

earlier correlations that C-fluorocurine must be 11, C-alkaloid Y is 111, and pleiocarpamine is I V (I). Additional evidence for the relationship between C-mavacurine and pleiocarpamine was provided as follows. Catalytic hydrogenation of pleiocarpamine in dilute acid solution gave 2,7-dihydropleiocarpamine (V; R = COOMe) which was reduced by lithium aluminum hydride t o the corresponding crystalline alcohol (V; R = CH20H). This product was also obtained by catalytic reduction of pleiocarpaminol and was shown

I

I1

C-Mavacurine

C-Fluorocurine

OH

~ H ~ O H Me I11 C-Alkaloid Y

H

Me

IV Pleiocarpemine

not to be identical with 2,7-dihydronormavacurine(VI). Epimerization of 2,7-dihydropleiocarpaminewith potassium t-butoxide did not cause complete inversion but the mixture, after reduction with lithium aluminum hydride, was separated t o yield 60 yo of V (R = CH20H) and 15% of the epimeric alcohol VI. The last substance was shown to be identical with 2 ,7-dihydronormavacurine. Attempts to define the position of the methoxycarbonyl group in pleiocarpamine by chemical methods were unsuccessful. However, oxidation of norfluorocurine (I1; N,-tertiary) with chromic acid in acetone gave a compound C18H18N202, the UV-spectrum of which was almost identical with that of N-acetylspiro-[cyclopentane-l,2’pseudoindoxyl] (VII). The IR-spectra of both compounds showed characteristic carbonyl absorptions in similar positions and the lactam

192

A. R. BATTERSBY AND H. I?. HODSON

function of the oxidation product was thereby indicated t o be in a sixmembered ring (1664 cm-1). The oxidation product was assigned structure VIII on this basis in accord with structure I1 for C-fluorocurine; further, the proved N-acylpseudoindoxyl chromophore provided evidence for the attachment of the hydroxymethyl group at position 16 in C-fluorocurine. H

H

H

Me

V

VI

bOMe

VII VIII

IX

Pleiocarpamine and C-mavacurine must both exist as a conformationally rigid ring system, the stereochemistry of which is shown in IX. No other mode of fusion of rings C, D, and E is possible and the sole problem of relative stereochemistry (with the exception of the stereochemistry of the ethylidene group) is therefore the configuration of the C-16 center in these alkaloids. The methoxycarbonyl group in pleiocarpamine is assumed t o have the /?-configuration depicted in IX (R1=COOMe, R2 = H) for the following reasons. First, the conversion under basic catalysis of pleiocarpamine into its C-16 epimer epipleiocarpamine (IX;R1= H, Rz = COOMe)is complete and in structure IX (R1=H, RZ= COOMe) the methoxycarbonyl

8.

ALKALOIDS O F CALABASH CURARE AND s&/Ch?WS

193

group is very much less hindered than in pleiocarpamine. Second, both pleiocarpamine and pleiocarpaminol are hydrogenated stereospecifically to the corresponding 2,7-dihydroderivatives (one product). This is to be expected since the bowl-like shape of the molecule (best seen in models) should allow ready hydrogenation only from the underside. A 1 : 1 mixture of pleiocarpamine and epipleiocarpamine was hydrogenated t o give a mixture containing only 2,7-dihydropleiocarpamine and unchanged epipleiocarpamine. Thus, under conditions allowing ready hydrogenation of pleiocarpamine, epipleiocarpamine is reduced only very slowly or not a t all. It is reasonable to suggest that the a-methoxycarbonyl group in epipleiocarpamine effectively screens the only side of the 2,7-double bond from which hydrogenation could readily take place. Thus the relative stereochemistry of C-mavacurine, C-fluorocurine, and pleiocarpamine is as depicted in formulas I, 11, and I V ; because of the co-occurrence of these alkaloids with others related t o corynsntheine and strychnine, these formulas may also give the absolute configurations. However, further work is necessary on this point. The relative stereochemistry of 2,7-dihydropleiocarpamine, 2,7dihydropleiocarpaminol, and 2,7-dihydromavacurine must be as illustrated in formula V(R = COOMe), V(R = CHzOH), and VI, respectively. This follows directly from the stereospecific hydrogenation of the 2,?-double bond in pleiocarpamine, pleiocarpaminol, and normavacurine described above. A similar argument leads to the stereochemistry of C-alkaloid Y. Oxidation of C-mavacurine with oxygen in the presence of platinum (see Volume VIII, p. 523) occurs a t the 2,7-double bond t o give C-alkaloid Y . Because the oxygenation is also expected t o be stereospecific, the stereochemistry of this alkaloid is almost certainly as shown in formula 111. A detailed study of the 100 Mc NMR-spectra of the three alkaloids shows that a complete assignment of all protons can be made on the basis of the proposed structures. The mass spectra were also in agreement ( 1 ) . The transformations of €2-dihydromavacuriiie discussed in Volume VIII, p. 526, can now be reinterpreted just as readily on the basis of structure X for this compound. €2-Dihydromavacurine (X) with methyl iodide undergoes C-methylation a t position 7 t o give the quaternary indoline compound ( X I ) which with base reversibly gives the methyleneindoline XII. An extension of this work has now shown that with methyl iodide XI1 undergoes a further transannular C-methylation, this time a t C-3 t o give the quaternary indoline XIII. I n contrast t o X I the UVspectrum of XI11 does not change on basification, presumably because the stereochemical requirements for a /?-elimination are not fulfilled ( 2 ) .

194

-QF&

A. R. BATTERSBY AND H. F. HODSON

OyJI ''H

"H kH20H XI

~ H ~ O H Me

x

Me

-0;.

Me'.

N

\3

"H kH20H XI11

Me

hH20H

Me

XI1

C-Mavacurine has been isolated in 0.1 76 yield from the root bark of a sample of Strychnos nux-vomica L. obtained from Indo-China, thus providing a link between American and non-American Strychnos species. The aerial parts of the same sample furnished strychnine, brucine, and vomicine, but no quaternary alkaloids ( 4 ) .

B. ALKALOIDS RELATED TO

THE

WIELAND-GUMLICH ALDEHYDE

The acetylation of the Wieland-Gumlich aldehyde (XIV; R = OH) and the preparation of diaboline, N,-acetyl Wieland-Gumlich aldehyde (XV; R = OH) ( 5 ) ,has been studied in some detail by Deyrup et al. ( 6 ) . Reaction of the aldehyde XIV (R = OH) with acetic anhydride in pyridine gave two isomeric diacetyl compounds C23H26N204. The major component was diacetyl Wieland-Gumlich aldehyde A (mp 203"-204") isolated by direct crystallization from the reaction product. Repeated chromatography of the mother liquor gave pure diacetyl Wieland-Gumlich aldehyde B, which could not be crystallized but was characterized as its crystalline picrate (mp 214"-215"). The spectroscopic properties of these isomers are in accord with their formulation as the C-17 epimeric 0,N-diacetyl derivatives XV and XVI (R = OAc). Neither epimer exhibits aldehyde absorption in the IRspectrum or aldehydic proton signals in the NMR-spectrum. Further,

* 8.

195

ALKALOIDS OF CALABASH CURARE AND Strychnos

l6 1 7

Qlq191g Ac

'H

: o

H

18

' 0

H

H XIV

xv R = OH, Diaboline R = OAc, Diacetyl Wieland-Gumlich Aldehyde A

R =OH, Wieland-GumlichAldehyde

R XVII

XVI R = OAc, Diacetyl Wieland-Gumlich Aldehyde B

the NMR-spectrum shows the allylic (2-19 proton signal as a broad multiplet, reflecting the nonequivalence of the C-18 protons to be expected if the >C=CH-CHzsystem is part of a ring. I n contrast, C-alkaloid A 19

(seeVolume VIII, p. 566) with a >C=CH * CHz * OH side chain shows the expected triplet for the C-19 and C-19' protons. The diacetyl derivatives are therefore confidently formulated as XV and XVI (R = OAc) and not as the corresponding open structure XVII. Acid-catalyzed hydrolysis of the isomeric diacetyl derivatives gave a mixture of diaboline, Wieland-Gumlich aldehyde, and starting material. However, aqueous alcoholic ammonia a t 20" effected selective hydrolysis of the 0-acetyl group ; under these conditions both epimers gave quantitative yields of diaboline (XV; R = O H ) , identical with the natural alkaloid. Reduction of diaboline and of the epimeric diacetyl compounds (XV and XVI ; R = OAc) with lithium aluminum hydride gave in all three cases a mixture of the diol XVIII (R = H) and the corresponding N,-ethyl derivative XVIII (R = Et) ; the former product was identical with the reduction product of Wieland-Gumlich aldehyde. This confirms that the configuration a t C-16 is the same for all four compounds, as here depicted, since inversion of configuration a t C-16 is improbable under the reduction conditions. Indeed, it is known (7) that the C-16

196

A. R. BATTERSBY AND H. F. HODSON

epimers of the very closely related 2,16-dihydroakuammicine (XIX ; R = COOH) are reduced exclusively to the corresponding epimeric alcohols X I X (R = CH20H). The molecular rotation of diacetyl Wieland-Gumlich aldehyde B (+192') differs from that of the isomer A (-131") by f323'. This is compared with the 300"-400" positive shift in going from the fl- to the a-form of acetylated D-aldopyranoses and is cited as evidence that the isomer A has structure XV (R = OAc) with the 17-acetoxy group in the fl-position; if this is so then diacetyl Wieland-Gumlich aldehyde B is XVI (R = OAc). Evidence from NMR-spectroscopy is also in favor of these assignments. The seven-membered ring readily adopts the preferred chair form shown in X X (absolute configuration based on that of strychnine) and since there is no magnetically anisotropic group close to the C-17 center the signal for the quasiequatorial proton of XX (R1= H, Rz = OAc) is expected a t higher field than that of the quasiaxial proton in the epimer X X (RI=OAc, Rz=H). The doublet for the C-17 proton in diacetyl Wieland-Gumlich aldehyde A is in fact a t higher field than the corresponding signal for isomer B, in keeping with the foregoing assignment. The hydrochloride of tlp Wieland-Gumlich aldehyde is converted by boiling ethanol into the single ethyl acetal XIV (R=OEt). Diaboline hydrochloride is similarly converted into an acetal XV (R = OEt) which is also formed by acetylation (acetic anhydride in pyridine) of XIV (R = OEt). Consideration of the chemical shifts of the C-17 protons in these acetals and of rotation shifts indicates the stereochemistry shown ; i.e., the acetal possesses the same configuration as the corresponding hemiacetal. Examination of the NMR-spectrum of Wieland-Gumlich aldehyde and diaboline in the light of the above interpretations indicates that the configuration a t the anomeric centre of both compounds is as shown in XIV and XV (R = OH). An independent study (8) describes the acetylation of diaboline with acetic anhydride in pyridine to give diacetyl Wieland-Gumlich aldehyde B. The rotation and melting point of picrate leave no doubt as t o its identity but here the base was obtained crystalline (mp 92'-94.5'). Obviously, the presence of the N,-acetyl group in diaboline must direct the steric course of O-acetylation. Investigation of the bark of Strychnos henningsii Gilg. resulted in the isolation of four nonquaternary alkaloids, diaboline, rindline, henningsamine, and henningsoline (9). Diaboline was fully characterized, including hydrolysis to the WielandGumlich aldehyde and preparation of the oxime from the latter compound. Rindline, C24H30N205 (mp 214"-216"), which had previously

8. ALKALOIDS OF CALABASH CURARE AND Strychnos

197

been isolated (10) from this species was not further investigated. The other two alkaloids had not previously been described and were studied in some detail ( 8 , U ) . Henningsamine, C Z ~ H Z ~ N(mp Z O 205"-206" ~ ; [a]= -43.9", C = 1 in chloroform ; picrate mp 229"-231 O), was isolated in quantities insufficient for extensive chemical degradative studies. However, consideration of the molecular formula (confirmed by high-resolution mass spectrometry) and the UV-, IR-, and NMR-spectra suggested an N-acetyldihydroindole structure together with an acetoxy group not involved with the chromophore. Absorption in the IR-spectrum a t 1742 cm-1 and 1656 cm-1 and NMR-proton signals a t 7.92 r and 7.61 r correspond to the 0-acetyl and N-acetyl groups, respectively (8). Considerable information was obtained from the mass spectra of several derivatives prepared on a 1-2 mg scale specifically for mass spectrometric studies. Henningsamine (M+, 394) was converted by acid hydrolysis to deacetylhenningsamine (M, 310 ; replacement of two acetyl groups by hydrogens) which on reacetylation with [2H6]-acetic anhydride gave a product of molecular weight 400. The mass spectra of these derivatives and that of the alkaloid itself, which showed peaks a t m/e 130 and 144 characteristic of unsubstituted dihydroindoles, confirmed the above conclusions. On hydrogenation over platinum in ethanol the alkaloid gives a product of molecular weight 396, indicating saturation of one double bond. Under the same conditions deacetylhenningsamine, however, gives a mixture of compounds of molecular weight 314 (absorption o f 2 moles of hydrogen) and 298 (hydrogenolysis of oxygen and absorption of 2 moles of hydrogen). This indicated the presence of an allylic oxygen and two double bonds (or equivalent unsaturation) and together with the foregoing evidence immediately suggests a structure related t o the WielandGumlich aldehyde. This received support from a comparison of the mass spectra of deacetylhenningsamine and Wieland-Gumlich aldehyde which indicated that these compounds have the same carbon skeleton. Henningsamine appeared, therefore, to be a diacetyl Wieland-Gumlich aldehyde. This was confirmed (8)when it was shown to give no meltingpoint depression on admixture with diacetyl Wieland-Gumlich aldehyde A (XV; R = OAc) (mp 203"-204") prepared as described by Deyrup et al. The second new alkaloid, henningsoline, C Z Z H Z ~ N(mp Z O ~207"-209" ; -200°, C = 1 in chloroform), is phenolic and its UV-spectrum suggested an N-acyldihydroindole chromophore ; a pronounced bathochromic shift in alkaline solution confirmed its phenolic nature. Analysis revealed the presence of one methoxyl group, shown to be a n anisole residue by I R (1250 cm-1)- and NMR (6.107)-spectra, and one N-acetyl

198

A. R. BATTERSBY AND H. B. HODSON

group (IR, CH3 a t 1374 cm-1 and NMR, 7.53 T). The NMR-spectrum showed two aromatic protons as an AB quartet and IR-absorption a t 800 cm-1 confirmed the presence of two adjacent aromatic hydrogen atoms. The IR-absorption a t 1634 cm-1 indicated that the amide carboxyl is hydrogen-bonded with the phenolic group, thus locating this group at the indolic 7-position; in confirmation, the latter resisted methylation with diazomethane. Taken together, these results lead to the partial structure XXI for the chromophore of henningsoline (11). The mass spectrum of henningsoline did not show the peaks a t m/e 144 and 130, characteristic of unsubstituted dihydroindole alkaloids. However, intense peaks a t m/e 190 and 176 (144 and 130 plus 46; replacement of H by OH and H by OMe = 46 mass units) indicated a substituted dihydroindole structure. Acetylation of henningsoline (M+, 398) with [2H,]-acetic anhydride gave a bistrideuteroacetyl derivative (M+, 488) indicating the presence of two hydroxyl groups in the alkaloid; this was confirmed by the preparation of 0-benzoyl (ester carbonyl a t 1709 cm-1) and 0,O-dibenzoylhenningsoline (ester carbonyls a t 1727 and 1721 cm-1). The bistrideuteroacetyl derivative exhibited the m/e 190 and 176 'peaks of the parent compound but these were weaker than new peaks a t m/e 191 and 177. These must arise by transfer of deuterium from the 0-acetyl residue

R

'H CHzOH CHzOH XVIII

R XIX

xx

XXI

XXII

Me

8.

ALKALOIDS OF CALABASH CURARE AND

Xtrychnos

199

to the aromatic ring, concomitant with the elimination of [ZHzI-ketene and provides yet more evidence that the aromatic nucleus carries an hydroxyl group. Hydrogenation of henningsoiine over platinum gave a mixture of products with molecular weights 400, 402, 384, and 386. The species M+, 386 was shown to be the major product of prolonged hydrogenation and must arise, as in the case of deacetylhenningsamine, by hydrogenolysis of oxygen and saturation of two double bonds. This again, as with henningsamine, suggested a structure related t o the WielandGumlich aldehyde and further support came from the observation that henningsbline forms an oxime. The most intense peak in the mass spectrum of the reduction product Mf, 386, and in the similar reduction product derived from deacetylhenningsamine, is a t m/e 168 in both cases. This indicates a similar alicyclic moiety for the two compounds. The structure X X I I which is 12-hydroxy-11-methoxydiaboline or a diastereoisomer is therefore proposed for henningsoline. Further support for this was obtained by a comparison of the mass spectrum of henningsoline with that of diaboline (11). Strychnos henningsii is a South African species and the isolation of diaboline and its derivatives therefrom established a direct chemical link between American and African species (see also p. 194).Diaboline and a diacetyl Wieland-Gumlich aldehyde have also been isolated from the bark of the South American species S. chlorantha Prog. (12).The latter was identified by color reactions, chromatography, and mass spectrum (molecular formula C Z ~ H ~ G Nbut ~ Oinsufficient ~), material was available for further work.

C. NORFLUOROCURARINE Previously (Volume VIII, p. 552) the Oppenauer oxidation of the ethylidene base X X I I I (R = CH20H) obtained by catalytic hydrogenolysis of the Wieland-Gumlich glycol (XVIII ; R = H ) had been described as

XXIII

XXIV Norfluorocurarine

200

A.

R. BATTERSBY AND H. F. HODSON

leading to norhemidihydrotoxiferine (XXIII ; R = CHO) which underwent air oxidation on paper chromatography to give norfluorocurarine (XXIV). The oxidation of X X I I I (R = CH20H) directly to XXIV with lithium t-butoxide and benzophenone in nitrobenzene has now been achieved on a preparative scale (13). Independently (14) it has been shown that the Oppenauer oxidation of the base X X I I I (R = CH20H) with potassium t-butoxide and benzophenone in benzene in the strict absence of air gives norfluorocurarine (XXIV) as the major product; although some of the aldehyde X X I I I (R=CHO) is formed, it shows no strong tendency to oxidize in air. Norfluorocurarine must therefore be the direct product of Oppenauer oxidation of X X I I I (R = CHzOH). 111. The Dimeric Alkaloids of Calabash Curare

A. C-CALEBASSINE The structure of C-calebassine diiodide has been determined by x - r a y crystallography (15). I n this way the constitution and absolute stereochemistry of C-calebassine determined by chemical and spectroscopic methods (Volume VIII, p. 566) has been confirmed.

B. TOXIFERINE-I, C-DIHYDROTOXIFERINE-I, AND RELATED ALKALOIDS The structures of toxiferine-I, C-dihydrotoxiferine-I, and related alkaloids contain a central eight-membered ring and the siting of unsaturation in this ring (Volume VIII, p. 539) relied heavily on interpretations of NMR-spectra. Although these interpretations were selfconsistent over a range of structures, some exceptional chemical shifts were postulated and it was thought desirable ( 1 4 )to confirm the NMRassignments by examination of alkaloids specifically labeled with deuterium in the 17 and 17’ positions (see XXVIII). Initial experiments showed that when nortoxiferine was heated in deuterioacetic acid (CH3.COOD) there was no exchange of deuterium with the alkaloid. Since these conditions were essentially those used for the dimerization of the Wieland-Gumlich aldehyde methochloride (Volume VIII, pp. 541, 547), dimerization of 17-deuterio WielandGumlich aldehyde methochloride (XXV)to 17,17’-dideuteriotoxiferine-I (XXVI; R = D central ring system only) should be possible without loss of deuterium.

8. ALKALOIDS

OF CALABASH CURARE AND Strychnos

xxv

201

XXVI

XXVII

XXVIII

XXIX

Wieland-Gumlich aldehyde was converted via the oxime, nitrile, carboxylic acid, and methyl ester, to the N,N-dimethylamide XXVII. Reduction of the amide with lithium diethoxyaluminodeuteride gave a 55 ”/o yield of 17-deuterio Wieland-Gumlich aldehyde (XXV; N , tertiary) which was methylated and then dimerized with pivalic acid to give a high yield of 17,17’-dideuteriotoxiferine-I (XXVI ; R = D central ring system). This in turn was converted to 17,17’-dideuterio-C-dihydrotoxiferine-I (XXVI; R = D central ring) by reaction with bromine in acetic acid followed by reductive removal of the bromine. A comparison of the NMR-spectra of the deuterium derivatives with those of the corresponding protium species (XXVI; R = H ) shows conclusively that the signal from the 17,17’ protons does indeed occur at the abnormally low field of 2.93 T,as previously postulated. 17,17‘-Dideuteriotoxiferine-Iwas converted by photooxidation to 17,17’-dideuterio-C-alkaloid E (XXVIII; R = D central ring system). Comparison of the NMR-spectrum of C-alkaloid E (XXVIII; R = H central ring) with that of the corresponding deuterated species (XXVIII ; R = D ) shows the only difference to be the loss of the strong signal a t 2.43 7,again, previously assigned to the 17,17’-protons. Finally, deuterated toxiferine-I and C-dihydrotoxiferine-I were converted by air oxidation to 17,17’-dideuterio-C-alkaloid A and 17,17’-

202

A. R. BATTERSBY AND H. F. HODSON

dideuterio-C-calebassine, respectively (XXIX, central ring system of both alkaloids). Comparison of the spectra of deuterium (XXIX; R = D ) and protium (XXIX; R = H ) species shows that the singlet (Volume VIII, p. 567) at 5.08 T must be assigned to the 17,17'-protons as had been assumed in the establishment of structure XXIX.

C. C-CURARINE AND RELATIVES The hydrolysis of C-curarine t o C-fluorocurarine (Vol. VIII, p. 569) with concentrated hydrochloric acid produces smaller amounts of two other compounds, ultracurine A and ultracurine B, notable for their very intense blue fluorescence in UV-light. The early investigations (16) led to the isolation of both of these degradation products as crystalline 8-anthraquinonesulfonatesand the empirical formula C40H44N4++ or C44H44N40++was tentatively proposed for ultracurine A ; analyses of

a CH

CH II

l

/

/

xxx

XXXI

eMe cx& - @ Me

CH II Io

CHO

CHCl

CH

I

Me/N\Ph XXXII

XXXIII

H

xxxv

XXXIV

QJ-Q CH

I

XXXVI

8. ALKALOIDS OF

CALABASH CURARE AND

Strychnos

203

the ultracurine B salt were consistent with a C ~ O H ~ ~ Nformulation. ~O++ The low R, values of the ultracurines were in agreement with a C4,, structure. It was also shown that concentrated hydrochloric acid converts ultracurine A to a mixture containing ultracurine B and C-fluorocurarine. Further work in connection with the structure of ultracurine A has now been reported (17).I t s UV-spectrum, identical in neutral and in 0.1 N acidic solution, undergoes a marked bathochromic shift in stronger acid solufion which is reversible upon dilution. This suggested a cyanine dye type of structure (XXX) which would form the mesomeric cation XXXI on acidification. The model compound X X X I I was therefore synthesized and its UV-spectrum was sufficiently similar to that of ultracurine A in strongly acidic solution to encourage the preparation of closer model systems. The aldehyde XXXIII was converted by phosgene into the vinylogous imidoyl chloride XXXIV which was condensed with 4a-methylhexahydrocarbazole XXXV in the presence of base to give the product XXXVI isolated and characterized as its yellow crystalline perchlorate. A series of related compounds was also prepared an' I the properties and spectra of the whole group of substances gives strengt) L to the assigned structures. The UV-spectrum of the base XXXVI is in such good agreement with that of ultracurine A that the same chromophore is assumed to be present in both molecules. The spectrum of ultracurine A in 7 0 % perchloric acid is not in such good agreement with that of the perchlorate (XXXVI ; protonated) but agrees well, however, with the spectrum of a 2 : 1mixture of XXXVI and XXXVI perchlorate. Thus, N , of ultracurine A is not completely protonated in 70% perchloric acid probably due to the influence of the quaternary N b atoms in the molecule. Considering the likely chromophore of ultracurine A and its origin from C-curarine, an obvious choice for its structure is XXXVII, formed by partial hydrolysis. The NMR-spectrum of ultracurine A shows no

XXXVII

XXXVIII

204

A. R. BATTERSBY AND H. F. HODSON

detectable signal corresponding t o an aldehydic proton and its UVspectrum indicates little extension of the chromophore of XXXVI. Both these facts could be explained by assuming an interaction (Tbond overlap) as depicted in XXXVIII between the aldehyde function and N , . Alternatively, ultracurine A could be the desformyl derivative of XXXVII. REFERENCES 1. M. Hesse, W. von Philipsborn, D. Schumann, G. Spiteller, M. Spiteller-Friedmann, W. I. Taylor, H. Schmid, and P. Karrer, Helv. Chim. Acta 47, 878 (1964). 2. W. G. Kump and H. Schmid, Helv. Chim. Acta 44, 1503 (1961). 3. M. F. Bartlett, R. Sklar, A. F. Smith, and W. I. Taylor, J . Org. Chem. 28, 2197 (1963). 4. A. Guggisberg, M. Hesse, H. Schmid, and P. Karrer, Helv. Chim. Acta 49, 1 (1966). 5. A. R. Battersby and H. F. Hodson, Proc. Chem. SOC.126 (1959). 6. J. A. Deyrup, H. Schmid, and P. Karrer, Helv. Chim. Acta 45, 2266 (1962). 7. M.-M. Janot, Tetrahedron 14, 113 (1961). 8. K. Riemann, J. S. Grossert, J. M. Hugo, J. Occolowitz, and F. L. Warren, J. Chem. SOC. 2814 (1965). 9. J. S. Grossert, J. M. Hugo, M. E. von Klemperer, and F. L. Warren, J . Chem.Soc.'2812 (1965). 10. M. M. Rind1 and M. L. Sapiro, Trans. Roy. SOC. S. Africa 23, 361 (1936); C A 30, 2976 (1936). 11. K. Biemann, J. S. Grossert, J. Occolowitz, and F. L. Warren,J. Chem.Soc. 2818 (1965). 12. H. Miiller, M. Hesse, P. Waser, H. Schmid, and P. Karrer, Helv. Chim. Acta 48, 320 (1965). 13. H. Fritz, E. Besch, and T. Wieland, Ann. 663, 150 (1963). 14. M. Grdinic, D. A. Nelson, and V. Boekelheide, J . A m . Chem. SOC. 86, 3357 (1964). 15. M. Fehlmann, H. Koyama, and A. Niggli, Helv. Chim. Acta 48, 303 (1965). 16. H. Fritz, H. Meyer, and T. Wieland, Ann. 633, 156 (1960). 17. H. Fritz, A. Krekel, and H. Meyer, Ann. 664, 188 (1963).

-Chapter

9-

THE ALKALOIDS OF ASPIDOSPERMA. OCHROSIA. PLEIOCARPA. MELODINUS. AND RELATED GENERA B . GILBERT Centro de Pesquisas de Produtos Naturnis. Faculdade de Farmcicia. Rio de Janeiro. Brazil

I . Introduction

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

I1. The Aspidospermine Group ........................................ A . Absolute Stereochemistry ....................................... B . Quebrachamine Derivatives ..................................... C . Syntheses ..................................................... D . Simple Aspidospermidine Derivatives .............................. E . The Vindoline Group ........................................... F. The Vincadifformine Group ..................................... G. 20-Oxygenated Derivatives of Vincadifformine ..................... H . Interrelation of Minovincine with Hexa- and Heptacyclic Alkaloids . . . I . Vindolinine and Tuboxenine ..................................... I11. The Meloscine Group

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

206 207 207 220 222 228 230 230 233 236 237 242

IV . The Aspidofractinine Group ........................................ A. Absolute Stereochemistry and Interconversions ..................... B. Pleiocarpoline, Pleiocarpolinine, and Kopsinoline ................... C . 10.1 1.Dioxopleiocarpine ........................................ D . d6-Kopsinene (Venalstonine), Epoxykopsinine (Venalstonidine), and Hydroxykopsinines ............................................ E . d6-8-Oxokopsinine and Its N-Oxide .............................. F. Heptacyclic Kopsane Group Alkaloids ............................ G. Fruticosine and Fruticqsamine ...................................

249 251 252 255

V. Cyclic Ethers and Lactones ........................................ A . Aspidoalbidine Derivatives ...................................... B . Obscurinervine, Neblinine, and Related Alkaloids . . . . . . . . . . . . . . . . . . C . Beninine and Related Alkaloids ..................................

260 260 261 265

244 244 246 247

VI . The Aspidospermatidine Group ..................................... 269 A . Limatine and Some Analogs ..................................... 269 B . Precondylocarpine ......................... ._.................. 270

V I I . Alkaloids Lacking the Tryptamine Bridge

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

A . Uleine Derivatives ............................................. B . Apparicine .................................................... C . Vallesamine ................................................... D . Ellipticine, Methoxyellipticine, and Olivacine .....................

205

271 271 272 273 279

206

B. QILBERT

VIII. Some Miscellaneous Alkaloids ....................................... A. Introduction ................................. B. Aspidodasycarpine ............................................. C. Pleiocarpamine, Fluorocarpamine, Mavacurine, and C-Fluorocurine . . .

219 279 280 285

I X . Double Alkaloids.. ................................................ A. Introduction . . ..... ....................... B. Pleiomutine ................................................... C. Vobtusine and Callichilino ...................................... D. Haplophytine ..................... ...........

291 291 292 295 302

References

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

303

I. Introduction The interval sinae the last review was written has seen the isolation of a number of new alkaloids but of few fundamentally new skeletal types. Meloscine (I) ( 1 ) and related alkaloids represent a completely novel group, whereas aspidodasycarpine (11) ( 2 ) is a new variation of the akuammigine type.

I

I1

A very significant advance in structure determination is the introduction of high-resolution mass spectrometry combined in some case9 with the use of computer programs (3, 3a, 4);this has been adapted to solve the structures of double alkaloids such as pleiomutine (Section IX,B) (5, 6 ) .There has been considerable activity in the synthetic field

CO2H

I11

602H IV

9. Aspidosperma

AND RELATED ALKALOIDS

207

and with the advances in our knowledge of biosynthesis (Chapter 8) an increasing tendency is noted to model syntheses on the probable biogenetic route (7, 8). Although a new universal numbering system, illustrated by formula 111, has been suggested (9; see also 9a) it has been decided to retain the old patterns of numbering (see IV) for aspjdospermine and derived alkaloids in this review, pending a general agreement on nomenclature. A list of new alkaloids and some of their derivatives together with plant sources and physical properties is given in Table I. 11. The Aspidospennine Group

A. ABSOLUTE STEREOCHEMISTRY Although the structure of ( - )-aspidospermine-N,-methiodide (V) was determined by X-ray crystallography (Volume VIII, p. 361) its Me

V

VI H

absolute stereochemistry remained unknown. The absolute configurations of two related compounds, however, have been determined by X-ray study of appropriate derivatives. These are cleavamine (VI ; 56, 57) and N-acetyl-7-ethyl-5-desethylaspidospermidine (VIII ; 58) synthesized from dihydrocleavamine (VII). Furthermore the indolenine ( - )tubifoline (IX), by virtue of its interrelation with 19,20-dihydroakuammicine (Volume VIII, p. 466) has the absolute configuration shown and its reduction product ( - )-tubifolidine (X) may reasonably be represented by X with 2p-H (59). N,-Acetyltubifolidine (XI) and VIII not surprisingly, were found (59) to have almost identical optical rotatory

t s

TABLE I

0

rn

PHYSICAL CONSTANTS AND PLANT SOURCES" Compound and plant sourcea

Formula

Melting point ("C)

Reference

[alD

Part 1. Quebrachamine group ( f )-N-Methylquebrachamine, b 10 ( + ) -N-Methylquebrachamine

(-)-N-Methylquebrachamine, c 12 Vincadine (3P-COzMe,BE-Et),XXIII, b Vol. VIII Vincaminoreine (N-Me, 3/3-COzMe, 5a-Et), XXII, b 14-1 6 Vincaminorine (N-Me, 3m-COzMe, 5a-Et), XXI, b 15-17 (+)-17-Methoxyquebrachamine(?), a 19

Voaphylline ( = 5~Et-6/3,7/3-epoxy), XXIVa k 54, 656; V 65n Rhazidine, XXV, J Vol. VIII, Q 66

CzoHzsNz

CzlHz8NzOz CzzHaoNzOz

70-72 88-89 82-84 70-85 136-1 38

CzzH30NzOz

130-13 1

CzoHzsNzO

157-160

C19Hz4Nz0

164-1 66

CzoHzsNzOa.Hz0

278-279

0"(e) +llO"(c) -80"(c) +92"(e) +27"(m) +46"(~)

10 11, 15 12 1 3 . Vol. VIII, p. 276 11,14-16 11, 13, 15-17

+73"(d) 19 $68" to 115"(c) +28"(c) 54, 65a, 65b -21°(e)

Vol. VIII, p . 505; 66

Part 2. Aspidospermidine group' ( - )-l,Z-Dehydroaspidospemidine, XVII, i 19b N,-Methylaspidospermidine, LXXXc, C 1 2 ; b 19c N,-Acetylaspidospermidine, c 12 0-Demethylpalosine ( 17-hydroxy-Na-propionyl) LXXXa, 0 61a 10-Oxocylindrocarpidine, ff 19d N,-Acetyl-N,-depropionylaspidoalbinol (N,-acetyl17,21-dihydroxy-15,16-dimethoxy), LXXXb P 61b Hydrochloride

C19H24Nz CzoHzsNz CziHzsNzO CzzHaoNzOz

Amorph. Amorph. 100-103 169

Cz3HzsNzOs CeaH3zNzOs

213 Amorph.

- 39"

267-269

+64'(w,m)

-225"(e) +21"(c) -15O(~) +118'(c)

19b 12,19c Vol. VIII; 12 61a 19d 84

W

E td M

E

Catharosine (~I~,3,4j3-dihydroxy-3-carbomethoxy-

141-143

N,-methyl), LXXXV, d I8 Vindorosine (A~,4,L?-acetoxy-3~-carbomethoxy-3~-

167

hydroxy-N,-methyl), LXXXIII, d 20 Deacetylvindoline (16-methoxycatharosine), LXXXIV, d 20a Ervamine (d~,3-carbomethoxy),LXXXVII, 20b Lochnericine (d~,3-~arbomethoxy-6,7-epoxy)~ LXXXVIII, d Vol. VIII Lochnerinine ( 16-methoxylochnericine),LXXXIX, d 20, aa 22a Echitovenidine (d2,3-carbomethoxy-20-8,8dimethylacryloxy), C I I I , j 23 ( -)-2O-Acetoxytabersonine (dz.6-20-acetoxy-3carbomethoxy), CI, g 26 Echitovenine [( )-6,7-dihydro-CI], CII, j 29 Tuboxenine (11,2O-cyclo),CXXVIII, h 27, i 19a

+

0

18

-3 l"(c)

20

163-165

Vol. VIII, p. 342; 20a

Amorph. 190-193 decomp.

20b 21,22

168-169

-424"(~)

20-22

162-163

-66Oo(c)

23

138-140

-284'(e)

26

168-170 139-140

+640"(c) +5O(C)

29 27

d

Part 3. Meloscine group Meloscine (3/3-H),I, g 1, 26 Epimeloscine (3cr-H),CXXXIII, g 26 Meloscandine (3-formyl?),CXL, g 1, 26 Melodinus alkaloid 4 (3-carbomethoxy),CXXXIX, g 26

CigHzoNzO CigHzoNzO CzoHzoNzOz CzlHzzNzOa

!?J

188-190

1 , 26 26 1, 26 26

Amorph.

Part 4. Aspidofractinine group (-)-Aspidofractinine, CXIII, i 19b, H 48 CivHz4N Kopsinic acid methochloride (N,-methyl-3CzlHz7ClNzOz carboxylate), k 30, 30a 20-Hydroxykopsinine (3-carbomethoxy-20-hydroxy), CZIHZ~NZO~ CLXIX, a 19 6(or 7)-Hydroxykopsinine, CLXVIII, a 19 CziHz6NzOs

101-102 282-295

-2O"(c) Vol. VIII; 19b -10O0(m,w) 3 0 , 3 0 a

187-192

-63"(c)

19a

190-1 97

-62O(c)

1 9 ~

@ ti

8

1 w 1 5 1

t.3

0 (0

TABLE 1-continued t.3

w

Compound and plant sourceb

Formula

Melting point ("C)

Reference

[aloe

0

Part 4. Aspidofractinine group-continued Venalstonine (D6-kopsinene), CLXIV, a 19, j 29 Venalstonidine (6,7-epoxykopsininc),CLXVI, a 19, 10,ll -Dioxopleiocarpine (N,,3-dicarbomethoxylO,ll-dioxo), CLXIII, k 31 A6,S-Oxokopsinene (D~,3-carbomethoxy-8-oxo), CLXX, a 19 d6,8-Oxokopsinene-Nb-oxide, CLXXII, a 19 CLVIII, Kopsinoline (3-carbomethoxy-Nb-oxide), i 32, k 32,132 Pleiocarpolinine (3-carbomethoxy-N,-methylN,-oxide), CLVII, i, k, 132 Pleiocarpoline (N,-3-dicarbomethoxy-Nb-oxide), CLVI, i, k, 132

140-142 230-236 285-287

--89"(c) -96"(~) -265"(~)

227-231

-990(c)

19

245-248 158-160

-48"(c) -7O"(c)

19 32, 79

210-211

-lIlo(c)

32, 79

td

-131"(~)

32, 79

8

234-235

9a, 29

SU, 29 31

W

8

e Part 5. Kopsane group Kopsanol(22-hydroxy), CLXXXIV, m, n 33; o 28 Epikopsanol (22-hydroxy), CLXXXV, m, n, 33 Kopsanone ( ~ Z - O X O ) ,CXLVIII, m, n, 33 10-Oxokopsanol, CLXXXIX 10-Oxoepikopsanol, CLXXXVIII, n 33 10,22-Dioxokopsane, CLXXXII, k 4 N,-Methyl-10,22-dioxokopsane, CLXXIV, k 4 N,-Carbomethoxy-l0,22-dioxokopsane,CLXXV, k 4

CzoHz4Nz0 CzoHz4NzO CzoHzzNzO CzoHzzNzOz CzoHzzNzOz CzoHzoNzOz CziHzzNzOz CzzHzzNz04

239-245 decomp. 196-197 161-163 310-311 decomp. 242-245 decomp. 298 269 264-265

+17"(c) -76'(~) -210(c)

+156"(c) +74"(c) +llO"(c)

33 33 33 33 33 4 4 4

Part 6. Aspidoalbidine and beninine groups Aspidoalbidine derivatives Fendleridine (aspidoalbidine), LXXXg, p 35

CigHzsNzO

185-186

35

+2O0(C)

17-Methoxy-N,-foimylaapidoslbidine,CCXIXa, c 12

CzlHzaNz03

208-210

Aspidofendlerine (16,17-dihydro~y-N,-acetyl), ccxx, p 35 Fendlerine (17-hydroxy-16-methoxy-N,propionyl), p 35, P 61b Perchlorate 2 1-0xoaspidoalbine ( 17-hydroxy-15,16dimethoxy - 21-ox0-N,-propionyl) , CCXXIa, r 36 21 -0xo-0-methylaspidoalbine ( 15,16,17-trimethoxy-21-oxo-N,-propionyl), CCXXIc, r 36 Beninine group Beninine, CCLIII, N 85 N,-Acetate

CzaHsoNzO4

278 decomp.

Cz3H30NzOrl

185-1 86

Cz4H3oNzOa

209-21 1 208-209

CZ5H32NZO6

184-185

+96'(c)

CzoHzsNzOz CzzHzsNz03

225-227 220

+llO(c)

12

35 t226"(c)

35, 61b 61b 36

F b

36

85

Part 7. Obscurinervane Group' Neblinine (d6,16-methoxy-22-methyl), CCXXIIIe, C23H26N204 8 37 Homoneblinine (d~,16-methoxy-22-ethyl), Cz4HzsNz04 CCXXIIIf, 8 37 Dihydroobscurinervidine (15,16-dimethoxy-22C24H30N~05 methyl), CCXXIIId, t 37 Obscurinervidine ( A # ,15116-dimethoxy-22-methyl), C24HzsNz05 CCXXIIIb, t 37 Dihydroobscurinerviee (15,16-dimethoxy-22-ethyl),C Z ~ H ~ Z N ~ O E , CCXXIIIC, t 37 Obscurinervine (La,15,16-dhethoxy-22-ethyl), CzsH3oNz05 CCXXIIIa, t 37

256-258 decomp.

-14"(~)

263-265 decomp.

37 37

189-190 decomp.

-440(c)

37

206-207 decomp.

-390(c)

37

184-185 decomp.

-6lo(c)

37

203-205 decomp.

-54"(c)

37 ~~

Part 8. Aspidospermatidine group Condyfoline (dl,l4,19-dihydro) N-Acetylaspidospermatidine, CCLVII, c 12

CisHzzNz CzoHz4Nz0

76-80 Amorph.

+348'(ea) -28"(e)

Vol. VIII; 59 12

TABLE 1-continued

c.3

+

c.3

Compound and plant sourceb

Formula

Melting point ("C)

Reference

[cLIDC

Part 8. Aspidospermatidine group-continued 12-Hydroxy-N-acetylaspidospermatidine (Limatinine), CCLIX, v 34; w 37a Limatine (12-hydroxy-M-propionylaspidospermatidme), CCLVIII, w 38 11,12-Dihydroxy-N-acetylaspidospermatidine, CCLX, e 24 11-Methoxylimatinine, w 37a 11-Methoxylimatine, w 37a Precondylocarpine ( d1,16-carbomethoxy-16hydroxymethyl), CCLXVI, c 12

CzoHz4NzOz

162-163

+170°(e)

34,37a

CziHz6NzOz

175-1 76

+1 66'(c)

38

CzoHz4Nz03

257-258

+160"(c)

24

CziHz6Nz03 CzzHzsNz03 CziHz4Nz03

139-140 75-78 143-146

+ 181"(c) + 16S0(c)

3 7a 3 7a 12

Part 9. Dasycarpidane' group (see Vol. VIII, p. 473) 208-210 Amorph. Amorph . 118-122 14S145 Amorph. 220

Des-N-methyldasycarpidone(1-oxo), x 2 , 3 9 Dasycarpidone (N,-methyl-1-oxo), x 2, 39; C 3% 3-Epidasycarpidone, ee 39a Dasycarpidol (1-hydroxy-N,-methyl), x 2, 39 Des-N-methyluleine (1-methylene), x 2, 39 3-Epiuleine, ee 39n Dehydrodes-N-methyluleine(43J4,l -methylene), x 2,39 1,13-Dihydro-13-hydroxyuleine ( 1-hydroxymethylN-methyl), x 2 , 39

Amorph.

-54'(e) -20°(e)

2 , 39 2, 39 39a 2, 39 2 , 39 39a 2, 39

-96'(e)

2, 39

+65"(c)

Part 10. Apparicine group (+)-Apparicine, CCLXX, x 2 CisHeoNz (-)-Apparicine, y, z, A, B 4 0 ; c 12; C 41 (no [aIn); D 4 2 ; d 4 % ; bb 4 2 b ; W 4 2 c ; cc 4 2 c ; dd 42c

192-194

+176"(c) -177O(c)

2 40

Vallesamine (1-nor-1-carbomethoxy-1-hydroxymethyl), CCLXXVII, c 12 0-Acetylvallesamine, CCLXXVIII, c 12

C~oHz~Nz03

163-165

+165O(c)

12, 43

CzzHz6Nz04

168-171

+155"(c)

12, 43

Part 11. Double alkaloids' Pleiomutine [ 15414'-eburnamyl) pleiocarpinine], CCCLVI, k Vol. VIII Villalstonine (macroline pleiocarpttmine) Aspidexcine, E 45 Aspidexcelsine, E 45 Aspidosperma dispersum alkaloid 1, F 28 Vobtusine, CCCLXXXIX? (see Chapter 9, Vol. VIII), T 95 Melodinus australis alkaloid

+

C4iH50N402

Amorph.

C4iH48N404 C4zH56N404 M + 622 C4iH5oN403 C43H50N406

Amorph. 76-81 212 234-237 302

C4iH46N403

Sinter 220

-97"(~)

Vol. VIII; 5, 6

-l4'(~) +72'(c)

VOl. VIII, p. 201; 44 24, 45 24, 45

-330"(~)

28 46, 85, 95

W

b $

% $ Q

+540(c)

19

w E!

Part 12. Alkaloids of miscellaneous types Highly aromatic bases l-Carbomethoxy-/3-carboline, CCCXV, k 49 CiaHioNzOe 1-Methyl-3-carboxy-/3-carboline, r 50 CiaHioNzOz 1-Methyl-3-carboethoxy-/3-carboline, CCCXVI, C14Hi~N20~ r 50 Indolo-[2,3d]-pyridocoline,CCCXIII, H 48 CisHioNz Dihydroindolo-[2,3d]-pyridocoline,CCCXIV, H 48 C15H12Nz Isotuboflavine, CCCXI, k 49 CiaHizNzO CisHioNzO Norisotuboflavine, CCCXII, k 49 9-Methoxyolivacine, Z 55e Ci8Hi6NzO Dihydrocorynantheol derivatives Ochrosandwine ( 10-hydroxydihydrocorynantheol- CzoHzgNzOzCl N,-methochloride), G 47

kid

166 300 222-223

49 50 50

Decomp. 252 263-265 282-284 291-293

48 48 49 49 55e

288-289 (capill.)

47

U

s

TABLE 1-continued Compound and plant source*

Formula

Melting point ("C)

Reference

[&"

Part 12. Alkaloids of miscellaneous types-continued

Dihydrocorynantheol derivatives-continued Huntabrine (lO.hydroxy-d~~~~~-~or~antheolCzoHz7NzOzCl N,-methochloride), k 30, 30a Aspidexcine ( 1 0 - m e t h o x y - ~ f ~ 6-carbomethoxy9~~0, Cg.zHzsNzO4. HzO corynantheol?),E 24 Rearranged corynantheol base Vallesiachotamine, CCCX, c 12 CziHzzNz03 Yohirnbine derivative 19-Dehydroyohimbine, D 42 CziHz4Nz03 CzzHz.sNz04 10-Methoxycorynanthine, E 55d Hydrochloride Sarpagine and Akuummiline derivatives Sarpagine-N,-methochloride,k 30, M 51a Strictamine = vincamidine (desacetoxymethylakuammiline), CCCXVII, J 52 Nervobscurine ( 10-methoxyakuammiline), CCCXVIIa, t 86 Aspidodasycarpine, 11, x 53 Pleiocarpamine derivative Fluorocarpamine (yhindoxyl), CCCXLVII, H 48

285-287

+54O(w)

Vol. VIII; 30

19 1

-65'(p)

24

252-255

+16Oo(c)

12, 51

245 decomp. 201

+106'(p)

42 55d

- 54.5"(m)

CzlH27CINzOz CzoHzzNzOz

275-280 +56'(m,w) 30, 30a 110-112 (hydrate, 80-83) +103O 52

CZZHZ6NZ04

Amorph.

-168'(~)

86

CziHz6Nz04

207-209

-lOl"(c)

2

Cl0HzzNz03

Amorph.

48

Part 13. Alkaloids of unknown structure' Pachysiphine, L 55 Hydrochloride Vallesia dichotomu, alk. 5, c 12 V . dichotoma, alk. 21

CZlH24N203 CzoHzsNz M + , 338

Amorph. 163 Amorph. 145-149

-455'(m)

55

-550(c)

12 12

Y

V . dichotoma, alk. 25 V . dichotoma, alk. 26 Melodinus australis, alk. 7 M . australis, alk. 8 M . australis, alk. 9

C23HZ8xZ07 CZZHZ6NZO6 CzoHz4NzOz CigHzzNzO

134-136 decomp. 209-210 decomp. 186-1 95 170-175 2 14-2 16

+88"(c)

+112"(c) +177"(c) -421"(~)

12 12 19 19 19

10 The following alkaloids described in Table I Volume VIII, p. 388 seq., or elsewhere in Volume V I I I have been isolated from new sources ; H 4 8 ; (+)-1,2-dehydroaspidospermidine, H 48, b 19c; as indicated: (-)-quebrachamine, a 1 9 ; (+)-quebrachamine, i 19a, b 1 9 ~rhazidine, aspidospermidine, H 4 8 ; N-acetylaspidospermidine,R 34; 17-methoxyaspidospermidine (deacetylaspidospermine), c 12 ; 17-hydroxyg N-acetylaspidospermidine (demethylaspidospermine), D 42; 0-demethylaspidocarpine, e 24; aspidocarpine, e 24, f 25, R 34 ; N,-acetyl2 N,-depropionyllimaspermine (limapodine), P 61b; aspidolimidinol (16-methoxylimapodine), P 61b; vincadifforrnine, c 1 2 ; kopsinine, i 19a, j 29; pleiocarpine, i 19a; pleiocarpinine, i 19a; N-acetylaspidoalbidine, c 1 2 ; haplocidine, c 12, Y 55c; 17-methoxy-N-acetylaspidoalbidine (0-methylhaplocidine),c 12; aspidolimidine, P 61b; dichotamine, e 12; 19,20-dihydrocondylocarpine(tubotaiwine), c 12; condylocarpine, a 19, c 12; stemmadenine, a 19, c 12, D 3 4 ; uleine, v 34, S 34; dihydrouleine, S 34; ellipticine, G 47; pleiocarpamine, H 48, c 1 2 ; pleiocarpamine methochloride, k 30; 10-methoxydihydrocorynantheol,U 34, X 556 ; hunterburnine-p-methochloride,k 30, G 47 ; u hunterburnine-a-methochloride,k 30; yohimbine, f 25, D 42, X 55b, Y 55c, E 55d; 8-yohimbine, D 42, X 55b, Y 55c; pseudoyohimbine, f 25; isoreserpiline, G 47; N,-methylisoreserpiline, G 47; reserpiline, 1 3 4 , R 34; carapanaubine, 1 3 4 ; akuammidine, a 19, g 26, H 48, Q 66; p N,-methylakuammidine, M 51a; picraline I 34; deacetylpicraline I 34; ajmaline, M 51a; tabersonine, W 55a, aa 22a; macusine-B, k 30n; normacusine-B, X 556; compactinervine, X 55b; 10-methoxy-19,20-dehydrodihydrocorynantheol, X 556 ; 0-acetylyohimbine, E 55d; M U Z 55e ; cylindrocarpidine, ff 19d; callichiline, N 98'. ( )-guatambuine,Z 55e; N-methyltetrahydroellipticine, Plant sources: a, Melodinus australis ( F . Mueller) Pierre; b, Vinca minor L.; c, Vallesio dichotoma Ruiz et Pav.; d, Catharanthus rosew G. Don= Vinca rosea L. = Lochnera rosea Reichb.; e, Aspidospermu spp.; f, A . oblongum A. DC.; g , Melodinus scandens Forst.; h, Pleiosirpa tubicina Stapf.; i, P. pycnantha (K. Schum.) Stapf. var. tubicina (Stapf.) Pichon; j, Alstonia venenata R.Br.; k, Pleiocarpa mutica Benth; 1, Hunteria eburnea Pichon; m, Aspidosperma macrocarpon Mart. ; n, A. Duckei Hub. ;0,A . verbascifolium Mull.-Arg.; p, A.fendleri Woodson; q, Haplophyton eimicidum A. DC.; r, Aspidosperma exalatum Monachino; s, A. neblinae Monachino; t, A . obscurinervum Azambuja; u, A . megalocarpon Mull.-Arg.; v, A . tomentosum Mart.; w, A . limae Woodson; x, A. dasycarpon A. DC.; y. A . olivaceum Miill.-Arg.; z, A. gomeziaiaum A. DC. ; A, A. eburneum Fr. Allem. ; B, A . multiflorum A. DC. ; C, A . australe Mull.-Arg. ; D, A . pyrieollum Miill.-Arg. ; E , A . excelsum Benth.; F , A . dispersum Miill.-Arg.; G, Ochrosia sandwicensis A. DC.; H, Gonioma kamassi E. May; I, Aspidosperma rigidum ( A .1axiJorum Kuhlm) Rusby ; J, Rhazya strieta Decaisne; K , Voacanga afiicana Stapf; L, Taber~naemontana(Conopharyngia)pachysiphon Stapf.; M, A. spegazzini Molf. ex Meyer; N, Hedanthera (Callichilia)burteri (Ho0k.f.) Pichon; 0 , T . amygdal~oliaSieber ex A. DC.; P, A. album (Vahl) R. Benth.; Q , A . quebracho-blamo Schlecht.; R, A. marcgravianum Woodson; S, A. nigricans Handro; T, Rejoua aurantica rn a

9

P 8

z

'

k s F1

2

TABLE 1-continued

ca w

Q,

Gaudich; U, A. nitidum Benth ex Mull.-Arg.; V, Conopharyngia longijlora Stapf; W, G . durissima Stapf; X, A. pruinosum Mgf.; Y , A. discolor A. DC.; 2, A . uargasii A. DC.; aa, Vinca herbacea W.K.; bb, Catharanthus lanceus (Boj. ex A.DC.) Pichon; cc, Conopharyngia holstii Stapf; dd, Schizozygia caffaeoides (Boj.) B a a . ; ee, Aspidosperrna subincanum Mart. ; ff, Tabernaemontana amygdalifolia Sieber ex A. DC. Rotation in ( c )chloroform; (d) dioxane; (e) ethanol; (ea) ethyl acetate; (m) methanol; (w) water; (p) pyridine. Pachysiphine, amorph, [a]=-455”(m), may be a stereoisomer of this structure ( 5 5 ) . The name “obscurinervane” refers to the dihydroobscurinervine skeleton unsubstituted at 14, 15, 16 and 22. f The name “dasycarpidane” refers to the skeleton

W

Includes alkaloids with one moiety of Pleiocarpa or Aspidosperma type, excepting Vinca alkaloids for which see Chapter 12, Volume VIII and Chapter 5 of this Volume. Some double alkaloids of unknown structure are included. This list has been limited to a few well-defined alkaloids from the genera under discussion or of other genera, where an aspidospermine type structure is possible.

8

9. Aspidosperma

217

AND RELATED ALKALOIDS

dispersion (ORD) curves since the main Cotton effect observed with extrema a t 264 mp and 236-238 mp is due to perturbation of the Nacyldihydroindole chromophore and therefore controlled by the stereochemistry a t positions 12 (7 in X I ) and 2. Since the relative configurations of many alkaloids were already known (Volume VIII) the use of ORD in conjunction with a number of interrelation sequences has now permitted the assignment of absolute configurations t o the majority of known naturally occurring representatives of the aspidospermidine (XII) and aspidospermatidine (XIII) groups (59; see also 19b, 60, 61). I n general H

H

’

Ac

IX

VIII

k (-)-X; R = H (+)-XI;R=Ac

a positive Cotton effect for an N,-acyldihydroindole indicated that C-11 is /I (as in VIII) or C-6 i s (as in X I ) and is characterized by a peak in the region 262-278 mp and a trough a t 224-247 mp varying with the position of the ultraviolet absorption band in the 250-265 mp region. A negative Cotton effect in the same region naturally indicates the opposite stereochemistry. Alkaloids derived from XI1 unsubstituted or bearing 0-acetate or methoxyl a t position 17 (in VIII) had 4 values generally in

l7

H XI1 Aspidospermidine

XI11 Aspidospermatidine

218

B. GILBERT

the range 20,000"-35,000' a t the longer wavelength extremum and above 50,000" a t the shorter wavelength. The presence of OH a t this position reduces the amplitude markedly and may introduce a shouldek a t about 240 mp. All of the compounds examined exhibit a weak Cotton effect corresponding to the UV-absorption at 285-290 mp. The sign of this is reversed on passing from 17-OH to 17-OAcor 17-OMe.Thus it is positive for ( + )-aspidolimidine (XIV) but negative for its O-acetyl and O-methyl

Me0

Q-d Q;& I H

H

Me0

/ " c

R

H... oH 'CH3 (

+ )-XIV

(-)-XV;R = A c ( +) - X V III; R = H

(-)-XVI Quebrachemine

derivatives. This Cotton effect which has no bearing on the C-2, C-12 stereochemistry is responsible for the observed sodium D-line rotation whose variations have been related to (3-17 substitution (Volume VIII, p. 416). It is presumably dependent upon the orientation of the N,-acyl substituent (59). The stereochemistry a t position 12 for a number of aspidospermidine-derived alkaloids is given in Table 11.For compounds that have already been related to (-)-aspidospermine (XV) the configuration at positions 2 , 5, and 19 follows (Volume VIII). The absolute configuration of quebrachamine (XVI) already related to that of aspidospermine (XV; see Volume VIII) has been firmly established by oxidative cyclization (mercuric acetate in acetic acid or potassium permanganate in dimethylformamide) of both enantiomers t o 1,2-dehydroaspidospermidine(XVII) of the opposite rotational sign, followed by reduction to aspidospermidine (XI1; 19b, 58). The similarity in the IR- and NMR-spectra as well as the ORD-curves of ( + )-XI1 and

9. Aspidosperma

219

AND RELATED ALKALOIDS

TABLE I1 ABSOLUTE CONFIGURATION OF SOMENATURALLY OCCURRING ASPIDOSPERMIDINE DERIVATIVES 12a(C-ll),5a(C-20)

Ref.'

12a(C-11),5a(C-20)

Ref."

+ +

( - )-Quebrachamineb ( ) - 1,2-Dehydroaspidospermidine ( )-Aspidospermidine

*, 58 *, 60 *, 59

( )-Quebrachaminel 60 ( )-17-Methoxyquebrachamine *,' 61 ( - )- 1,2-Dehydroaspidospermi-

( - )-Demethoxypalosine ( )-N-Deacetylaspidospermine ( -)-Vallesine ( -)-Aspidospermine ( )-Demethylaspidospermine ( -)-Palosine (+)-Aspidocarpine ( )-Aspidolimine ( -)-Pyrifolidine ( )-Limapodine ( )-Limaspermine ( )-Spegazzinidine ( -)-Cylindrocarpidine ( - )-Cylindrocarpine ( )-Haplocidine

+

*, 59 *, 61 *

+

59 59

( )-Pyrifolidine ( )-Vindoline ( -)-Vincadifformine ( - )-Tabersonine ( -)-Minovincine ( -)- 16-Methoxyminovincine

+ +

+

* *, 59 59

*

+ + +

* * *

+

* * *

( + )-Haplocine ( )-Aspidoalbine ( - )-Dichotamine ( -) -Neblinine ( -)-Obscurinervidine ( -) -0bscurinervine

+

+ +

dine

( -)-Minovincinine ( -)-Lochnericine ( -)-Lochnerinine

60

*

62

* *

63 63

63 61

61

*

37

*

37 37 37

Reference to chemical correlation with alkaloid of known absolute configuration or to direct determination by ORD or X-ray crystallography; asterisk (*) indicates that this was described in Volume VIII, Chapter 14. No asymmetry at (2-12. Correlation made with (-)-enantiomer.

( + )-deacetylaspidospermine (XVIII) which is derived from ( - )aspidospermine (XV) leaves no doubt that the configuration of ( + )-XI1 is C-2-m-H,C-lB-fl-H,C-5-fl-Et (Sl),and the above cyclization is therefore

(

+ )-XVII

220

B. GILBERT

stereospecific, the stereochemistry a t C-12, C-2, and C-19 being determined uniquely by that a t C-5 in quebrachamine (XVI; 58). Even when inversion a t C-5 could occur during thereaction byway of an allylic cation, as in the series VII+XX it does not (58, 64).

VII

XIX

I

2 steps

xx B. QUEBRACHAMINE DERIVATIVES The alkaloids vincaminorine (XXI) and vincaminoreine (XXII) have + )-quebrachamine isobeen shown to be 3-carbomethoxy-N,-methyl-( mers (cf. Volume V I I I ; 15).Further evidence in support of this has been XXI; XXII; XXIII;

R Me Me H

COzMe U

B

B

published ( 1 1 , 1 3 , 6 5 ) Ready . hydrolytic decarboxylation of either alkaloid to ( + )-N,-methylquebrachamine limits the carbomethoxyl group to positions 3 and 11, and position 3 may be chosen for both on biogenetic grounds and from mass spectral breakdown. Vincaminorine has the C-3 proton strongly deshielded a t 6.25 ppm compatible with a conformation in which this atom is compressed onto N,.Such a conformation may be constructed when the carbomethoxyl

9. Aspidosperma

AND RELATED ALKALOIDS

221

group is cis to the ethyl side chain as in XXI. The resulting hindrance of N , could also account for the low basicity of vincaminorine (cf. Trojhek et al., 11). Since vincaminorine and vincaminoreine are interconvertible under alkaline conditions which permit epimerization at position 3, structure XXII may be allocated to the latter, which is also the more stable thermodynamically (11, 13). Vincadine (XXIII) is N,-demethylvincaminoreine (13, 65) and vincaminoridine (XXIV) is 16-methoxyvincaminorine (65).

I

Me

XXIV

COzMe XXIVE Voaphylline = Conoflorine

The structure of voaphylline ( 5 4 ) , also named conoflorine (65a),has been shown to be XXIVa (65a, 65b), possibly identical with XCVI (Section 11,F). Rhazidine (Volume VIII, p. 505) in the form of its chloride has been shown to be the quaternary derivative (XXV) of the 12-hydroxyindolenine (XXVI; Volume VIII, p. 358) which is obtained by oxidation of quebrachamine (XVI) (66). In neutral and acid solution the UV-spectrum (A 236, 293 mp) corresponds to a dihydroindole (neutral spectrum), in strongly alkaline solution or in heptane a hydroxyindolenine spectrum (A22210,281,292, 307 mp) is observed. The facile ring closure of XXVI at first caused a misinterpretation of the experimental results (66a) although it was known that the 12-hydroxyindolenine (XXVI) and its acetate (XXVII) could be readily obtained from rhazidine and reduced with LiAlH4 to ( - )-quebrachamine.

xxv

XXVI; R = H XXVII; R = A c

222

B. GILBERT

C. SYNTHESES

A number of new syntheses of the aspidospermine skeleton have appeared. One of these by Y. Ban and his co-workers is quite similar in general approach to the Stork synthesis (Volume VIII), although no common intermediates were involved (67). Methyl propyl ketone condensed with 2 moles of acrylonitrile t o give the bisnitrile XXVIII. Simultaneous partial hydrolysis and ring closure gave the unsaturated keto amide X X I X with UV-absorption a t 284 mp ( E , 36800). Hydrogenation under alkaline conditions gave a single hydroxylactam (XXX) in which the relative stereochemistry is unknown at two positions, although the rings are thought to be cis-fused. Acid hydrogenation gave the lactams X X X I and X X X I I but an epimeric hydroxylactam (epiXXX) was obtained together with X X X under neutral hydrogenation conditions. Both epimers on carrying through the series XXX+ XXXIII-tXXXIV gave the same keto amine XXXIV showing that there was no difference in stereochemistry a t the ring junction. XXXIV differs from Stork’s intermediate (Volume VIII, p. 366, formula XXX-G) which is therefore presumably trans-fused. From this point on the synthesis follows that of Stork through the stages XXXIV+XXXIX+( & )XV, but due to the different stereochemistry identical products were only obtained on reaching ( )-deacetylaspidospermine (XVIII). (Note that X L is a by-product formed following enolization of XXXVIII away from the ring junction.) Although no change of stereochemistry is implied in Ban’s synthesis the fact that the final product (XVIII) is identical with that obtained by Stork and Dolfini results from the indolenine-indole equilibrium involving reversible cleavage of the C-12, C-19 bond of X X X I X (or its stereoisomer, see Volume VIII, p. 366, formula XXX-K). I n fact all four amorphous stereoisomers of the key intermediate XXXVII are known, and by way of this equilibrium all may be converted into ( 2 )-aspidospermine (XV) in which the preferred stereochemistry is taken up. Stork’s intermediate is XLI (67)with the C-19 hydrogen atom trans t o the (2-12 atom, the C-5 ethyl group, and the nitrogen lone pair. NMR-studies showed that Ban’s previous intermediate XXXVI had the C-19 proton trans to that a t C-12 (J12,19 = 10 cps), whereas the absence of IR-absorption a t 2700-2800 cm-1 in XXXVII [and its o-methoxyphenylhydrazone (XXXVIII)] showed that in this isomer the C-19 hydrogen is cis to the nitrogen lone pair. The other two isomers, XLIX and L, were prepared in quite a different manner by Kuehne and Bayha (68). Their synthesis starts with proline ethyl ester (XLII) which by way of N-alkylation to XLIII and Dieckmann cyclization gave the unstable

9. Aspidosperma

223

AND RELATED ALKALOIDS

XXVIII

HO &-HO&O H H

XXIX

H H

xxx

XXXIII

I

R

H h H

o

XXXI; R = O XXXII; R = Hz

Oppenauer

J.

@ f

f

0

0 H H

xxxv

XXXIV

XXXVI

1

:,liy. \

N'

Me0

XXXIX

XVIII

-%=OAc

-o@

QNHJ@ Me0

XXXVIII

I

XL

XXXVII

XLI

224

B. GILBERT

keto amine (XLIV).A Wittig synthesis gave XLV but the double bond could not be isomerized directly to the a$-enamine position and XLV was therefore hydrogenated to the amine (XLVI) which could then be oxidized to the enamine (XLVII). The third ring was introduced in a single step condensation with methyl acrylate to give the vinylogous amide (XLVIII, h 325 mp) which could be reduced selectively to either of the isomers XLIX and L with cis hydrogen atoms a t C-12 and C-19. Both could be converted in the manner described to ( f )-aspidospermine (XV) or ( )-quebrachamine (XVI; 68). Biogenetic synthesis of the aspidospermine skeleton requires the O preparation of an intermediate with the skeleton of the C ~ mevalonatederived unit from which the aliphatic carbon skeleton of rings C and D is built and its subsequent condensation with tryptamine. Such a

6 XLII

XLIV

XLIII

9 9 I

PhsP4HCHs

~

Me0

ck

XLVII

5 3

XLVI

XV and XVI

0

XLVIII

XLV

H' L

9. Aspidosperma

225

AND RELATED ALKALOIDS

synthesis has been achieved very simply (7‘). A C ~ compound O of the correct skeleton was obtained by alkylation of the pyrrolidine enamine of Stork’s intermediate (LI) with ally1 bromide. The product (LII) readily condensed with tryptamine to give the lactam (LIII). This could be cyclized in the desired manner by the action of boron trifluorideetherate to give a product whose UV- ( A 265 mp, E 5180) and NMR-spectra (no olefinic proton) were compatible with the indolenine structure (LIV). LIV could be reduced dirsctly (LiAlH4) or via the 8-lactam (LV) to 3-methylaspidospermidine (LVI) which on acetylation yielded the

&-&

P

CHO COzMe

R~

CHs

CHs.

LIV R I Rz

T

% + L 1 >

-HZ

LV H 0, LVI H Hz LVII AC Ha

_ j

CHO COzMe

/

LII

6 LVIII

& & LIII

\

N’

__t

MeOzC

LX

N

I

LXI

T LIX

\

Ri

LXII LXIII LXIV LXV

R1 H H H Ac

RE

Ra

Ra

OMe 0 H 0 H HZ H He

226

B.

GILBERT

N,-acetyl derivative (LVII). The mass spectrum of LVI and the NMRspectrum of LVII support the structures assigned ( 7 ) .A similar synthesis using the cyclic intermediate (LIX) prepared from 1,2,5,6-tetrahydrobenzaldehyde (LVIII) gave, in a similar manner, the hexacyclic indolenine lactani (LXI). The methanol adduct (LXII) was successively reduced as before to the indoline 8-lactam (LXIII) and hence t o the aspidospermidine derivatives LXIV and LXV (69). I n both syntheses apparently only one stereoisomer was obtained as final product. Either synthesis could be modified to give derivatives of the eburnamine skeleton ( 7 , 6 9 ) A . similar route has more recently been used to synthesize ( )-apidospermidine (XII) itself (69e). Investigation into the final step involved in the biosynthesis of the aspidospermim and iboga alkaloids led to another general synthetic route t o the aspidospermidine alkaloids (8).The conversion of dihydrocleavamine (4c(-H, VII) to 7P-ethyl-5-desethylaspidospermidine (XX) and thence to its N-acetyl derivative (VIII) was mentioned in Section II,A. I n parallel work carbomethoxydihydrocleavamine (4/3-H, LXVI) (for difference of configuration a t C-4, see Gorman et al., 69a) was con-

_. H

k VII

XX: R = H VIII: R=Ao

\

LXVI 2.s"

-- H

'-H

H

I

COzMe

R LXIX; R = H LXX; R = A c

LXVIII

LXXI

9. Aspidosperma

227

AND RELATED ALKALOIDS

verted t o the isomeric derivatives LXIX and LXX which probably differ from XX and V I I I only in the epimeric 7-configuration (69b). I n this case the first product obtained with the aspidospermidine skeleton was ( - ) -pseudovincadifformine (LXVII) whose strong negative rotation indicates the C-12 configuration shown. The mass spectra of this compound and its derivatives LXIX and LXXI (69c)leave no doubt of their

-I'-v

EtOzC EtOzC

OCHzPh

EtI NaOEt

EtOzC

OCHzPh

EtOzC

LXXII

LXXIII

-

EtOzC

P O C H Z P h LXXIV

ArCHeCOeEt PhsCNa

EtOzC

'OzEt

OCHzPh

LXXV

LXXVI

i

LiAlH4

\ LXXVII

&

LXXVIII ; R = CHzPh LXXIX; R = H

F~sozclz

H

( * )-XVI

LXXX

L

228

B.

GILBERT

aspidospermidine skeleton. Relatively strong M- 1 and m/e 190 peaks in the spectra of X X and LXIX are perhaps related to the different location of the ethyl group but in general the differences registered between the mass spectra of the 5- and 7-ethyl series are too small for safe distinction. Some doubt therefore exists as to the location of this group in naturally occurring alkaloids whose structures are based solely on this spectrometric method. Subsequent total synthesis of ( ~fr)-dihydrocleavamine (4a-H,VII) constitutes a total synthesis of X X (69d). The route used in this total synthesis was also applied (8)to the synthesis of ( & )-quebrachamine (XVI)whose conversion to aspidospermidine (XII) has been described (Section 11,A). Diethyl y-benzyloxypropylmalonate (LXXII) was ethylated to the malonate (LXXIII) which by hydrolysis, decarboxylation, and reesterification gave ethyl a-(y-benzyloxypropy1)butyrate (LXXIV).Alkylation with ethyl bromoacetate gave a product (LXXV) in which the entire nontryptaminic skeleton of aspidospermidine is present. Condensation with tryptamine gave the succinimide (LXXVI) whose carbonyl groups were reduced with lithium aluminum hydride to give the amine (LXXVII). This product, oxidized to an imine by mercuric acetate, underwent ring closure on the desired side of N b (the other side being more hindered), as was established by NMR-spectroscopy (C-19 singlet), to give LXXVIII. The benzyl group was removed and the resultant alcohol (LXXIX)converted to the quaternary salt (LXXX) by mesylation. An Emde reduction of this resulted, as was t o be expected, in c-3, Nb cleavage to give ( & )-quebrachamine (XVI) (8).

D. SIMPLEASPIDOSPERMIDINE DERIVATIVES A number of alkaloids representing new variations in substitution of the aspidospermidine skeleton have been isolated (Table I).Among these are O-demethylpalosine (LXXXa ; 6 f a ) and the 2 l-hydroxyderivative, N-acetyl-N-depropionylaspidoalbinol(LXXXb ; 61b). The structures of these compounds were determined largely by NMR- and mass-spectrometry as described in Volume VIII, followed by interrelation with known alkaloids. 1O-Oxocylindrocarpidine (LXXX1) is another recent addition to this group (f9d). The reisolation of a number of simple aspidospermidine derivatives, previously found in A . quebracho-blanco Schlecht (Volume VIII), has been reported from Vallesia dichotoma Ruiz et Pav. ( 1 2 ; Table I). Alkaloid 5 from this plant has a mass spectrum similar to that of N,methylaspidospermidine (LXXXc) but differs from this alkaloid in having the C-21 terminal methyl triplet a t 0.88 instead of 0.6 ppm. The

9. Aspidospema

AND RELATED ALKALOIDS

229

Qf& MeoQ~-CH~OH Me0

OH

,'

OH

COEt

LXXXa

Ac LXXXb

I H

Me

LXXXC

LXXX 1

NMR-spectrum also excludes the possibility of a 7-ethyl isomer (LXXXd) by comparison with the two known N,-H isomers (XX and LXIX). The C-19 epimer (LXXXe) of N,-methylaspidospermidine also proved to be spectrally different (strong M- 1 peak in mass spectrum). LXXXe was synthesized from N-acetylaspidoalbidine (LXXXf) via the intermediates LXXXg to k. As previously shown (Volume VIII, p. 450) reduction of the carbinolamine ether of aspidoalbidine derivatives gives both 19-epimers (LXXXi and j) (12).

CHzOH

I

R

I

I

Me

LXXXF; R = A c LXXXg; R = H LXXXh; R=CHO

CHzOR

i-

Me

LXXXi

R

LXXXd; R=Me X X ; R = H , 8-Et LXIX; R = H , or-Et

LXXXj; R = H LXXXk; R = T s

Me LXXXe

230

B. GILBERT

E. THE VINDOLINEGROUP As indicated in Table 11 (Section I1,A) the absolute configuration of natural (+)-vindoline (LXXXI) has been shown t o be the opposite of that represented in Volume V I I I , by X-ray analysis of leurocrystine methiodide (62).Leurocrystine (LCR = vincrystine), a double alkaloid formed from N,-demethyl-N,-formylvindoline (LXXXII) and velbanamine, has been related to VLB (vincaleukoblastine = vinblastine), derived similarly from vindoline (LXXXI) and velbanamine (Volume VIII, and Chapter 5 this volume ;3 , 7 1 , 7 2 ) .The correlation of cleavamine of known absolute configuration (Section I1,A) with vincaleukoblastine provides independent confirmatory evidence (7'0). Vindorosine (LXXXIII) has been shown, mainly by physical methods (including NMR- and ORD-data) to be demethoxyvindoline (20).Deacetylvindoline (LXXXIV,20a) and catharosiiie (deacetylvindorosine, LXXXV ;18)

LXXXI LXXXII LXXXIII

Ri

Rz

OMe OMe H

Me Ac CHO Ac Me Ac

Ra LXXXIV LXXXV

Ri

Rz

RB

OMe H

Me Me

H H

have also been found naturally (Table I).A review of the chemistry of vindoline and derived double alkaloids may be found in Neuss et al. ( 7 2 ~ ) . Microbiological deacetylations as well as reduction of the 6,7-doubie bond have been reported (72b). Two double alkaloids whose structures have been the subject of recent study are leurosidine (vinrosidine= VRD) (7%) and Catharine (72d), and synthetic approaches t o such alkaloids have been reported (72e).

F. THE VINCADIFFORMINE GROUP The structures of a number of alkaloids related to vincadifformine (LXXXVI) have been determined, Among these ervamine (LXXXVIII

9. Aspidosperma

23 I

AND RELATED ALKALOIDS

is a stereoisomer of this compound a t position 5 (20b).Many alkaloids are functionalized a t positions 6 and 7, and among these are the pair lochnericine (LXXXVIII) and lochnerinine (LXXXIX) from Vinca Tosea (Volume VIII, Chapter 12). Lochnericine, CzzH26N203, already known to contain the /3-anilinoacrylate chromophore, was shown by modified Kuhn-Roth oxidation to have a C-ethyl group but resistance to catalytic hydrogenation excluded a double bond (20).The ethyl group was confirmed by a distorted triplet in the NMR-spectrum a t 0.79 ppm,

LXXXVI

LXXXVII

xc

while an N-H absorption a t 8.93 ppm located the active hydrogen atom (20,22)on N,. Four aromatic protons and a methyl singlet a t 3.76 pprn confirmed the partial structure XC. The remainder of the structure follows from mass spectral data obtained with a series of transformation products, which could be interpreted in terms of a vincadjfformine-like structure. I n the first place, the remaining oxygen atom, thought t o be ethereal since no hydroxylic or lactonic properties were observe& was located in ring D, since, in the mass spectrum of lochnericine, the base peak attributable to the D ring, appeared a t m/e 138 (fragment c ) , The mass spectra of two dihydroindoles (XCI) and (XCII) obtained by zinc-sulfuric acid methanol reduction, confirmed the location showing c peaks a t m/e 138 and 170, respectively. The NMR-spectrum o f lochnericine showed no absorption in the range 3.80-5.80 ppm and oxygen substitution a t C-8 could therefore be excluded while a Bohlmann band a t 2815 cm-1 was indicative of a hydrogen atom on (2-19 trans to the lone pair on N,. The oxygen atom is thus limited t o an eyoxide grouping at C-6 and C-7 and lochiiericine may be formulated as LXXXVIII. I n agreement with the postulated epoxide structure lochnericine was converted to an unsaturated hydroxyzcetate (XCIII) on heating with glacial acetic acid and to a reduced hydroxyacetate (XCIV) with zinc and acetic acid. Lochnericine underwent the familiar loss of COzMe on hydrolysis with 5 N hydrochloric acid to give an indolenine which could be reduced with alkaline potassium borohydride to an indole. Although these products

E.3

w

E.3

'./

ROAc,

\

H COzMe

2.

/

xcv p

mlon

COzMe Ri XCII OH or OMe X C N OHorOAc

LXXXVIII; R = H LXXXIX; R = OMe

XCIII; R1 =OH or OAc, Rz=OAc or OH H

H

COzMe

1. 5N HCI, 125"

XCI

N

4

/

c

138

Rz OMe or OH OAcorOH

9. Aspidosperma AND RELATED

ALKALOIDS

233

were not fully characterized, sufficient IR-, and UV-, and mass-spectral evidence was accumulated to permit allocation of the structures XCV and XCVI (6,7-epoxy-(+ )-quebrachamine) to them (21, 22). Lochnerinine (LXXXIX) was shown to be an aromatic methoxylochnericine by the 30 mass unit shift of the indolic peaks in its mass spectrum as compared with those of lochnericine (22). Reduction with zinc and acetic acid gave a dihydroindole whose UV-spectrum was closest t o that of 7-methoxyhexahydrocarbazoleand the methoxy group was therefore placed a t the 16-position (21, 22). Lochnerinine is the epoxide of 16-methoxy-(- )-tabersonine with which it co-occurs in Vinca herbacea (22a).

G. 20-OXYGENATED DERIVATIVES O F VINCADIFFORMINE The 20-oxygenated vincadifformines, ( - )-minovincinine (XCVII) and ( - )-minovincine (minoricine, XCVIII), were mentioned in Volume VIII (63) and their interrelation and correlation with vincadifformine (LXXXVI), vincadifforminane (XCIX), and vincadifforminol (C) are shown in the formulas. To their number have now been added ( - )-20acetoxytabersonine (CI) (26), the enantiomeric dihydra. derivative, ( + )-echitovenine (CII), and 20-(~,/3-dimethylacryloxy)-vincadifformine or ( - )-echitovenidine (CIII) (23).Also a dextrorotatory ( + )-minovincinine (CIV, not necessarily an enantiomer of XCVII since the 20stereochemistry of both is undehermined) has been isolated and shown to be 20-deacetylechitovenine (23). The UV-spectrum of ( +)-echitovenine (AmiLx 228, 298 and 328 mp) in conjunction with characteristic IR-absorption (1610, 1670 cm-1) revealed the presence of the /3-anilinoacrylate chromophore while a n IR-peak a t 1728 cm-1 indicated a further ester grouping. The mass spectrum showed peaks corresponding t o those of the known ( -)-20acetoxyvincadifformine (CV; Volume VIII, p. 377) (63) and these may be enantiomers although no comparison seems to have been made. Reduction of the 2,3-double bond of echitovenine t o give CVI followed by dilute sulfuric acid treatment gave a compound for which structure CVII was proposed (without stereochemical implications) on the basis of the principal mass spectrometric peaks which were found a t m/e 324, 253, and 194 (interpreted as the molecular ion and fragments a and b , respectively). The ready formation of such a six-membered lactone was taken as evidence of oxygenation a t C-20 rather than C-21 leading to structure CII for echitovenine (29). The stereochemistry represented in CVII seems the least strained from models and it is possible that all the

XCVIII ( -)-Minovincine

\

WolffKishner

LXXXVI Vincadiff onnine

XCVII

o:;5'-l \

21

COzMe R CI;* OAc CV;* OAc

XCIX; R=CH3 C; R =CHzOH

( - ) -Minovincinine

\

COzMe 6,7

A dihydro dihydro

*

R CII;* OAc C N ; * OH Stereochemistry at 12 follows from rotation. Other stereochemistry is probable but rigid evidence seems to be lacking.

9. Aspidosperma

AND RELATED ALKALOIDS

235

principal stereochemical features of this interesting derivative, including the configuration a t C-20, could be elucidated by NMR-spectroscopy. Hydrogenation of the 6,7-double bond of ( - )-2O-acetoxytabersonine (CI) gave ( - )-echitovenine (26).

CVI*

CVII* M+ 324

H

a mfe 253

b mle 194

* See footnote to preceding formulas. Echitovenidine (CIII),like echitovenine, from AZstonia wenenata R.Br., had the same spectral characteristics of the /&anilinoacryIate chromophore, again with an additional carbonyl peak in the IR-spectrum at 1705 cm-1 compatible with an a$-unsaturated ester group. The mass spectrum showed the empirical formula to be C Z ~ H ~ Z N with Z Othe ~ base peak a t m/e 222. On the basis of a vincadifformine-like structure this 2 peak would correspond to the D-ring fragment with a C ~ H 7 0 substituent weighing99massunits. M- 99andM- (99 28)peakswereinfactpresent and peaks a t m/e 122, 123 corresFond to loss of 99 and (99 + 1)units from the base peak. Since zinc and acid reduction followed by hot aqueous acid treatment gave a lactone (the enantiomorph of CVII) similar to that obtained from echitovenine (CII) the substituent could be placed at C-20. It was identified as /3$-dimethylacryloxy by hydrolysis to fl,P-dimethylacrylic acid and by the NMR-spectrum of echitovenidine which showed two non-equivalent dlylic methyl group peaks a t 1.74 and 2.05 ppm with a vinyl proton at 5.14 ppm. The C-21 methyl group appeared as the expected doublet a t 0.95 ppm (23).

+

236

B . GILBERT

H. INTERRELATION OF MINOVINCINE WITH HEXA-AND HEPTACYCLIC ALKALOIDS The transformation of a pentacyclic aspidospermine-type to a hexacyclic one was mentioned in Volume VIII, p. 429, as an as yet unsolved problem and one on which the determination of absolute configuration of the latter type might depend. A manner of achieving interconversion was recognized by Schnoes and Biemann (73)although it was not applied to the correlation of configurations. Minovincine (XCVIII) contains the /3-anilinoacrylate system and is therefore subject t o acid hydrolysis of

XCVIII Minovincine

CXII

CVIII

1

CXIII Aspidofractinine

R R' CIX H H CX D H CXI H D

t h e vinylogous urethane, N-C=C-COZMe, with the loss of the carbomethoxy group and formation of an indolenine of structure CVIII. This indolenine was not isolated, however, since it is subject to ring closure between the activated terminal methyl and the ketimine group, a reaction which forms part of the proposed biosynthetic route for the hexacyclic alkaloids ( 7 4 ) . The structure of the product (CIX) was determined by mass spectrometry to be of the hexacyclic type whose breakdown pattern is well established (Volume VIII, p. 423). I n order to leave no doubt of the structures of fragments observed deuterium labeling was made in three positions (1, 3, and 4) in the derivatives CX, CXI, and CXII. Thus labeling a t N , (position 1, CX), marked the m/e

9. Aspidosperm

AND RELATED ALKALOIDS

237

130 and 144 peaks of CIX as due to indolic fragments since they rose by 1 mass unit, but showed that m/e 109 and 138 were definitely not since they remained unchanged in CX. The structure c which could be assigned to m/e 138 (for formation see Volume VIII) underwent appropriate shifts

c k ’ = H , m/e 138 R’=D, m/e 140

m/e 141

m/e 124

on deuteration at C-3 (CXI), reduction to the monodeuterio alcohol (CXII), and elimination of the C-4 oxygen to give aspidofractinine (CXIII) (73).The mass spectrum of the latter was already known (Vol. VIII). This interconversion was extended by Schmid and his collaborators to the determination of the absolute configuration of the hexa- and heptacyclic groups (74a).

I. VINDOLININE AND TUBOXENINE The structure (CXIV) of vindolinine (from Vinca rosea L.) was presented in Volume VIII. The determination of a structure of such complexity, without the isolation of cleavage products but rather by the very careful establishment of the structures of unisolated mass spectral breakdown products, is illustrative of modern trends in natural product chemistry. Elucidation of mass spectral breakdown requires labeling and vindolinine was labeled in seven positions in a series of over 30 derivatives in which the carbon-nitrogen skeleton is still intact or largely so (75, 7 6 ) . Earlier evidence, elementary analysis, mass spectrometric molecular weight determination, and UV- and NMR-spectrometry established that vindolinine was CzlH24Nz02, a dihydroindole unsubstituted in the benzene ring. One double bond was evident from hydrogenation under neutral conditions which gives dihydrovindolinine (CXV) and from NMR-data which show two vinyl protons. That it was the only one followed from perhydrogenation which further saturated only the benzene ring, and the alkaloid is thus hexacyclic. Among absorptions recognizable in the NMR-spectrum of vindolinine and many derivatives were a dihydroindolic NH (3.7-4.7 ppm), the methyl of the ester group, and a C-methyl group which appeared as a doublet at 0.70 to 1.03 ppm (J= 6.5-7.0 cps) the position and splitting varying with the derivative.

238

B. GILBERT

CXIV CXXIII CXXIV

H H H

COzMe H CH3

CXXVI CXXV

CH3 H

D C

H

H COzMe H

CXVII

cxx

ZCOsMe O A

H

H CHO CH3

CXV

&

~

COzMe CO2Me CHzOH

~

CH3 6OzMe

CXVI

This methyl group, also detectable by Kuhn-Roth, was clearly located on a carbon atom which bore one hydrogen atom. Other evidence may be summarized as follows :

1. Rings D and E The more basic nitrogen atom, N b , lies a t the junction of six- and five-membered rings, D and E, respectively, since permanganate oxidation of N,-formyldihydrovindolinine (CXVII) gives two lactams, one the 8-lactam (CXVIII, minor product, v, 1632 cm-l), the other the 10lactam (CXIX, V , 1670 em-1). No rearrangement occurred during the

CXIX CXXII

CHO CHDz

COzMe CDzOH

=O D

CXVIII CXX CXXI

CHO CH3 CHDz

COzMe CHaOH CDzOH

=O H D

9. Aspidosperma

239

AND RELATED ALKALOIDS

production of CXIX since its reduction with LiAIH4 gave N-methyldihydrovindolininol (CXX), the same product arising by reduction of CXVII. Lithium aluminum deuteride reduction of the two lactams permitted labeling of positions 8 and 10 and the observation of appropriate mass changes in fragments c and d , which evidently come from this part of the molecule (compare CXX, CXXI, and CXXII in Table 111) TABLE I11

CHANGES IN MASS OF FRAGMENTS

n

b

d

C

Fragment Structure

CXIV CXV CXX C X X I and C X X I I

a 93 Absent

b*

107 110

c*

120, 122, 122, 124,

121, 123, 123, 125,

d*

122 134, 135 124 136, 137 124 136 126 138

* Plus or minus one hydrogen atom. (7’6).Changes in the mass of c and d as well as b, are also observed on passing from vindolinine (CXIV) to dihydrovindolinine (CXV) and in addition the fragment a disappears on hydrogenation. The double bond is thus in these fragments whose masses suggest the piperidine ring D fragments of the aspidospermine alkaloids. The 6,7-positions may be allocated to this function since allylic hydrogenolysis of the C-8, N , , bond of vindolinine occurs readily with production of a new methyl group i n CXVI detectable by NMR- and Kuhn-Roth determination. C-5 is quaternary since the NMR-vinyl absorption of vindolinine and many derivatives showed a coupling pattern due to only two allylic proton neighbors, already located on C-8. If the molecule is assumed to contain the usual “tryptamine” moiety, comprising rings A and B, C-11, C-12, and N b , the evidence presented already indicates an aspidospermine-type skeleton with five-membered ring E and six-membered

240

B. GILBERT

D and with a C2 unit t o be expected a t C-5 corresponding to the ethyl side chain of aspidospermine.

2. R i n g s A , B, a n d C A number of mass spectrometric fragments were recognized to contain the indolic portion of the molecule. Some, for example e , did not contain the COzMe group, while others such as f did. Labeling of N , with CH3, CHD2, and CzH5 changes the masses of both types e and f,but changes in the nature of Rz from COzMe to CHzOH, CDzOH, CHzOAc, CDzOAc, CH3, and CHzD (the last by reduction of the tosylate, -CHzOTs) affected only the mass of type f fragments. Two of the nonindolic carbon atoms of fragment e come from the tryptamine bridge C-11 and C-10 since C-10 labeling (see above) causes the appropriate shift in mass. Now the carbomethoxyl group of vindolinine is attached to a carbon atom which also bears one hydrogen atom since it may be epimerized by base [giving isovindolinine (CXXIII)]; when reduced to methyl (as in CXXIV) this methyl group appears in the NMR-spectrum as a doublet (1.2 ppm, J =8 cps). The hydrogen atom thus located CL to the carbomethoxyl may be replaced by deuterium if the epimerization is

Qq!QlO

n&J:

Ri

RI

e

f

RZ

conducted with sodium methoxide in MeOD and in the mass spectrum of the product (CXXV), an increment of one unit in the mass of fragment e (as well as,f)is observed. Thus the carbon atom bearing the carbomethoxyl group is the third nonaliphatic member of e , and most logically would be C-3 in an aspidospermidine-like skeleton. The correctness of this view is borne out by the observation of the NMR-absorption of the C-2 proton in CXXVI as a doublet (3.85 ppm, J = 4.5 cps), indicative of a single vicinal proton.

3. The CH-CH3

Bridge

The above evidence favored a partial structure, CXXVII, in which C-5 and C-12 are necessarily quaternary. On biogenetic grounds therefore

I

the -CHCH3

group must represent C-20,21 of the aspidospermidine

9. Aspidosperma

AND RELATED ALKALOIDS

241

CXXVII

framework and the sixth ring present must be formed by linking C-20 and C-11, if rings smaller than five-membered are excluded. If this bridge has the absolute configuration shown in CXIV (not proved) then a C-3 carbomethoxyl group lying on the opposite side of the molecule would be expected to be axial in a boat ring C and to suffer ready epimerization, as is in fact observed (75, 76). The structure of tuboxenine (CXXVIII) was briefly reported in 3180, 1605, and 739 cm-I), UV-, and Volume VIII, p. 419. I R NMR-(4 aromatic H) data were in accord with a dihydroindole unsubstituted in the benzene ring or on N,. N,-Acetyl-(CXX1X)and N,-formylderivatives (CXXX) were prepared. A notable feature in the NMR spectrum of tuboxenine was the presence of a methyl doublet a t 0.85 ppm (J= 7 cps) comparable with that of vindolinine (CXIV). Tuboxenine did not have the double bond of vindolinine and its molecular formula, ClSH24N2, therefore showed it t o be hexacyclic. A comparison of the mass spectra of tuboxenine and dihydrovindolinine (CXV) showed parallel fragmentation, the peaks a-e of the latter appearing a t the same positions in the former, while the molecular ion peak and peaks such as f containing the COzMe group in dihydrovindolinine appeared 58 mass units lower down in the spectrum of tuboxenine. Tuboxenine is thus decarbomethoxydihydrovindolinine (CXXVIII ; 27). pseudo-Kopsinine is apparently the 2-epimer of dihydrovindolinine ( 76a).

CXXVIII; R = H CXXIX; R = Ac CXXX; R=CHO

242

B. GILBERT

111. The Meloscine Group

The apocynaceous genus Melodinus is a recently discovered member of the restricted group of genera which yield aspidospermine-type alkaloids. The species M. scundens Forst. is particularly interesting since four of its alkaloids have undergone an oxidative rearrangement with expansion of the five-membered ring B to six members with concurrent reduction of ring C to five members. These alkaloids are thus no longer dihydroindoles but dihydroquinolones. Besides akuammidine (CXXXI), ( - )tabersonine (CXXXII) and ( - )-2O-acetoxytabersonine (CI) were found in the plant and are precursors of the meloscine alkaloids ( I ) Of the four other alkaloids present, two, meloscine (I)and epimeloscine (CXXXIII) are epimers of composition ClgHzoNzO. Meloscine contains an o-disubstituted benzene ring (urnax 754 em-1; NMR, 4 aromatic protons) which forms part of an acylaniline chromophore (A,,, 229, 253 with shoulder a t 285 mp, vc0 1672 em-1; NMR; N-H a t 9.5 pprn). Two double bonds present may be readily hydrogenated with the production of tetrahydromeloscine (CXXXIV). One of these is in a terminal viiiyl group (vmax 1640 em-1; NMR,* 5.15, 2 protons; 5.8 ppm, 1 proton), the other cis-disubstituted (NMR, 2 protons between 5.75 and 6.05 ppm). The coupling patterns* showed that the terminal vinyl group (ABC pattern) was attached to a quaternary center, whereas the disutstituted double bond (ABX2 pattern, decoupled) lay between a quaternary center and a methylene group whose far downfield absorption (3.2 in I ; 4.4 in I, MeCl; 3.81, 4.17 pprn in CXXXIII, HC1) showed that it lay adjacent to nitrogen. This information taken in conjunction with a strong m/e 134 peak in the mass spectrum of meloscine, shifting to m/e 138 in tetrahydromeloscine (CXXXIV), suggests the partial structure CXXXV which could give rise to fragment u , reminiscent of aspidospermine fragmentation. The fact that the basic nitrogen atom, N,, lies a t the junction of fiveand six-membered rings was established by oxidation of tetrahydromeloscine (CXXXIV) to a mixture of y (CXXXVI, v,,,,, 1686, 1727 em-1) and &lactams (CXXXVII, vlnax 1680, 1690 cm-1). The six-membered ring may be opened in meloscine methochloride by hydrogenation under alkaline conditions which gives rise t o a series of Emde bases (CXXXVIII) in which one or both of the double bonds has also been reduced. The presence of the sequence CH2-CH2-N in the fivemembered ring could be demonstrated by spin decoupling* and this left only four hydrogen atoms attached to carbon unaccounted for. One of these, absorbing in the NMR-spectrum as a downfield singlet (3.53

* Observed in tho spectra of meloscine methochloride and epimeloscine hydrochloride.

CXXXI

I

CXXXII; R = H CI; R=OAc

CXXXV

\

CHO

H

H cxxxr1r Epimeloacine

CXLI

CXL?

I

\ H CXXXIV

o!P H

CXXXVII

b

COzMe

\

H

1,

CXXXVIII

($p

R=H,m/e214 R = D , m/e 215

H

244

B. GILBERT

ppm) shifting further downfield in N,,-salts (4.5 in meloscine methochloride, 4.77 ppm in epimeloscine hydrochloride) could be placed in part structure CXXXV on C-19. The remaining three protons formed an ABX pattern (AB centered a t 2.5 and X a t 3.3 ppm in ImHCI; decoupled) which persisted in the lactam (CXXXVII). Meloscine (I) contains one hydrogen atom attached to carbon exchangeable by deuterium under alkaline conditions and this must be placed adjacent to the amide carbonyl group on C-3. It is retained in the m/e 214 fragment b in the mass spectra of the Emde bases (CXXXVIII). This hydrogen atom must be responsible for the X portion of the ABX pattern, whose AB protons may be placed on C-4, adjacent to the quaternary C-5. These data are now only consistent with structure I for meloscine. The mass spectra of meloscine (I)and epimeloscine (CXXXIII) are very similar. The latter epimerizes to the former in the presence of a strong base and possesses the same exchangeable hydrogen atom. Models show structure I to be the more stable and it is therefore allocated to meloscine, its 3epimer having the less stable trans-BC junction. Another alkaloid present, termed alkaloid-4, has a carbomethoxy group, removed by sodium methoxide treatment. Acid hydrolysis and decarboxylation gives meloscine (I); on the basis of this result and NMRdata alkaloid-4 may be ascribed the structure CXXXIX. Meloscandine, which accompanies the above alkaloids, may also be converted to meloscine (I)either by heating or base-catalyzed solvolysis. The empirical formula, CzoHzoNzOz, and an extra carbonyl absorption a t 1748 cm-1 suggest a formyl substituent a t C-3 (structure CXL) but the absence of a formyl proton in the NMR-spectrum casts doubt on the monomeric structure. Comparison of the ORD-curves of tetrahydromeloscine (CXXXIV) and tetrahydroepimeloscine (3-epi-CXXXIV) with those of aspidospermidine derivatives (Section II,A ; 59) leads to the probable absolute configurations shown. Biogenetically this group of alkaloids may be derived from tabersonine-like bases by way of an intermediate such as CXLI (1,77).

IV. The Aspidofiactinine Group A. ABSOLUTE STEREOCHEMISTRY AND INTERCONVERSIONS The absolute configurations presented in Volume VIII must now be reversed. Molecular rotation measurements already indicated that the and pleiocorrect absolute configurations of aspidofractinine ((3x111)

9. Aspidosperrna

245

AND RELATED ALKALOIDS

CXIII Aspidofractinine

CXLIIa Kopsine

carpinine (CXLII) were as indicated in the formulas (19b, 60). This was fully confirmed by the correlation of kopsine (CXLIIa) with ( - )minovincine (XCVIII ; 74a), which together with previously described (Volume VIII, p. 421) and the following intercorrelations establishes the absolute stereochemistry of many members of the group.

R

R

OeH

OzMe

CXLVI; R = H CLI; R = M e

CXLIII; R =COzMe CXLIT; R=Me

kOaH CXLVII ;R =H

200"

R

H

CHzI CXLVIII ; R =H CLII; R=Me

CL Kopsene

CXLIX

246

B. GILBERT

( - )-Pleiocarpine (CXLlII).may be converted to kopsinine (CXLV) in two steps via the intermediate monocarboxylic acid CXLIV. Prolonged hydrolysis in aqueous ethanol gives kopsinic acid (CXLVI)together with its 3-epimer (CXLVII). Kopsinic acid on pyrolysis yields in 45 yoyield the heptacyclic ( - )-kopsanone (CXLVIII) a remarkable ring closure which parallels the production of kopsane (CL) from kopsinyl iodide (CXLIX) (Volume VIII, p. 443; see Section IV,F) ( 4 ) . Even better yields of N-methylkopsanone (CLII) were obtained from N-methylkopsinic acid (CLI) or directly from pleiocarpiniiie (CXLII) by heating a t 200" (78). A similar ring closure occurs with pleiomutine (Section IX,B). The reaction is reversible when there is a carbonyl group in position 10 ( 4 ) ;this together with other interrelations within the kopsane group will be described in Section IV,F)

B. PLEIOCARPOLINE, PLEIOCARPOLININE, A N D KOPSINOLINE These three alkaloids occur in two species of Pleioearpa and Hunteria eburnea and were originally attributed the structures CLIII-CLV (32). Although NMR-evidence for the hydroxymethylene group attached to C-3 was not obtained the presence of this group was suspected from the production of formaldehyde on heating pleiocarpoline. Later evidence,

Q-

R

c,Hzvo-~~"

CLIII; R =COzMe CLIV; R=CH3 CLV; R = H

UUZMe CLVI; R = COzMe CLVII; R=CHs CLVIII; R = H

however, which almost certainly relates t o the same alkaloids, showed that the true structures are represented by CLVI-CLVIII (79). This evidence may be summarized as follows. The alkaloids are water-soluble showing that a highly polar group is present ; they readily decompose in methanol (32) or may be reduced catalytically (79) to pleiocarpine (CXLIII), pleiocarpinine (CXLII), kopsinine (CXLV), respectively. Hydride and deuteride reductions gave the same products as are obtained from these last three alkaloids and no new C-C bond could therefore

9. Aspidosperma

AND RELATED ALKALOIDS

247

be present. The aromatic region of the NMR-spectra of the new alkaloids, however, differs from that of the pleiocarpine group in the presence of a downfield double doublet (near 8 ppm, J = 7 and 2 cps) which can be unambiguously ascribed to the C-14 proton since the C-17 proton absorption also downfield in pleiocarpoline (CLVI) shifts upfield when the N-COzMe group is replaced by N-Me or N-H. The highly polar group is therefore close to C-14, that is, in the region of N , rather than C-3. Now the mass spectrum of pleiocarpoline (CLVI), obtained with ion-source inlet, consists of two superimposed spectra, one, that of pleiocarpine (CXLIII) with m/e 396 (M+), 368 (M- 28), 124, and 109 (see Volume VIII), the other, weaker, of a dehydropleiocarpine (CLIX) with 122, and 107. The last two peaks place the double bond of m/e 394 (Mf), CLIX in the D-ring. These two sets of peaks are compatible with an N-oxide structure such as CLVI, being produced by direct loss of oxygen (to CXLIII) or rearrangement to a carbinolamine and loss of water (to CLIX). Confirmation of structure CLVI for pleiocarpoline was obtained

(+$ \

...

.*

COzMe CLIX ; R = COaMe CLX; R = M e

by ferrous sulfate reduction to pleiocarpine and by synthesis from the latter by hydrogen peroxide oxidation. The formaldehyde produced on heating (32) evidently comes from the carbomethoxyl function. Vacuum distillation of pleiocarpolinine (CLVII) gave not only pleiocarpinine (CXLII), 3-epipleiocarpinine, and a dehydropleiocarpinine (CLX), but also N-methylkopsanone (CLII) in the formation of which one mole of methanol and an oxygen atom have been eliminated (79).

C. 10,l1-DIOXOPLEIOCARPINE Another oxidized form of pleiocarpine, which occurs in Pleiocarpa mutica, was shown by high-resolution mass spectrometry t o be

C23H24NzOs (31). Losses of CO, CO+C2H4, and CO+C4H602 were indicative of the presence of a cyclic carbonyl, -CHz-CHzand

248

B. GILBERT

-CH(COzMe)-CHzgroups. No loss of C,H, was recorded and alkyl groups were therefore considered to be absent. The UV-spectrum, although different from that of pleiocarpine, was indicative of an N-acyldihydroindole chromophore and IR-absorption a t 1770 and 1725 showed that a five-membered ketone as well as ester groups were present. Two methoxyl 3-proton singlets appeared in the NMR-spectrum. Lithium aluminum hydride reduction gave two products. Mass spectrometry showed that both were of the pleiocarpine group since the characteristic m/e 124, 110, and 109 peaks were present. The molecular weights, 340 and 326, correspond to the reduction of CO (lactam) t o CH2, CO (ketone) to CHOH, COzMe to CHzOH, and N-COzMe to N-CH3 (340) or NH (326) and the products can be reasonably represented as 11-hydroxy-N-methyl- (CLXI) and 1 1-hydroxykopsinyl alcohol (CLXII),respectively. On this basis the structure of the alkaloid is CLXIII.

CXLIII

pyridine CrOs

aLp6-9 \

. *.

*.

a

+ LiAlH4 \

COzMe COaMe CLXIII

*.,/

R CHzOH CLXI; R = CH3 CLXII; R = H

Confirmatioil of this structure and, in particular, that the lactam carbonyl group is located a t C-10, was obtained by chromic oxidation of pleiocarpine to CLXIII, a reaction which occurs in two steps, the first being the production of the five-membered pleiocarpine- 10-lactam (cf. Volume VIII, pp. 439 and 361-363). The mass spectral breakdown of 10,ll-dioxopleiocarpine (CLXIII) is unusual and the structures a and b may be proposed for its dominant peaks a t m/e 310 and 240, respectively (31).

a 310

b 240

9. Aspidosperma

AND RELATED ALKALOIDS

249

D. d6-KOPSINENE(VENALSTONINE), EPOXYKOPSININE (VENALSTONIDINE), AND HYDROXYKOPSININES The two first-named alkaloids were isolated both from Alstonia venenata R.Br. (29) and from Melodinus australis (F.M.) Pierre (19). UV- and IR-data showed the first, venalstonine, to be a dihydroindole unsubstituted on N , and containing an ester group (29). The NMRspectrum shows four aromatic protons and a carbomethoxyl methyl absorption. I n the vinyl region absorption appears due to two protons on a cis-double bond (19, 29). The mass spectrum differed from that of kopsinine (mol. wt. 338, CXLV) in that many principal peaks were found O Z (M) , 28), at mass numbers two units lower: 336 (M+, C Z ~ H Z ~ N Z308 135, 122, 121, and 107 (compare Section IV,B and Volume VIII, p. 416). The evidence thus indicates that the alkaloid is a dehydrokopsinine and that the double bond is located in the D ring (29).Catalytic reduction in fact gave kopsinine (CXLV). The 6,?-position for the double bond is shown both by its resistance to lithium aluminum hydride reduction which gives d6-dehydrokopsinyl alcohol (CLXV), whose mass spectrum retains the m/e 135-107 series; and by the downfield position, 3.5 ppm, of the C-8 two proton absorption in the NMR-spectrum. The alkaloid is thus d6-kopsinene (CLXIV; 19, 29).

CLXIV k-Kopsinene

CLXV

The second alkaloid, venalstonidine, also a dihydroindole, contains one additional oxygen atom as is shown by its mass spectrally determined molecular weight, 352, which corresponds to the formula C21H24N203.Again IR-(1728 cm-I), NMR-(3.74 ppm), and the mass spectrum (m/e 293, M- 59) showed the presence of a -COzMe function. Absorptions due to four aromatic protons and the dihydrindolic N-H were also present in the NMR-spectrum. The mass spectrum was of the kopsinine (CXLV) type, the difference appearing in the ring D fragments (Volume VIII, pp. 423-426) which were displaced 14 units from m/e 109, 124 to m/e 123 and 138. There is thus either a carbonyl group or an oxide ring in ring D. The alkaloid is not reduced by sodium borohydride

250

B. GILBERT

and quantitative IR-comparison with kopsinine and other alkaloids showed that the carbonyl absorption at 1728 cm-1 is exclusively due to the ester group. A ketone is thus excluded and an ether ring of four or more members is further excluded by the fact that mild LiAlH4 reduction gives a diol, CzoH~6NzOz(CLXVII) with ring D peaks a t m/e 125 and 140. The oxygen atom is thus present as an epoxide which may be placed a t the 6,7 positions on NMR-evidence (4protons between 3.0 and 3.65 ppm, C-8H2, C-VH, C-6H) leading to structure CLXVI for the alkaloid venalstonidine, which is 6,7-epoxykopsinine (19, 29). R

+OH

H

3

0T5$jOH H

R CLXVI Venalstonidine

COzMe

CLXVII; R=CHzOH CLXVIII; R =C02Me

CLXIX

m/e 109

140

Among other alkaloids which accompany the above in M . australis are two hydroxykopsinines (mol. wt. 354). The nature of the aromatic portion and functional groups was established as before by IR-, UV-, and NMR-methods. One, ascribed the structure CLXVIII, gave ring D mass spectral peaks a t m/e 125 and 140. A hydroxyl group a t C-8 would shift the remaining C-8 proton downfield of 5 ppm. As no such signal was observed the hydroxyl group was tentatively placed a t positions 6 or 7. The other shows the ring D peaks a t m/e 109 and 140 and this practically restricts the hydroxyl group to positions 20 and 21. The first step in mass spectral breakdown is the loss of the C-20-C-21 bridge, and this step is documented by a strong peak a t m/e 310 in the present case. As a fragment, m/e 140, with a hydroxyl group on C-21 would be expected to lose formaldehyde and give m/e 110 (Volume VIII, p. 415), the low intensity of this peak leads to the more probable 20-hydroxykopsinine structure, CLXIX (19).

9. Aspidosperma AND RELATED ALKALOIDS

25 1

CLXIXa R.=H CLXIXb R = OMe

The structures of kopsaporine (CLXIXa) and kopsingine (CLXIXb) (Volume VIII, p. 356) have now been elucidated (79a).

E.

d6-8-OXOKOPSINENE AND

ITSN - O X I D E

Two of the alkaloids of M . australis are distinguished by a strong IR-carbonyl absorption around 1660 cm-1 which may be attributed to an amide function, in addition to the usual ester band a t 1730 em-1. A third band a t 1600 cm-1 may be attributed to a double bond conjugated with the former. One alkaloid, C21H22N203 by mass spectrometry, has UV-absorption corresponding to superimposed cr$-unsaturated amide and dihydroindole chromophores, and from IR- and NMR-data the aromatic portion is unsubstituted. NMR-spectra furt'her show the double bond to be cis in a six-membered ring (2 protons at 5.93 and 6.24 ppm J = 10 cps) with no coupled vicinal protons. It must therefore lie between a quaternary center and the amide carbonyl group leading to structure CLXX. This structure was confirmed 6y hydrogenation to the known 8-oxokopsinine (CLXXI ; Volume VIII, p. 428). The accompanying alkaloid, CzlHzzNz04 by mass spectrometry, differs in the following respects. It contains one more oxygen atom, but apart from the molecular ion, 16 units higher, the mass spectrum is largely identical with that of 0

COzMe CLXX

D

COzMe CLXXI

CLXXII

252

B . GILBERT

CLXX. The cis double bond is present but one of the vinyl proton doublets is shifted downfield to 6.58 ppm. The UV-spectrum exhibits only the dihydroindole chromophore. These differences can be attributed to the effect of an N-oxide group and the alkaloid was provisionally given structure CLXXII. Hydrogenation to CLXXI could not be achieved (19). The 8-oxokopsinines are characterized in the mass spectrum by three intense peaks at m/e 227, 214, and 195, probably corresponding to indolic fragments. The ring D peaks are relatively weak. In the NMRspectrum a characteristic one proton double doublet appears at 4.2-4.5 ppm perhaps attributable to one of the C-10 protons. This last feature is also seen in the spectrum of Ld 69, a double alkaloid of unknown structure which occurs in the same plant (19).

F. HEPTACYCLIC KOPSANE GROUPALKALOIDS A number of new heptacyclic alkaloids have been isolated from Pleiocarpa mutica and from the Aspidosperma species, A. duckei and A. macrocarpon. Three P . mutica alkaloids (CLXXIII, CLXXIV, and CLXXV) are ketolactams and differ only in their N,-substitution (a), the N,-unsubstituted one (CLXXIII) being the third lactam mentioned in Volume VIII, p. 504. The related nature of the three alkaloids was clear from high-resolution mass spectrometry which established their molecular formulas as CZOHZONZO~, CzlH22N202, and C22H22N204, respectively. The N,-substituents, which could be identified by IR- and NMR-spectrometry (CLXXIII, N,-H, 3380 cm-1; CLXXIV, N,-CH3, 2.60 ppm; CLXXV, Na-C02Me, 3.85 ppm) were located on N, by the observation of a mass spectrometric peak at C12H11Nf in CLXXIII which shifted to C13H13Nf in CLXXIV and to C14H13NO~fin CLXXV. From its hydrogen content this peak must be aromatic and therefore contain the indolic N,, its variation in composition following the substituent change. The resemblance of the N-methyllactam (CLXXIV) to the known decarbomethoxykopsine-10-lactam (CLXXVI ; see Volume VIII, pp. 442-443) was clear from IR-(1685 and 1760 cm-1) and NMRspectra (C-11 one proton singlet at 3.73 ppm, C-8 equatorial hydrogen broad doublet at 4.24 ppm) and the structures illustrated with carbonyl groups at positions 22 and 10 became likely ones for the alkaloids. Confirmatory evidence could be obtained by following changes in fragment a in the mass spectra of the reduced derivatives (CLXXVII and CLXXVIII) obtained by the action of lithium aluminum hydride and deuteride, respectively, on CLXXIV. The shift from m/e 109 (R = H ) to m/e 111 (R = D ) shows that the amide carbonyl was located in this part of the molecule while the ketonic carbonyl was not (4).

9. Aspidosperma

MeOzC CLXXIV

253

AND RELATED ALKALOIDS

H

CLXXV

CLXXIII

/

I

I

LiAlD,

LiAlHr

OH CLXXVIII

CLXXVII; R =CH3 CLXXXIII; R = H

1

I

CLXXVI

DCD MeaSO

CH3

CH3

CLII

CXLII

COzMe a R=H, m/e 109 R = D , m/e 111

@ \

CH3

.,.

**

COzMe CLXXIX

CLXXX

CLXXXI; R = OTs CLXXXII; R = I

254

B. GILBERT

Three correlations with hexacyclic compounds confirmed the proposed structure for Na-methyl-10,22-dioxokopsane (CLXXIV).Alkaline cleavage of the p-dicarbonyl system followed by esterification of the resulting carboxylic acid gave pleiocarpinilam (CLXXIX ; Volume VIII, p. 439). Oxidation of Na-methylkopsanol (CLXXVII)gave Na-methylkopsanone (CLII) which, as already described (Section IV,A and B), has been synthesized from pleiocarpinine (CXLII; 78, 79). Wolff-Kishner reduction of CLII gave Na-methylkopsane (CLXXX) which could be synthesized, as for kopsane itself (Section IV,A), from Na-methylkopsinyl tosylate (CLXXXI) or iodide (CLXXXII) ( 4 ) . The two accompanying lactams were correlated with CLXXIV by lithium aluminum hydride reduction. CLXXV gave Na-methylkopsanol (CLXXVII) as well as kopsanol (CLXXXIII, undefined stereochemistry at C-22), whereas CLXXIII furnished only the latter ( 4 ) . The two possible epimers of CLXXXIII, kopsanol (CLXXXIV) and epikopsanol (CLXXXV) occur with the corresponding ketone, kopsanone (CXLVIII),in the above-mentioned Aspidosperma species (33).The unsubstituted dihydroindolic chromophore and the functional groups were apparent from IR-, UV-, and NMR-measurements and the heptacyclic nature of the molecules from their mass spectra and elementary analyses. The alkaloids were interrelated and the skeleton established by Wolff-Kishner reduction of kopsanone (CXLVIII) to kopsane (CL).

4

CXLVIII Kopssnone

CLXXXIV; R = H CLXXXVI ; R =AC

CLXXXIX ; R =H CXCI; R t A c

1 V

CL; R = H 2 CLXXIII; R = O

CLXXXV; R = H CLXXXVII ; R = AC

R

"

CLXXXVIII; R = H CXC; R=Ac

9. Aspidosperma

AND RELATED ALKALOIDS

255

Further confirmation of the structure came from oxidation of kopsanone to 10,22-dioxokopsane (CLXXIII, occurring naturally in P. mutica) whose NMR-spectrum showed the expected C-11 and C-19 one proton singlets and the deshielded equatorial C-8 proton (broad doublet at 4.22 ppm, J = 13.5cps) already observedin the corresponding ketolactam (CLXXVI) derived from kopsine (Volume VIII). The orientation of the hydroxyl groups in the two epimeric kopsanols was established by nuclear magnetic double resonance (NMDR) examination of their acetates (CLXXXVI and CLXXXVII). The angles between the proton on C-22 and its two neighbors on C-3 and C-11 in kopsanol acetate (CLXXXVI) are such that substantial coupling constants (8.5 and 5 cps) are observed, while in epikopsanol (CLXXXV) the C-22 proton is practically perpendicular to its neighbors and thus does not couple, appearing as a singlet a t 3.80 ppm moving to 4.84 ppm in the diacetate (CLXXXVII). The ready formation of this N,-0-diacetate of epikopsanol contrasts with the difficulty of acetylation of N , in kopsanol (CLXXXIV) and points to assisted acetylation of nitrogen in the former, confirming the proximity of the hydroxyl group (3 3 ). An accompanying lactam was identified as 10-oxoepikopsanol (CLXXXVIII)from the singlet absorptions of the C-11and C-22 protons, which showed not only that there was no hydrogen atom on C-10, but that the same perpendicular orientation of the C-11 and C-22 hydrogens obtained. Synthesis of the two 10-oxokopsanols (CLXXXVIII and CLXXXIX) from epikopsanol and kopsanol by chromic oxide-pyridine oxidation of their respective acetates to CXC and CXCI followed by alkaline hydrolysis confirmed that CLXXXVIII represents the correct structure of the naturally occurring alkalbid (33).

G. FRUTICOSINE AND FRUTICOSAMINE These alkaloids were described briefly in Volume V I I I (p. 444) and they could then be ascribed the partial structure CXCII in which the ketonic carbonyl group should be placed in a six-membered ring. Subsequent work (80-82) has shown that the bases are indeed heptacyclic (perhydrogenation; NMR) like kopsine and has led to structure CXCIII for fruticosine while fruticosamine has structure CXCIV, epimeric a t c-3. In aspidospermine-type alkaloids an acyl or carbomethoxyl group on N , deshields the C-2 proton (Volume VIII, p. 367) and the absence of NMR-absorption due to such a C-2 proton in the spectra of fruticosine, fruticosamine, and N,O-diacetyldecarbomethoxyfruticosine (CXCV)

256

B. GILBERT

signifies a fully substituted 2-position. The N,-carbomethoxyl group also deshields the C-17 aromatic proton (Volume VIII, p. 434) and this effect is observed in fruticosine (C-17 H, 7.70 ppm; see also Battersby and Gregory, 83).However, in fruticosamine, which possesses the N,-COZMe, it is not observed, and this is due to the fact that the unreactive secondary hydroxyl group of this alkaloid is hydrogen bonded t o the carbomethoxyl 0

Ht3z C C

6OzMe CXCII

CCI

as is evidenced by its IR-(vUC14, 3440 cm-1) and NMR-(5.5 ppm, broad singlet) absorption. The hydroxyl group must therefore be located on (3-3, and in view of the ready conversion under mild conditions of fruticosamine (CXCIV) into fruticosine (CXCIII), the hydroxyl group is probably similarly placed in the latter, the absence of hydrogen bonding pointing t o a stereochemical difference. I n fact the interconversion of the two alkaloids [also possible with the decarbomethoxy derivatives (CXCVI and CXCVII)] may be explained as a retroaldol ring opening to the aldehydic intermediate (CXCVIII; 82) or its enol (see below; 81) which then ring closes to give predominantly the more stable alcohol (CXCIII)in which steric hindrance between C-22 and the C-3 hydroxyl group is relieved. Fruticosine undergoes very ready Hofmann degradation (cf. kopsine, Volume VIII) to the a7/3-unsaturatedketone (CXCIX) with two widely separated vinyl singlets (5.78 and 4.16 ppm) indicating a 2-methylenecyclohexanone structure. Additionally, the ready Hofmann ring opening places the ketonic carbonyl beta to N,. Hydrogenation of the methine (CXCIX) gave the dihydromethine (CC).The C-11 proton in this derivative appears as a quartet coupled only to the new methyl group (C-10). C-12 is thus quaternary and partial structure CCI may be deduced. The dihydromethine (CC) undergoes permanganate oxidation to a sixmembered lactam (CCII, v, 1637 cm-1) while fruticosine itself gives a five-membered lactam (CCIII, v , 1700 cm-1). Thus N, lies a t the junction of five- and six-membered rings. The six-membered piperidine ring is also evidenced by mass spectral peaks, for example, a t m/e 110 and 123 in the spectrum of the methine CXCIX which may be allocated the structures a and b (see p. 258).

9. Aspidosperma

RI

AND RELATED ALKALOIDS

257

RZ

CXCIII COzMe H CXCV Ac Ac H H CXCVI

CXCVIIT

CXCIX

CCIII

C X C N ; R=COzMe CXCVII; R = H

OH

MeOzC

cc

CCII

Evidence for the presence of a quaternary center a t C-5 arises from NMR-studies. For example, in fruticosine (CXCIII) the protons a t C-3 and C-4 appear as coupled doublets a t 4.81 (C-3H shifted in diacetate, CXCV, to 5.93 ppm; see 81, 82) and 2.55 ppm ( a t o carbonyl), respectively, the coupling constant of 6.5 cps corresponding t o a 30"-40" angle between them. Apart from coupling to the hydroxyl proton clarified by NMDR-spectra no other coupling was observed; therefore there are no hydrogen atoms on C-2 and C-5. I n the case of fruticosamine (CXCIV) the C-3 and C-4 protons absorb as singlets since they are mutually

258

B . GILBERT

perpendicular. The foregoing evidence, coupled with the biogenetically probable presence of a tryptamine unit, leads to partial structure CCIV. The presence of a single proton on C-19 and the expected AMX pattern of absorption for the C-10 and C-11 hydrogens are seen in the NMRspectrum of fruticosine and fruticosamine. Since all the carbon atoms are present in CCIV, it only remains to link C-20 and C-21 to arrive a t full structure CXCIII for this alkaloid, the orientation of the C-3 hydroxyl group being established by evidence cited above. For fruticosamine the epimeric structure CXCIV follows (80-82). Me\?

@ \ ;H .

M9e\

MeOzC a 110

b 123

cc HO

*.*

CCIV

A completely independent proof of the structure of the alkaloids follows from their interconversion with isokopsine (CCV; Volume VIII, p. 444) (81). Oxidation of either fruticosine or fruticosamine with dimethyl sulfoxide and acetic anhydride gave a diketone, C2zH22N204,which was assigned the structure CCVI, since by borohydride reduction it gave a mixture of fruticosine, fruticosamine, and dihydrofruticosamine (CCVII). Hydrolysis of the diketone gave a keto acid (CCVIII) which is also the periodate cleavage product of isokopsine (CCV). Comparison of the methyl esters (CCIX, v, 1715, 1727 and 1742 cm-l) obtained from each source showed identity, including rotation, and the absolute configuration of fruticosine and fruticosamine are thus established since isokopsine (CCV) has been related to kopsine (Volume VIII). Acyloin condensation and reduction of chano-fruticosine methyl ester (CCIX) gave dihydroisokopsine (CCX) characterized as its 0-acetate, decarbomethoxy, and N-methyldecarbomethoxy derivatives as identical with the borohydride reduction product of isokopsine. Cleavage of dihydroisokopsine with lead tetraacetate in pyridine gave the aldehyde (CXCVIII) which with cold alkali yielded fruticosine (CXCIII)which has thus been synthesized from kopsine (81). Interestingly, borohydride reduction of the chano ester (CCIX) gave not a hydroxy ester but cyclic derivatives (CCXI and CCXII) of the corresponding hydroxyaldehyde (81). Although some doubt has been cast on the intermediacy of the chano aldehyde (CXCVIII) in the fruticosamine+fruticosine transformation (81), other alkaline degradations of fruticosine clearly stem from the

9. Aspidosperma

MeOaC

I

H CXCIII

259

AND RELATED ALKALOIDS

CXCVIII

Fruticosine

Po

//...I

ccx

@'

PMSO

"

MeOzC

MeOzC

MeOzC

0 CCVI

MeOzC

CCVIII; R =OH CCIX; R = O M e

,

0

ccv

, Hd

CXCIV; R = 0 CCVII; R = H, OH

further reaction of this aldehyde or its carbanion (82). By prolonged heating of fruticosine (CXCIII) with strong alkali, hydride transfer occurs away from the C-3 aldehyde (CXCVIII) to the ketonic carbonyl and a hydroxy acid (CCXIII) results. Acid-catalyzed decarboxylation then leads to the chano base (CCXIV), CIgH24N20, an alcohol. The structure of this compound is largely based on the NMR-spectra of its N,O-diacetate (CCXV) and N-acetate (CCXVI), in which the coupling constants of the C-2 and C-22 protons were determined by NMDRspectroscopy. Wolf-Kishner reduction of fruticosine leads to a product

OH

260

B. GILBERT

of the expected composition, C20H24N20, with OH and NH functions (v, 3590, 3392 em-1). However, the difficulty of acetylation and the absence of NMR-absorption between 6.4 and 3.5 ppm in the spectrum of the N,O-diacetate (CCXVIII) showed that no secondary -CHOAc group was present. This NMR-spectrum also excludes a C-2 proton and on this basis the product may be recognized as 22-hydroxyisokopsane (CCXVII) formed by the mechanism illustrated (82).

CCXIII

Ri CCXIV H CCXV Ac CCXVI Ac

Rz H Ac H

CCXVII; R = H CCXVIII; R=Ac

V. Cyclic Ethers and Lactones A. ASPIDOALBIDINE DERIVATIVES New alkaloids based on the aspidoalbidine skeleton include the 1 7-methoxy-Na-formyl (CCXIXa)and 1 7-methoxy-Na-acetyl(CCXIXb) derivatives ( 1 2 ) ,aspidofendlerine (CCXX ; 35) and 2 1 -0xoaspidoa1bine

(CCXXIa; 36). Kromantine (Volume VIII, p. 505) turns out to be the N-acetyl analog (CCXXIb) of aspidoalbine described in Volume VIII, p. 445 (84a).The structures of these alkaloids were readily deduced from NMR- and mass-spectral data as described in the previous volume and also by correlation with known compounds. For example, CCXX was methylated t o aspidolimidine (XIV) and CCXXIa to 21-0x0-0-methyl-

9. Aspidosperma AND

RELATED ALKALOIDS

261

aspidoalbine (CCXXIc), an alkaloid which occurs in Aspidosperma exalatum and which has been related to aspidoalbine (Volume V I I I ) via N,-depropionyl-O-methyl-2 1-0xoaspidoa1bine (CCXXId) and N,depropionyl-0-methylaspidoalbinol(CCXXII; 36).

CCXIXa; R =CHO CCXIXb; R = AC

CCXX XIV CCXXIb

Ri Rz CCXXIrt H COEt CCXXIc Me COEt CCXXI? Me H

H OH H OMe OMe OMe

CCXXII

The mass spectral breakdown of Iactones such as CCXXIh and CCXXIc has been the subject of a detailed study using high resolution and deuteration (36)in an attempt to elucidate the structure of the m/e 160 base peak which appears in the mass spectra of this series. The initial loss of COz from the lactone ring blocks the normal decomposition. The m/e 160 peak, CIIHIIN+, is accompanied by a satellite at m/e 174, ClzHlsN+, and the latter contains all the aliphatic carbon atoms including C-2 and C-12 but excluding the carbonyl C-21. Cleavage of the indole ring is unique in Aspidosperma alkaloids.

B. OBSCURINERVINE,NEBLININE, AND RELATED ALKALOIDS The structures of this group of bases were briefly reported in Volume VIII. The interest of their chemistry and establishment of their absolute configuration warrants a fuller account here.

0

CCXXIIIa CCXXIIIb CCXXIIIe CCXXIIIf

Ri Me0 Me0 H H

Rz CCXXIIIC CCXXIIId CCXXIIIg

Et Me Me Et

Ri Me0 Me0 H

Rz Et Me Me

od-.R Ri ~ CCXXIV CCXXvII CCXXV

Et Et Me

Rz H Ac H

R3 _ H Ac H

_

CCXXVI CCXXIX CCXLIII CCXLIV

Rz

Ri Me0 Me0 H

Et Et Me Me

H

R3 H

H

H H

R4

H Ac H Ac

1 Me0

/

z0H

zOAc

t-

Me0

\

R

\

Me0

CCXXXI; R = H CCXXXII; R = D

CCXXXV CCXLII

Ri Me0 H

Rz Et Me

CCXXX CCXLV

CCXXXIII CCXXXIV CCXLVI CCXLVII ~

~~~~

Ri Me0 H

RI Me0 Me0

H

H

Rz Et Me

R.Et Et Me Me

Ra.

H

Ts H Ts

9. Aspidosperma

263

AND RELATED ALKALOIDS

Six alkaloids are known (CCXXIIIa to f ) and their occurrence is listed in Tab1 3 I (37). Two, dihydroobscurinervine (CCXXIIIc) and dihydroobscurinervidine (CCXXIIId) may be derived from obscurinervine (CCXXIIIa) and obscurinervidine (CCXXIIIb), respectively, by hydrogenation of the 6,7-double bond. The molecular formulas of the alkaloids follow from mass spectrometry and elementary analysis. The presence of a five-membered lactone ring (v, 1750 cm-I), and an oxygenated dihydroindole chromophore was deduced while acetylatable functions were found to be absent. The UV-spectrum did not alter in acid indicating that quaternization of N , is sterically prevented. NMR-spectra showed that the obscurinervine group (CCXXIIIa to d) had two methoxyl groups and one aromatic proton while neblinine (CCXXIIIe) and its homolog (CCXXIIIf) have one methoxyl and two o-disposed aromatic protons. The mass spectra show very little fragmentation, but divide the alkaloids into two groups, those (CCXXIIIa, c, and f ) which lose methyl and ethyl from the molecular ion, and those (CCXXIIIb, d, and e) which lose only methyl. I n the NMR-spectrum the former show a 3-proton triplet (J=7,cps) a t 0.95 ppm while the latter show a methyl doublet (J=6 cps) at about 1.1 ppm, indicating that the bases differ by a secondary ethyl or methyl group. The 6,7-vinyl protons in the unsaturated alkaloids appear as a relatively sharp signal a t 5.72 ppm, reminiscent of tabersonine (Volume VIII) and which disappeared in the dihydro derivatives. When the lactone ring was reduced with lithium aluminum hydride then the resulting diols (for example, CCXXIV-CCXXVI) exhibited an aspidospermine-type fragmentation pattern. I n the unsaturated series (CCXXIV, CCXXV) the D-ring fragments ( a and b ) could be seen to contain the double bond and an alcoholic oxygen atom. I n the dihydro series (CCXXVI)fragment b was absent and that corresponding to a was two units heavier (c). That the alcohol group is a primary one resulting from reduction of the lactonic carbonyl is shown by its increase of two units (fragment d ) when LiAlD4 is used for the reduction. The unsaturated diols showed a more normal ABXz pattern for the 6,7-double bond, while the diacetate (CCXXVII) showed the presence of primary (-CHzOAc, AB pattern at 4.12 ppm) and secondary (-CHOAc, double doublet, 5.23 ppm,

a 138

b 137

c

140

d 140

264

B. GILBERT

J = 9 and 5 cps) acetate groups. The molecules must therefore contain an aspidospermine framework and the partial structure CCXXVIII. The protons on C-20 can in fact be clearly recognized as an AB pattern (2.02 and 2.57 ppm, J = 18 cps in CCXXIIIb) in the NMR-spectra of the original alkaloids. Further information on the aliphatic portion of the molecule was obtained by preparation of the primary monoacetate (CCXXIX) from which Moffat oxidation gave the keto acetate (CCXXX) and thence the keto alcohol (CCXXXI).I n the mass spectrum of this last compound a ring D peak corresponding to e was observed in addition to the c fragment. Neither of these ring D peaks moved in the deuberated dihydroobscurinervinolone (CCXXXII). This confirms the NMR-evidence for partial structure CCXXVIII and places the original secondary alcoholic oxygen atom on C-4 of an aspidospermidine skeleton. Finally the aliphatic portion of the molecule was fully reduced by Wolff-Kishner reduction of CCXXX to dihydroobscurinervinol (CCXXXIII) and thence via the tosylate (CCXXXIV) to dihydroobscurinervinane (CCXXXV). Very significant in the mass spectra of this series are the indolic peaks, the principal of which in the obscurinervine and dihydroobscurinervine series appears at m/e 260. This peak, although weak, is seen in the spectra of the parent alkaloids and persists unchanged through the series of transformations described above. It therefore cannot contain C-3 t o C-10 and C-19 and the following evidence leads to structure CCXXXVI for this ion. From UV- and NMR-evidence a further aromatic alkoxy group must be present in dihydroobscurinervine (CCXXIIIc) in addition to the two methoxyls already noted. Two protons of a CHz-0grouping are present in the NMR-spectrum (4.12 and 4.28 ppm). The m/e 260 peak shifts t o m/e 246 in the obscurinervidine (CCXXIIIb) series and to m/e 216 in the neblinine (CCXXIIIe)series and thus contains the secondary alkyl group mentioned above. Furthermore, N , is substituted and the seventh ring of these alkaloids must be present as shown in CCXXXVI

CCXXVIII

CCXXXVI

R1 RZ

m/e

OMe Et 260 OMe Me 246 H Me 216

9. Aspidosperrna

AND RELATED ALKALOIDS

265

which contains all of the atoms not present in CCXXVIII and thus leads to the full structures for the alkaloids ( 3 7 ) . Three partial syntheses confirmed these structures. Depropionylaspidoalbiiie (CCXXXVII) alkylated on flawith 2-iodopropan- 1-01gave two epimeric alcohols (CCXXXVIII). The more polar of these was cyclized via the monobrosylate to the ether (CCXXXIX) and thence by reduction of the carbinolamine ether with lithium aluminum hydride t o the two aspidoalbinol derivatives (CCXL and CCXLI). The major product (CCXL) was identical with dihydroobscurinervidinol prepared from obscurinervidine (CCXXIIIb) in the same way as was described above for dihydroobscurinervinol (CCXXXIII). The C- 19 epimers CCXL and CCXLI are distinguished by mass spectrometry, the C-19 epimer giving a strong M-1 peak absent in CCXL. A similar synthesis using 2-iodo-butan-1-01gave dihydroobscurinervinol (CCXXXIII). As the absolute stereochemistry of aspidoalbine (N-propionylCCXXXVII) was not known, a synthesis of dihydroneblinane (CCXLII) was undertaken from ( + )-aspidocarpine (CCXLVIII) of known absolute configuration. Dihydroneblinane (CCXLII) corresponds to dihydroobscurinervinane (CCXXXV) and was prepared in a similar way from neblinine (CCXXIIIe)by way of the intermediates CCXXIIIg, CCXLIII, CCXLIV, CCXLV, CCXLVI, and CCXLVII. N,-Alkylation of deacetylaspidocarpine (CCXLIX) gave, as before, two 22-epimeric alcohols (CCL and CCLI) which were converted to their cyclic derivatives (CCXLII and CCLII). One of these (CCXLII)was identical with dihydroneblinane, thus establishing the absolute stereochemistry of neblinine (CCXXIIIe)a t all centers except C-22. This remaining center was settled by NMR-comparison of the two epimers CCXLII and CCLII. The C-22 methyl group of CCXLII lies under the 17,18 bond and is shielded (1.10 ppm), whereas that of CCLII lies in the plane of the aromatic ring and is deshielded (1.44 ppm). Since the ORD-curves of neblinine (CCXXIIIe) and of obscurinervine (CCXXIIIa) and its companions are of the same sign the latter may be assigned the same absolute configuration, an observation that may also be extended to aspidoalbine (37).

C. BENININEAND RELATED ALKALOIDS As has been seen 2 1-oxygenated aspidospermidines may form rings terminating a t C-4 and C-19. Beninine (CCLIII)is the first representative of a group in which a similar ring terminates a t C-6 (85).The molecular formula, CzoH2sNzOz, by mass spectrometry, showed the alkaloid to be

CCXLVIII ; R =AC CCXLIX; R = H

AH

flMe

HOCHz

ccxxxVrII

CCL

CCLI

/

9. Aspidosperma

x R x x

V V

AND RELATED ALKALOIDS

+

267

268

B. GILBERT

hexacyclic, and IR-(u, 3378 cm-I), UV-(neutral and acid), and NMRdata show that the 17-methoxy-dihydroindolestructure also found in deacetylaspidospermine is present. Acetylation gives N,-acetylbeninine (CCLIV) with UV-absorption similar to that of aspidospermine and the absence of NH or OH absorption shows that the second oxygen atom of beninine is ethereal. The mass spectral fragmentation of beninine is aspidospermine-like showing M - 28 (loss of (2-3, C-4) and indolic peaks a t m/e 160 and 174; particularly significant are the ring D peaks which appear at m/e 138 (base peak) and 166 (138 + 28). The ethereal oxygen atom is thus in this region. Reduction of beninine (CCLIII) with lithium aluminum hydride under vigorous conditions removes only the aromatic methoxyl t o give CCLV, with unchanged ring D fragments, and the oxygen atom can therefore form neither an epoxide nor a carbinolamine ether. Assuming on biogenetic grounds and by analogy with aspidospermine that a Cz chain is attached a t C-5 a five-membered ether ring

CCLIII CCLIV CCLV

Ri Rz OMe H OMe Ac H H

1 Me0

H G

b m/e 110

would terminate a t C-6. The m/e 138 peak would thus be represented by fragment u and an accompanying peak a t m/e 110 by b. Some further evidence was adduced from the mass spectrum of 1,2-dehydrobeninine (CCLVI) a degradation product of another alkaloid from C . burteri, which on hydride reduction yields beninine. The principal peak a t m/e 239 was ascribed the structure c on the basis of the previously postulated breakdown pattern of 1,2-dehydroaspidospermidinescontaining the C-20, C-21 carbon atoms attached to C-5 (85). On present evidence beninine forms one part of the double alkaloid vobtusine (Section IX).

9. Aspidosperma AND

269

RELATED ALKALOIDS

VI. The Aspidospermatidine Group A. LIMATINEAND SOME ANALOGS Five new derivatives of aspidospermatidine have been found in Aspidosperma species while the reisolation of N-acetylaspidospermatidine (CCLVII)from Vallesia dichotomahas permitted better characterization of this base and its deacetyl derivative aspidospermatidine (XIII) (12).Three new alkaloids are limatine ( 12-hydroxy-N,-propionylaspidospermatidine) (CCLVIII) (38),its N,-acetyl analog (CCLIX) (34, 37’a), and 11,12-dihydroxy-N,-acetylaspidospermatidine (CCLX) (24).As described in Volume V I I I these alkaloids were recognized by the intense m/e 136peak in their mass spectra. The 12-hydroxylgroup could be; recognized by NMR-(H-bonded OH, 10.7 ppm) and IR-(H-bonded C=O, v, 1630 cm-1) spectra, as well as by the extreme difficulty of methylation. O

N

@ ‘

N

I

R CCLVII; R = A c XIII. R = H

&N

Q @ \

R’

0l 2

I

14

T

20

H

H.. j \ R z ‘0

Ri

CCLVIII CCLIX CCLX CCLXa CCLXb

H H OH OMe OMe

Rz Et Me Me Me Et

CCLXI; R = E t CCLXII; R = M e

The ethylidine side chain was located in the first two cases by hydrogenation to the 14,19-dihydroderivatives(CCLXI and CCLXII) in which a diagnostic peak appears at M - 41. This peak is insignificant when the side chain is located a t position 20 (Volume VIII). Further evidence was adduced from the NMR-spectra in which the isolated C-3 proton is found as a singlet superimposed on the C-2 proton quartet (4.38 ppm) (12, 34, 38). Rotatory dispersion measurements have shown that CCLVIII and CCLIX have the absolute configuration illustrated (Section I1,A) (34,

270

B. GILBERT

59). The positive rotation of CCLX points to the same configuration for this alkaloid (23). The 11-methoxy derivatives (CCLXa) and (CCLXb) recently isolated from Aspidosperma limae (37a) have the same absolute configurations. B. PRECONDYLOCARPINE The leaf extract of Vallesia dichotoma contains a series of four alkaloids which represent an interesting biogenetic series (12).The first, probably stemmadenine (CCLXIII) has been isolated also from Aspidosperma pyricollzcm Mull.-Arg. fruits (34)and its occurrence in the green parts of plants may be significant of its r61e as a precursor of other alkaloids. Two others were condylocarpine (CCLXIV) and 14,19-dihydrocondylocarpine (tubotaiwine, CCLXV; see Volume VIII, pp. 457-462). The fourth alkaloid, precondylocarpine, was attributed the structure CCLXVI on the following evidence (12). The mass spectrum shows a molecular ion peak 30 units higher than that of condylocarpine (CCLXIV) but the rest of the spectrum is very similar for the two alka1oids:The NMR-spectra are also similar but differ in that precondylocarpine has absorptions (2 protons, singlet, 3.95 ppm; 1proton, 5.4 ppm) which may be attributed to a primary CHzOH group attached to a fully substituted

* H HOCH2 COzMe

CCLXIII Stemmadenine

CCLXVI Precondylocarpine

@ oT@ H

\CO2Me

CCLXIV Condylocarpine

\

\

COzMe

CCLXV

I CCLXVII

CCLXVIII; R = CHe CCLXIX; R = H, CHs

9. Asppidosperma AND

RELATED ALKALOIDS

271

carbon atom. This group accounts for the added 30 mass units and as the UV-spectrum (A 221, 280 mp) excludes the condylocarpine chromophore it was placed on C-16. The absence of I R - and NMR-evidence for an indolic N H is in accord with structure CCLVI. Confirmation came from the direct conversion of precondylocarpine t o condylocarpine (CCLXIV) under alkaline conditions, as well as the LiAIH4 reduction of both alkaloids to a common oxygen-free product, 16-methyleneaspidospermatidine (CCLXVII) recognizable from its mass spectrum. A similar reduction of dihydrocondylocarpine (CCLXV) gave the corresponding 14,lg-dihydro derivative (CCLXVIII) and thence the ietrahydro compouhd (CCLXIX) whose mass spectrum fully confirmed the location of the ethyl side chain a t C-14 (12).

VII. Alkaloids Lacking the Tryptamine Bridge A. ULEINE DERIVATIVES A number of new uleine-like alkaloids were briefly described in Volume VIII (p. 473). These are listed in Table I and details of their chemistry have now been published (2, 39). NMR (39a)and methiodide formation rates (86a) show that the 3-ethyl group of these bases is oriented away from N b . The 3-epimers of uleine and dasycarpidone have been isolated (39a).De-ethyldasycarpidone has been synthesized (8%).

B. APPARICINE The structure of apparicine (CCLXX) was mentioned in Volume VIII. It has proved to be a widespread alkaloid, both enantiomeric forms existing in nature. Some details of its chemistry are now presented. The UV- and mass-spectra of apparicine closely resemble those of uleine (CCLXXI) except that the molecular ion appears a t m/e 264, two units lower than that of uleine. Since apparicine is usually co-occurrent with uleine the possibility that it was dehydrouleine was attractive, but although the NMR-spectrum revealed an ethylidene side chain, it also showed that no N-methyl group was present. I n place of this group there appeared a two proton AB pattern (4.27, 4.47 ppm, J = 18 cps) which could be ascribed t o a methylene group between indole and nitrogen (position 6 in CCLXX). I n fact apparicine methiodide suffered ready nucleophilic attack on the gramine-like C-6 (compare uleine, Volume V I I I p. 471). Thus lithium aluminum hydride gave CCLXXII with a

272

B. GILBERT

new aromatic methyl absorption a t 2.33 ppm and sodium methoxide gave CCLXXIII in which the aromatic -CHzOMe grouping was characterized by NMR-absorption (CHz singlet, 4.61 ppm ; OMe, 3.38 pprn). The presence of piperidine moieties in these degradation products was apparent from the intense m/e 122 and 124 fragments in the mass spectra which could be ascribed to fragment a and its dihydro derivative. Dehydrogenation of CCLXXII followed by permanganate oxidation of the product gave 3,4-pyridinedicarboxylicacid (CCLXXIV) locating the points of attachment of the aromatic portion and ethylidene side chain. It remained to distinguish between two possible structures, CCLXXII R

CCLXX Apparicine

CCLXXI Uleine

CCLXXVI

CCLXXII; R = H CCLXXIII; R =OMe

CCLXXV

a 122

9. Aspidosperma AND RELATED ALKALOIDS

273

and CCLXXV for the lithium aluminum hydride product, both consonant with the above data. This distinction was achieved by NMDRspectra in which, beginning with the allylic methyl group, C-10, the (X is N or a double bond) was sequence H3C-CH=C-CH2-X demonstrated. Further decoupling experiments revealed the sequence

I

H2C=C-CH(Y)-CH2-CH2-X

(X and Y are N or double bonds). These sequences may only be found in CCLXXII and this leads to structure CCLXX for apparicine itself (87). An alternative invert structure CCLXXVI for apparicine was excluded on biogenetic grounds (43).The names pericalline, tabernoschizine, and gomezine are synonyms of apparicine (86). C. VALLESAMINE Together with aspidospermine and vallesine (Volume VIII), vallesamine (CCLXXVII)is one of the principal alkaloids of Vullesia dickotomu. Elementary analysis and mass spectrometry established the molecular formula CzoH24N203. An accompanying minor alkaloid, O-acetylvallesamine (CCLXXVIII), although not obtainable from vallesamine by acetylation, was identified by spectral comparison and by acid hydrolysis to the parent base. Spectral methods led to the identification of a carbomethoxyl group (v, 1715; 3.74 ppm, M - 59 fragment), an ethylidene side chain (methyl doublet, 1.71, vinyl quartet, 5.53 ppm), and an unsubstituted indole nucleus. The indole N-H is highly deshielded (9.85 ppm) indicating the probable proximity of the carbomethoxyl group. The NMR-spectrum of vallesamine further exhibits two AB patterns due to geminal protons. One of these is displaced about 0.5 ppm downfield in the spectrum of the O-acetate (CCLXXVIII),the splitting widening from 10to 18cps. This is therefore due to a hydroxymethylene group attached to a fully substituted carbon atom which is confirmed by the observation of M - 30 and M - 31 peaks in the mass spectrum of vallesamine (CCLXXVII). The second AB pattern closely resembles that of the C-6 methylene of apparicine (CCLXX, present in the same plant) and pointed to the probability of a similar skeleton for the two alkaloids. In fact gramine-like reactions are undergone by vallesine similar to those suffered by apparicine and uleine. Thus, for example with acetic anhydride in methanol, electrophilic attack by the anhydride at N , followed by nucleophilic attack by methanol at C-6 results in the opening of ring C and the production of CCLXXIX. Reaction of Vallesamine methiodide with sodium methoxide similarly opens ring C but

a~w a ~ I

I

t

MeOH AcaO

I

H

I

CHzOH

1

MeOzC

CCLXXIX

1

NaOMe

2

CHzOR

CCLXXVII; R = H CCLXXVIII; R =AC /I

1. Me1

2. LiAlHd

6

H

MeOzC

a lo

, I

1 H HOCHz

CHzOH

ccxm

2. NaOMe

R

R COzMe Series

CHzOMe

MeOzC

CCLXXX CCLXXXI CCLXXXII CCLXXXIII

Me Me Ac AC

fl t~

fl 01

A B A B

A-series (3-10 deshielded

F

F4-

&

GSS

F4 W W R

9. Aspidosperma

h a

g-

AND RELATED ALKALOIDS

275

276

B. GILBERT

in this case simultaneously brings about retroaldolic loss of the hydroxymethylene group (as formaldehyde) to give two inseparable epimeric esters [CCLXXX (major) and CCLXXXI (minor)]. Under similar conditions the N-acetyl compound (CCLXXIX) loses formaldehyde to give two other esters (CCLXXXII and CCLXXXIII). The retroaldol reaction places the alcoholic function /3 to the carbomethoxyl carbonyl and the grouping C(C,)( CY)(CH20H)(C02Me), is thus present. The two esters (CCLXXXII and CCLXXXIII) were separated and the marked shielding of the allylic methyl group (1.08ppm) in CCLXXXIII permitted allocation of the B-series stereoformula to this epimer (a trans disposition of the 7-8 and 9-10 bonds and of the C-1, C-2 hydrogens ( J = 12 cps) is assumed). Lithium aluminum hydride reduction of the two N-methyl esters (CCLXXX + CCLXXXI) gave two N-methyl alcohols (CCLXXXIV)of the A and B series, respectively, with a similar NMR-difference. The A-series N-ethyl alcohol (CCLXXXV) was also prepared from CCLXXXII. In both retroaldol reactions the A-series esters preponderated and if these represent the nonepimerized series then the relative stereochemistry of vallesine (CCLXXVII) may be deduced. However, this evidence appears to be inconclusive at present. Proof for the skeletal structure of vallesine come from its interrelation with apparicine (CCLXX). Tosylation of the epimeric mixture (CCLXXXIV)gave the quaternary salt (CCLXXXVI, X = OTs-) which on conversion to the hydroxide (X=OH-) and pyrolysis underwent Hofmann degradation to CCLXXII identical (including ORD-data) with the degradation product from ( - )-apparicine (Section VI1,B). The two alkaloids thus have the same skeleton and absolute configuration at C-2 (43). In a nucleophilic solvent acetylation of vallesamine (CCLXXVII) results in the opening of ring C as seen above. With acetyl chloride in methylene chloride rearrangement occurs, the ethylidene double bond furnishing electrons to C-6, and itself suffering attack by the carbonyl oxygen atom. The resulting compound CCLXXXVII contains a five-membered lactone (v, 1770 cm-I), an N-acetyl (v, 1630-1600 cm-1; 2.00 and 2.05 ppm, double singlet due to hindered rotation), asecondary and no longer allylic methyl group (0.87 ppm, doublet, J = 7 cps), and a hydroxymethylene group which can be acetylated to give CCLXXXVIII. Carbobenzoxylation of vallesamine gives an analogous product (CCLXXXIX) which could be catalytically deacylated to the amine (CCXC) which gave the same N,O-diacetate (CCLXXXVIII). The NMR-spectra of the more soluble carbobenzoxyamide (CCLXXXIX) and of its acetate (CCXCI) were in accord with the structure illustrated exhibiting two geminal AB patterns due to the

9. Aspidosperma AND RELATED ALKALOIDS

4

\

2

'p

J

I

p:

277

278

B . GILBERT

isolated methylene groups a t C-7 and C-12, respectively. Oxidation of the N-acetylamide (CCLXXXVII) gave the aldehyde (CCXCII, v, 1770, 1750, 1640-1600 cm-1) while lithium aluminum hydride reduction gave the triolamine (CCXCIII), whose structure was in accord with its mass spectrum. The mass spectrum of vallesamine (CCLXXVII) is characterized by a primary loss of the oxygen functions after which the pattern resembles that of apparicine. The ring C open derivatives cleave first a t C-1, C-2 and the fragmentation of these was followed by comparison of the spectra of CCLXXIX, CCLXXXII, CCLXXXV, CCLXXXIV, its deuterated derivative CCXCIV, and the diol CCXCV (43).

Ra+R*J +R /

H

CH(0Et)Z

Me

H

Me

CCXCVI; R = H CCXCIX; R = O M e

CCXCVII; R = H

CCXCVIII; R = OMe

/

xxxpm Rz

R3

CCC CCCVI CCCIX

Me

Ri

Rz

H Me H

Me OMe Me H H H

CCCVII; R = M e CCCVIII: R = H

R3

Me

Me

tke

CCCI

CCXCVI

-

cccm

CCCII

e’” I

c-

ey ( $ )

CeHsNHN

Me

cccv

Me

CCCIV

9. Aspidosperma

AND RELATED ALKALOIDS

279

D. ELLIPTICINE, METHOXYELLIPTICINE, AND OLIVACINE The antitumor activity of these alkaloids has led to renewed interest in their synthesis. Saxton's synthesis of ellipticine (CCXCVI; Volume VIII, pp. 477-480), the most adaptable t o large-scale production, has been shortened by two steps by the direct cyclization of the intermediate (CCXCVII) in 90-100 01'' phosphoric acid. The same route has been used t o synthesize 9-methoxyellipticine (CCXCIX) from 5-methoxyindole (CCXCVIII) (88). This alkaloid, earlier thought t o be S-methoxyellipticine (CCC) on the basis of UV- and fluorescence-spectra (47),is identical with the methoxyellipticine referred t o in Volume VIII. Another simple but relatively low yielding synthesis of ellipticine builds up the molecule from the ring D end (89).N-Methyl-4-piperidone (CCCI) condensed with pent-2-ene-4-one gives the unsaturated ketone CCCII. Alkylation to CCCIII is followed by the Fischer indole synthesis via the pheiiylhydrazone CCCIV to give N-methyloctahydroellipticine (CCCV) which may be dehydrogenated to ellipticine (CCXCVI). Both routes were used to obtain non-naturally occurring derivatives of ellipticine of which the N,-methyl derivative (CCCVI) showed some biological activity (88). Schmutz and Wittwer's synthesis of olivacine (CCCVII) has been improved and adapted t o the preparation of modified pyridocarbozoles (90).Among simpler derivatives that have been prepared are CCCVIII (90) and CCCIX (89). 9-Methoxyolivacine has been found naturally (Table I, 55e).

VIII. Some Miscellaneous Alkaloids A. INTRODUCTION Among new alkaloids that have been isolated from the genera under consideration are vallesiachotamine (CCCX ;5 1 ) ,isotuboflavine (CCCXI), and norisotuboflavine (CCCXII ; 49). The chemistry of'these is described in accompanying chapters of this volume. The known indolo-[2,3,d]pyridocoline (CCCXIII) and its dihydro derivative (CCCXIV)have been isolated from the strongly basic fraction of Gonioma kamassi (48). Simple P-carbolines that have been isolated include 1-carbomethoxy13-carboline (CCCXV; 49) and 3-carboethoxyharman (CCCXVI; 50). Some other dihydrocorynantheol and yohimbine derivatives are listed in Table I. The absolute stereochemistry of the methoxydihydrocorynantheol group has been firmly established by a series of interconversions (55c). Strictamine ( = vincamidine, CCCXVII) is desformoakuammiline ( 5 2 ) .Nervobscurine (1O-methoxyakuammiline, CCCXVIIa has been isolated from A . obscurinerwium (alkaloid 6 ; 37, 86).

280

B. GILBERT

B. ASPIDODASYCARPINE Aspidodasycarpine (11)was the first alkaloid isolated from Aspidosperma to bear a close relation to picraline (CCCXVIII) an alkaloid typical of the genus Picralima but which has subsequently turned up in A . rigidum. Elementary analysis and spectrometry showed that aspidodasycarpine had the molecular formula C21HZsNZ04, had a dihydroindole nucleus unsubstituted in the benzene ring, a carbomethoxyl group, and an ethylidene side chain. Acetylation gave a diacetate

a;...!0-3 COzMe

/

cccx Vallesiachotamine

CCCXIII

R‘

CHO

Ri CCCXI; R = E t CCCXII; R = M e

CCCXIV

Rz

CCCXVII H H CCCXVIIa M e 0 CHzOH

CCCXV; R1= COZMe, Rz = H CCCXVI; R 1 = M e , R z = C O z E t

(CCCXIX, two 3-proton singlets, 2.16 and 1.92 ppm) which from its IR-spectrum (6.18 p ) and feeble basicity was acetylated on N,. The other acetyl group was not located on N , since the UV-spectrum was unchanged and was therefore on oxygen. One of the remaining oxygen atoms of aspidodasycarpine is thus alcoholic and the other was provisionally considered to be ethereal. The nature of the hydroxylic oxygen was deduced from base treatment of aspidodasycarpine which results in retroaldolization to “desformoaspidodasycarpine ” (CCCXX). The diacetate (CCCXIX) underwent a similar loss of formaldehyde to give the N-acetate (CCCXXI) which also resulted from CCCXX by acetylation. This retroaldolization is ii familiar property of alkaloids containing geminally placed hydroxymethylene and carbomethoxyl groups. Treatment of desformoaspidodasycarpine (CCCXX) with formaldehyde and alkali did not replace

9. Aspidosperm

AND RELATED ALKALOIDS

281

the lost hydroxymethylene group on C-16 but rather introduced this group on t o AT, t o give CCCXXII (N-CHzOH, AB pattern, 4.15 and 4.40 ppm, J = 9 cps). CCCXXII is also available directly from aspidodasycarpine (11)by the action of formaldehyde and alkali and readily loses the N-methylol group under mild acid conditions t o regenerate CCCXX. Reduction of the N-methylol derivative with lithium aluminum hydride gave the N-methyl derivative (CCCXXIII). The molecular formula of this compound, CzoHzsNZOz, contained two hydrogen atoms more than the reduction of the -C02Me and N-CH20H groups would account for. The ether ring has thus been opened. Reduction with lithium aluminum deuteride gave CCCXXIV containing four deuterium atoms, one of which must mark the point a t which the ethereal C-0 link has been cleaved. Mass spectrometry here assisted greatly in piecing together the structure. Aspidodasycarpine (11)shows a base peak a t m/e 108. Substituents on N , show up in this fragment, the intense peaks observed being N-Ac (m/e 150 and 108), N-Me ( l 2 2 ) , N-CHzD (123), N-Et (CCCXXV, 136), and N-CDzCHa (CCCXXVI, 138). I n view of the known presence of an ethylidene group this peak can be reasonably interpreted as a (see p. 284), placing N h in a six-membered ring. At the same time less intense indole peaks are observed, unaffected by substituent variations on N,. I n the spectra of aspidodasycarpine and the nondeuterated derivatives described, the lower molecular weight fragment appears a t m/e 130 attributable to the familiar fragment b . I n the two deuterated compounds CCCXXIV and CCCXXVI this peak moves t o m/e 131. Since only a carbinolamine ether would be expected t o cleave with lithium aluminum hydride or deuteride this shift can be attributed t o a deuterium atom a t C-2 to which the ethereal oxygen atom is attached in aspidodasycarpine. A partial structure CCCXXVII can now be presented for the alkaloid. The location of one as yet unidentified carbon atom results from examination of the indolic product (CCCXXVIII) which is produced together with CCCXXIX on zinc-hydrochloric acid reduction of aspidodasycarpine diacetate (CCCXIX). The NMR and I R spectra reveal

I

that the geminal ArOCHz-C-COZMe

I

group has been replaced by

I (two one-proton singlets, 6.20 and 5.63 ppm; conju-

HzC=C-COZMe gated ester, 5.85 p). NMR-spectra further establish the presence of the sequence SrC6HzC5HzOH,C-6,Hz appearing a t 3.0 ppm and C-5,Hz a t 3.85 (triplet) shifted t o 4.30 ppm in the diacetate CCCXXX. Confirmation of this side chain is seen in the mass spectra of CCCXXVIII

nyq HOCH,

COzMe

__--

o---<EBH4

q

COzMe

AcOCHz

NaOMet reflux

----- -6

-NH

COzMe

----- -0'

.NH H

H -'

--

.N W

I1

CCCXX

CCCXVIII Picraline

Aspidodasycarplne

EOAc

CCCXIX

CCCXXI

CCCXXII

8 td

M

2

/ G N

d

m

9. Aspidosperma AND RELATED ALKALOIDS

x

Y

283

284

U

B. GILBERT

b R = H 130 R = D 131

CCCXXVII

9

and CCCXXX where loss of CHzOH(Ac) and CHzCHzOH(Ac) may be observed. Now since this chain must contain the ethereal oxygen atom of aspidodasycarpine and one terminal of this ring has been located on C-2 the other, barring a four-membered ring, must be on C-7 and aspidodasycarpine contains the moiety CCCXXXI. Returning t o the indole (CCCXXVIII), NMR-spectra show one-proton multiplets a t 5.0 (Ar-CH-N) and 2.2 ppm (C=C-CH-C=C) as well as an AB system of which one branch appears a t 4.49 ppm (J=13 cps, N-CHz-C=). I n conjunction with mass spectral peaks at m/e 156 (indole accompanied by mle 130,144), 194, and 236 which can be attributed to the fragments c , d and e , this evidence leads to the full structure CCCXXVIII with the piperidine ring linked t o the indole through C-2, C-3. Structure I1 now becomes the logical structure for aspidodasycarpine, the zinc and acid reduction t o CCCXXVIII being explained by a mechan-

CCCXXXI

c 156

CCCXXXII

R

d ; R = H 194 e: R = A c 236

9. Aspidosperma

AND RELATED ALKALOIDS

285

ism such as CCCXXXII. Struct,ureI1is confirmed by the direct potassium borohydride reduction of picraline (CCCXVIII) of known structure (91) and absolute configuration (92) which gave desformoaspidodasycarpine (CCCXX) identified with the aspidodasycarpine degradation product through the N-hydroxymethyl derivative (CCCXXII) (2, 53).

C. PLEIOCARPAMINE, FLUOROCARPAMINE, MAVACURINE,AND C-FLUOROCURINE The structure of pleiocarpamine (CCCXXXIII) was briefly reported in Volume V I I I (p. 201), and since its discovery it has proved to be widespread in the family Apocynaceae, both free and as part of double alkaloids. As an example of the unusual cage-like molecules found among the indole alkaloids it is worthy of note particularly for the exceptional shielding and deshielding effects seen in its NMR-spectrum and those of its derivatives. Physical and analytical methods showed that pleiocarpamine was an indole with the molecular formula CzoHzzNzOz, unsubstituted in the benzene ring, but substituted on N , since no IR-bands due to OH or NH were present. One methoxyl group could be located in a carbomethoxyl (double C-0 in CC14, v, 1770, 1736 cm-l) and one C-methyl in an ethylidene side chain. The carbomethoxyl group is secondary since pleiocarpamine (CCCXXXIII) can be converted to epipleiocarpamine (CCCXXXIV) which retains all the functional groups of the original alkaloid and whose similar mass spectrum is evidence for an unchanged skeleton. Epimerization in deuteromethanol results in the introduction of one deuterium atom which NMR and mass spectra show is locatedon the carbon atom, C-16, which bears the carbomethoxyl group (in CCCXXXV). Both pleiocarpamine and epipleiocarpamine may be reduced with lithium aluminum hydride to the corresponding primary alcohols, CCCXXXVI and CCCXXXVII, respectively. The latter, epipleiocarpaminol (CCCXXXVII), its methochloride, and methiodide proved to be identical with normavacurine, mavacurine chloride, and mavacurine iodide, respectively (93). The evidence previously obtained (Volume VIII, pp. 522-527) for the structures of mavacurine and C-fluorocurine may now be interpreted in terms of CCCXXXVII-methochloride for the former and CCCXXXVIIImethochloride for the latter. Pleiocarpamine and its epimer thus have one or other of the structures CCCXXXIII and CCCXXXIV. Distinction between the two as well as confirmatory evidence were obtained by extensive decoupling studies a t 100 Mc. These established the presence of the series XZCH-CH(X)-CHZ-CHXZ (X represents a

-

1. KOtBu, MeOH

LiAlHI

H'

H

'\,

COzMe CCCXXXIV; R = H CCCXXXV; R = D

CCCXXXIII Pleiocarpamine

CHzOH CCCXXXVII Normavacurine

Hz, Pt, H +

H

1 Methochloride

4 CCCXXXVI R = H (R=D)

CCCXLI

2,7 -Dihydromethiodide

9. Aspidosperma AND RELATED ALKALOIDS

287

288

B. GILBERT

deshielding group) and H3C-CH==C(C)-CH2 whose carbon atoms are numberedrespectively 16,15,14,3and 18,19,20,21in the stereoformula CCCXXXIX. The chemical shifts observed are listed in Table IV. TABLE IV NMR-DATAFOR PLEIOCARPAMINE AND DERIVATIVES Proton on carbon atom Structure CCCXXXIII CCCXXXIV CCCXXXVI" CCCXLb CCCXLI

16

15

5.26 4.74 4.61 4.2 4.03

3.54 3.68 3.43 2.4 3.25

14

3

2.3 2.4

3.78 3.78

1.93

3.1

18 1.48 1.63 1.65 0.77 1.55

19

21a

21b

5.22 1.68 5.16 0.93 5.29 1.05 0.77 -0.27 5.33 4.31

2.53 2.48 2.44 1.92 3.0

Pleiocarpaminol also shows an A,B pattern a t 3.67 and 4.40 pprn due to the CHzOH group. * The C-20 proton absorption of 19,2O-dihydromavacurine (CCCXL) appears at 1.60 ppm, its coupling constant (11 cps) with the C-21a proton indicating its trans relationship and hence the 8-configuration of the ethyl group. The CHzOH protons are centered a t 4.1 ppm. CCCXL was prepared from norfluorocurine (CCCXXXVIII) via 19,20-dihydrohydronorfluorocurine (CCCXLII).Norfluorocurine is the only alkaloid in this series whose 19,20 double bond is readily hydrogenated although 19,20-dihydropleiocarpaminehas been obtained by cleavage of dihydrovillalstonine ( 4 4 ) .

Particularly noteworthy here are the shifts of the C-21 protons denominated 21a and 2 l b ; 21a is a t unusually high field for a proton between nitrogen and a double bond [cf. picraline (CCCXVIII), C-21H a t 3.14, 3.72 pprn ( 9 4 ) ; N-methyldihydroapparicine (CCLXXII), C-21H a t 2.87, 3.08 ppm]. When the double bond is reduced as in 19,20-dihydromavacurine (CCCXL) the value reaches -0.27 ppm. This can only be attributed t o shielding by the aromatic system and in fact models show that this proton is held directly over the C-2, C-7 double bond of the indole ring. When this double bond is reduced as in 2,7-dihydropleiocarpamine (CCCXLI) the shielding effect disappears (Table IV) though this is primarily due to the changed conformation (stereoformula CCCXLIII). The relatively deshielded position of the C-2 l a proton in pleiocarpamine with respect t o epipleiocarpamine enables the allocation of the /3COzMe configuration (stereoformula CCCXXXIX, RI=C02Me) to the former. I n contrast with the C-21 protons the c-15 proton is considerably deshielded partly due to the fact that it lies in the plane of the 19,ZO

9. Aspidosperma

289

AND RELATED ALKALOIDS

H

CCCXXXIX CCCXXXIII; R1= C02M0, Rz = H CCCXXXIV; R1 = H , Rz = COzM0

CCCXLVI

cccxLI II

CCCXL

t

CCCXXXVIII Norfluorocurine

CCCXLII

double bond. When this is reduced (CCCXL) it moves > 1 ppm upfield. I n accord with the stereochemistry assigned, allyiic and homoallylic coupling is observed from the C-18 and 19 protons to C-21a but not to the C-15 and C-21b hydrogens. The relatively ready hydrogenation of the 2,7-indolic double bond in pleiocarparnine (CCCXXXIII) is evidently associated with relief of steric compression. Epipleiocarpamine (CCCXXXIV) could not be so reduced due to the fact that the cr-COzMe blocks the a-face, the only side on which hydrogenation can occur. The two epimeric 2,7-dihydro alcohols (CCCXLIV and CCCXLV) could be prepared from 2,7-dihydropleiocarpamine (CCCXLI), the former by direct hydride reduction, the second as a minor product after previous epimerization a t C-16. The methiodide of CCCXLV proved to be identical with 2,7-dihydromavacurine iodide. Further evidence for the attachment of C-16 to N , comes from the preparation of the lactam CCCXLVI by Jones oxidation of norfluorocurine (CCCXXXVIII). This compound, C18H18N202, is an N,-lactam 9, 1668 since N , still reacts with methyl iodide. Its IR- ( ~ ~ 1 7 1#-indoxyl, cm-1, six-ring lactam) and UV- (A 236,258,324,347 mp) spectra are close

290

B. GILBERT

to those of model compounds. Attempts to degrade the carbomethoxyl group of pleiocarpamine itself were unsuccessful. The #-indoxy1 analog of this alkaloid, fluorocarpamine (CCCXLVII), has been found in Gonioma kamassi (48). The mass spectra of the pleiocarpamine group alkaloids are simple and characteristic. Loss of the C-16 substituent (COZMe or CHzOH) gives a peak a t m/e 263 shifted t o m/e 264 in 16-deuterioepipleiocarpamine (CCCXXXV) and t o m/e 265 in 19,20-dihydronormavacurine(CCCXL) but retained a t m/e 263 in pleiocarpaminol-17dz (CCCXXXVI, R = D). Further decomposition probably involving initial retro-Diels Alder cleavage of ring C gives fragment a a t m/e 180 shifted to m/e 181 in the 16-deuterio compound (CCCXXXV) but split between mje 180 and 182 in the dihydro compound (CCCXL). The 2,7-dihydro series show peaks a t m/e 135 and 107 which may be represented as c and d formed from the initial cleavage product, b. Norfluorocurine and fluorocarpamine

15

a'

a 180 CCCXLVII Fluorocarpamine

q -q b

c

+

HOCHz

e

f 265

135

d 107

9. Aspidosperma

r

R-X

291

AND RELATED ALKALOIDS R

R

LiAlHa

+ THF. A

CHzOH CCCXLVIII

Me

CHzOH CCCLIV

CHzOH CCCXLIX: R = H CCCL: R = M e

Me

CHzOH CCCLII; R = H CCCLIII; R = Ma

H

'CH20H

CCCLI

CCCLV

(CCCXLVII) exhibit a base peak at m/e 121 ( 9 ) formed from the fragment f,mass 265, which is also registered. The structures of the Emde degradation product, e,-dihydromavacurine (Volume VIII, pp. 526-527) and its methiodide, can now be reformulated as CCCXLVIIIeCCCXLIX and CCCL$CCCLI. Both may be reduced by lithium aluminum hydride to dihydroderivatives (CCCLII and CCCLIII). The "alkaline" form of the methiodide (CCCLI) reacts with methyl iodide once more t o give a compound which is formulated as CCCLIV, although its UV-spectrum does not alter in alkali to that of the a-methyleneindoline chromophore (as CCCLI). The cis disposition of C-3H- and C-2-N bonds precludes Hofmann opening. CCCLII and its epimer CCCLV have also been prepared by successive catalytic reduction (with or without alkaline epimerization a t C-16), salt formation, and LiAIH, reduction of pleiocarpamine (CCCXXXIII) (93). The total synthesis of pleiocarpamine has been described (96').

IX. Double Alkaloids A. INTRODUCTION Till recently progress has been made with double alkaloids only when they could be split into their component fragments. Even then the

292

B. GILBERT

structures were not always completely soluble by chemical methods ; in the case of leurocrystine the X-ray method provided the finishing touches. However, the use of high-resolution mass spectrometry in conjunction with isotopic labeling is now permitting progress with the noncleavable bases. Vinca alkaloids are mentioned in Section I I , E and details of their chemistry as well as tha.t of the AZstonia double alkaloids will be found in the appropriate chapters of this volume.

B. PLEIOMUTINE The structure of pleiomutine (CCCLVI) was resolved by two groups simultaneously using very similar methods (5, 6). Mass spectrometry established the molecular formula, C41H50N402, and previously obtained data (Volume VIII) showed that the alkaloid had indole and indoline chromophores, no OH or NH group, one methoxyl group presumably in a carbomethoxyl (v, 1730 cm-I), one N-methyl group, and no hydrogenatable double bond. Lithium aluminum hydride reduction gave an alcohol, C40H50N40 (CCCLVII, v, 3650 cm-I), confirming the presence of COzMe in the alkaloid. Heating with 4 N hydrochloric acid gave a little pleiocarpinine (CXLII) but mainly the acid (CCCLVIII) and the ring-closed kopsanone derivative, pleiomutinone (CCCLIX). The important cleavage product, pleiocarpinine (CXLII) could be obtained in better yield by refluxing ploiomutine with 50 yo phosphoric acid, but the other fragment, later seen to be eburnamenine (CCCLX) was not stable under the acid conditions. The ring D peaks, a and b of pleiocarpi-

CCCLX

CCCLXT; R = OH CCCLXII; R = H

Exlc5i$j Me

CCCLVI; R = COzMe CCCLVII: R=CHzOH CCCLVIII: R = COzH CXLII

CCCLIX E = 14'-eburnamyl

9. Aspidosperma

293

AND RELATED ALKALOIDS

nine a t m/e 109, 124 are prominent in the mass spectrum of pleiomutiiie but the indole-containing fragments of pleiocarpinine are shifted to mass values 278 units heavier. Pleiomutinine must therefore contain pleiocarpinine with a substituent mass 279 which must be located on the aromaticring o r a t C-11. (C-4to C-lOandC-20,21arepresentinthering-D fragments and a hydrogen atom a t C-3 is necessary for the formation of 6 . ) The accurately measured mass 279 corresponds t o CIgH23N2 and taking into account the indolic UV-component and that the NMRspectrum of pleiomutine shows the terminal methyl of an ethyl group (triplet, 0.88 ppm), a likely fragment is represented by the skeleton of eburnamine (CCCLXI). The known fragmentation of dihydroeburnamenine (CCCLXI1)resultsin the production of ions c (M - 29), d (M - 70), and e (M- 72) by loss of the ethyl group and atoms of rings C and D. Peaks corresponding t o these losses occur in the mass spectrum of pleiomutine. It is reasonable t o suppose therefore that the pleiocarpinine moiety is attached a t some point in rings A, B, and E. I n the lower mass range a series of peaks occur containing only C, H, and N (for example, m/e 185, 252, and 265) (see Charts I and 11).These can be derived from dihydroeburnamenine by plausible fragmentation paths. All retain rings A and B but lack one or more atoms of ring E. I n the upper mass range appear a series of complementary peaks whose accurately determined mass show that they contain the balance of the pleiomutine molecule (for example a t m/e 445,378, and 365). The remaining principal peaks in the spectrum of pleiomutine are derivable by simultaneous fragmentation of both moieties in the manner illustrated. The presence of the eburnamyl portion was eventually established by reductive hydrolysis with tin and hydrochloric acid of pleiomutine which gave dihydroeburnamenine (CCCLXII). Furthermore, eburnamine

y) 'T' 4 CH2'

21

a 109

20

b 124

Efl 'q Me

Me

E = 14'- eburnamyl ( = 279)

506

R m/e observed H 266 + 278 = 544 COzMe 324 + 278 = 602

E

COzMe

q M~ 493

CHARTI. Fragments from pleiocarpinine breakdown.

COzMe

294

B. GILBERT

/ M-29 = 601

M-70=560

M-72 = 558

d

C

f?

Peaks retaining ring E intact

QqJJ 07% 265, CisHziNz+

365, Cz3HzgNzOz+ P = 15-Pleiocarpinyl

253, Ci,HzoNz+

378, Cz4HsoNzOz+ Complementary pairs

CHART 11. Fragments from eburnamine breakdown.

(CCCLXI) and pleiocarpinine (CXLII) condense under acid conditions to give pleiomutine (CCCLVI) ( 5 , 6 ) . The point of attachment, already limited by the above mass spectral information, was established by NMR spectrometry and deuteration studies. Pleiomutine contains only 7 aromatic protons; on treatment with 4 N-DCl, 5 of these disappear in the NMR-spectrum, the remaining pair appearing as a 2-proton singlet (7.16 ppm). Brief treatment of the pentadeuterioderivative (CCCLXIII) with HC1 removes one deuterium atom (to CCCLXIV) and the NMRspectrum now shows an ABM pattern, A and B, the original protons, now showing ortho-meta and meta coupling, while M, the new proton, is more shielded and shows o-coupling. This pattern is compatible with partial structure CCCLXV but not, for example, with CCCLXVI. Cleavage of pleiomutine under deuterated acid conditions (D3P04) gives a bisdeuteriopleiocarpinine which must be 1 5 , 1 7 - d ~(CCCLXVII) since it is also obtained from pleiocarpinine itself by acid deuteration. On the other hand, cleavage of pleiomutine with tin and DCl gives hepta- and octadeuteriodihydroeburnamenine (CCCLXVIII). I n the mass spectrum of pentadeuteriopleiomutine (CCCLXIII) all those fragments which

9. Aspidosperma

295

AND RELATED ALKALOIDS

were considered above to contain the eburnamine indole nucleus are shifted four units to higher mass, whereas those containing the pleiocarpinine aromatic ring are increased by only one unit. Part structure CCCLXV is therefore in the pleiocarpinine moiety which is linked via C-15 to the eburnamyl portion in which the aromatic ring is unsubstituted. A C-16 linkage is excluded by the production of CCCLXVII on DCl hydrolysis of pleiomutine.

R

HM

CCCLXV

CCCLXVI

c

D

CO2Me

CCCLXIII; CCCLXIV;

R =D R=H

CCCLXVII

CCCLXVIII; R = H or D

Attachment a t the 14’-position in the eburnamyl portion is established, not only by the above mass spectrometric and synthetic evidence, but also by the fact that in the hepta- and octadeuteriodihydroeburnamenine mass spectra fragments c and d retain ali the deuterium atoms. Since two of these must have been introduced through reversible imine-enamine interconversion and two by reduction of an enamine double bond the only reasonable distribution is that shown in CCCLXVIII and the pleiocarpinine linkage is therefore a t C-14’. The axial proton a t C-14 in eburnamine (CCCLXI) appears a t 5.4 ppm ( J = 5 and 10 cps). Similar coupling constants observed for a one proton absorption a t 5.0 ppm in the spectrum of pleiomutine (CCCLVI) may be attributed to the C-14‘ hydrogen atom which is thus axial (5). C. VOBTUSINE AND CALLICHILINE Vobtusine is the first noncleavable double alkaloid for which something approaching a complete structure has been presented (46, 85). Although a widespread alkaloid, its structure has resisted attempts at

296

B. GILBERT

solution over a long period because of the failure to split the alkaloid into its component parts. Cleavage can be achieved in the mass spectrometer and with high resolution the problem reduces to that of identifying the fragments, knowing their molecular formulas, and the variations undergone when chemical operations of a superficial nature are performed. Vobtusine, C43H~oN406,was shown by standard physical and analytical methods to contain two active hydrogen atoms, seven aromatic hydrogens, one methoxyl, one carbomethoxyl, but no C- or N-methyl. The UV- spectrum is the sum of /I-anilinoacrylate (CCCLXIX) and 17-methoxy-N-alkyldihydroindole(CCCLXX) chromophores. The former, common to a number of alkaloids such as vincadifformine and akuammicine, was carried through a well-established series of transformations (CCCLXIX+CCCLXXI, CCCLXXII, CCCLXXIII, CCCLXXIV, CCCLXXV). These changes, to what is designated part A of the molecule, were accompanied by the expected molecular weight changes and in each case the UV-spectrum was the sum of the B chromophore (CCCLXX) with the modified A chromophore, showing that no other reaction had occurred. A further series of products was obtained, under acid conditions in which the B portion suffered dehydration. According to the nature of the acid and the temperature, the products were anhydrovobtusine (CCCLXXVIII), apovobtusine (CCCLXXIX), and demethylapovobtusine (CCCLXXX), the UV-spectra corresponding to the sum of the appropriate A chromophore and a B chromophore which could now be recognized as a methylene indoline with a fully substituted double bond (no vinyl protons) as in CCCLXXVI or CCCLXXVII. LiAlH4 or NaBH4 reduction and catalytic hydrogenation reduced only the A portion of apovobtusine (CCCLXXIX) to a dihydroindole (CCCLXXXI) giving dihydroapovobtusine (CCCXXXII). The B portion double bond could only be reduced with zinc and acid (85) or nascent diborane (as),to give the products tetrahydroanhydrovobtusine (CCCLXXXIII) and tetrahydroapovobtusine (CCCLXXXIV), the appropriate sum of chromophores (CCCLXXXV+ CCCLXXXVI or CCCLXXXI) being observed. With nascent perdeuterioborane, dihydroapovobtusine (CCCLXXXII) gave B-dz-tetrahydroapovobtusine (CCCLXXXVII). All of these derivatives showed the expected molecular weights and additionally the dehydration of the B portion requires the presence in vobtusine of a tertiary hydroxyl group (not acetylated, no vinyl protons after dehydration) which cannot be in a carbinolamine grouping (resistant to reduction) and is therefore restricted to the position marked with ail asterisk in CCCLXXVI or CCCLXXVII. There is no further

9. Aspidosperma

297

AND RELATED ALKALOIDS

cccLxxIII

CCCLXXII M+, 674

CCCLXIX M+, 718

1

I

CCCLXXI M+, 660

CCCLXXIV M+, 676

M+, 692

CCCLXXV M+, 696

Part B is unaltered in the above six derivatives

I* c CCCLXXXI ; R =H CCCLXXXVI; R = COaMe

CCCLXXVII

CCCLXX

.C;”-y+c Ro

c

CCCLXXVI Part A CCCLXXVIII (CCCLXIX) CCCLXXIX (CCCLXXI) CCCLXXX (CCCLXXI) CCCLXXXII (CCCLXXXI)

QT&c Me0

C

CCCLXXXV R M+ Me 700 Me 642 H 628 Me 644

Part A R CCCLXXXIII (CCCLXXXVI) H CCCLXXXIV (CCCLXXXI) H CCCLXXXVII (CCCLXXXI) D

M+ 704 646 648

298

B . GILBERT

hydroxyl group present since the two active hydrogens have been accounted for and apo derivatives show no M-HzO peak, nor is there any other carboriyl group as the IR-spectrum of decarbomethoxy derivatives attests. (A medium strength band a t 1713 em-1 is attributed to the evidently strained C=C double Fond in CCCLXXVI derivatives since it disappears when t)his is reduced.) The remaining two oxygen atoms are therefore ethereaI. B : b , 504

A

: a

COzMe CCCLXXIX

I

R CCCLXXIII H CCCLXXIV H CCCLXXV D CCCLXXXIII H

R

'

CHzOH CH3 CDzOH COzMe

c

d

b

130 562 504 130 504 131 565 504 130 574 488

COzMe n \+

N3B Q)---Ibxz CH

R

R R'

d

P

b

With this information in hand the mass spectral breakdown patterns of the various derivatives are very informative. The indolic portion of part A , for example, is unsubstituted since the loss of C13H12N02 (probably fragment a ) produces a peak a t m/e 504 (fragment b ) in vobtusine which persists in the spectra of the reduced A products CCCLXXIII, CCCLXXIV and CCCLXXV. The latter three compounds and tetrahydroanhydrovohtusine (CCCLXXXIII) also show the expected indolic fragments ( c and homolog) as well as the complementary portion (d). CCCLXXV contaiiis four deuterium atoms in part A and in the cleavage just mentioned one is retained in c and three in d. These two types of fragmentation are characteristic of the vincadifformine and aspidospermidine skeleton and this was therefore assigned

9. Aspidosperma

AND RELATED ALKALOIDS

299

to part A in which the B portion must be attached a t some point between C-5 and (2-8, on C-19, or on two carbon atoms C-20,21 not yet located ((3-10 excluded by observation of c homolog a t m/e 144). Fragmentation of part B can also be interpreted on the basis of an aspidospermidine skeleton. Indolic peaks with composition corresponding to e and its homolog appear in the spectra of all those derivatives that do not contain a double bond in part B (which would inhibit the normal breakdown). When two deuterium atoms are introduced into B (CCCLXXXVII) one appears in the fragment e and therefore one end of the double bond of the apo and anhydro derivatives is present therein. If part structure CCCLXXVII for “apo-B” were correct then formation of e from its dihydro derivative would involve a cleavage and double hydrogen transfer very difficult to envisage. CCCLXXVI therefore represents the most acceptable arrangement for “ apo-B.” Another intense peak a t m/e 138 accompanied by a satellite a t m/e 110 and insensitive to modifications of parts A and B is reminiscent of the ring D fragment of beninine (CCLIII) an alkaloid which, as mentioned in Section V,C, occurs with vobtusine in Callichilia (Hedanthera)barter;. This peak may therefore be ascribed provisional structure f. Fragment g, the complement of,f, appears in apovobtusiiie (CCCLXXIX)a t M - 138 (504, C33H34N302+), while in vobtusine (CCCLXIX) and derivatives (CCCLXXI-CCCLXXIV) which retain the part B hydroxyl group the position of the peak is at M- 156 (M- 138-H~O).I n the spectrum of vobtusine a stronger peak, g’, is seen at m/e 504 (C33H34N302+)corresponding to simultaneous loss of the carbomethoxyl group in g. This fragment (g or g‘) then undergoes further decomposition documented in a number of cases by a metastable peak [e.g., dihydrovobtusine (CCCLXXXVIII), 564 to 365 (m* 236.2)l t o a fragment h (or h’) which varies with variations in A but not with variations in B. Thus h represents A C3H30. These additional atoms contain the last unaccounted oxygen atom of vobtusine and since this never appears in B fragments it is probably involved in an ether ring internal to part A. Thus h may be depicted as illustrated, partly by analogy and partly by identification of a smaller fragment a t m/e 149 (i) which appears to derive from it. The methylene group placed a t C-7 in h and i could also be a t a number of other positions such as, for example, C-20. Other identified fragments confirm the above data but the problem of how the two parts of vobtusine are united is as yet unsolved. If the beninine-like structures for A and B are correct then the junction contains two carbon atoms, those linked to N,, and C-3 of part B and one ring. The methylene group provisionally a t C-7 in h and i is one of the bridge atoms. A partly obscured AB pattern due to geminal protons

+

300

w

c

B . GILBERT

1 I II

aa

++

E CV

\ / g

sj

B

9

9'

CCCLXIX intact 562(M-156) 504 CCCLXXXVIII intact 564(M-156) CCCLXXIII intact 536(M-156) CCCLXXIX -HzO 504(M-138) CCCLXXVIII -HzO 562(M--138)

h, 363 2,3-Dihydro-h, 365

h', 305

i , 149

B. GILBERT

302

adjacent to nitrogen (5.14 and 3.09 ppm, J = 12 in vobtusine) is apparently without further coupling and on this basis spiro structures such as CCCLXXXIX have been suggested as working hypotheses (46, 85). Callichiline, C42H48N405, accompanies vobtusine in nature, and its structure is undoubtedly very similar. CCCXC is among structures which have been suggested for this alkaloid (97, 98).

COzMe

cccxc CCCLXXXIX

D. HAPLOPHYTINE X-Ray crystallographic investigation of the dihydrobromide, supported by chemical studies of the acid cleavage product (CCCXCI), has shown that haplophytine, C37H4oN407, has structure CCCXCII (99).

Me0

CCCXCI

0 CCCXCII

9. Aspidosperm

AND RELATED ALKALOIDS

303

REFERENCES 1. K. Bernauer, G. Englert, and W. Vetter, Ezperientia 21, 374 (1965). 2. J. A. Joule, M. Ohashi, B. Gilbert, and C. Djerassi, Tetrahedron 21, 1717 (1965). 3. K. Biemann, Advan. Chemotherapy 3, 95 (1964). 3a. K. Biemann and W. McMurray, Tetrahedron Letters 647 (1965). 4. H. Achenbach and K. Biemann, J . Am. Chem. Soc. 87,4944 (1965). 5. M. Hesse, F. Bodner, and H. Schmid, Helv. Chim. Acta 49, 964 (1966). 6. D. W. Thomas, H. Achenbach, and K. Biemann, J. Am. Chem. SOC.88, 1537 (1966). 7. J. E. D. Barton and J. Harley-Mason, Chem. Commun. 298 (1965). 8. J. P. Kutney, N. Abdurahman, P. Le Quesne, E. Piers, a n d I . Vlattas, J . Am. Chem. SOC.88, 3656 (1966). 9. J. Le Men and W. I. Taylor, Ezperientia 21, 508 (1965). 9s. J. Trojanek and K. Blaha, Lloydia 29, 149 (1966). 10. J. Mokrf and I. KompiB, Chem. Zvesti 17, 852 (1963). 11. J. Trojanek, 0. Btrouf, K. Blaha, L. DolejB, and V. Hanui, Collection Czech. Chem. Commun. 29, 1904 (1964). 12. A. Walser and C. Djerassi, Helv. Chim. Acta 48, 391 (1965). 13. J.Mokrf,I.KompiB,M.Shamma,andR.J. Shine,Chem. & Ind. (London)1988(1964). 14. J. Trojanek, 0. Qtrouf, K. Kavkova, and Z. Cekan, Collectioia Czech. Chem. Commun. 25, 2045 (1959). 15. J. Mokrf, I. Kompii, L. Dubravkova, and P. SepEoviE, Tetrahedron Letters 1185 (1962). 16. D. Zachystalova, 0. Btrouf, and J. Trojanek, Chem. & Ind. (London) 610 (1963). 17. J. Trojanek, J. Hoffmannovb, 0. Strouf, and Z. Cekan, Collection Czech. Chem. Commun. 24, 526 (1959). 18. B. K. Moza and J. Trojanek, Chem. & Ind. (Londoiz) 1260 (1965). 19. H. H. A. Linde, Helv. Chim. Acta 48, 1822 (1965). 19a. W. G. Kump, M. B. Patel, J. M. Rowson, and H. Schmid, Helv. Chim.Acta 47, 1497 (1964). 19b. B. W. Bycroft, D. Schumann, M. B. Patel, and H. Schmid, Helv. Chim. Acta 47,1147 (1964). 1%. J. Mokrf, I. KompiZj, and G. Spiteller, Collection Czech. Chem. Commun. 32, 2523 (1967). 19d. H. Achenbacb, Tetrahedron Letters 1793 (1967). 20. B. K . Moza and J. Trojanek, CoZEection Czech. Chem. Commun. 28, 1419 (1963). 20a. D. Groeger, K. Stolle, and C. P. Fanshaw, Naturwiss. 52, 132 (1965). 20b. V, M. Malikov, P. K. Yuldashev, and S. Yu. Yunusov, Dokl. Akad. Nauk. Uz. SSR 20, 21 (1963); C A 59, 11584 (1963). 21. B. K. Moza, J. Trojhek, A. K. Bose, K. G. Das, and P. Funke, Tetrahedron Letters 2561 (1964). 22. B. K. Moza, J. Trojbnek, A. K. Bose, K. G. Das, a n d P . Funke, Lloydia 27,416 (1964). 22a. B. Pyuskyulev, I. KompiS, I. Ognyanov, and G. Spiteller, Collection Czech. Chem. Commun. 32, 1289 (1967). 23. €3. Das, K. Biemann, A. Chatterjee, A. B. Ray, and P. L. Majumder, Tetrahedron Letters 2483 (1966). 24. P. Relyveld, Ph.D. Thesis, University of Utrecht (1966). 25. K. H. Palmer, Can.J. Chem. 42, 1760 (1964). 26. K. Bernauer, G. Englert, and W. Vetter, in publication. 27. C. Kump, J. Seibl, and H. Schmid, Heh. Chim. Acta 47, 358 (1964). 28. L. D. Antonaccio, 8.Gilbert, and L. A. Paes Leme, unpublished results (1966).

304

B. UILBERT

29. B. Das, K. Biemann, A. Chatterjee, A. B. Ray, and P. L. Majumder, Tetrahedron Letters 2239 (1965). 30. Z. M. Khan and M. Hesse, Helw. Chim. Acta 48, 1957 (1965). 30a. Z. M. Khan, M. Hesse, and H. Schmid, Helw. Chim. Acta 50, 625 (1967). 31. H. Achenbarh and K. Biemann, Tetrahedron Letters 3239 (1965). 32. C. Kump, J. Seibl, and H. Schmid, Helv. Chim. Acta 48, 1002 (1965). 33. J. M. Ferreira Filho, B. Gilbert, M. Kitagawa, L. A. Paes Leme, and L. J. Durham, J . Chem. Soc., C, Org. 1260 (1966). 34. R. R. Arndt, S. H. Brown, N. C. Ling, P. Roller, C. Djerassi, J. M. Ferreira F., B. Gilbert, E. C. Miranda, S. E. Flores, A. P. Duarte, and E. P. Carrazzoni, Phytochemistry 6, 1653 (1967). 35. R. H. Burnell, J. D. Medina, and W. A. Ayer, Can. J . Chem. 44, 28 (1966). 36. K. S. Brown, Jr., W. E. Sanchez L., A. de A. Figueiredo, and J. M. Ferreira F., J . Am. Chem. Soc. 88, 4984 (1966). 37. K. S. Brown, Jr. and C. Djerassi, J . Am. Chem. SOC.86, 2451 (1964). 37a. M. Pinar and H. Schmid, Helv. Chim. Acta 50, 89 (1967). 38. M. Pinar, B. W. Bycroft, J. Seibl, and H. Schmid, Helw. Chim. Acta 48, 822 (1965). 39. M. Ohashi, J. A. Joule, B. Gilbert, and C. Djerassi, Ezperientia 20, 263 (1964). 39a. A. J. Gaskell and J. A. Joule. Unpublished work (1967). 40. B. Gilbert, A. P. Duarte, Y . Nakagawa, J. A. Joule, S. E. Flores, J. Aguayo B., J. Campello, E. P. Carrazzoni, R. J. Owellen, E. C. Blossey, K. S. Brown, Jr., and C. Djerassi, Tetrahedron 21, 1141 (1965). 41. M. A. Ondetti and V. Deulofeu, Tetrahedron 15, 160 (1961). 42. R. R. Arndt and C. Djerassi, Ezpperientia 21, 566 (1965). 420. G. H. Svoboda, J . Pharm. Sci. 52,407 (1963). 42b. R. N. Blomster, R. E. Martello, N. R. Farnsworth, and F. J. Draus, Lloydia 27, 480 (1964). 42c. U. Renner and P. Kernweisz, Ezperientia 19, 244 (1963). 43. A. Walser and C. Djerassi, Helw.Chim. Acta 47, 2072 (1964). 44. M. Hesse, H. Hurzeler, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, Helw. Chim.Acta 48, 689 (1965). 45. P. Relyveld, Pharm. Weekblad 100, 614 (1965). 46. J. Poisson, M. Plat, H. Budzikiewicz, L. J. Durham, and C. Djerassi, Tetrahedron 22, 1075 (1966). 47. W. Jordan and P. J. Scheuer, Tetrahedron 21, 3731 (1965). 48. R. Kaschnitz and G. Spiteller, Monatsh. 96, 909 (1966). 49. H. Achenbach and K. Biemann, J . Am. Chem. Soc. 87,4177 (1965). 50. W. E. Sanchez L. and K. S. Brown, Jr., Anais Acad. Bras. Cizncias 39 (1968), in publication. 51. C. Djerassi, H. J. Monteiro, A. Walser, and L. J. Durham, J . Am. Chem. SOC. 88, 1792 (1966). 51a. 0.0. Orazi, R. A. Corral, and M. E. Stoichevich, Can. J . Chem. 44, 1523 (1966). 52. J. Mokrj., I. KompiB, H. K. Schnoes, K. Biemann, A. Chatterjee, and G. Ganguli, J . Org. Chem. 31, 1641 (1966). 53. M. Ohashi, J. A. Joule, and C. Djerassi, Tetrahedron Letters 3899 (1964). 54. N. Kunesch, B. C. Das, and J. Poisson, I U P A C Symp. Chem. Nat. Prod., Stoclcholm, 1966, Abstract Book, p. 89. 55. M. B. Pate1 and J. Poisson, Bull. SOC.Chim. France 427 (1986). 55a. B. C. Das, E. Fellion, and M. Plat, Compt. Rend. Acad. Sci. 264, C, 1765 (1967). 55b. P. Roller and C. Djerassi. Unpublished work (1967).

9. Aspidospemna

AND RELATED ALKALOIDS

305

55c. N. J. Dastoor, A. A. Gorman, and H. Schmid, Helv. Chim. Acta 50, 213 (1967). 55d. P. R.Benoin, R. H. Burnell, and J. D. Medina, Can. J. Chem. 45, 725 (1967). 55e. R.H. Burnell and D. D. Casa, Can. J. Chem. 45, 89 (1967). 66. J. P.Kutney, J. Trotter, T. Tabata, A. Kerigan, a n d N . Camerman, Chem. & I n d . (London) 648 (1963). 57. N. Camerman and J. Trotter, Actu Cryst. 17, 384 (1964). 58. A. Camerman, N. Camerman, J. P. Kutney, E. Piers, and J. Trotter, Tetrahedron Letters 637 (1965). 59. W. Klyne, R. J. Swan, B. W. Bycroft, and H. Schmid, Helv. Chim. Acta 49, 833 (1966). 60. D. Schumann, B. W. Bycroft, and H. Schmid, Ezperientia 20, 202 (1964). 61. W. Klyne, R.J. Swan, B. W. Bycroft, D. Schumann, and H. Schmid, Helv. Chim. Acta 48, 443 (1965). 61a. H. Achenb&ch, Tetrahedron Letters 6027 (1966). 61b. C. Ferrari and L. Marion, Can.J. Chem. 42, 2705 (1064). 62. J. W. Moncrief and W. N. Lipscomb, J . A m . Chem. SOC.87, 4963 (1965). 63. M. Plat, J.Le Men, M.-M. Janot, H. Budzikiewicz, J. M. Wilson, L. J. Durham, and C. Djerassi, Bull. Soc. Chim. France 2237 (1962). 64. J. P.Kutney and E. Piers, J. Am. Chem. Soc. 86,953 (1964). 65. J. Mokrf and I. Kompih, Lloydia 27, 428 (1964). 65a. J. J. Dugan, M. Hesse, U. Renner, and H. Schmid, Helv. Chim. Actu 50, 60 (1967). 65b. N. Kunesch, B. C. Das, and J. Poisson, Bull. Soc. Chim. France 2155 (1967). 66. S. Markey, K. Biemann, and B. Witkop, Tetrahedron Letters 157 (1967). 66a. M. Spiteller-Friedmann, R. Kaachnitz, 0. Spiteller, A. Chatterjee, N. Adityachaudhury, and G. Ganguli, Monatsh. 95, 1228 (1964). 67. Y. Ban, Y. Sato, I. Inoue, M. Nagai, T. Oishi, M. Terashima, 0. Yonemitsu, and Y. Kanaoka, Tetrahedron Later8 2261 (1966). 68. M.E.Kuehne and C. Bayha, Tetrahedron Letters 1311 (1966). 69. J. E.D.Barton, J. Harley-Mason, and K. C. Yates, Tetrahedron Letters 3669 (1965). 69a. M. Gorman, N. Neuss, and N. J. Cone, J . A m . Chem. SOC.87,93 (1965). 69b. J. P. Kutney, R. T. Brown, and E. Piers, J . A m . Chem. Soc. 86,2286 (1964). 69c. J. P.Kutney, R. T. Brown, and E. Piers, Lloydia 27, 447 (1964). 69d. J. P.Kutney, W. J. Cretney, P. Le Queane, B. McKague, and E. Piers,J. A m . Chem. Soc. 88,4756 (1966). 69e. J. Harley-Mason and M. Kaplan, Chem. Commun. 915 (1967). 70. J. P. Kutney, R. T. Brown, and E. Piers, Can.J . Chem. 44, 637 (1966). 71. N. Neuss, BulLSoc. China. France 1509 (1963). 72. N. Neuss, M. Gorman, W. Hargrove, N. J. Cone, K. Biemann, G. Buchi, and R. E. Manning, J. Am. Chem. Soc. 86, 1440 (1964). 72a. N. Neuss, I. S. Johnson, J. G. Armstrong, and C. J. Jansen, Adwan. Chemotherapy 1, 133-174 (1964). 72b. G. E.Mallett, D. S. Fukuda, and M. Gorman, Lloydia 27, 334 (1964). 72c. N.Neuss, L. L. Huckstep, and N. J. Cone, Tetrahedron Letters 81 1 (1967). 72d. D. J. Abraham, N. R. Fanisworth, R. N. Blomster, and R. E. Rhodes, J. Pharm. Sci. 56, 401 (1967). 7%. J. Harley-Mason and Atta-ur-Rahman, Chem. Cvmmun. 1048 (1967). 73. H.K. Schnoes and K. Biemann, J . Am. Chem. Soc. 86, 5693 (1964). 74. E.Wenkert, J. Am. Chem. Soc. 84, 98 (1962). 748. A. Guggisberg, A. A. Gorman, and H. Schmid, private communication (1966);also cited in Kump et al. ( 7 8 ) .

306

B. GILBERT

75. C. Djerassi, S. E. Flores, H. Budeikiewicz, J. M. Wilson, L. J. Durham, J. Le Men, M. M. Janot, M. Plat, M. Gorman, and N. Neuss, Proc. Natl. Acad. Sci. U.S. 48, 113 (1962). 76. C. Djerassi, M. Cereghetti, H. Budzikiewicz, M. M. Janot, M. Plat, and J. Le Men, Helv. Chim. Acta 47, 827 (1964). 76a. N. Abdurakhimova, P. K. Yuldashev, and S. Y. Yunusov, Dokl. Akad. Nauk SSSR, 173, 87 (1967); C A 67, 54320 (1967). 77. K. Bernauer, 4th I U P A C S y m p . Nat. Prod., Stockholm, 1966, Abstract Book, p. 90. 78. C. Kump, J. J. Dugan, a n d H . Schmid, Helv. Chim. Acta 49, 1237 (1966). 79. D. W. Thomas, H. Achenbach, and K. Biemann, J. Am. Chem. SOC.88, 3423 (1966). 79a. D. W. Thomas, K. Biemann, A. K. Kiang, and R. D. Amarasingham, J. Am. Chem. SOC.89, 3235 (1967). 80. A. R. Battersby, J. C. Byrne, H. Gregory, and S.F. Popli, Chem. Commun. 786 (1966). 81. A. Guggisberg, M. Hesse, W. von Philipsborn, K. Nagarajan, and H. Schmid, Helv. Chim. Acta 49, 2321 (1966). 82. A. R. Battersby, J. C. Byrne, H. Gregory, and S. F. Popli, J.Chem. SOC., C, Org. 813 (1967). 83. A. R. Battersby and H. Gregory, J. Chem. SOC.22 (1963). 84. A. Guggisberg, T. R. Govindachari, K. Nagarajan, and H. Schmid, Helv. Chim. Acta 46, 679 (1963). 84a. P. Relyveld, Pharm. Weekblad 98, 503 (1963). 85. A. A. Gorman, V. Agwada, M. Hesse, U. Renner, and H. Schmid, Helv. Chim. Acts 49, 2072 (1966). 86. H. J. Monteiro, Ph.D. Thesis, Stanford University (1966); Dissertation Abstr. 27, B, 1096 (1966). 86a. M. Shamma, J. A. Weiss, and R. J. Shine, Tetrahedron Letters 2489 (1967). 86b. A. Jackson and J. A. Joule, Chem. Commun. 459 (1967). 87. J. A. Joule, H. Monteiro, L. J. Durham, B. Gilbert, and C. Djerassi, J. Chem. SOC. 4773 (1965). 88. J. W. Loder, AustralianJ. Chem. 19, 1947 (1966). 89. R . N. Stillwell, Dissertation Abstr. 25, 2769 (1964). 90. C. W. Mosher, 0. P. Crews, E. M. Acton, and L. Goodman, J. Med. Chem. 9, 237 (1966). 91. A. Z. Britten, G. F. Smith, and G . Spiteller, Chem. & Ind. (London) 1492 (1964). 92. L. Olivier, J. LBvy, J. Le Men, M.-M. Janot, H. Budzikiewicz, and C. Djerassi, Bull. SOC. Chim. France 868 .(1965). 93. M. Hesse, W. von Philipsborn, D. Schumann, G. Spiteller, M. Spiteller-Friedmann, W. I. Taylor, H. Schmid, and P. Karrer, Helv. Chim. Acta 47, 878 (1964). 94. L. J. Durham, N. Bhacca, and H. Budzikiewicz, Tetrahedron Letters 5 (1965). 95. G. B. Guise, E. Richie, and W. C. Taylor, AustraZianJ. Chem. 18, 927 and 1279 (1965). 96. 0. N. Tolkachev, V. G. Korobko, T. A. Shapiro, N. A. Preobrazhenskii, and M. V. Lomonosov, Khim. Geterots. Soed. 313 (1967);Index Chemicus 26, 84645 (1967). 97. M. Plat, N. Kunesch, J. Poisson, C. Djerassi, and H. Budzikiewicz, Bull. SOC.Chim. Prance 2669 (1967). 98. V. Agwada, A. A. Gorman, M. Hesse, and H. Schmid, Helv. Chim. Acta 50, 1939 (1967). 99. I. D. Rae, M. Rosenberger, A. G. Szabo, C. R. Willis, P. Yates, D. E. Zacharias, G. A. Jeffrey, €3. Douglas, J. L. Kirkpatrick, and J. A. Weisbach, J . Am. Chem. SOC. 89, 3061 (1967).

-CHAPTER

10-

THE AMARYLLIDACEAE ALKALOIDS W . C. WILDMAN Iowa State University. Ames Iowa

I . Introduction and Occurrence ...................................... I1 Lycorine-Type Alkaloids ............................................

.

.

A 1-0-Acetyllycorineand Poetaminine ............................ B . 2-0-Acetyllycorine(Aulamine) .................................... C. Amaryllidine ................................................... D . Falcatine ...................................................... E . Golceptine and Goleptine., ...................................... F Hippamine (2-0-Methyllycorine).................................. G. Jonquilline .................................................... H . Lycorine ...................................................... I . Methylpseudolycorine, Galanthine, and Pluviine .................... J . Narcissidine ................................................... K . Nartazine ..................................................... L. Nerispine ...................................................... M. Norpluviine .................................................... N Parkacine ..................................................... 0. Parkamine and Neflexine., ...................................... P . Suisenine ...................................................... Q . Ungiminorine .................................................. R . Zephyranthine ................................................. I11. Lycorenine-Type Alkaloids .......................................... A Albomaculine and Nerinine ...................................... B. Candimine ..................................................... C . Clivimine and Clivonine ......................................... D . Hippeastrine ................................................... E . Homolycorine and Lycorenine . . . . ............................. F. Krigenamine ................... ............................. G. Krigeine and Neronine .......................................... ............................ H . Masonine and Oduline ........... I . Neruscine ..................................................... J . Nivaline and Unsevine .......................................... K . Penarcine ..................................................... L . Radiatine ..................................................... M . Urceoline and Urminine ......................................... IV . Galanthamine-Type Alkaloids ................................ 307

.

.

.

308 321 321 322 322 323 323 325 325 325 330 331 332 332 332 332 333 333 333 334 334 335 337 338 340 340 343 344 345 345 345 347 347 348 348

.

W C . WILDMAN

308

V . Crinine-Type Alkaloids ............................................. A 3-O-Acetylnerbowdine .. ......................................... B Alkaloid 13 (11-Hydroxyvittatine) ................................ C Alkaloid 16 (Maritidine) ......................................... D. Amaryllisine ................................................... E. Ambetline ..................................................... F. Annapowine ................................................... G . Bowdensine and 0,O-Deacetylbowdensine . ......................... H . Buphanamine .................................................. I . Buphanidrine, Buphanisine, and ( + )-Epibuphanisine. . . . . . . . . . . . . . . . J Crinalbine, Crinamidine, and Related Alkaloids .................... K . Crinine, Vittatine, and Related Alkaloids ........................... L . Crinamine. Haemanthamine, and Their 6-Hydroxy Derivatives ....... M . Haemultine and Fiancine ........................................ VI Montanine, Coccinine, and Manthine ..................................

. . .

.

.

352 354 355 356 357 358 360 360 361 362 362 364 370 373 375

VII . Tazettine-Type Alkaloids ........................................... A . Tazettine., .................................................... B . Criwelline ..................................................... C . Macronine .....................................................

378 378 381 381

VIII . Unclassified Alkaloids and Other Substances ...........................

382

I X . Alkaloids of Undetermined Structure

................................. X . Biosynthesis ...................................................... References ........................................................

387 387 400

.

I Introduction and Occurrence

More than sixty plants of the Amaryllidaceae have been examined for alkaloids in the past 6 years . Major contributions in isolation have been made by research groups in Germany. Sweden. Russia. Egypt. South Africa. and China . Exchange of alkaloid samples has not been frequent. and undoubtedly many of the alkaloids cited in Section I X will prove to be duplications . Typically a new alkaloid found in the family occurs in exceptionally minute amounts. Thus in laboratories not equipped with modern NMR- and mass spectrometers characterization often has been limited t o simple physical constants. combustion analyses. and general comments about the I R - and UV-spectra . Several notable advances have been made in the analytical aspects of the alkaloids . Most alkaloids have proven amenable t o separation and identification by gas phase ( I ) . paper (2). and thin-layer ( 3 ) chromatography . The potential of the latter method is particularly striking . Four alkaloids were isolated from Pancratium maritimum by 1960 using conventional chromatographic and crystallization methods . However.

10.

309

THE ABURYLLIDACEAE ALKALOIDS

two-dimensional thin-layer techniques revealed the presence of a t least 37 alkaloids in the plant (3).At the preparative level, a combination of crystallization, column chromatography, and countercurrent distribution permitted the isolation and identification of 11 alkaloids (representing more than 80% of the total bases) in Ammocharis coranica ( 4 ) . Preparative thick-layer chromatography holds great promise for the future. Recent structural studies have provided two new types of alkaloids based on the 6,11-methanomorphanthridine(5) and the biphenyl ring systems (6). However, the structures of most new alkaloids are merely substitutional variants within the ring systems cited in Volume VI of this series. Although the structures of most major alkaloids have been established with certainty by chemical methods, IR-, NMR-, and mass spectroscopy have proved invaluable in confirming many structures and in exploring subtle points of stereochemistry. These same instruments offerthe greatest hope for the structural elucidation of the numerous minor components. Many of these alkaloids which have been reported with meager or ambiguous experimental data have been placed reluctantly in Sections I1 to VIII of this chapter. Table I covers all alkaloid isolations in the family that have been reported in the period between the writing of Volume VI and June, 1966. TABLE I

BOTANICAL DISTRIBUTION Plant Amaryllis belladonna L. var. purpurea major

Amaryllis parkeri Worsl.

Alkaloid Acetylcrtranine Amaryllidine Ambelline Caranine Galanthamine Galanthine Lycorenine Lycorine Caranine Haernultine Hippeastrine Lycorine Methylpseudolycorine Parkacine Parkamine Petomine Urminine

Percent' 0.023 0.0002 0.047

0.0002 0.0006 0.0001 0.0004 0.064 0.016 0.0008 0.0007 0.017 0.001 -

0.064 0.0004 0.001

Reference 8

8 8 8

8 8 8 8

8 8 8 8 8 9 8, 10 8 8

310

W. C. WILDMAN TABLE I-continued Plant

Alkaloid

Ammocharis coranica (Ker-Gawl) Acetylcaranine Herb. Ambelline . Buphanidrine Buphanisine Caranine Coranicine Crinamine ( )-Epibuphanisine ( + )-Epicrinine 6-Hydroxycrinamine Lycorine Brunsdonnine Brunsdonnn tubergenii ( A . Caranine belladonna L. x Brunsvigia Coruscine rosea (Lam.) Hannibal) Galanthine Lycorine Pseudolycorine Brunsvigine Brunsvigia cooperi Baker Brunsvinine Crinamine Lycorine Ambelline Brunsvigia sp. Buphanamine Buphanidrine Nerbowdine 3-Acetylnerbowdine Buphane disticha Herb. Buphacetine Buphanamine Buphanidrine Buphanisine Crinamidine Crinine Distichamine Lycorine Nerbowdine Undulatine Clivia miniata (Hook.) Regel Clivimine Clivonine Lycorine Clivatine Clivonine Hippeastrine Lycorine Miniatine Crinum erubescens Ait. Crinamine 6-Hvdroxvcrinamine

+

Percent" 0.006 0.008 0.011 0.012 0.006 0.020 0.180 0.042 0.19 0.32 0.21 0.081 0.001 0.001 0.001 0.002 0.001 0.22b -

0.032'

o.oloa 0.0005 0.007 0.013 0.01 0.0018 0.0001 0.042 0.058 0.051 0.004 0.022 0.016 0.001 0.033 0.056 0.015' 0.002= 0.03' 0.0005 0.001 0.001 0.023

0.11 0.28

Reference 4 4 4 4 4 4 4 4 4 4 4 11 11 11 11 11 11 12 12 12 12 13 13 13 13 14 14 14,15 14,15 14 14 14 14 14 14,15 14 16 16 16 16 16 16 16 16 17 17

31 1

10. THE AMARYLLIDACEAE ALKALOIDS TABLE I-continued Plant ~

Alkaloid

Percent‘

C. fmbriutulum Baker

Crinum hybrid “Ellen Bosanquet ”

C . Zaureiztii Durand and DeWild.

C. macrantherum Engl.

C . moorei J . D. Hook.

I. ycorine Crinamine 6-Hydroxycrinamine Lycorine Buphanamine Crinamidine Crinine Fiancine Galanthine Haemanthamine Lycorine Powellamine Powelline Tazettine Ambelline Carmine Crinamidine Crinine Galanthamine Haemanthamine Lycorine Powelline Tazettine Acetylcaranine 0-Acetylmacranthine Crinamine Criwelline 0,O-Diacetylmacranthine Lycorine Macranthine Macronine Acet ylcaranine 1-Acetyllycorine Crinamidine Crinine Galanthamine Lycorine Methylpseudolycorine Powelline

C. powellii Hort.

Reference

-

~

Undulatine Belladine Crinamidine Crinamine

0.16 0.04 0.26 0.16 0.002 0.004 0.003 0.0005 0.0003 0.001 0.036 0.0003 0.003 0.0005 0.036 0.012 0.018 0.036 0.006 0.048 0.972 0.024 0.036 0.0008 0.004 0.005 0.002 0.004 0.09 0.003 0.002 0.0002 0.03gd 0.022d 0.060 0.008d 0.0002 0.048 0.026‘ 0.0004 0.0084 0.013d 0.0006

-

-

17 17 17 17 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 18 19 19 19 19 19 19 19 19 20 21 21 20 21 20 20 21 20 20 21 20 11 11 22

312

W. C. WLLDMAN

TABLE I-continued Plant G. powellii Hort.

C . powellii Hort. var. album

C. powellii Hort. var. harlemenae

C . powellii Hort. var. krelagei

Alkaloid Crinine Crinine (phenolic) Haemultine 6 -Hydroxycrinamine Hippeastrine Lycoramine Lycorine Methylpseudoly corine Narcissidine Neflexine Neruscine Petomine Powellamine Powellidine Powelline Undulatine

Percent'

-

-

-

Caranine Crinalbine Crinine Criwelline Haemanthamine Ismine Lycorine Powelline

0.0002 0.0024 0.025 0.0002 0.0024 0.00002

Ambelline Crinine Cripaline Dihydrohaemanthamine Galanthine Lycorine Powelline Tazettine 0-Acetylcrinine (krepowine) Caranine Crinamidine Crinamine Crinine

0.0002 0.017

Galanthamine Krelagine Lycorine

0.0084

0.0072

-

0.0008 0.0002 0.05 0.005 0.0007 0.0020 0.002 0.0003 0.0005

0.03 0.012 0.0008 0.0004 0.0008 0.004

0.042 0.004

Reference

22 22 11 11 11 11 22 22 22 11 11 22 22 22 22 11 23 23 23 23 23 6 23 23 20 20 20 20 20 20 20 20 18 18 20 20 20 23 20 23 20 23 20 23

313

10. THE AMARYLLIDACEAE ALKALOIDS TABLE I-continued Plant

Alkaloid Powelline

C. zeylanicum L.

Galanthus elwesii Hook. f.

G. nivalis L.

0. nivalis var. gracilis L. B. woronovii Losinsk.

Haemanthus katherinae Baker

H . multijlorus Martyn H . natalensis Pappe

H . tigrinus Jacq.

Hippeastrum auliculum Herb. var. robustum (A. Dietr.) Voss

Tazettine Undulatine Crinamine 6-Hydroxycrinamine Lycorine Elwesine Flexinine Galanthamine Lycorine Tazettine Criwelline Galanthamine Haemanthidine Hippeastrine Lycorine Magnarcine Masonine Nartazine Narwedine Tazettine Galanthamine Galanthamine Galanthine Tazettine Galanthamine Haemanthamine Haemultine Hippeastrine Lycorenine Lycorine Lycorine Montanine Haemanthamine Haemanthidine 6-Hydroxycrinamine Coccinine Manthine Montanine 2-0-Acetyllycorine (aulamine) Ambelline Chlidanthine Fiancine

Percent" 0.008 0.006 0.003 0.0002 0.10 0.24 0.05 0.002 0.0005 0.026 0.033 0.023

0.22-1.36'

-

__ 0.002 0.002 0.0004 0.0004 0.01 0.009 0.005 0.01 0.085*

1.00 0.41b 0.91b 0.01 0.02 0.10

-

-

Reference

20 23 20 20 17 17 17 18 18 18 18 18 24 24 24 24 24 24 24 24 24 24 25 26 26 36 18 18 18 18 18 18 27 27 28 29 29 28,29 5 5 5 24 24 24 24

314

W. C. WILDMAN

TABLE I-continued Plant

Alkaloid

Percent“

Reference -

Hippeastrum auliculum Herb. var. robustum (A. Dietr.) Voss

H . brachyandrum Baker [Habranthus brachyandrus (Baker) Scaly]

H . candidum Herb. Hippeastrum ap.

Hippeastrum hybrids “Anna Pawlowna ”

“King of the Striped ”

“Orange Fire”

‘‘ Queen of the Whites”

Galanthine Hippauline Lycorine Montanine Narcissidine Neruscine Norpluviine Pseudolycorine Ambelline Crinamidine Hippandrine Lycorenine Lycorine Narcissidine Undulatine Urceoline Candimine Lycorine Crinine Galanthamine Galanthine Haemanthamine Hippamine Lycorine Narcissidine Tazettine Annapowine Crinamidine Haemanthamine Lycorine Haernanthamine Hippeastrine Lycorine Tazettine Galanthamine Haeman thamine Hippeaatrine Lycorine Powelline Ambelline Galanthine Hippawine Hippeastrine Lycorine Narcissidine Pluviine

-

-

-

0.013 0.003 0.022 0.003 0.033 0.006 0.0008 0.015 0.12 0.085 0.001 0.002 0.001 0.003 0.002 0.033 0.0006 0.0045 0.003 0.008 0.01 0.052 0.004 0.001 0.016 0.0003 0.0005 0.0005 0.003 0.042 0.0005 0.0008 0.002 0.004 0.0004 0.004 0.0006 0.006

24 24 24 24 24 24 24 24 30 30 30 30 30 30 30 30 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 31 32 32 32 32 32 32 32

10.

315

THE AMARYLLIDACEAE ALKALOIDS

TABLE I-continued Plant

Alkaloid

Percent“

Reference

~

“Salmon J o y ”

Hymenocallis nmericana Roem.

H . festalis Hort.

H . harrisiana Herb.

Ismene hybrid “Sulphur Queen” [ H . ealathina Nichols x H . amancaes (Ruiz and Pavon) Nichols]

Ismene sp. Leucojum aestivum L.

Galanthamine Haemanthamine Lycorine Narcissidine Powelline Haemanthidine Hippeastrine Lycorenine Lycorine Nerinine Tazettine Caranine Galanthine Haemanthamine Lycorine Narcissidine Tazettine Caranine Galanthine Haemanthamine Haemanthidine Lycorine Narcissidine Pseudolycorine Tazettine Galanthamine Galanthine Haemanthamine Lycorine Narcissidine Tazettine Ismine Aestivine Galanthamine Lycorenine Lycorine

Lyeoris aurea Herb.

Nivaline (ungerine) Galanthamine Homolycorine Lycoramine Lycorenine Lycorine Pseudolycorine Tazettine

0.005 0.014 0.022 0.003 0.003 0.006 0.012 0.002 0.047 0.004 0.017 0.0002 0.0002 0.002 0.002 0.0006 0.014 0.0003 0.0005 0.001 0.01 0.002 0.0005 0.0001 0.04 0.003 0.001 0.001 0.002 0.002 0.004 0.002 -

0.19 0.01-0.54 0.003 0.26 0.01 -

-

-

-

32 32 32 32 32 33 33 33 33 33 33 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 34 6 35 36, 37 38 38 37 38 35 39 39 39 39 39 39 39

316

W. C. WILDMAN

TABLE I-continued Plant

L. radiata Herb.

L. squamigera Maxim.

Narcissus jonquilla “Golden Sceptre ”

Narcissus sp.

N . poeticus Hort. var. ornatus

Narcissus pseudonarcissus L. “King Alfred”

Alkaloid Same alkaloids as L. aurea Radiatine Epigalanthamine Galanthamine Hip peastrine Homolycorine Lycoramine Ly corenine Lycorine Pluviine Pseudolycorine Squamigerine Tazettine Vittatine Galanthamine Goleptine Haemanthamine Hippeastrine Homolycorine Jonquilline Lycorenine Masonine Poetaricine Tazett ine Galanthamine Galanthine Homolycorine Lycorenine Nartazine Poetaminine Poetaricine Tazettine Galanthamine Galanthine Haemanthamine Homolycorine Lycorine Poetamine Poetaminine Poetaricine Tazettine Galanthamine Galanthine Haemanthamine

Percent“

Reference 39 40 39 39 39 39 39 39 39 39 39 39 39 39 41 9 41 41 41 41 41 41 41 41 42 42 42 42 42 42 42 42 43 43 43 43 43 43 43 44 43 45, 46 46 45

10. THE AMARYLLIDACEAE ALKALOIDS

317

TABLE I-continued Plant “Twink” Nerine bowdenii W . Wats.

Alkaloid 0-Methylnorbelladine Acetylcaranine 1-Acetyllycorine Ambelline Base N B Belladine Bodamine Bowdensine Buphanidrine Buphanisine Crinamidine Crinamine Crinine ( )-Epicrinine Lycorenine Lycorine Methylpseudolycorine Nerbowdine Pluviine Undulatine Acetylnerbowdine Amaryllidine Ambelline Base N B Buphanamine Crinamidine Dihydroambelline Lycorine Narcissidim Undulatine Ambelline Buphanamine Crinamidine Crinine Flexine Flexinine Lycorine Powellamine Powelline Undultttine

+

N . crisp5 Hort.

N . Jezuosa Herb. (whiteblooming)

Percent“

-

0.002

0.05

0.06

-

0.01 0.02 0.002 0.01

0.003 0.01 0.008

0.045

0.002

0.03

0.001 0.0008 0.008

0.01 0.005 0.001 0.05 0.0005

0.004 0.002 0.003 0.006

0.001 0.002 0.02 0.06 0.0002 0.0005

0.005 0.01

N . Jemosa Herb. (pinkblooming)

Flexamine Galanthamine Galanthine Haemanthamine Ly corin e

-

-

Reference 47 24 21 21 24 21 24 21 21 21 21 21 21 21 24 21 24 21 24 21 48 48 48 48 48 48 48 48 48 48 32 32 32 32 32 32 32 32 32 32 49 24 24 24 24 24

318

W. C . WILDMAN

TABLE I-continued Plant

A1kaloid

Percent"

Reference

~

N.Jexuosn Herb. (pinkblooming)

N . krigei Barker

N . undulata (L.) Herb.

Pancratium arabicum Sick.

P . 1onqiJorum Roxb. P . maritimum L.

Neflexine Nerifline Neruscine Undulatine Didehydrokrigenamine Krigeine Krigenamine Lycorine N eron in e Buphanamine Crinine Lycorine Nerispine Nerundine Undulatine Galanthamine Haemanthidim Homolycorine Lycorenine Lycorine Pancratine Sickenbergine Tazettir 2 Ly corin c Norneronine Alkaloid 13 Alkaloid 16 Alkaloid 3 1 Demethylhornolycorine Galanthamine Haemanthidine Homolycorine Hordenine Lycorenine Lycorine Poetaricine Sickenbergine Tazettine

P . sickenberqii Asch. and scheinf. ex Boiss.

Vittatine Galanthamine Haemanthidine Homolycorine Lycorine Sickenbergine

24 24 24 24 50 50 50 50 50 10 10 10 10 10 10 51 51 51 51 51 51 51 51 51a 51a 3 3 3 51 51 3, 51 51 3 51 51 3 3 51 51 3 3 51 51, 52 51, 52 51, 52 51

10.

THE AMARYLLIDACEAE ALKALOIDS

319

TABLE I-continued Plant

Alkaloid Tazettine Alkaloids K, L, M, 0

Galanthamine Haemanthidine Lycorine Sickenbergine Tazettine Vittatine P. tri$orum Roxb. Lycorine Sprekelia formosissima L. (Herb.) Ismine Sternbergia Zutea (L.) Roem. Haemanthamine and Schult. Haemanthidine Ly cor in e Tazettine Lycorine Ungernia minor Vved. Ungiminorine U . severtzovii (Regel.) B. Fedtsch. Base C17H19N03 Hippeastrine Lycorine Narwedine Nivaline Tazettine Ungiminorine Unsevine U.tadshikorum Vved. Galanthamine

P . tortuosum Herb. ( P . tortifolium Boiss.)

Haemanthidine Lycorine Tazettine

U . tkphaera Bunge

Hippeastrine (trispherine) Lycorine

Nivaline Tazettine

Percent"

-

0.0024

0.36

0.16 0.018

-

0.0014" 0.04 0.003' 0.018 0.01" 0.21 0.093 0.0021" 0.003-0.1" 0.02-0.08 0.02-0.61" 0.3-0.64 1.5"

0.06

0.03* U . victoris Vved.

Trispheridine Galanthamine Haemanthidine Hordenine Lycorine

0.0004 0.16a3c 0.009b~c 0.06bsc

0.02"c

Reference

51, 52 52 51 51 51 51 51 51 53 6 54 54 54 54 55 55 56 56 56 56 56 56 56 56 57 57 57 57 57 57 57 57 58-60 58 58 58 58 58 58 58 58, 60 61 61 61 61

320

W. C . WILDMAN

TABLE. I-continued Plant

U . victoris Vved. Vallota purpurea (Ait.) Herb.

Zephyranthes hybrid “Ajax”

2. candida Herb.

2. tubispatha (Ker) Herb.

Alkaloid

Percent“

Reference

Tazettine Galanthamine Haemanthamine Vallopurfine

-

61 62 62 62

Crinine Haemanthamine Lycorine Narcissidine Nerinine Tazettine Haemanthidine Lycorine Nerinine Tazettine Zephyranthine

0.0042 0.0012 0.05 0.0003 0.0012 0.0012

18 18 18 18 18 18

0.0008 0.024 0.0004 0.002

63 63 63 63 63

Lycorine Nerispine Powelline Tubispathine

-

0.006 -

-

-

44 44 44 44

Based on fresh bulb weight unless noted to the contrary.

* Based on dry weight. Leaves. Seeds. ‘ Roots.

Chapter 9 of Volume V I discussed the relative stereochemistry of the individual alkaloids. The present chapter contains many structures of known relative and absolute configuration. X-ray data have now provided the absolute configurations of galanthamine and lycorine. Because of numerous interconversions between the lycorine and lycorenine types of alkaloids, the absolute configurations of many of the latter also are known with certainty. The absolute configuration of the alkaloids in the chemically interrelated crinine, tazettine, and montanine groups rests on the applicability of Mills’ rule for allylic alcohols ( 7 ) .This rule may not be valid for allylic epimers which contain an optically active center adjacent t o an aromatic chromophore. However, the assignments of absolute configuration within these three alkaloidal systems by this rule are consistent with the known chemical correlations. Degradative evidence for the correctness of these empirical assignments is given in Section

VII.

10.

THE AMARYLLIDACEAE ALKALOIDS

32 1

11. Lycorine-Type Alkaloids

Lycorine ( I ; R, R1= H) is the most abundant alkaloid in the Amaryllidaceae. Classic chemical degradations elucidated the fundamental carbon skeleton and the positions of most functional groups within this nucleus. More subtle problems associated with the position of olefinic unsaturation and the relative and absolute configuration of the alkaloids have been examined by modern chemical and instrumental methods. Simultaneously, fundamental research in NMR-, CD-, ORD, and mass-spectroscopy has been furthered by the ready accessibility of this series of closely related compounds. I n contrast to the alkaloids discussed in Sections V, VI, and VII, the lycorine-type alkaloids provide mass spectra which are not greatly affected by most minor structural changes. Alkaloids of the lycorine type containing 3,3a-unsaturation form intense fragmentations resulting from the loss of carbon atoms C-1 and C-2 and the substituents attached thereto. Alkaloids of the lycorine type lacking 3,3a-unsaturation do not lose the C- 1-C-2 bridge, and the base peak in the spectrum of dihydrolycorine is 288 (M-1). This striking spectral contrast should prove t o be a valuable method for characterization of alkaloids in the group (64,64a). A comparison of the molecular rotations of lycorine and 2-epilycorine provided the first evidence for the absolute configuration of alkaloids of the lycorine type by the application of Mills' rule. The development of suitable chemical methods of interconversion between the lycorine- and lycorenine-type alkaloids permitted a n additional correlation between the two types by the Hudson-Klyne lactone rule. These assignments have recently been shown to be correct by X-ray crystallographic methods (65). With these findings the structure and absolute configuration of lycorine is described by I (R, R1 = H). The absolute configurations of many of the alkaloids discussed in Section I11 also are secure because these alkaloids have been interrelated and converted to known compounds of the lycorine series. A. ~-~-ACETYLLYCORINE AND POETAMININE Poetaminine (mp 221"-223" decomp.; [a]k4 +loo" in EtOH), was isolated from Narcissus poeticus var. ornatus and assigned the molecular formula C17H21N05 (43).I n more recent isolation and chemical studies (42) the formula was revised to C ~ ~ H I ~ N and O it ~ was , proposed that poetaminine is the optical antipode of 1-0-acetyllycorine ( I ; R = Ac, R1= H).

322

W. C. WILDMAN

The UV- and IR-spectra of poetaminine and l-O-acetyllycorine were identical. Acetylation of poetaminine afforded an 0,O-diacetate, and hydrolysis of the alkaloid provided deacetylpoetaminine. The I R spectrum of the diacetate was identical with that of 0,O-diacetyllycorine (I;R , R1 =Ac). The IR-spectrum of deacetylpoetaminine was reported to have hydroxyl and methylenedioxy absorption, but no comparison with the IR-spectrum of lycorine (I; R , R1= H), which is extremely rich

I

I1

in detail, was reported. I n mixture melting point determinations, the pairs, 1-0-acetyllycorine-poetaminine and 0,O-diacetyllycorine-Oacetylpoetaminine, showed no depression. A mixture of lycorine and deacetylpoetaminine gave a slight melting point depression (about 10" a t 260").Whenequalweightsof either poetaminine and l-O-acetyllycorineor deacetylpoetaminine and lycorine were crystallized, each pair afforded a "homogeneous" compound that had no optical activity ( 4 2 ) .No other physical property for these racemates was reported nor were optical rotations for O-acetyl- and deacetylpoetaminine given.

B. 2-0-ACETYLLYCORINE (AULAMINE) Aulamine, ClgH19N05 (mp 230"-231"; ["ID -38" in CHC13), was l u ~robusturn and was found to be isolated from Hippeastrum ~ u l ~ c uvar. identical with 2-O-acetyllycorine (I; R = H , R1= Ac) prepared by partial synthesis ( 2 4 ) .

C. AMARYLLIDINE This alkaloid, Cl~H19N05(mp 204", [a],, +64" in CHC13), forms a hydroperchlorate salt (mp 134"-135"). It appears to contain two vicinal hydroxyl groups and the IR-spectrum is reported t o be similar to that of parkamine. From these data, it is suggested that amaryllidine is an ar-methoxyparkamine (8).

10.

323

THE AMARYLLIDACEAE ALKALOIDS

D. FALCATINE This alkaloid was shown t o be an ar-methoxycaranine (11)by degradative methods. The inertness t o oxidation of the C-1 hydroxyl group in contrast to that of caranine and dihydrocaranine suggested the methoxyl group was located a t (3-11 and structure I11 was proposed for falcatine (66).Proof that the methoxyl group was situated a t C-11 was obtained by an unambiguous synthesis of IV, the product from successive selenium dioxide and potassium ferricyanide oxidations of falcatine (66). The

0

IV

I11

1. Ha, R-Ni 2. HNOi

(aNo2 CHBO

COOH

1. SOCla ____, 2. indoline

0

0 V

VI

synthesis of IV from V follows t h e path first used by Humber et aE. ( 6 7 ) . Two syntheses of the C-8 methoxy isomer of I V have been completed and it has been shown that this isomer is not identical with the phenanthridone obtained by the degradation of falcatine (68, 69).

E. GQLCEPTINE AND GOLEPTINE Goleptine, C17H21N04 (mp 141"; [a]= -99" in CHC13), was isolated from the Narcissus hybrid "Golden Sceptre" (9). It forms a picrate (mp 174") and a perchlorate (mp 21 1" decomp.). It was characterized as a tertiary phenolic base containing two methoxyl groups, one aliphatic hydroxyl, and a double bond which is not in conjugation with the aromatic ring. Goleptine was assigned padial formula VII because

324

W. C. WILDMAN

VII

IX

VIII

x

methylation of the phenolic hydroxyl with diazomethane afforded galanthine (VIII) (69). Hydrolysis of goleptine with 10 % hydrochloric acid provided a demethyl compound (IX) which was identical with golceptine, also isolated from Golden Sceptre." Golceptine (mp 146"-148"; [a]","-156" in CHC13) forms a picrate (mp 170") and a tri-0-acetyl derivative (mp 188" decornp.). Methylation of golceptine with diazomethane gave a monomethyl ether (mp 157") which could be converted t o 0,O-diacetyl (mp 211") and dihydro (mp 211') derivatives by standard methods. If the conversion of VII t o VIII is valid, 0-methylgolceptine, 0,O-diacetyl-0-methylgolceptine, and dihydro-0-mebhylgolceptine should be identical with methylpseudoIycorine ( X ; R, R1= H ; mp 235"-240" decomp.), 0,O-diacetylmethylpseudolycorine ( X ; R, R1= Ac; mp 174"-175"), and dihydromethylpseudolycorine (mp 192"-196" decomp.), respectively. Although combustion analyses for the compounds derived from golceptine were in agreement with the assigned structures, no comparisons either in melting point or optical rotation were made between the golceptine and methylpseudolycorine series. There appears to be little agreement between the two. gave a monoPartial hydrolysis of 0,O-diacetyl-0-methylgolceptine acetyl derivative that was oxidized by manganese dioxide t o an a$unsaturated ketone. Reduction of this ketone with sodium borohydride gave 0-methylgolceptine and a C-2 epimer. The latter formed an isopropylidene derivative (70).

10.

THE AMARYLLIDACEAE ALKALOIDS

325

F. HIPPAMINE(2-0-METHYLLYCORINE) This alkaloid (mp 162"; [a]=-72" in EtOH) was isolated in low yield from an unidentified Hippeastrum species. A mixture melting point with 2-0-methyllycorine (I; R = H , R I =CH3) obtained by partial synthesis was not depressed (31). G. JONQUILLINE Jonquilline (mp 188"-190" decomp.; [a],, -325" in CHC13) was isolated from the Nurcissus "Golden Sceptre" (41). The alkaloid contained neither 0- nor N-methyl groups. The UV- and IR-absorption spectra indicated the presence of 0-acetyl and a,p-unsaturated ketone functions. Jonquilline is formulated as 1-0-acetyl-2-lycorinone (XI) since reduction of the alkaloid with either sodium borohydride or lithium aluminum hydridegave a diol, C I ~ H ~ ~(mp N 1O6 7 O~) , which was identified as 2-epilycorine (XII). 0

XI

XI1

H. LYCORINE By 1956 it was reasonably well established that lycorine was correctly represented by I (R, R1= H) or its mirror image. Subsequent chemical and spectroscopic studies have verified this structure as well as the relative and absolute stereochemistry depicted. 1-0-Acetyl-2-lycorinone (XI), prepared by the manganese dioxide oxidation of 1-0-acetyllycorine, was reduced by sodium borohydride and subsequently hydrolyzed t o give a mixture of lycorine and 2-epilycorine (XII). I n contrast with lycorine, 2-epilycorine forms an isoprogylidene derivative, and therefore the hydroxyl groups a t C-1 and C-2 are cis in the latter. Catalytic hydrogenation of 2-epilycorine, which contains an equatorial (31-2 hydroxyl, follows the course found for caraiiine (XIII) which is uiisubstituted a t C-2. With a platinum catalyst in glacial acetic acid, a-dihydro-2-epilycorine (XIV; R = OH) is the major product, while hydrogenation with a

326

W. C. WILDMAN

palladium catalyst in ethanol gives a mixture of XIV (R = OH) and the “/?-isomer” (XV; R = OH). Both a- and /?-dihydroepilyoorines could be related to a- and /?dihydrocaranine (XIV; R = H and XV; R = H, respectively) by reduction of the respective 2-0-monotosylates with lithium aluminum hydride.

5

R

XI11

xv

XIV

Application of Mills’ rule ( 7 ) t o the pairs lycorine-epilycorine and O,O-diacetyllycorine-O,O-diacet1yl-2-epilycorine showed that the epi series was more negative in molecular rotation, and hence the configuration a t C-2 should be as in I (R, R I =H) for lycorine ( 7 1 ) .The absolute configuration shown for lycorine has been confirmed by X-ray methods (65).Supplementary evidence for the structures of lycorine and several derivatives has been obtained from detailed CD-, ORD-, and NMRstudies (72). a-Dihydrolycorine (XIV, R = OH) reacts with phosphorus oxychloride to form a characterizable chlorohydrin which is formulated as XVI. Methanolic potassium hydroxide converted XVI into a 2-0-methyl ether (dihydrohippamine), presumably via the epoxide XVII. Milder

XVI

XVII

10.

'

THE AMARYLLIDACEAE ALKALOIDS

327

alkaline conditions (sodium bicarbonate, potassium acetate, or chromatography on alumina) resulted in the conversion of XVI to XVII, a compound obtained earlier by the action of base on dihydrolycorine-2monotosylate. The structure of XVII was proved by the formation of XVI in dilute hydrochloric acid and a-dihydrolycorine in dilute sulfuric acid. Zinc dust and acetic acid converted XVI to an olefin (XVIII), the UV absorption spectrum of which showed no conjugation wibh the aromatic ring. Catalytic reduction of XVIII gave ( - )-a-lycorane (XIX) (73). An alternate synthesis of ( - )-a-lycorane involves the zinc dust and catalytic reduction of 1-0-acetyl-2-lycorinone (XI) t o l-deoxy-adihydro-2-lycorinone (XX) followed by thioketal formation and reduc$on with Raney nickel ( 7 4 ) .The structure of a-lycorane was verified by s$nthesis ( 7 5 ) . 0

xx

XXI

0

XXII

Diene condensation of 3,kmethylenedioxy-P-nitrostyrene and methyl hexa-3,5-dienoate afforded the adduct (XXI). Catalytic reduction of the olefinic and nitro groups occurred with spontaneous formation of the lactam (XXII). Lithium aluminum hydride reduction of XXII followed by Pictet-Spengler cyclization afforded ( )-a-lycorane, identical in its IR-spectrum with ( - )-a-lycorane. Hydrogenation of 0,O-diacetyllycorine (I;R, R1= Ac) in ammoniacal ethanol with palladium-charcoal, followed by hydrolysis, afforded a separable mixture of a-dihydrocaranine (XIV; R = H), caranine, ( - )-a-lycorane, and P-dihydrocaranine (XV, R = H) ( 7 4 ) . A modified Oppenauer oxidation of P-dihydrocaranine gave a ketone (XXIII; R, R1= 0 ; Rz, R3 = H ) which could be converted in low yield to ( - )-Plycorane (XXIII; R, R1, Rz, R3=H), (mp 72"-73"; [a]=-143") via the ethylene thioketal and Raney nickel reduction. The presence of an

328

W. C. WILDMAN

XXIII

J

enolizable h drogen a t C-llb in the ketone placed the stereochemistry a t this center * some doubt, and indeed the ketone appears t o be an equilibrium mixture of epimers a t C-1l b . However two additional ( - )$lycorane preparations are known which do not permit epimerization a t this center. 1-0-Acetyl-p-dihydrolycorinone (XXIII;R = OAc; R1= H ; Rz,R3 = 0),prepared by hydrogenation of 1-0-acetyl-2-lycorinone (XI) with palladium catalyst, was converted t o ( - )-p-lycorane by zinc dust and acetic anhydride and subsequent removal of the carbonyl group by thioketal formation and reduction. A simple synthesis of ( - )-p-lycorane was reported in the reduction of 1-0-acetyl-P-dihydrolycorinoneby Clemmensen and catalytic methods ( 7 4 ) . A stereospecific synthesis of ( k )-p-lycorane has been reported (75). Catalytic reduction of the Diels-Alder adduct (XXIV) proceeded with 0 - N acyl migration t o form a hydroxy amide which was oxidized t o the

XXIV

xxv

XXVIII

XXIX

10.

329

THE AMARYLLIDACEAE ALKALOIDS

ketone (XXV).The future ring D was constructed by the condensation of XXV with carbethoxymethylenetriphenylphosphorane,hydrolysis, and catalytic reduction. From studies in model systems, it was established that the product had the stereochemistry depicted in XXVI. Reduction of XXVI by lithium aluminum hydride and Pictet-Spengler cyclization gave the phenantbridine XXVIII. Ring D was closed by tosyl chloride to form the quaternary tosylate (XXIX; X = tosyl). Hofmann degradation of XXIX (X = OH) afforded ( 5 )-P-lycorane. The conversions of lycoriile and caranine derivatives t o a- and Plycoranes take advantage of the stereoselective catalytic reduction of the 3-2a double bond. I n these transformations, the configurations of the asymmetric centers at Cllb and Cllc are the same as in the parent alkaloids. Because of the trans relationship between the C1-hydroxyl and the Cll,,-hydrogen, dehydration of the alkaloids and their a- and P-dihydro derivatives occurs readily with phosphorus oxychloride and pyridine to give 1,11 b unsaturation. Catalytic reduction of these olefins

xxx

XXXI

XXXII

XXXIII

XXXIV

xxxv

provides compounds with unnatural configurations at Cllb. Thus cc-dihydro-1,11b-lycorene (a-anhydrodihydrocaranine) (XXX) and 1,Ilb,3,3a-lycoradiene (XXXI) were hydrogenated by palladium in acetic acid to ( - )-y-lycorane (XXXII). Oppenauer oxidation of cc-dihydrocaranine occurred with epimerization at C:1lb to form a-dihydrocaranone (XXXIII). Thioketal formation and Raney nickel reduction of XXXIII gave XXXII. P-Dihydro-l,11b-lycorene was reduced by palladium in ethanol to ( + )-y-lycorane, presumably via an l l b , l l c intermediate. A fourth lycorane, ( + )-a-lycorane, (XXXV), was formed along with ( - )-/3-lycorane when P-dihydro-1 ,llb-lycorene was hydrogenated with platinum in acetic acid ('76). ( k )-a-Dihydrocaranone and ( 5 )-a-lycorane have been synthesized recently in a very simple manner. 2-Bromo-4,5-methylenedioxybenzyl

330

W. C . WILDMAN

bromide was condensed with 2,5-dihydro-4-methoxyphenethylamine. The resultant secondary amine was cyclized to N-(2-bromo-4,5-methylenedioxybenzyl) octahydroindol-6-one by hydrochloric acid. Amination of the product with sodamide and treatment of the product with lithium piperidide gave ( i )-a-dihydrocaranone. Thioketalization and Raney nickel reduction afforded ( f )-a-lycorane ( 7 6 ~ ) .

I. METHYLPSEUDOLYCORINE, GALANTHINE,AND PLUVIINE Because pluviine and methylpseudolycorine are less abundant than their methylenedioxy analogs, caranine and lycorine, it was desirable to find methods of interconversion between the two series of alkaloids so that observations in the methylenedioxy (lycorine) series would also be applicable t o the dimethoxy (methylpseudolycorine) series. Ethanolic potassium hydroxide cleaved a-dihydrocaranine (XIV; R = H) to an ethoxy methyl ether (XXXVI)which was converted t o a-dihydropluviine (XXXVII) by acid hydrolysis and methylation with diazomethane (77).

[ fiQ H 0 //',

HC2H50-CH2-

0

0

__f

\

HOO/,/ C

H

CH30

XXXVI

3

O

a

q

\ XXXVII

CH30 CH30 XXXVIII

It had been shown earlier than galanthine (XXXVIII;R = OCH3) was hydrolyzed by acid to methylpseudolycorine (XXXVIII; R = OH) and was converted, in part, to pluviine (XXXVIII; R = H) by sodium and amyl alcohol (66).Recent spectral studies have reconfirmed the structures assigned. Galanthine and hippamine show identical hydroxyl stretching frequencies in dilute solution in chloroform (3602 and 3624 cm-1). The former may be attributed to the bonding of the C-1-hydroxyl wibh the aromatic .rr-electroncloud. The latter frequency is typical of an unbonded secondary hydroxyl group. Comparable values of 3595 and 3624 cm-1

10.

THE AMARYLLIDACEAE ALKALOIDS

331

were found for caranine. The presence of a trans C-2-oxygenated substituent in galanthine is evident from the mass spectrum (64) and the absence of strong intramolecular hydrogen bonding. 2-Epilycorine shows hydroxyl stretching frequencies a t 3578 and 3619 em-1. Methylpseudolycorine was not sufficiently soluble in solvents to permit spectroscopic examination (78). However, the structure assigned to methylpseudolycorine is assured since its mass spectrum is very similar to that of lycorineand differs from that of lycorine by 16 mass units (CH4) (64).

J. NARCISSIDINE On the basis of degradative studies, narcissidine was assigned the structure XXXIX. The partial absolute stereochemistry described in XXXIX is derived from the isolation of pluviine from the sodium and amyl alcohol reduction of narcissidine (66).The absolute and relative

2SO 9CH3 -

OCH3

CH30

cH30a Hzf+r CH30

CH30

XXXIX

'

N

XL

stereochemistry of pluviine has been related to that of both lycorine and caranine. The vicinal glycol function was assigned because dihydronarcissidine was cleaved by periodic acid. The mass spectrum of narcissidine confirms the molecular formula C18H23N05 (m/e 333)) but the fragmentation is inconsistent with the C-l,C-2 substitution of XXXIX. On the basis of mass spectral studies with lycorine derivatives and with pluviine, galanthine, and methylpseudolycorine, XXXIX should give rise to major fragments a t m/e 273 and 272 by loss of C-1, C-2, and hydrogen and hydroxyl groups attached t o these atoms. No peaks are found a t Chese values buC strong peaks occur at m/e 259 and 258 (M-74 and M-75) representing the loss of C3H602 and C3H702,respectively. The loss of 74 mass units is derived directly from the parent ion because a metastable ion a t m/e 200.9 (2592/333= 201.4) was detected (64).It is clear from these data that the aliphatic methoxyl group of narcissidine must be a t C-2, and the alkaloid may be reformulated as XL. The cis arrangement of the oxygenated substituents a t C-1 and C-2 is indicated by the presence of hydroxyl stretching frequencies in dilute solution of 3544 and 3612 cm-1 (78).The configuration of the C-4-hydroxyl has not been determined.

332

W. C. WILDMAN

K. NARTAZINE This alkaloid (mp 185"-186"; [a]=-120" in CHC13) has been identified as 0,O-diacetyldihydrolycorine ( 2 4 ) .

L. NERISPINE Nerispine, C17H19N04 (mp 194"-195"; [a]D -210" in CHC13), is a tertiary base containing one aliphatic hydroxyl group as well as methylenedioxy and methoxyl substitution in the aromatic ring. The alkaloid was converted by sodium and amyl alcohol to a mixture of caranine and a-dihydrocaranine. This result has led t o the suggestion that nerispine is related t o falcatine (111)and differs in the position of the double bond and/or the configuration of the hydroxyl group (24).While these variations are certainly possible, it should be noted that all alkaloids of the lycorine type isolated to date have olefinic unsaturation a t C-3-C-3a and an a-hydroxyl a t C-1. It would seem possible that nerispine is the 8-methoxy isomer of falcatine.

M. NORPLUVIINE With the determination of the absolute configuration of pluviine, norpluviine can be assigned the stereostructure XLI.

XLI

XLII

N. PARKACINE This alkaloid (mp 223"-224"; ["ID +58" in CHC13) was isolated from Amaryllis parkeri. It formed picrate, perchlorate, and methiodide salts (mp's 197", 240", and 272", respectively). Catalytic reduction gave a dihydro derivative (mp 189"-190") which could be acetylated t o form a triacetate. Sodium and amyl alcohol converted parkacine to a mixture of

10.

THE AMARYLLIDACEAE ALKALOIDS

333

methylpseudolycorene and pluviine. The alkaloid formed an isopropylidene derivative with acetone, and the second hydroxyl was assigned t o the 2-a-position. The third hydroxyl was placed at (3-4 because narcissidine could be hydrolyzed by acid t o parkacine. From these data parkacine was described by structure X L I I (9, 78, 7 9 ) .

0. PARKAMINE AND NEFLEXINE Parkamine (mp 251"-253"; [.ID +66" in CHC13) forms a picrate (mp 178" decomp.), a perchlorate (mp 245" decomp.), and a methiodide (mp 298" decomp.). Functional group analysis showed the presence of a methylenedioxy group, two methoxyl groups, and a hydroxyl capable of acetylation. Catalytic hydrogenation afforded a dihydro derivative (mp 167"). A second dihydro compound (mp 176") was isolated and may represent either a polymorphic form or a stereoisomer of the first. Sodium and amyl alcohol converted parkamine t o a mixture of caranine, adihydrocaranine, and lycorene. Vacuum pyrolysis of parkamine afforded anhydrofalcatine lactam (IV). These data are consistent with the formulation of the base as a 2-methoxyfalcatine (XLIII) ( 8 ) .Neflexine, [a],, f65" in CHC13; picrate, mp 195"-196"), C I ~ H ~ ~(mp N O 249"-250"; ~ possesses an IR-spectrum similar t o that of parkamine, but gives no color with concentrated sulfuric acid ( 2 4 ) .

P. SUISENINE Suisenine (80)has been found t o be a mixture of lycorine and pseudolycorine ( 8 1 ) .

Q . UNGIMINORINE Ungiminorine, C ~ ~ H I ~(mp N 206"-208" O ~ ; [a]D -29" in CHCl3), forms a picrate (mp 174'-175"), a methiodide (mp 246"-248'), and an 0,O-diacetyl derivative (mp 173"-174"). It has been assigned the partial

334

W. C. WILDMAN

structure XLIV from the observations that the alkaloid forms hydrastic anhydride upon oxidation with permanganate, and lycorene and caranine with sodium and amyl alcohol (82).

R. ZEPHYRANTHINE Zephyranthine (mp 201"-202"; [a]= -43.2" in CHC13) was isolated from Zephyranthes candida. It forms a picrate (mp 194"-195") and a methiodide (mp 294"-295" decomp.). It is stable to catalytic hydrogenation but forms an 0,O-diacetate and an isopropylidene derivative. The alkaloid is identical with a-dihydro-2-epilycorine (XIV; R = OH) (63).

111. Lycorenine-TypeAlkaloids Alkaloids of this series encompass all bases derived from the [2]benzopyrano[3,4g]indole nucleus. Although homolycorine and lycorenine are moderately abundant, most of the alkaloids of this type occur either in very minor amounts in accessible plants or in large quantities in species that are diacult t o obtain. There is a close structural similarity between the alkaloids of the lycorine and lycorenine types. A hypothetical cleavage of XLV between nitrogen and C-7, followed by 180" rotation of the hexahydroindole -011,.

XLV

TL

CHI-NO,,.

XLVI

moiety about the C-lla-C-llb bond, ring closure of the C-1 oxygen and C-7, and N-methylation affords XLVI. A reverse transformation would involve N-demethylation and C-7-0 cleavage of XLVI, 180" rotation about C-lla-C-llb, followed by C-7-N ring closure. It is quite likely that a process comparable t o XLV-tXLVI takes place in the biosynthesis of the alkaloids in this group. Interconversions in both directions have been accomplished ilz vitro. These transformations have served t o interrelate the alkaloids of Sections I1and I11structurally and stereochemically.

10. THE

335

AMARYLLIDACEAE ALKALOIDS

Absolute configurations were first assigned to alkaloids of this section both by chemical transformations to compounds in the lycorine series where Mills' rule had been applied and by Klyne's modification of the Hudson lactone rule. This extension states that lactones possessing the absolute configuration of XLVII are more positive in molecular rotation than derivatives in which the lactone ring is opened. If this rule is applicable t o the alkaloids of this section, the conversion of homolycorine (XLVIII; [MI, +268') Lo tetrahydrohomolycorine (XLIX ; [MI, -322") requires that homolycorine and tetrahydrohomolycorine have the absolute configurations shown in XLVIII and XLIX. These assign-

H

& &

,c=o

CH30

(CHz)n

CHsO

\

-

'

CHsO

CHs0

\

0 XLVIII

XLVII

OH CHzOH

XLIX

ments are in agreement with the recent X-ray determination of the a.bsolute configuration of dihydrolycorine (65). A. ALBOMACULINE AND NERININE By 1956, chemical degradations of albomaculine had led t o the conclusion that the alkaloid was an ar-methoxyhomolycorine. It was not certain a t that time whether the isolated double bond was a t C-3-C-3a or C-3a-C-4 or whether the third aromatic methoxyl was a t C-8 or (3-11. Neither the relative nor the absolute configuration of the alkaloid was known. Since nerinine was oxidized to albomaculine, i t was considered an ar-methoxylycorenine (83). Chemical and spectroscopic

Ri L

LI

LII

336

W. C. WILDMAN

evidence has now accumulated which removes these uncertainties and proves that albomaculine and nerinine possess structures L (R, R1= 0) and L ( R = H , R l = O H ) , respectively (84-87). I n a definitive study of several alkaloids in this group, it was shown that alkaloids substituted by methoxyl a t C-11 reacted a t a slower rate with methyl iodide than their homologs having only hydrogen a t this position (85). This was found to be true for selected hemiacetals, lactones, and cyclic ethers (LI). I n the tetrahydro derivatives (LII), produced by the lithium aluminum hydride reduction of either the hemiacetals or lactones, there was little difference in the rate of methylation. This was attributed to greater flexibility aboub the C-lla-C-1 l b bond. Since albomaculine and its cyclic ether were methylated by methyl iodide a t a rate comparable with that found for homolycorine and deoxylycorenine, the third aromatic methoxyl was assigned t o C-8. This assignment has been corroborated by additional chemical and spectroscopic data. An aryl hydrogen located a t C-8 would be expected to be deshielded in comparison with other aromatic protons by virtue of the lactone carbonyl group peri to it. I n homolycorine, the c-8 and C-11 protons occur a t 7.62 and 7.01 ppm, respectively. I n albomaculine the lone aromatic proton is not deshielded and shows a chemical shift a t 6.86 ppm. Under forcing conditions albomaculine methohydroxide afforded an unstable methine (LIII ; R = H) in 30 yo yield. Methylation provided LIII (R=CH3), the NMR-spectrum of which was in accord with the

1

YOOH

It0 LIII

assigned structure. Oxidation of' L I I I (R = CH3) gave a trimethoxybiphenyl carboxylic acid (LIV), the structure of which was proved by synthesis (84). Chemical degradations of nerinine have also been carried out and supplement the results obtained for albomaculine. Catalytic reduction of nerinine (L; R = H , R1 =OH) gave a separable mixture of GC- and P-deoxydihydronerinines (LV ; R = OCH3and LVI ;R = OCH3,respectively). Reductive demethoxylation with sodium and amyl alcohol converted these compounds to a- and P-deoxydihgdrolycorenine(LV, R = H ; and

10.

THE AMARYLLIDACEAE ALKALOIDS

337

LVI, R = H, respectively) (86). The absolute configurations assigned to the asymmetric centers of albomaculine and nerinine at C-5a, C-1lb, and C-llc are based both on this interconversion and on Freudenberg's "rule of shift.'' Oxidation of a hemiacetal alkaloid to the corresponding lactone is accompanied by a 200"-300" levorotatory shift.

R

LVI

LV

B. CANDIMINE This alkaloid (mp 218"-220"; ["ID +222" in CHC13) was isolated from Hippeastrum candidum. It formed picrate (mp 220") and perchlorate (mp 177"-179") salts as well as a monoacetyl derivative (mp 239"-241" decomp.). Chemical and spectral analyses of candimine demonstrated the presence of one methylenedioxy, one methoxyl, one N-methyl, one hydroxyl, and one lactone group. The hydroxyl group of candimine was shown to be allylic by manganese dioxide oxidation t o an a,/% unsaturated ketone (mp 176").

n

LVII

Lithium aluminum hydride converted candimine to a vicinal diol, and it was suggested that the alkaloid was a methoxyhippeastrine (31). Recent spectral data have shown that the alkaloid is best represented by LVII or its mirror image. Unlike hippeastrine which gives a single dihydro derivative upon catalytic reduction, candimine gives two isomeric dihydro compounds (mp 167" and 183"). Hydrogenation studies in both the lycorine- and lycorenine-type alkaloids have demonstrated

338

W. C . WILDMAN

that an axial substituent a t the allylic positions (C-2 in the former;

C-5 in the latter) directs the approach of hydrogen from the opposite face of the molecule. The presence of either a carbonyl group, two hydrogens, or an equatorial hydroxyl in these allylic positions permits reduction to occur from either side of the molecule, and two dihydro derivatives are produced. These observations suggest that the C-5-hydroxyl of eandimine is equatorial and cis t o the lactone oxygen a t C-5a. The methoxyl of candimine is assigned the C-8 position from NMR-data which indicate that the aromatic proton is not deshielded (88).Candimine has not been converted 60 any other alkaloid of this series, and no evidence has been given t o show that the aromatic substitution pattern of LVII is correct. NMR-data require that (3-11 be unsubstituted, but an 8,9-methylenedioxy- 10-methoxy arrangement is possible as well,

C. CLIVIMINEAND CLIVONINE Renewed investigations on the alkaloids of Clivia rniniata have afforded two new bases, clivimine andminiatine. Clivimine (mp 264"-266" decomp. ; [a],,+32" in CHC13) is a novel alkaloid in the family and contains three basic nitrogen atoms. The molecular formula, C43H43N3012, has been verified by mass spectroscopy (78, 89). Reduction of the alkaloid with lithium aluminum hydride gave tetrahydroclivonine (mp 172.5"-173.5" ; ["I, +22" in CHC13) and 3,5-bis(hydroxymethyI)2,6-dimethylpyridine. Alkaline hydrolysis of clivimine afforded 2,6dimethyl-3,5-pyridine dicarboxylic acid and a hydroxy amino acid

& :(OH

CHzOH

0

LVIII

LIX

LX

10.

THE AMARYLLIDACEAE ALKALOIDS

339

which could be converted to clivonine by acid-catalyzed cyclization and treatment with dilute base (89, 90). These degradations show that clivimine is a diester derived from the condensation of 2,6-dimethylpyridine-3,5-dicarboxylicacid and two molecules of clivonine. Structure LVIII was proposed for clivonine in 1956 (91).Tetrahydroclivonine (LIX) was formed by the lithium aluminum hydride reduction of either clivimine or clivonine. LIX afforded the cyclic ether LX with acid. A comparison of the rates of periodate cleavage for LIX, tetrahydrohippeastrine, and dihydrolycorine showed that LIX was a cis glycol. The latter two, known to be trans glycols, reacted at a much slower rate (90). The weak coupling between the C-5 and C-5a protons (J= 3.0 cps) is consistent with the cis stereochemistry assigned. However, the coupling between the protons at C-5a and C-llb is exceptionally large (J5a,Ilb = 12.5 cps) and it has been proposed that the B :C ring fusion of clivonine is trans. NMR-evidence has suggested that the C-3a-C-2 bond is axial with respect to ring C and the C:D ring fusion is cis. ORD- and CD- evidence has been cited to support these assignments (91a).From these data clivonine and clivimine are best represented by LXI and LXII, respectively.

0 LXI

. C H s k A

LXII

0

It is very possible that clivonine, isolated from C. miniata, is an artifact and is derived from the hydrolysis of clivimine during isolation procedures.

340

W. C. WILDMAN

D. HIPPEASTRINE Structure L X I I I (without stereochemical implications) was assigned to hippeastrine in 1956 (92). The absolute and relative stereochemistry of hippeastrine is evident from the conversion of tetrahydrohippeastrine

H

II

0 LXIII

CH3 LXIV

I-

LXV

(LXIV), produced by lithium aluminum hydride reduction of the alkaloid, to lycorine /3-methiodide (LXV)by treatment withp-toluenesulfonyl chloride followed by iodide ion (92).

E. HOMOLYCORINE AND LYCORENINE These alkaloids are among the most abundant of the bases derived from the [2]benzopyrano[3,4g]indole nucleus in the Amaryllidaceae family, and the title of this section is derived from this fact. Lycorenine (LXVI)was one of the first Amaryllidaceae alkaloids t o be studied and a summary of the chemical degradations leading t o this structure (without stereochemical implications) has been given in Volumes I1 and VI. Lycorenine and the corresponding lactone, homolycorine (LXVII), not only serve as the reference alkaloids of the group for recent spectmscopic studies but also provides a chemical correlation with the lycorine-type alkaloids. Several important chemical interconversions are given below.

10. THE AMARYLLIDACEAE ALKALOIDS

341

n

LXVI

LXVII

LXIX

II 0 LXX

I

I

1. LiAIH4 2. TsC1, I-

LXVIII

1. LiAIH4 2. TsCI, I-

By methods analogous t o those cited in the section on hippeastrine, homolycorine (LXVII) afforded a diol upon reduction with lithium aluminum hydride. Treatment with p-toluenesulfonyl chloride followed by iodide ion gave pluviine j3-methiodide (LXVIII) (mp 232"-233"). This salt was not identical with the known pluviine a-methiodide (mp 259"-261"). Structure proof for LXVJII rests on the pyrolysis of its methochloride t o pluviine and anhydromethylpseudolycorine. This interconversion relates the asymmetric centers of pluviine t o those of homolycorine and lycorenine. Comparable reactions with a- and 8dihydrohomolycorine (LXIX and LXX, respectively) converted these compounds to the metho salts of a- and P-dihydropluviine (LXXI and

342

W. C. WILDMAN

LXXII, respectively) (93).These reactions interrelate stereochemically the dihydrolycorine- and dihydrolycorenine-type alkaloids. I n both ring systems the a-dihydro series.hasa C :D cis ring fusion. The p-dihydro series is trans at this junction. Cyanogen bromide reacts with a-dihydrocaranine (XIV; R = H) to form two cleavage products, LXXIII and LXXIV (R = CN). Reduction n

of the latter with lithium aluminum hydride provided a secondary amine (LXXIV ; R = H) which was methylated by formaldehyde and formic acid to provide LXXIV (R = CH3).Basic fission of the methylenedioxy group, hydrolysis, and methylation afforded a-deoxydihydrolycorenine (LXXV) (77). The nature of the oxidant as well as the C : D ring fqsion in the deoxydihydrolycorenines determines the type of reaction product to be obtained. a-Deoxydihydrolycorenine (LXXV)formed the lactam (LXXVI) when treated with potassium permanganate in acetone. Potassium dichromate in sulfuric acid reacted with LXXV to form a-dihydrohomolycorine (LXIX) which could be oxidized further to a lactone-lactam by

LXXVI

LXXVII

0 LXXVIII

10.

THE AMARYLLIDACEAE ALKALOIDS

343

permanganate. P-Deoxydihydrolycorenine (LXXVII ; R = CH3) was oxidized by potassium dichromate in sulfuric acid to the corresponding lactone but further oxidation with permanganate gave the N-formyl derivative LXXVIII. l$ydrolysis of LXXVIII afforded a neutral lactam (LXXIX; R = 0) which was converted to ,8-dihydropluviine (LXXIX; R = Hz) by lithium aluminum hydride (94). These transformations provide another method of interconversion between the lycorenine- and lycorine-type alkaloids.

R LXXIX

F. KRIGENAMINE

This alkaloid (LXXX) (mp 210"-211"; [.ID +210° in CHC13) was isolated from Nerine krigei. It formed a methiodide (mp 235"-237" decomp. ; [a]D +150" in HzO) and a methoperchlorate (mp 248"-249" decomp.). Like lycorenine and nerinine, krigenamine forms a mixture of a- and P-deoxydihydrokrigenamines upon catalytic reduction with a platinum catalyst by hydrogenolysis and nonstereospecific reduction of the double bond. Lithium aluminum hydride converted the alkaloid to a diol (LXXXI) which was treated with tosyl chloride followed by hydrogen iodide to form falcatine methiodide.

n

LXXX

LXXXI

This conversion defines the absolute and relative configuration of krigenamine as shown in LXXX. The diol (LXXXI) may be converted to a cyclic ether, deoxykrigenamine, the catalytic hydrogenation of which affords both a- and P-deoxydihydrokrigenamine (50).

344

W. 0. WILDMAN

Manganese dioxide converts krigenamine to the corresponding lactone, oxokrigenamine. Although this product and neronine have been isolated from N . krigei, they are apparently artifacts formed by the disproportionation of the analogous hemiacetals in the presence of base (50).

G. KRIGEINEAND NERONINE Structures LXXXII and LXXXIII (without stereochemical implications or the position of the aromatic methoxyl located) were proposed in Volume VI for krigeine and neronine, respectively. More recent chemical and spectral studies permit complete structures to be written. Krigeine, neronine, and several of their derivatives react with methyl iodide a t a rate significantly slower than analogous alkaloids lacking

n

B

o

LXXXII

\ 0 LXXXIII

the methoxyl at C-11. This information provided the first evidence for the location of the aromatic methoxyl group in neronine and krigeine. This assignment has been verified by NMR-studies. I n neronine and oxokrigenamine, the lone aromatic proton is deshielded (7.30 and 7.34 ppm, respectively) by the lactonic carbonyl group peri to it when compared with the values found for the analogous C-6-hemiacetal or deoxy compounds. Using lycorenine, krigenamine, and their related lactone derivatives as NMR-model substances, it was possible to show that the C - l l b and C-llc-hydrogens are trans to each other and that rings B and C are cis-fused in krigeine and neronine. The change in [MIDin the conversion of LXXXII to LXXXIII is -254". This compares favorably with -202" reported in the conversion of lycorenine to homolycorine. Thus krigeine and neronine were assigned the absolute configuratiofis shown in LXXXII and LXXXIII. Norneronine (mp 238"-240" decomp. ; [c(]D +90° in MeOH) has been reported in Pancratium 1ongiJorum. It forms an 0,O-diacetate (mp,pS"250" decornp.). When treated with ethereal diazomethane, it afforded a methyl ether identical with neronine (51a).This conversion, together

10.

345

THE AMARYLLIDACEAE ALKALOIDS

with the spectral properties of the alkaloid, suggests that the base is 11demethylneronine.

H. MASONINE AND ODULINE These rare alkaloids were reported in Volume VI of this series as the methylenedioxy analogs of lycorenine and homolycorine. The NMR-

LXXXIV

LXXXV

LXXXVI

spectrum of masonine (LXXXIV) shows a close correspondence in chemical shifts and mass spectrum peak profiles t o that of homolycorine. Homolycorine and masonine have very similar ORD-curves and it is very likely that they have the same absolute configuration. The NMRspectra of oduline (LXXXV) and lycorenine show a similar close relationship (88,94a).Recent studies confirm the assigned structure since oduline can be converted to caranine P-methiodide by lithium aluminum hydride reduction, tosylation of the diol, and treatment with an Amberlite resin (94a).

I. NERUSCINE This alkaloid was found t o be identical with deoxylycorenine (Volume VI, p. 338) and now may be assigned the complete structure LXXXVI.

J. NIVALINEAND UNSEVINE Largely from spectroscopic data nivaline was assigned the tentative structure (LXXXVII) (without stereochemical implications) (91). Recent studies on the alkaloids of Ungernia sewertzovii have demonstrated the presence of the related hemiacetal, unsevine (LXXXVIII). Isolation and characterization studies in the Ungernia and Leucojum spp. are complicated by the assignment of alkaloid names to substances

346

W. C. WILDMAN

which have proved to be either mixtures or known alkaloids of another name. Thus " ungeridine " is a mixture of tazettine, hippeastrine, and ungerine," the latter alkaloid being identical with nivaline (56, 95-98). Methylation of hippeastrine (LXIII) with potassium and methyl p-toluenesulfonate afforded nivaline (LXXXVII) (98). The reverse reactions could be accomplished by refluxing nivaline with 17 yohydrochloric acid (96). ( 6

LXIII

I OCH3

0

LXXXVII

LXXXVIII

Unsevine (LXXXVIII) (mp 173"-174"; ["ID +170" in CHC13) formed hydrobromide (mp 180°-1830), oxalate (mp 192"-194"), and methiodide (mp 249"-250") salts (99). Oxidation of uiisevine with either silver oxide (98) or chromium trioxide (56) afforded nivaline. Additional degradations of nivaline and unsevine follow the classic patterns established in the homolycorine and hippeastrine structural elucidations. Unsevine is oxidized by potassium permanganate to hydrastic acid (97, 100, 101). Hofmann degradation of either nivaline or unsevine affords the methine base LXXXIX (97, 100). I n the case of unsevine, this reaction must

d+(&

(0 0

o\

\

0 LXXXIX

0

xc

occur with concurrent oxidation of the hemiacetal group t o the corresponding lactone. A second Hofmann degradation on the methohydroxide of LXXXIX afforded XC (98). The same lactone can be obtained from exhaustive methylation of hippeastrine (98). Lithium aluminum hydride reduction of either LXXXVII or LXXXVIII afforded a diol (XCI) (mp 154"-155") which could be cyclized to the ether (XCII), characterized as the hydrobromide (mp 235"-236") (56, 95, 99).

10.

THE AMARYLLIDACEAE ALKALOIDS

347

XCII

XCI

Catalytic reduction of nivaline appears to form a single dihydro derivative (mp 139”;[“ID -29.3” in MeOH). Two successive Hofmann degradations of this material followed by oxidation with potassium acid. permanganate gave 4,5-methylenedioxybiphenyl-2,3’-dicarboxylic Catalytic reduction of XCI is reported to give two dihydro derivatives (mp 167”;[“ID -49’; and mp 187’; [aID $40.3”) which are considered optical antipodes (96).

K . PENARCINE This alkaloid, C18H21N04 (mp 171”-172’; [“Iu +110’ in CHC13) was isolated from the Narcissus hybrid “Peeping Tom” in 1958 (102).It is considered a diastereomer of homolycorine.

L. RADIATINII Radiatine was isolated from Lycoris radiata and is assumed to be an artifact arising from the processing of the plant with ethanol. The “alkaloid ” (XCIII) can be converted to hippeastrine by acid hydrolysis

XCIII

and oxidation with potassium dichromate. Reduction of hippeastrine with 0.25 mole of lithium aluminum hydride and acetal formation with ethanolic hydrogen chloride afforded radiatine (40).

348

W. C. WILDMAN

M. URCEOLINE AND URMININE These alkaloids were reported t o be stereoisomers of nerinine and neroiiine in Volume VI. No additional work has been reported. IV. Galanthamine-TypeAlkaloids

No new members of this series have been reported, but the structures of the individual alkaloids are now reasonably certain, based on the degradative, synthetic, biosynthetic, and X-ray research of the past six years. This group of alkaloids includes bodamine, chlidanthine, galanthamine, epigalanthamine, narcissamine, narwedine, and nivalidine. Because the alkaloids are so closely related, it is most convenient t o discuss them as a group rather than individually. Structure XCIV (R = CH3) (without stereochemical designations) was cited in Volume VI as the most likely structure for galanthamine.

xcv

XCIV

CH3

XCVI

This assignment is in full accord with more recent findings. It was noted that the hydroxyl group of ( )-galanthamine showed strong intramolecular hydrogen bonding t o the oxide bridge, and these two groups were placed c i s to each other (103).The C-3 epimer, ( )-epigalanthamine, had only unbonded hydroxyl absorption in dilute solution a t 3625 cm-1. The more stable c i s ring fusion a t C-4a and C-4b can be assigned because ( - )-narwedine (XCV) racemizes (via XCVI) but does not epimerize under basic conditions. The absolute configuration of galanthamine was first derived by application of Mills’ ruIe t o ( - )galanthamine and its C-3 epimer, ( - )-epigalanthamine (base I X ,

10.

349

THE AMARYLLIDACEAE ALKALOIDS

XCVII). Both the relative and absolute stereochemistry cited for ( - )-galanthamine have been substantiated by X-ray methods ( l U 4 ) . Bodamine (mp 208'-210'; [aID +O" in CHC13) forms hydriodide (mp 245" decomp.) and methiodide (mp 265" decomp.) salts. The IR-spectrum of the alkaloid is identical with that of ( - )-galanthamine and bodamine is considered t o be ( f )-galanthamine ( 2 4 ) . Oxidation of XCIV with either manganese dioxide or chromium trioxide afforded ( - )-narwedine (XCV). This ketone is racemized excepCH30@ OH

.'.

CH30

kq

OH

,

\

N

\

N

\

CH3 XCVII

H

XCVIII

tionally readily by warm ethanol or chromatography on alumina. Thus ( - )-epigalanthamine (XCVII), when oxidized by manganese dioxide and subjected t o purification procedures, affords racemic XCV. Both ( + )-galanthamine (mp 121"-123") and ( )-epigalanthamine (mp 199") are formed when ( f )-narwedine is reduced with lithium aluminum hydride. These compounds are readily separated by chromatography and recrystallization. The resolution of either ( ? )-XCIV or ( )-XCVII was unsuccessful by standard methods. However, both partially racemic ( - )-narwedine ([a]D -88') and ( + )-narwedine ([.ID +36") were obtained from the crystallization of the reaction product from the manganese dioxide oxidation of ( - )-galanthamine with acetone and ethanol, respectively. Both products had IR-spectra identical with that of ( 5 )-narwedine and were racemized in ethanol to ( + )-narwedine a t the same rate. This spontaneous partial formation of ( + )-narwedine during crystallization from ethanol was found t o be caused by trace amounts of unreacted ( - )-galanthamine. When a 2 : 1 mixture of ( + )-narwedine and ( - )-galanthamine was crystallized from ethanol containing 10 7 , triethylamine, there was isolated ( + )-narwedine ([aID f306") which was further purified t o [.ID +405" by recrystallization from benzene. (-)-Narwedine could be obtained from ( ? )-narwedine by a similar process using a mixture of ( + )-galanthamine and ( + )-epigalanthamine as a resolving agent. Lithium aluminum hydride reduction of the ( - )-narwedine gave a mixture of ( - )-galanthamine and ( - )-epigalanthamine which was separable by conventional methods. These phenomena cannot be attributed t o gross seeding effects since ( + )narwedine in ethanol when seeded with either ( + )- or ( - )-liarwedine

350

W. C. WILDMAN

gave no significant resolution. Resolution cannot depend upon the particular functional groups present i n the resolving agent since several 0-acetyl and dihydro derivatiyes as well as N-metho salts of ( - ) galanthamine and ( + )-epigalanthamine are effective. The resolution process is best explained a t present by the adsorption of traces of ( - )-galanthamine on the surface of developing narwedine crystals. Such a surface might either encourage the crystallization of ( + ) narwedine or inhibit the deposit of ( - )-narwedine (103). Narwedine ([a]=+looo) was reported t o be a constituent of "Texas" daffodils (105).Repetition of this extraction in another laboratory (103) afforded a mixture of ( )-narwedine and ( - )-galanthamine after chromatography. Recrystallization from benzene gave narwedine ( [ a ] =+52"). Because of the ease of racemization and its resolution phenomenon in the presence of traces of various galanthamine derivatives the sign of optical rotation of the naturally occurring narwedine is unsettled. Novel crystallographic behavior has been noted in other members of this group. The alkaloid "narcissamine" was described in Volume VI as the N-demethyl derivative of ( - )-galanthamine. A more recent investigation of narcissamine has revealed several facts not consistent with this assignment. Narcissamine showed an anomalously low rotation (["ID -13") when compared with ( - )-galanthamine. Narcissamine absorbed only 0.5 equivalent of hydrogen under catalytic conditions. The reduction product was pure but completely racemic. Finally, the NMR-spectrum of narcissamine showed only one olefinic proton by integration. These facts were shown to be consistent with the postulate that narcissamine is a quasi-racemic mixture containing equimolar amounts of ( - )-N-demethylgalanthamine (XCIV; R = H) and ( + )-Ndemethyldihydrogalanthamine (XCVIII). It was possible to separate these substances in small amounts by thin-layer chromatography. ( - )-N-Demethylgalanthamine (mp 156"-158"; [.ID -62" in CHC13) showed a plain negative ORD-curve which was quite similar to that of ( - )-galanthamine. ( + )-N-Demethyldihydrogalanthamine(mp 77"-78", hydrate, and 134"; [a]=+38.2" in CHC13) showed a plain positive ORDcurve comparable with one expected for " ( + )-dihydrogalanthamine." When XCIV ( R = H ) and XCVIII were mixed in approximately equal amounts, the melting point behavior was comparable with that of narcissamine. " 0,N-Diacetylnarcissamine " (mp 209"-210") and " Nacetyl narcissamine" (mp 167"-168"), prepared by partial hydrolysis, were found to be quasi-racemates. The latter derivative provided a facile method of separation since only ( - )-N-demethylgalanthamine was oxidized by manganese dioxide (106).

10. THE AMARYLLIDACEAE ALKALOIDS

35 1

An in vitro application of the phenyl-phenyl oxidative coupling hypothesis and the resolution of ( _+ )-narwedine mentioned earlier have been combined to provide a synthesis of ( - )-galanthamine. p-Hydroxybenzaldehyde cyanohydrin (XCIX) was reduced and hydrolyzed t o

I

CN XCIX

cH3013cH0 +

CI

C (R = OH, R1= H ) by hydriodic acid. Benzylation of this product and conversion t o the acid chloride provided an acylating agent for CII, which was prepared from 0-benzyl isovanillin (CI). The amide (CIII; R, Rz = CHzCsH5, R1= 0) was reduced by lithium aluminum hydride and palladium-on-charcoal t o the desired phenol (CIII; R, R1,RZ= H), the structure of which was verified by conversion t o belladine (CIII; R, Rz = CH3 ; R1= H ) by diazomethane. Manganese dioxide, leaddioxide, silver oxide, and potassium ferricyanide were effective in the oxidation of CIII (R, R1,R Z= H) to ( 5 )-narwedine. A maximum yield of 1.4 yowas obtained. Polymerization products predominated in all cases (103). Galanthamine is epimerized by dilute mineral acid to ( - )-epigalanthamine (base I X , XCVII) (107, 108). The isomerization product was first assigned the improbable and incorrect structure CIV (109).Oxidation of XCVII with manganese dioxide afforded ( k )-narwedine (109). The NMR-spectrum of narwedine showed the expected A13 quartet for the olefinic protons. Each of the C-1-H components was found to be a doublet (J= 2 cps). Decoupling experiments showed that this splitting was the result of long-range coupling with the C-4a proton. This was verified by deuteration studies (107). Narwedine is converted to hydroxyapogalanthamine (CV; R , R1= H ; Rz=OH) by hot hydriodic acid. The structure of the compound was established by the synthesis of the trimethyl ether CV (R, RI= CH3; Rz = OCH3). The biphenyl CVI (R = CHO, R1= COOCH3) was prepared by the Ullmann method. Condensation with nitromethane and lithium aluminum hydride reduction of the product afforded CVI

352

W. C. WILDMAN

cH30&oH\

CIV

CH3

cv

CHI

CVI

(R = CHzCHzNHz, R1= CH2OH). Conversion to the benzyl bromide with phosphorus tribromide and alkaline cyclization gave CV (R, R1= CH3; Rz = OCH3; NH instead of NCH3). N-Methylation with formaldehyde and formic acid completed the synthesis (110). Nivalidine (CV ; R = CH3; R1, R2 = H) has been isolated from Galanthus nivalis var. gracilis and identified as 6-0-methylapogalanthamine (109). The compound may be an artifact arising from the action of mineral acid on galanthamine or epigalanthamine. Although no specific spectral data are presented, a report has been published that the NMR-spectrum of chlidanthine is similar to that of galanthamine, thus supporting the assigned structure CVII ( 4 2 ) .

H0@0cH3

CH3 CVII

V. Crinine-Type Alkaloids Fourteen alkaloids possessing the 5,l Ob-ethanophenanthridine nucleus were reported in Volume VI in 1960. A period of six years has seen the number swell to a t least thirty-five with many concurrent advances in structure and stereochemistry.

10. THE AMARYLLIDACEAE ALKALOIDS

9

(OqN

w

353

n ROQ

N

0

CH30 CVIII

In 1960 the pattern of substitution for the more common alkaloids containing both an aromatic methylenedioxy and methoxyl group was ambiguous. Because powelline had been converted to crinine derivatives with sodium and amyl alcohol, it was known that the methylenedioxy group was in the 8,9 position in the powelline-related compounds as well.

(OWN Q’OH

o\

R

cx a ; R = H ; crinine b ;R = OCHs ; powelline

Rz CXII a: R, R1, R 2 = H ; vittatine b; R = O H , Rl=CHS, R z r H ; haemanthamine C;R = O H , R1=CH3, R z = O H ; haemanthidine

(0-9 o\

R CXI a: R = H ; buphanisine b; R = OCH3; buphanidrine

R CX I I I a ; R = OCH3, R1= H; crinamidine b ; R=OCHs, R I = C H ~ undulatine ; C ;R , R1 = H ; flexinine

CH30 CXIV Crinamine

OCH3

cxv

Nerbowdine

354

W. C. WILDMAN

However, the methoxyl group could be a t either C-7 or C-10. The former position has been shown to be correct by the Birch reduction of powellane (CVIII) to the phenol (CIX ; R = H). Methylation with diazomethane gave the dimethyl ether (CIX; R = CH3) which was synthesized in a manner analogous to that used for ( f )-crinane (CVIII; no methoxyl at, C-7) (111, 112). Hydrogen bonding and NMR-studies are consistent with the aromatic substitution pattern given in CVIII (111). With this information on the location of the aromatic methoxyl group in alkaloids containing three aromatic oxygenated substituents, the structures of twelve of the original alkaloids can be described below. They serve as convenient reference compounds for discussions of the newer bases. A. 3-O-ACETYLNERBOWDINE This alkaloid (mp 207'-209'; [aID -116' in CHC13) was isolated from Buphane distichu and Nerine crispa (14, 48). The 0-acetyl group was evident from the NMR- and IR-spectra. Nerbowdine (CXV) was formed when the alkaloid was hydrolyzed. Complete structural determination required that a choice be made between C-1 and C-3 for the location of the acetoxyl group. Examination of the NMR-spectra of 0,O-diacetylnerbowdiiie (CXVI ; R = Ac), 0-acetyldihydrobuphanamine (CXVII), and AcO /,,,,,

,.OAC

(0 O CH30

q

9 N

CH30 CXVII

CXVI

CXVIII

0-acetyldihydrocrinine (CXVIII) showed that the methylenedioxy protons of CXVI ( R = A c ) and CXVII are doublets a t 5.73 and 5.78 ppm ( J = O . 2 cps). The methylenedioxy group of CXVIII is a singlet (5.88 ppm). Since the new alkaloid shows only a singlet a t 5.88 ppm, the acetoxy group was assigned to C-3 (113).

10.

355

THE AMARYLLIDACEAE ALKALOIDS

B. ALKALOID13 (11-HYDROXYVITTATINE) This base (mp 248"-250"; [.IU +12" in MeOH) has been isolated from Pancratium maritimum ( 3 ) and Rhodophiala bijida (114). It forms an 0,O-diacetyl derivative (mp 178"-180"). Upon mild treatment with mineral acid. it was converted to apohaemanthamine (CXIX).

cxx

CXIX

Allylic rearrangement during acid treatment has been extremely uncommon in the alkaloids of this family, and it was concluded that alkaloid 13 was 11-hydroxyvittatine (CXX).The configuration of the hydroxyl group a t C- 11 could be assigned as depicted in CXX because epicrinamine (CXXI ; R = OCH3, R 1 = H) and epihaemanthamine (CXXI; R = H , Rl=OCHB) give only poor yields of CXIX with acid (115).The configuration a t C-3 in CXX was assigned the /?-configuration because the ORD-spectrum was more in agreement with that found for haemanthamine than with that of crinamine. The 0,O-diacetyl derivative of CXX could be hydrolyzed by very weak base t o a mixture of CXXII and CXXIII. The two isomers were easily identified since CXXII gave an a,/?-unsaturated ketone (mp 176"-177" ; ~2:: 1728 and 1675 em-1; 224 mp, E = 16,600) upon oxidation with manganese dioxide. Oxidation of CXXIII with acetic anhydride and

(&% I \ CXXI

N' CXXII

CXXIII

f

,>

356

W. C. WILDMAN

dimethyl sulfoxide (DMSO) gave, in high yield, an isomeric ketone (mp 148"-150"; vgz; 1722 and 1743 em-1). Its UV-spectrum showed bands characteristic of the C-11 ketones (Xg,","," 324 infl., ~ = 2 1 4 0 ;313, E = 2960; 295, E = 4650; and 249 mp, E = 3270). Mesylation of CXXIII and treatment with sodium methoxide gave a good yield of montanine (Section VI). Hydrolysis of the reaction from the mesylation of CXXIII with dilute aqueous sodium bicarbonate provided CXXIV (R = CH3CO ; mp 194"-196"). This product could be acetylated t o an 0,O-diacetate (mp 128"-130") or hydrolyzed to a diol (CXXIV; R = H ; mp 130"-132"). Although CXXIV (R = H) had been suggested for the structure of brunsvigine ( 5 ) , neither the melting points nor IR-spectra showed any correlation (114).

CXXIV

C. ALKALOID 16 (MARITIDINE) This base, C17H21N03, was isolated from P. maritimum collected in Rhodes ( 3 ) . To date it has not been isolated from Pancratium spp. collected in other areas (81).Recent chemical studies on purified material have given corrected physical constants (mp 263"-265"; [ c c ] ~+26" in MeOH). The NMR-spectrum showed the presence of two aromatic methoxyl groups (3.78 and 3.93 ppm). Oxidation of maritidine with manganese dioxide gave an a,B-unsaturated ketone (mp 140"-141 " ; ["Iu +230" in MeOH; h$2:'3 5 . 9 8 ~ ; 284, ~ = 3 5 5 0 ,and 228 mp E = 19,300).Methylation of the ketone with methyl iodide and subsequent Hofmann degradation afforded an optically inactive methine base (CXXVI) which could be converted t o a tetrahydro derivative and a methiodide (mp 280" decomp.), neither of which had optical activity. These reactions parallel those found for the methylenedioxy analogs, vittatine (CXIIa) and crinine (CXa). The insolubility of maritidine in

cxxv

CH3 CXXVI

10.

THE AMARYLLIDACEAE ALKALOIDS

357

chloroform prevented detailed examination of its NMR-spectrum. However, oxomaritidine (CXXV; R = 0 instead of OH) and oxovittatine showed identical NMR-spectra when the dimethoxy-methylenedioxy substitution differences were disregarded. The mass spectra of crinine and maritidine showed comparable fragmentations with a constant difference of 16 mass units (114). Maritidine is of significance because it is the first alkaloid with the 5, lob-ethanophenanthridine nucleus to contain dimethoxy rather than methylenedioxy substituents a t C-8-C-9.

D. AMARYLLISINE This phenolic alkaloid (mp 255"-258") was isolated from Amaryllis belladonna. Although combustion data for the base and several derivatives suggested the molecular formula C17H19N04, the correct composition, ClSH23N04, was established by mass spectroscopy. The phenolic nature of amaryllisine was apparent from the typical shift of the UV-spectrum in base, the IR-spectrum of the 0-acetyl derivative (mp 183"-185"; ,A, 5.67p), and facile methylation with diazomethane t o an 0-methyl ether (mp 99"-100"; [aID-16" in CHC13). One double bond was evident from the formation of a single dihydro derivative (mp 243"-245"). Lack of material prevented further chemical degradation, but structure CXXVII (R = H) could be assigned with certainty from the NMR- and 2

,fi..OCH3

CH3O

CXXVII

mass-spectra. The former showed three 3-proton singlets a t 3.87, 3.80, and 3.37 ppm and can be assigned t o the two aromatic and single aliphatic methoxyl groups, respectively. The typical AB quartet representing the C-6 protons was found a t 4.56 and 3.92 ppm (J= 17 cps). The lone aromatic proton appeared as a singlet a t 6.72 ppm and was shifted to 6.60 ppm in dihydroamaryllisine. This upfield shift is commonly observed in the alkaloids of this group containing C-1 ,C-2-unsaturation and results from the removal of the deshielding of the C-10-proton caused by the double bond. The phenolic hydroxyl could be placed a t C-9 because the

358

W. C . WILDMAN

anions of amaryllisine and dihydroamaryllisine were shifted 14 and 13 cps upfield, respectively, from the free phenols (116). Positive assignment of the crini'ne-type nucleus was possible from mass spectral studies which demonstrated that ,amaryllisine and buphanidrine produced, in the high mass region, very comparable fragmentation differing by a constant 2 mass units. A similar correlation was found for the mass spectra of dihydroamaryllisine and dihydrobuphanidrine. The allylic methoxyl of CXXVII (R = H) was placed cis t o the phenyl since the alkaloid and its derivatives had relatively small rotations. From other compounds of the series it is known that the C-3-epimer would possess a considerably larger optical rotation. The absolute configuration of amaryllisine (as given in CXXVII ; R = H) is derived from the observation that amaryllisine and ( - )-crinine have similar plain negative OR'D-curves between 589 and 436 mp (117).

E. AMBELLINE Initial characterization of this alkaloid, C18H21N05 (mp 260"-261"; +32" in CHC13), permitted the expanded molecular formula, C ~ S H ~ ~ N ( O ~ C H ~ ) ( O Cto H~ be) ~assigned. O H , The UV- and IR-spectra 288 mp, indicated that one aromatic methoxyl group was present (A, 6.16 p). Ambelline (CXXVIII) was stable to chemical ~ = 1 3 8 0 A;,, methods of reduction but gave a single dihydro derivative (CXXIX) upon catalytic reduction. Oxidation of ambelline and dihydroambelline with chromium trioxide and pyridine provided the corresponding ketones (CXXX and CXXXI) in good yield. The ketones showed IR-carbonyl absorption near 5.73 p. The UV-spectra showed no evidence of conjugation of the carbonyl group with any unsaturation, but multiple bands near 292 and 315 mp suggested r-electron overlap between the carbonyl and the aromatic ring. Similar effects had been noted in the haemanthamine and crinamine series (115). Oxodihydroambelline (CXXXI) was reduced by methanolic sodium borohydride to a mixture of dihydroambelline (CXXIX) and epidihydroambelline (CXXXIII ; R = OH). Treatment of the latter with thionyl chloride followed by lithium aluminum hydride gave dihydrobuphanidrine (CXXXIII; R = H). This direct interconversion of ambelline and dihydrobuphanidrine established the absolute configuration of the basic nucleus as well as the relative configuration of the aliphatic methoxyl. The position and configuration of the secondary hydroxyl group as well as the location of the double bond were determined by a combination

[.ID

10.

THE AMARYLLIDACEAE ALKALOIDS

359

of instrumental and chemical methods. The carbonyl absorption of 0x0- and dihydrooxoambelline locates the hydroxyl group of ambelline

in the &membered ring. Since the alkaloid is not a carbinolamine, the hydroxyl can only be a t C-11. The configuration of the hydroxyl groups in CXXVIII andCXXIX could be assigned by hydrogen-bonding studies. Both ambelline and dihydroambelline are strongly hydrogen bonded (3564 cm-1). By analogy with haemanthamine and crinamine, the alternate hydroxyl configuration would show large differences in hydroxyl stretching frequency between the natural alkaloids and their corresponding dihydro derivatives (115).The NMR-spectrum of ambelline shows an AB pattern for the two olefinic protons (6.58 and 5.88 ppm). The proton at higher field is further split by coupling with the single proton a t C-3 (J= 5 cps). This provides unequivocal evidence for the location of the double bond (118).

I

CH30

CXXVIII

It CHsO CXXX

I

J.

CXXXII

CHBO CXXXI

I I

360

W. C. WILDMAN

Because biosynthetic experiments were planned for ambelline, a degradative route analogous to that used for crinamine and haemanthamine was completed. The substituted sarcosine (CXXXII) was formed when the methiodide of CXXX was treated with strong alkali (118). Dihydroambelline (CXXIX) (mp 198"-199"; [a]= -12.6' in CHCls) has been isolated from Nerine crispa (48).

F. ANNAPOWINE The alkaloid, C ~ C H ~ (mp ~ N 219"; O ~ [aID+74" in CHC13), was isolated from the Hippeastrum hybrid "Anna Powlowna". It forms picrate (mp 249" decomp.) and hydriodide (mp 221" decomp.) salts. The compound gives a red color with concentrated sulfuric acid. It is classified as a " crinine-type " alkaloid because the IR-spectrum of annapawine is very similar to that of powellamine and crinine (32).

G. BOWDENSINE AND

O,O-DEACETYLBOWDENSINE

Bowdensine (CXXXIV; R, R1= CH3CO) and its 0,O-deacetyl derivative have been isolated from Nerine bowdenii (21). Bowdensine has not been isolated in crystalline form but is concentrated in the crude alkaloid fracticn forming chloroform-soluble hydrochlorides. Bowdensine ([a]=+ 17.3" in CHC13) forms a methiodide (mp 284"-285" decomp.;

0

0 CH30 CXXXIV

CH30

cxxxv

CH30 CXXXVI

10.

THE AMARYLLIDACEAE ALKALOIDS

361

[.ID + 9.8" in EtOH) and a hydroperchlorate-acetone solvate (mp 260"-262" decomp.). The crude alkaloid fraction affording chloroforminsoluble hydrochlorides contains traces of 0,O-deacetylbowdensine (CXXXIV; R , R1 =H) which probably is derived from the hydrolysis of the diester. Analytical and spectroscopic data indicate that bowdensine contains two acetoxyl groups, a tertiary non-methylated nitrogen atom, and an aromatic ring substituted by both methylenedioxy and methoxyl. No olefinic unsaturation could be detected. Alkaline hydrolysis of bowdensine gave CXXXIV (R, R1 = H ) (mp 277"-278" decomp.) (21). Selective mesylation of CXXXIV (R, R1= H ) afforded a monomesylate (CXXXIV; R = H , R1=Ms) which could be reduced to dihydrobuphanamine (CXXXV) with lithium aluminum hydride. The vicinal hydroxyl group at C-2 was demonstrated by periodate cleavage of 0,O-deacetylbowdensine to a dialdehyde (not isolated) and alkaline cyclization to CXXXVI (119).No evidence has been presented for the configuration of the C-2 substituent, but the very high melting point and insolubility of deacetylbowdensine suggests a trans configuration with the hydroxyl a t (2-1.

H. BUPHANAMINE Evidence was cited in Volume VI (p. 359) to show that buphanamine contained the basic ring system of CVIII with hydrqxyl substitution a t C-1 and a nonconjugated double bond. The configuration of the former and the position of the latter were not determined with certainty a t that time. Buphanamine was not oxidized by manganese dioxide and a nonallylic alcohol might be suspected. Pyridine-chromium trioxide oxidized buphanamine to an a$-unsaturated ketone, oxobuphanamine (CXXXVII). Lithium aluminum hydride reduction of CXXXVII afforded both buphanamine (CXXXVIII ; R = H, R1= OH) and epibuphanamine (CXXXVIII; R = OH, R1= H). Although the position of the double bond in buphanamine might be in the 3,4-position of CXXXVIII and migrate to the conjugated (2-3) position of CXXXVII in the

CH30 CXXXVIII

362

W. C. WILDMAN

oxidation process, bond migiation under reductive conditions is unlikely, thus establishing C-2-C-3 unsaturation in the parent alkaloid (120).The a-configuration of the C-1 hydroxyl group in buphanamine was demonstrated by hydrogen bonding studies (121). If the hydroaromatic ring of CXXXVIII is considered to be in the half-chair form, equatorial and quasi-equatorial hydroxyl groups a t C-1 are in an unfavorable position for hydrogen bonding to the n--electrons of either the olefinic double bond or the aromatic ring. Both epibuphanamine and dihydroepibuphanamine (CXXXVIII; R = OH, R1= H, no C-2-C-3 unsaturation) show little evidence of intramolecular hydrogen bond3614 and 3616 ern-1, respectively). Both buphanamine ing (v,,, (v,,,, 3584 and 3613 cm-1) and dihydrobuphanamine (vmilx 3599 cm-1) contain intramolecularly bonded hydroxyl groups. I n the latter, only bonding to the n--electronsof the aromatic ring is possible. The hydroxyl absorption of buphanamine suggests hydrogen bonding of the C-1 hydroxyl to both n--electron systems.

I. BUPHANIDRINE, BUPHANISINE, AND ( + )-EPIBUPHANISINE The structure proof and physical constants for buphanisine (CXIa) were described i n VoIume VI (p. 358). Buphanidrine (CXIb) was considered an ar-methoxybuphanisine because it was converted to buphanisine by sodium and amyl alcohol and hydrolyzed to powelline with mineral acid. Although acid hydrolysis of allylic ethers can provide rearranged allylic alcohols, it has been shown that 0-methylation of crinine and powelline afforded buphanisine and buphanidrine, respectively. With the assignment of the aromatic methoxyl group of powelline to C-7, the structure of buphanidrine is described by CXIb. ( + )-Epibuphanisine (mp 123"-125"; [aID+141" in CHC13) was isolated in minor amounts from Ammocharis coranica ( 4 ) .It formed a perchlorate salt (mp 244"-246" decomp.; [aID +88" in EtOH). Methylation of ( + )-epicrinine (CXXXIX ; R = H) with potassium and methyl-ptoluenesulfonate afforded CXXXIX (R = CH3),identical with the natural ( + )-epib.uphanisine ( 4 ) .

J. CRINALBINE, CRINAMIDINE, AND RELATED ALKALOIDS Crinalbine, C17H19NO5 (mp 235"-236" decomp. ; [aID-23" in CHCls), forms methiodide (mp 265" decomp.) and 0,O-diacetyl hydroperchlorate (mp 160"-161") salts. The two hydroxyl groups of the alkaloid are

10.

363

THE AMARYLLIDACEAE ALKALOIDS

considered to be vicinal. It is a tertiary base containing aromatic methoxyl and methylenedioxy groups. From these data.and a comparison with the properties of crinamidine, it was suggested that crinalbine is the optical antipode of crinamidine (23). The identity and structure of crinamidine itself is still the subject of controversy. The alkaloid is reasonably common in Buphane, Crinum, Habranthus, Hippeastrum, and Nerine species (11,14, 18, 20, 21, 30-32, 48).The first isolation of the alkaloid from Crinum moorei describes it as a levorotatory base (122).I n the experimental section of t h s same paper the specific rotation was given as +24". The alkaloid was assigned the structure CXL because it gave a positive test for a vicinal glycol and the IR-spectrum was very similar to that of powelline (123). OH

CHaO' CXXXIX

CXL

An alkaloid (mp 232"-233"; [a]= -7" in CHC13) having the same composition as crinamidine, C17H19N05, was isolated from both Crinum moorei and Nerine bowdenii (21).Because o f the isolation from identical plants, the similarity of melting points of both the alkaloids and their methiodides (mp 265" decomp. vs. mp 263"-265" decomp.), this material was considered identical with the crinamidine isolated earlier by Boit (122).Evidence leading to the assignment of structure CXIIIa (without absolute stereochemical implications) for crinamidine was presented in Volume VI (p. 361) and in a detailed scientific paper (124). Chemical and spectroscopic evidence for the structures of crinamidine (CXIIIa), undulatine (CXIIIb), flexinine (CXIIIc), and nerbowdine (CXV) was cited in Volume V I and subsequently in scientific journals (49,124).A t that time only the relative stereochemistry of the alkaloids

364

W. C. WILDMAN

was known. Since they have been interrelated with either ( - )-crinane or ( + )-powellane, their absolute configurations have been established. Tubispacine (mp 197"-199"; [mID -145" in CHC13) was converted to oxopowelline (CXLI) by zinc dust and could be resynthesized from CXLI by the action of alkaline hydrogen peroxide. Lithium aluminum

CH30 CXLII

hydride reduction of tubispacine gave CXV and the 3-hydroxy epimer. These reactions parallel those cited in the structure proof of crinamidine, flexinine, and nerbowdine (124), and tubispacine should be identical with epoxyoxopowelline (CXLII) (125). Fiexamine, C I ~ H ~ ~(mp N O226"-228" ~ decomp. ; ["ID i 0 " in CHClS), was isolated from N . jlexuosa and forms a methiodide (mp 245'). The IR-spectrum of flexamine appears to be similar to that of crinamidine, but in contrast to crinamidine, flexamine gives no color with sulfuric acid ( 2 4 ) .Flexine, also isolated from N . jiezuosa, has the same molecular formula as flexamine and crinamidine. This alkaloid (mp 212"; [.ID +75" in CHC13) forms picrate (mp 242" decomp.) and methiodide (mp 221" decomp.) salts. The IR-spectrum is similar t o those of flexamine and crinamine (32). No degradative work has been reported for either flexamine or flexine, and the alkaloids are placed in this section solely by the criterion of the IR-similarity.

K. CRININE,VITTATINE,AND RELATED ALKALOIDS Crinine (CXa) and its enantiomer, vittatine, are the simpIest alkaloids described in this section. Together with powelline (CXb), these alkaloids have provided reference compounds t o interrelate not only the alkaloids of this section, but those of Sections VI and VII as well. Proof of the structures for crinine, vittatine, and powelline was given in Volume VI. The absolute configurations of the alkaloids cited in this section and those in Sections VI and VII are in agreement with Mills' rule and are consistent with numerous interconversions within the given ring systems of the sections. Chemical evidence has been reported t o support these assignments (126).

10.

CXLIII

THE AMARYLLIDACEAE ALKALOIDS

365

CXLIV

Several minor alkaloids deserve brief comment. Elwesine (mp 218"219"; [a]=-32" in CHC13) forms a monoacetyl derivative (mp 149"-150") and is identical with dihydrocrinine (CXLIII) (18). ( + )-Epicrinine (mp 209"-210"; [.ID -1-136" in CHC13) was isolated from N . bowdenii and found t o be the optical antipode of (-)-epicrinine which had been obtained earlier from the lithium aluminum hydride reduction of oxocrinine (21). Krepowine (mp 142'-143") was hydrolyzed by ethanolic potassium hydroxide t o crinine. A comparison of 0-acetylcrinine and krepowine indicated they were identical (18). Powellamine, C ~ ~ H I ~(mp N O198"-200"; ~ [aID -49" in CHClS), was isolated from Crinum powellii. It formed picrate (mp ISSO), hydroperchlorate (mp 258"), and methiodide (mp 224"-226") salts. Functional groups in the alkaloid included an aromatic methylenedioxy and one allylic hydroxyl. The allylic nature of the latter was confirmed by manganese dioxide oxidation to an a,P-unsaturated ketone (mp 167"; ; : :A 5.99). I n contrast t o crinine, powellamine gave a purple color with concentrated sulfuric acid and was oxidized by potassium permanganate to 3,4-methylenedioxyphthalicacid. Structure CXLIV or the C-7-C-S methylenedioxy isomer must be considered likely structures. The absolute configuration of powellamine has not been determined (22). Cripaline (mp 198'-199'; [aJD+50' in CHC13) appears t o be the optical antipode of powellamine. The melting points of the alkaloid and its picrate and hydroperchlorate salts are, within experimental error, the same as those reported for powellamine. The IR-spectra of cripaline and powellamine are identical, and equal weights of the two alkaloids gave a racemic compound (mp 201'). Cripaline was oxidized by manganese dioxide to a ketone (mp 166') which was reduced catalytically t o a dihydro derivative (mp 158"). Oxodihydrocripaline formed a dibenzylidene derivative (mp 134"). These data are consistent with the assigned structure (CXLIV) for the alkaloids. Up to the present time there have been no chemical degradations of powellamine or cripaline which indicate either the nature of the basic ring system or the position of the aromatic substitution. Efforts directed toward the synthesis of crinine and several of its transformation products have been successful.

366

W. C. WILDMAN

CXLV

CXLVI

H CXLVII

CXLVIII

The tetralone (CXLV) was prepared by a series of conventional steps. When submitted to the Schmidt reaction, it afforded both CXLVI (R = 0, R1= H) and the undesired isomer (CXLVII) in approximately equal amounts. The conversion of CXLVI (R = 0, R1= H) t o CXLVIII (R = CH3) was accomplished by hydrolysis of the ester and oxidation to a

so(do

o

6

/

0

0 ‘H CXLIX

0 CL

CLI

CLII R

CLIII

H ‘

10. T H E

AMARYLLIDACEAE ALKALOIDS

367

3-ketone which was protected as the ethylene ketal. Methylation of the resultant lactam, lithium aluminum hydride reduction, and ketal hydrolysis completed the synthetic sequence t o tetrahydrooxocrinine methine (CXLVIII; R=CH3) (127). Reactions of a similar type were used earlier in syntheses of demethyldeoxylycoramiiie (128, 129). Hydrolysis of CXLVI (R = 0, R1= H) and oxidation with pyridinechromium trioxide gave the ketolactam (CXLIX)which was brominated

CLIV

CLV

+

CH300C

H ' CLVI

0 CLVII

CLVIII

CLIX

and dehydrobrominated t o CL. Ketalization of CL with ethylene glycol and p-toluenesulfonic acid afforded a cyclized product CLI (R, R1= 0 ; RzR3=O(CH2)20), which was converted t o the tertiary amine by successive treatment with lithium aluminum hydride, thionyl chloride, and lithium aluminum hydride. Removal of the ketal group afforded ( )-dihydrooxocrinine (CLI; R , R1= H ; Rz, R3 = 0). Resolution provided the enantiomers, dihydrooxocrinine (CLII; R , R1= 0) and dihydrooxovittatine (CLIII ; R , R1= 0).Meerwein-Ponndorf reduction of the enantiomers afforded dihydrocrinine (CLII ; R = OH, R1= H) and dihydrovittatine (CLIII; R = H, R1= OH), respectively, while lithium aluminum hydride reduction afforded the cor?.esponding C-3 epimers

(139).

368

W. C . WILDMAN

Several short and novel syntheses of substituted crinanes have been reported. 3,4-Methylenedioxyphenylmaleicanhydride (CLIV) provided the Diels-Alder adduct (CLV)" upon condensation with butadiene. The adduct contains the proper cis orientation of the phenyl and hydrogen atom for ring C in the crinine-type alkaloids. The anhydride was opened by sodium methoxide t o form the half-ester (CLVI ; R = COOH). Curtius degradation afforded an isocyanate (CLVI ; R = NCO) which was cyclized to the lactam (CLVII) with trifluoroacetic acid. Standard reactions converted CLVII to CLVIII, and the latter was cyclized in good yield t o CLIX (mp 217"-219"). Sodium borohydride reduced CLIX t o a mixture of 6,ll-diol epimers which have not been separated or characterized t o date (231). I n a second novel route t o an oxygenated crinane, CLX (R=OH) was converted successively to the chloride (CLX; R = C1) and aziridine

CLX

CLXI

H CLXII

CLXIII

(CLX ; R = CH&H.,-N-) derivatives. The latter was cyclized t o CLXI by sodium iodide (132).Catalytic hydrogenation of CLXI in ethanol with a platinum catalyst afforded preponderantly the cis-dihydro derivative (CLXII). Pictet-Spengler cyclization of this isomer gave ( )-1-0x0crinane (CLXIII, also called oxodemethoxydihydrobuphanamine) in 79 yoyield (133). One total synthesis of ( & )-crinine and ( f )-epicrinine has been achieved. Ethyl-N-acetylpiperonylglycinate(CLXIV) was condensed with methyl vinyl ketone and cyclized to CLXV (R= COOCzHs).Saponification and decarboxylation of this product gave CLXV (R = H) which was reduced t o a mixture of the epimeric alcohols (CLXVI). I n the crucial step of the synthesis, CLXVI was treated with 1,l-dimethoxy-

* All compounds in the synthctic sequence are raccmic. To clarify stereochemical prescntation, only onc enantiomer is depicted.

10.

THE AMARYLLIDACEAE ALKALOIDS

369

1-dimethylaminoethaneto give a 50 %yield of a mixture of CLXVII and the trans-diamide." Hydrolysis of this mixture provided CLXVIII in 40 %yield. The cis-hexahydroindole ring fusion in CLXVIII was demonstrated by conversion to ( f )-crinane. Reduction of CLXVIII with lithium aluminum hydride followed by Pictet-Spengler cyclization afforded ( f )-a-desoxycrinine (CLXIX). Conversion of CLXIX to ( 5 )crinine was accomplished by selenium dioxide oxidation in acetic acid and saponification of the resultant acetate. The structure of the synthetic cripine was confirmed by oxidation to ( _+ )-oxocrinine [( f )CLXX; mp 172"-173'1 which was reduced by sodium borohydride to ( 5 )-epicrinine [( k )-CLXXI, R = H, R1= OH; mp 235.5"-237'1 (134). 0

CLXV

CLXIV

9H

* All

CLXVI

cLxvrr

CLXVIII

CLXIX

CLXX

CLXXI

compounds in tho synthetic sequence are racemic. To clarify stereochemical presentation, only o m cnaritiomcr is depicted.

370

W. C. WILDMAN

L. CRINAMINE, HAEMANTHAMINE, AND 6-HYDROXY DERIVATIVES

THEIR

Degradative evidence was cited in Volume VI (pp. 365-373) for the gross structures of crinamine (CXIV), haemanthamine (CXIIb), and haemanthidine (CXIIc). The "milk and wine" crinum which is common t o the southern United States has been found to contain considerable quantities of crinamine and a new alkaloid which was identified as 6-hydroxycrinamine (C1,XXII) (17). The latter alkaloid also is quite abundant in Haemanthus natalensis (29). 6-Hydroxycrinamine, C17H19N05 (mp 135"-140° and 210"; [.IU +46" in CHCIs), formed a dihydro derivative (mp 251"-252" decomp.). The alkaloid formed apohaemanthidine (CLXXIII) upon treatment with acid. Methylation of 6-hydroxycrinamine with methyl iodide afforded a quaternary salt which was converted

0

I

OH CLXXII

I

OH

CLXXIII

to a chloroform-soluble tertiary base, C ~ ~ H Z ~(mp N O211"-212"; ~ [.ID +277" in CHC13),when treated with cold, dilute alkali. This product was found t o be criwelline, an alkaloid isolated earlier from C. powellii (92).The structure of criwelline (CLXXIV; R = H, R1= OCH3, Rz = OH) was established by 0-methylation of the alkaloid t o 0-methylcriwelline (CLXXIV; R = H , R1, R2 = OCH3). This product, C19Hz3N05 (mp 127",128"; ["ID +214" in EtOH; methiodide, mp 271"-273" decomp.; methopicrate, mp 21lo-212O), was found t o be identical with O-methylisotazettine, the structure and stereochemistry of which had been determined earlier (93,135-137).

10.

THE AMARYLLIDACEAE ALKALOIDS

371

The configuration of the hydroxyl groups of the alkaloids a t C- 11 was demonstrated by hydrogen-bonding studies (115).Crinamine (CXIV) and haemanthamine (CXIIb) both showed weakly bonded hydroxyl groups in their IR-spectra (v 3591 and 3598 cm-1, respectively), compat,ible with bonding t o either the r-system of the double bond or the aromatic ring. Neither dihydrocrinamine nor dihydrohaemanthamine showed hydrogen bonding (v 3625 cm-1) in the IR-spectrum and the 11-hydroxyl groups in each alkaloid could be assigned the configuration depicted in CLXXII. Confirmatory evidence was obtained from the IR-spectrum of epihaemaiithamine (formed by the reduction of the corresponding C- 11 ketone) and its dihydro derivative. Both epihaemanthamine and dihydroepihaemaiithamine showed strong hydrogen bonding (v 3560 cm-1); in these compounds, the hydroxyl groups must be located as in CLXXV. The configuration of the hydroxyl group a t C- 11 0S

(0

HO--O C-

\

1

~ ~H---H ~ - 35

*’.

N-

CLXXV

in 6-hydroxycrinamine and haemanthidine is best determined by analogy with crinamine and haemanthamine and by an examination of the reaction mechanism of the conversion of CLXXII t o criwelline. Compounds such as CLXXV do not form apo derivatives. Since haemanthidine and 6-hydroxycrinamine form CLXXIII readily, the C- 11 hydroxyl configuration shown in CXIIc and CLXXII, respectively, appears correct. It has been proposed that the rearrangement of CXIIc and CLXXII to tazettine and criwelline, respectively, involves an int,ramolecular hydride transfer from C-11 t o C-6 by way of the intermediates CLXXVI and CLXXVII. Evidence for this process was obtained by the synthesis 0cH3

CLXXVI

CLXXVII

372

W. C. WILDMAN

of 6-hydroxycrinamine-6,ll -dZ. Methylation and treatment with base gave criwelline-8-dz as proved in its NMR-spectrum which showed no protons present a t the benzylic position (138). The configurations of the allylic methoxyl groups with respect t o the aromatic ring in haemanthidine and 6-l~ydroxycrinaminehave been established by the interconversions to tazettine and criwelline. The assignment of configuration of the allylic methoxyls of crinamine and

CLXXIX

CLXXVIII

a; R = OCOCH2N(CHa)z b; R = NCH3CH2COOH

haemanthamine with respect to the aromatic ring relies more heavily on instrumental methods. In Volume VI (p. 367), it was reported that dihydrotazettine and dihydrohaemanthamine gave the same product (CLXXVIII) via Hofmann degradation and hydrogenation-hydrogenolysis. It has been shown by NMR-data that the methines obtained from dihydrotazettine and oxodihydrohaemanthamine contain only one vinyl proton. Theirstructuresshould becorrectedto CLXXIXaandCLXXIXb, respectively (139).The formation of these methines can be rationalized

CLXXX HO-

\

CLXXXI

10. THE

AMARYLLIDACEAE ALKALOIDS

373

by the reaction mechanisms cited in formulas CLXXX and CLXXXI.

It is still likely that CLXXVIII represents the hydrogenation-hydrogenolysis product of each methine, but this structure is less certain, since the configuration of the benzylic asymmetric carbon atom has been destroyed in CLXXIXa and CLXXIXb. The relative configurations assigned to the allylic methoxyl and phenyl groups in CXIV and CXIIb are consistent with NMR-, mass-spectroscopic, and biosynthetic data (140-143). The mass spectra of many alkaloids containing the 5,lOb-ethanophenan$hridine (crinane) nucleus have been examined (141). The spectra frequently are quite complex and require high-resolution techniques to better understand the fragmentation patterns. It is particularly significant that both crinamine and 6-hydroxycrinamine have a low abundance of their molecular ions and show a facile loss of methanol. Although the latter elimination occurs also in haemanthamine and haemanthidine, the molecular ions in these alkaloids are very in tense. It is not possible to assign a configuration to the hydroxyl group a t either haemanthidine or 6-hydroxycrinamine. These alkaloids and all derivatives containing a hydroxyl group a t C-6 were found t o exist in solution as an equilibrating mixture of C-6 epimers (142).The NMRspectra of all 6-hydroxy compounds of this ring system were anomalous in that the benzylic proton and the aromatic proton a t C-7 each showed two chemical shifts. Dihydrohaemanthidine (hippawine) has been isolated from the Hippeastrum hybrid "Queen of the Whites " (32),and dihydrohaemanthamine was detected in Crinum powellii var. harlemense (20). Krelagine, C17H19N04 (mp 202"; [a]= +290" CHC13) forms picrate (mp 268" decomp.), methiodide (mp 260" decomp.), and methoperchlorate (mp 233" decomp.) salts. The functional groups of krelegine are the same as those of crinamine. Vigorous oxidation of the alkaloid affords hydrastic acid. The IR-spectrum is almost identical with that of crinamine. Krelagine, however, gives a red color with concentrated sulfuric acid whereas crinamine remains colorless under these conditions (23).

M. HAEMULTINE AND FIANCINE Chemical evidence was cited in Volume VI (p. 368) suggesting structure CLXXXII for haemultine, an alkaloid of Haemanthus multijiorus. Of primary importance in this assignment was the isolation of haemultine from the reduction of either crinamine or haemanthamine with sodium

CLXXXIV

and n-amyl alcohol. This finding indicated the basic ring system as well as the absolute configuration of the alkaloid. Standard analytical information was in accord with the proposed structure. Dihydrohaemultine was oxidized to a ketone showing carbonyl absorption a t 1751 cm-1 (as the hydriodide). Structure CLXXXII, as proposed for haemultine, is of particular interest since it represents the first alkaloid of the family to contain no oxygenated substituent in the hydroaromatic ring. This novelty prompted a reexamination of the alkaloids of Haemanthus multi$orus and the reductive demethoxylation of crinamine and haemanthamine. Conflicting results were obtained (27). When haemanthamine was treated with sodium and n-amyl alcohol, dihydrohaemanthamine and two isomeric demethoxyhaemanthamines were isolated. The two isomers differed only in the position of an unconjugated double bond since both compounds afforded the same dihydro derivative (mp 225"-227"; [&ID440" in CC14). The a-isomer was assigned structure CLXXXII since it showed a single intramolecularly hydrogen-bonded hydroxyl group at 3590 cm-1, identical in frequency with that found for crinamine and haemanthamine. The jl-isomer was considered to be CLXXXIII because it showed both bonded and unbonded hydroxyl absorption a t 3625 and 3585 cm-1. Hydrogen bonding to the olefinic rr-electronsin CLXXXIII appears to be less favorable than in CLXXXII. Crinamine was demethoxylated by sodium andn-amyl alcohol todihydrocrinamine and CLXXXIII. Under the same considitions, apohaemanthamine (CXIX) afforded only CLXXXII. Neither CLXXXII nor CLXXXIII corresponded in all the physical properties with those reported for haemultine, but the melting points of the methiodide and picrate derivatives of CLXXXIII are in good agreement with those given for haemultine. The melting points of oxodihydrohaemultine (CLXXXIV) and oxodihydro-&-(or/3-)demethoxyhaemanthamine are essentially identical.

10.

THE AMARYLLIDACEAE ALKALOIDS

375

After the characterization of a- and /3-demethoxyhaemanthamine, obtained by degradative procedures, two different samples of H . multi$orus were examined for alkaloid content by gas phase and paper chromatography. Neither CLXXXII nor CLXXXIII could be detected by these sensitive methods. Lycorine and montanine could be isolated by standard column chromatographic methods. A sample of authentic haemultine was found by paper chromatography to be a mixture of CLXXXII and CLXXXIII. There remains the possibility that the "authentic sample " came from a reductive demethoxylation process rather than from a direct isolation. Thus the existence of an alkaloid represented by either CLXXXII or CLXXXIII is in doubt. The physical constants of fiancine were reported in Volume VI (p. 403). A more recent reported has revised the specific rotation to +75" in CHC13 and included an O-acetyl hydroperchlorate derivative (mp 224"-236" decomp.). When treated with sodium and n-amyl alcohol, fiancineaffords haemultine, and the alkaloid is considered an ar-methoxy derivative of CLXXXII (24).

VI. Montanine, Coccinine, and Manthine These alkaloids occur frequently in South African Haemanthus species. Small quantities are found in H. muZti$orus which is grown as an ornamental plant in southern United States (27).Montanine and coccinine are isomeric and possess the expanded molecular formula C~~H~~N(O~CHZ)(OCH~)(OH). Both alkaloids absorb more than one equivalent of hydrogen under catalytic conditions. Neither alkaloid was oxidized by manganese dioxide. Oppenauer oxidation of either alkaloid afforded a key degradation product, dehydrococcinine (CLXXXV; R=CH3, R1, R 2 = H ; mp 191"-193"; [.ID +40" in CHC13). Dehydrococcinine was amphoteric and formed an 0,N-diacetate. The IR-spectrum of the diacetate (vmaX 1761 and 1639 cm-1) indicated that dehydrococcinine was a secondary aminophenol. Dehydrococcinine reacted with diazomethane to form an 0,N-dimethyl derivative (CLXXXV;R, R1, R2 = CH3) in low yield. Hofmann degradation of this product gave a racemic product (CLXXXVI), the UV-spectrum of which was consistent with a 1,l-diarylethylene. In an attempt to improve the yield of CLXXXV (R, R1, Rz=CH3), N-methylation with formaldehyde followed by O-methylation with diazomethane was tried, The product from this reaction sequence was found to be CLXXXVII (R = CH3) and this structure was confirmed by total synthesis utilizing CLXXXVIII as starting material.

376

W. C. WILDMAN

CLXXXV

CLXXXVII

CLXXXVI

CLXXXVIII

The formation of dehydrococcinine from either montanine or coccinine may be explained by oxidation of the alkaloids under Oppenauer conditions to CLXXXIX followed by /I-elimination of the tertiary amino group and tautomerization of the resultant dienone.

CLXXXIX

cxc

Complete stereochemical structures for montanine, coccinine, and manthine were obtained by a novel rearrangement of several 11hydroxylated derivatives of the crinane nucleus to montanine-type derivatives. Mesylation of haemanthamine (CXIIa) and treatment with aqueous alkali afforded a sulfur-free isomer of haemanthamine. Similar treatment of crinamine (CXIV) provided two substances having the same molecular formula and functional groups as crinamine. Isohaemanthamine (CXC; R = O H , R,, R 3 = H , Rz=OCH3) was oxidized by manganese dioxide to an a$-unsaturated ketone (CXC; R , R1= 0, Rz = OCH3, R3 = H). Sodium borohydride reduction of the ketone

10.

THE AMARYLLIDACEAE ALKALOIDS

377

afforded the C-2 epimer of isohaemanthamine (CXC;R1=OH, R, R3 = H , Rz = OCH3). Hofmann degradation of CXC (R, R1= 0, Rz = OCH3, R3=H) afforded CLXXXV ( R = H , R1, Rz=CH3) which could be 0-methylated by diazomethane to form 0,N-dimethyldehydrococcinine. The isomeric products obtained from crinamine were named u- and /3-isocrinamine and were assigned structures CXC (R, R2 = H, R1= OH, R3 = OCH3) and CXC (R = OH, R1, Rz = H, R3 = OCH3),respectively. Botn isocrinamines were oxidized to the same ketone (CXC; R, R1= 0, Rz=H, R3=OCH3) by manganese dioxide. The same ketone was formed by the alkaline epimerization of oxoisohaemanthamine (CXC; R, R1= 0, R2 = OCH3,R3 = H). Methylation and Hofmann degradation of the ketone afforded CLXXXV (R, R1, R2 = CH3) after treatment with diazomethane. The stereochemistry of the various C-2,C-3 isomers of CXC cited above was compatible with intramolecular hydrogen bonding studies in the IR-data. Direct chemical comparison of the isohaemanthamine and isocrinamine series with montanine and coccinine was achieved by selective 0-methylation of the hydroxy methoxy isomers using potassium and methyl p-toluenesulfonate. Using this technique, isohaemanthamine (CXC; R = OH, R1, R3 = H, R2 = OCH3) was converted t o a dimethyl ether (CXC; R,, R,=H, R, R2 = OCH3) which proved to be identical with manthine. Manthine also could be synthesized by either the 0-methylation of montanine or the mesylation of haemanthamine and treatment with methanolic sodium methoxide. Montanine, in turn, is CXC (R = OCH3,R1, R3 = H, R2 = OH). 0-Methylation of epiisohaemanthamine (CXC, R1= OH, R, R3 = H, R2 = OCH3) and coccinine gave the same 0,O-dimethyl ether. This correlation permits coccinine to be assigned structure CXC (R1= OCH3, R, R3 = H, Rz = OH). A mechanism has been proposed for the rearrangement of the mesylate derivatives of haemanthamine and crinamine to the 5,l l-methanomorphanthridine (montanine) nucleus. Attack of base on the mesylate of haemanthamine (CXCI ; R2 = OCH3, R3 = H) would be predominantly

CXCI

378

W. C. WILDMAN

from the side away from the pseudsaxial methoxyl group affording a trans relationship for the functionalgroups a t C-2 and C-3. Inthemesylate of crinamine (CXCI ; Rz = H, R3 = OCH3) the pseudoequatorial methoxy group permits attack of base from both sides of the molecule and two isomers, a- and /3-isocrinamine, are found ( 5 ) . The physical constants of manthidine, a minor alkaloid in several Haemanthus spp., were reported in Volume VI. The alkaloid appeared anomalous since it contained 16 carbon atoms in the basic nucleus. Recent analytical and mass spectral data have indicated that the correct expanded molecular formula is C ~ ~ H ~ ~ N ( O ~ C H Z ) ( O C H The ~)(OH). UV-spectrum is consistent with the presence of a methylenedioxy aromatic substitution and an aliphatic methoxyl group. The IRspectrum in the 1250-1450 cm-1 region resembles that found in the alkaloids of this section. The alkaloid shows a strong intramolecularlybonded hydroxyl group (v 3567 cm-1) and structure CXC (R = OCH3, R1, R2 = H, R3 = OH) has been proposed for the alkaloid (5).

VII. Tazettine-Type Alkaloids A, TAZETTINE Tazettine (CLXXIV ; R = OCH3, R1= H, Rz = OH) is one of the more abundant of the Amaryllidaceae alkaloids, and structural studies on the base began more than thirty years ago (143). The degradative evidence cited in Volume VI for the structure of tazettine referred frequently to personal communications. Many of these data have been

CXCII

CXCIII

CXCIV

10. TIIE AMARYLLIDACEAE ALKALOIDS

379

published in complete papers (136, 144). With the chemistry of the crinine- and montanine-type alkaloids discussed earlier in the chapter, it is now possible to complete a unified picture of the stereochemical basis for the structures cited in Sections IV, V, and VI. The cis phenyl-methoxyl relationship assigned to tazettine rested on the synthesis of CXCII ( R = H ) and its conversion by standard steps to CXCIII, a degradation product of dihydroisotazettinol. Since tazettinol and isotazettinol were known to differ only in the configuration of the C-3-hydroxyl group, the phenyl and hydroxyl were cis in the former and trans in the latter. These reactions have been reinvestigated, and it has been found that chloromethylation of either CXCII (R = H) or the free hydroxy acid affords two products, CXCII (R=CHzCl) and CXCIV, both of which can be converted to CXCIII. The structure of CXCII (R=CHZCl) was proved by alkaline hydrolysis and acidic relactonization to form CXCII (R = CHzOH). This product formed the analogous aromatic aldehyde (CXCII ; R =CHO) upon oxidation. Basic hydrolysis and subsequent acidification of either CXCII (R = CHzOH) or CXCIVresults in no interconversion of the isomeric lactones. However, hydrogen chloride in acetic acid reacts with CXCII (R=CHzOH) to form both CXCIV and CXCII (R = CHzC1) (136). The a-configuration of the methylamino group at C-4a in tazettine (CLXXIV; R = OCHs, R1= H, Rz = OH) was assigned originally from basicity measurements. The facile Hofmann degradation of tazettine and many of its derivatives suggested the group possessed an axial conformation. These assignments required a cis C:D ring fusion. More incisive data are available a t the present time from both the degradative and synthetic studies on the alkaloids of Section V and from spectroscopic studies. The cis C:D ring fusion of the crinine-type alkaloids is assured from recent syntheses in this group, earlier degradative studies on the analogous octahydroindoles (145, l 4 6 ) , and the formation of apohaemanthamine (CXIX) and apohaemanthidine (CLXXIII). The cyclic ethers cannot be formed if the B:C ring fusion is cis (115, 131, 133, 134). Direct chemical correlations between buphanisine (CXI ; R = H), haemanthamine (CXIIb), and haemanthidine (CXIIc) have been achieved, and there is little possibility that tbe ring junction would be altered during these interconversions (115, 147). The haemanthidine (or 6-hydroxycrinamine) conversion to tazettine (or criwelline) does not involve these asymmetric centers, and the C:D ring fusion in tazettine and criwelline should also be cis (138). The configuration of the hydroxyl group at C-6a in CLXXIV is defined by the nature of the B : D ring junction. Chemical evidence

380

W. C. WILDMAN

suggests it is cis fused. The hemiketal group is stable both t o acid and t o carbonyl reagents. Treatment of 0-methyltazettine methine methiodide (CXCV) with potassium t-butoxide gave, among other products, CXCVI and CXCVII. These unsaturated ketones differed only in the 0 II

cxcv

CXCVI 0

0

CXCVII

CXCVIII

CXCIX

position of the conjugated double bond since they both afforded the same dihydro derivative. Isomer CXCVI showed a UV-spectrum characteristic of an a,b-unsaturated ketone (A, 230 mp, E = 10,800) which was unaffected by pH. The UV-spectrum of CXCVII was strongly pH dependent. I n acidic ethanol its spectrum in the 230-240 mp region showedno evidence of the a$-unsaturated ketone chromophore. Stmcture CXCVIII was implied for CXCVII in acid solution. Degradations of dihydrotazettinol (CXCIX ; R = OH, R1, RZ= H) or dihydroisotazettinol (CXCIX; $, Rz = H , R I =OH) substantiate the structural assignments of CXCVI and CXCVII. A key intermediate in the sequence was CXCIX (R, R l = O , Rz=CH3) which could be converted to CXCVII. Quaternization of CXCIX (R, R1= 0, R, = CH3) followed by hydrogenolysis gave the dihydro derivative of either CXCVI or CXCVII. Hofmann

10.

THE AMARYLLIDACEAE ALKALOIDS

38 1

degradation of the methohydroxide of CXCIX (R, R1= 0, Rz = CH3) afforded CXCVII. These transformations prove the structures assigned to CXCVI and CXCVII and show that the amino group of the latter can return to its original point of attachment under acidic conditions. If rings B and D were trans-fused, 1,4-addition of the amino group would occur only with CXCVI (148). The methine alcohol (CLXXIX; R = OH), formed by the Hofmann degradation of dihydrotazettine and hydrolysis, provides an ideal compound for the chemical determination of the absolute configuration of tazettine. With numerous chemical interconversions between the alkaloids'of Sections V, VI, and VII, such a n assignment for tazettine may be applied t o the crinine- and montanine-type alkaloids as well. Ozonization of CLXXIX (R = OH) followed by treatment with refluxing performic acid gave a p-methoxyadipic acid, the dimethyl ester of which was identical with dimethyl ( + )-R-methoxyadipate (CC) having a known structure and absolute configuration (126).The origin of this product from CLXXIX (R = O H ) is quite clear, and the structure of CC is % ' H HOOCf Y O C H 3 HOOC'

cc compatible with the absolute configurations previously assigned t o the alkaloids of Sections V, VI, and VII on the basis of Mills' rule.

B. CRIWELLINE Criwelline (CLXXIV; R = H, R1= OCH3, Rz = OH) was isolated in minute amounts from Crinumpowellii Hort. (92).It occurs in C. macrantherum (19),C. powellii Hort. var. album (23),and Galanthus nivalis (24). It is of interest that the alkaloid is extremely rare, although its C-3 epimer, tazettine, is very abundant. Plants containing tazettine often contain haemanthidine as well. I n several Crinum spp., large quantities of 6-hydroxycrinamine could be isolated, but no criwelline could be detected even by thin-layer techniques (149).The structure of criwelline was discussed in Section V,L. C. MACRONINE Macronine (mp 203"-205"; ,lI.[ +413" in CHC13) was isolated from Crinum macrantherum. Preliminary characterization indicated that the

382

W. C. WILDMAN

alkaloid contained one NCH3, one OCH3,and a a-lactone group which was conjugated with an aromatic ring containing a methylenedioxy group (19). These data would suggest that the base should be classified with those in Section 111. The structure of macronine was obtained from the observation that the IR-spectrum of the alkaloid was identical with that of a degradation product of 6-hydroxycrinaniine (CLXXII). If CLXXII is methylated with methyl iodide in refluxing methanol and subsequently treated with base, the product is not criwelline but CCI (R=OCH3, R, = H, Rz = CH3). Acid hydrolysis of this product and basification OCH3 --

R' CCI

CCII

afforded criwelline. Oxidation of CCI (R = OCH3, R1= H , Rz = CH3) with chromium trioxide in acetic acid gave a lactone (CCI; R, R 1 = 0, Rz = CH3) which was identical with macronine. This structure was confirmed by an alternate synthesis via CCII, the product of the manganese dioxide oxidation of 6-hydroxycrinamine. Hydrolysis of CCII afforded CCI (R, R1= 0, R2 = H) which could be methylated by formaldehyde and reduced by sodium borohydride to provide the N-methyl derivative (macronine) (150).

VIII. Unclassified Alkaloids and Other Substances Several substances have been detected in the course of Amaryllidaceae alkaloid isolations which cannot be classified within any of the previous sections. Of these, belladine and 0-methylnorbelladine are basic substances of singular importance in the biosynthesis of the alkaloids of the family. Further discussion of these bases is reserved for Section X. Hordenine has been isolated from Pancratium maritimum ( 3 )and Ungernia victoris (61).It appears to be a metabolite of tyrosine, an important amino acid percursor of the alkaloids of the family. Ismine, C15H15N03 (mp 99.5'-100.5"; [.ID +O' in CHCl3; picrate, mp 158'-159"), has been isoleted from a n unidentified Ismene spp., Crinum powellii, and Sprekelia formosissima in minute amounts ( 6 ) .

10.

383

THE AMARYLLIDACEAE ALKALOIDS

The substance contains an N-methyl group, two active hydrogen atoms, and an aromatic methylenedioxyphenyl group. No methoxyl groups were 1735 and found. Acetylation provided a neutral 0,N-diacetate 1650 cm-1). Ismine condensed with p-nitrobenzenediazonium chloride to form a red dye, and it was suspected that the substance was represented by CCIII. Treatment of ismine (CCIII) first with acid and then

CCIII

CCIV

with potassium ferricyanide afforded 8,9-methylenedioxy-5-methyl6-phenanthrjdone (CCIV), a compound of known structure ( 6 ) .Ismine has been synthesized from 3,4-methylenedioxy-2'-nitrobiphenyl(CCV; R = H) by chloromethylation to CCV (R = CHzCl) and hydrolysis to the

(yy? CHzOR

0

CCV

CCVI

corresponding alcohol CCV (R = CH20H). Catalytic hydrogenation afforded CCVI (R = H). Ethyl chlorocarbonate converted CCVI (R = H) to CCVI (R=COOCzHs), which was reduced by lithium aluminum hydride t o ismine (151). Two neutral substances, narciclasine and narciprimine, have been isolated from Narcissus incornparabizis. The former, C14Hl~N07(mp 232"-234" decornp.) has strong antimitotic activity. It contains four

CCVII

CCVIII

TABLE I1

W 00

rp

PHYSICAL CONSTANTS OF AMARYLLIDACEAE ALKALOIDS OF UNDETERMINED STRUCTURE AND THEIRPRODUCTS OF TRANSFORMATION AND DEGRADATION Compound

Formula

Melting point ("C)

[a]D

Aestivine Hydrochloride Hydrobromide Alkaloid 31 Picrate 0,O-Diacetyl

196195 205-207 153-154 2 13-2 16 186186 181-1 85

-15l0(EtOH)

Base NB (crispanine) Picrate Hydroperchlorate Brunsdonnine Hydriodide Hydroperchlorate Methiodide

139-141 201 decomp. 221 decomp. 253 248 decomp. 232 decomp. 280-281 decomp.

+78O(CHC13)

Brunsvigine 0,O-Diacetyl Dihydro Picrate Methiodide Hydrochloride Methiodide Brunsvinine Picrate Buphacetine Deacetyl Clivatine

243 184 203 218 186 218-220 (245) 252 140-142 (202) 67-69 182-183 264-266 decomp. 166-169

-77'(EtOH)

(solvent)

Functional groups

References 35

-63'(CH30H)

OzCHz

24,48

+75'(CHC13)

+1l0(EtOH)

+30°(EtOH)

12 -73"(CHC13)

OzCHz, (OCH3)z, OH, OAc

14

+52O( CHC13)

OzCHz, lactone

16

Coranicine 0,O-Diacetyl Hydroperchlorate Methiodide 0,O-Diacetylrnacranthine Distichamine Hippacine Hippandrine Picrate

Amorphous 118-119 192-194 decomp. > 300 decomp. 219-221 161-162 245-246 194 179

+156"(CHC13) +90°(EtOH)

Hippauline Hydroperchlorate Macranthine 0-Acetyl 0,O-Diacetyl O,O,O-Triacetyl Manthidine Miniatine

+10°(CHC13)

24

Y

-19"(CHC13) -2 6' (CHC13) 44"(CHC13) -2O(CHC13)

19

P

Nerifline Hydriodide

163-164 175 decomp. 238-240 222-224 2 19-22 1 181-191 269-272 206-208 (237-238) 152 162-163

Nerundine Hydroperchlorate Methiodide Picrate Poetamine Hydroperchlorate Methiodide Picrate

256 decornp. 221 decornp. 286 decornp. 168 258-260 248 decornp. 191 decornp. 246 decomp.

Poetaricine 0-Acetyl Hydroperchlorate Picrate

273 decornp. 165 228-230 decornp. 190

4

+44"(CHC13)

19 14 9 h 30

-56' -1 lO'(CHC13)

c,

0

+

1 K

P

2

5

87 24

F ii

Lk k-

-95O( CHC13)

10

E

F

-16O"(EtOH)

-60" (Et OH)

OzCHz, COOR

43

U m

44 0

OD

cn

TABLE 11-ontinued Compound Powellidine Hydroperchlorate Picrate Rulodine Hydriodide Sickenbergine Squamigerine Trispheridine Hydrochloride Hydrobromide Hydronitrate Vallopurfine Picrate Picrolonate

Formula Ci6H17N03 B .HC104 B . CsH3N307 C17HziN04 B.HI CuiHigN05 Ci~HziNo~i CiciHiiN03 B.HC1 B.HBr B.HN03 CisHz3N05 B .CsH3N307 €3. CioHsN405

Melting point ("C) 207-269 177 198 193 135-136 110 decomp. 260 140-14 1 283-285 decomp. 272-274 decomp. 197-198 decomp. 244-247 decomp. 193 decomp. 360 decomp.

[aID (solvent)

Functional groups

+ lOO"(CHC13)

References 22

-15"(CHC13)

OzCHz, NCH3, OH

16

+165'(CHC13) 00

OzCHz, OCH3, NCH3, OH OzCHz

39 60

-9O"(EtOH)

OzCHz

62

51

4 a

10. THE AMARYLUDACEAE ALKALOIDS

387

hydroxyl groups, one of which is phenolic. I n addition, one methylenedioxy group and one conjugated olefinic double bond are present. Diazomethane reacts with narciclasine to form an 0-methyl ether which can be oxidized to cotarnic acid. Nacriclasine forms a dihydro derivative, and zinc dust distillation of the alkaloid affords phenanthridine. Structure CCVII has been proposed for nacriclasine. Narciprimine (CCVIII ; mp 300"-320" decomp.) is formed when narciclasine is treated with cold, concentrated hydrochloric acid (152).Aside from their chemotherapeutic potential, the substances should be of considerable biosynthetic interest.

IX. Alkaloids of Undetermined Structure A list of these alkaloids is given in Table 11.This compilation does not include alkaloids of the same category which were reported in Volume VI and for which no additional information has been published. The listing of alkaloids in this table is somewhat arbitrary. Several of the alkaloids classified in preceding sections have been assigned on the basis of weak or equivocal data such as similar IR-spectra. Many of the alkaloids cited in Table I1 have not been subjected to modern criteria of purity and may prove to be mixtures. X. Biosynthesis With the exception of the substances discussed in Section VIII and clivonine, all alkaloids of the Amaryllidaceae contain a fundamental ring system of fifteen carbon atoms which may be divided into two parts containing seven- and eight-carbon atoms. The former consists of the aromatic ring (ring A) and the benzylic carbon atom which is contiguous to either nitrogen or oxygen. The eight-carbon fragment is composed of a six-membered hydroaromatic (or cycloaliphatic) ring and a two-carbon side chain which is attached invariably to the basic nitrogen atom. These fragments have been referred to as C-6-C-1 and C-6-4-2 units, respectively. Biosynthetic studies using radioactive tracer techniques have concentrated on the major alkaloids of Sections 11, IV, V, and VII because of their availability and ease of degradation. It is very likely that the biosynthesis of the lycorenine and montanine-type alkaloids will not differ from the pattern already established. These alkaloids probably arise from the lycorineand crinine-type alkaloids by oxidation and/or rearrangement. It has been shown that tazettine is derived from haemanthidine by such it process.

388

W. C . W I L D M A N

Radioactive alkaloid precursors have been introduced into plants of the family by several methods. These include syringe injection into the bulb or flower stem, leaf absorption, and the culture of floral primordia upon a suitable nutrient. Incorporation of radioactive precursors by root feeding or by 14CO2 has not produced significant incorporation of the label into the alkaloids. Many of the tracer experiments have included degradations to locate the site of radioactivity. Classic methods of functional group analysis have served for the isolation of the one-carbon units, OCH3, 02CH2, and NCH3. Degradative sequences, developed originally in the course of structural studies with a given alkaloid, were adapted to identify the benzylic carbon atom adjacent to nitrogen or oxygen and each of the carbon atoms of the two-carbon side chain of the C-6-C-2 unit. Aromatic tritium atoms were detected by vigorous oxidation of the alkaloid to hydrastic acid, followed by anhydride or imide formation. Degradations commonly used for lycorine, galanthamine, haemanthamine, haemanthidine, tazettine, and belladine are outlined below in Figs. 1-5. Carbon atoms enclosed in parentheses indicate the atom of the original alkaloid nucleus which has been isolated and identified.

ccx

CCIX

0 CCXII

0 CCXIII

+

CCXIV

COa(C4)

FIG. 1. Degradation of lycorine.

10.

Galanthamine (XCIV)

389

THE AMARYLLIDACEAE ALKALOIDS

2. 1. CHaNa m r

Emde

CH32& CH3 CCXV

CCXVI

CCXVII FIG.2. Degradation of galanthamine.

Although biogenetic speculation on the origin of the Amaryllidaceae alkaloids was rife in the 1950's, actual tracer studies began in 1960. Many research groups participated in the program, and it is fortunate that the results proved largely to be complementary rather than duplicative. Early phases of research dealt with the possible amino acid precursors of the alkaloids. A crucial intermediate period required the experimental testing of the hypothesis that the alkaloids were formed by an oxidative phenyl-phenyl coupling process. Most recent problems have been Haemanthamine (CXIIb) or crinamine (CXIV)

CrOs_

Hofmann

I CHs CCXIX

CCXVIII

+

CH3OH (C-3-methoxyl)

-

CHaNH-TS

Hn

0

+

eat.

CHsNHCHaCOOH

1. TaCl

2. F.lectrolysis

+

CHaO(C1z)

+

COa(Ci1) CCXX (C-6)

Ph(OAc),

CCXIX

co2(c-11)

+

CHzO(C-12)

FIG 3. Degradation of haemanthamine and crinamine.

0 W

0

Haemanthidine

1. CHsI

2. OH-

(CXIIC)

tazettine (CLXXIV; R=OCH3, R1 =H, Ra=OH)

Hofmann

HCl

___t

M

CHnOCOCHzN(CH3)2 CCXXI

+

3

CH30H (C-3-methoxyl)

? $

P

0

+

U (CH3)2N-CHzCOOH. HCl

z

c1-

U ( C H ~ ) & H+~C H ~ O+ co2 Kobe CCXXII (C-6 of CXIIc, C-8 of tazettine)

(NCHs of tazettine) ((2-6of tazettine, C-12 of haemanthidine) (C-11 of haemanthidine, C-6a.of tazettine)

FIG.4. Degradation of haemanthidine and tazettine.

10.

391

THE AMARYLLIDACEAE ALKALOIDS

concerned with more subtle steps of biosynthesis-a more precise understanding of the nature of the C-6-c-1 and C-6-C-2 precursors, the stereochemistry of hydroxylation processes, and the phenomena of alkaloid interconversions. Logical amino acid precursors for the alkaloids include phenylalanine and tyrosine, and these were among the first examined. Table I11 cites the plants which were fed radioactive amino acids and related

CCXXIII Belladine

+

cH30 1 . Brz 2. OH-

C CH30 H 3 0 ~ C H ~ N ( C H ~ ) ~ ((2-1’of belladine)

ccxxv

CCXXIV

c H 3 0 0 C H O H

HI04

>

cH30-,

I (C-2 of belladine) CHzOH CCXXVI CCXXVII FIG.5. Degradation of belladine.

+

CH2O (C-1 of belladine)

substances, the alkaloids isolated, and the per cent of incorporation of the tracer into the given alkaloid. Incorporation of tracer into a given alkaloid seldom exceeded 1.00 yo. Precursors affording Iess than 0.001 yo incorporation can be assumed to have a minor role in the biosynthetic process. Although phenylalanine and tyrosine are closely related in chemical structure and in mammalian metabolism, these amino acids form separate sections of the Amaryllidaceae alkaloids. Phenylalanine contains no oxygen in the aromatic ring; yet it serves as a primary precursor of the C-6-C-1 fragment in alkaloids which may contain as many as three oxygenated substituents in ring A. Tyrosine is a universal precursor of ring C and the two-carbon side chain (CS-CZ). Phenylalanine is not

TABLE I11

0

W

p.l

INCORPORATION OF AMINOACIDSAND RELATED SUBSTANCES INTO AMARYLLIDACEAE ALKALOIDS Precursor

Plant

Alkaloid

Narcissus “ Deanna Durbin ”

Lycorine Norpluviine Haemanthamine Norpluviine Caranine L ycorine Galanthamine Lycorine“ Haemanthamine Lycorine Lycorine Galanthamine Lycorine Haemanthamine“ Haemanthidine Tazettine Haemanthamine Haemanthidine 6-Hydroxycrinamine Lycorine Ambelline Belladine Lycorine Crinamine 6-Hydroxycrinamine Lycorine

Narcissus “Twink”

Narcissus “King Alfred”

Narcissus “Texas” Narcissus incomparabilis Galanthus elvesii Sprekelia formosissima

H a e m n t h u s natalensis

Narcissus incomparabilis Nerine bozodenii

Crinum erubescens

Incorporation 0.00 0.00 0.08 0.15 0.08 0.23 0.013 0.13 0.44 0.22 0.14 0.04 0.20 0.16 0.97 0.19 1.18 0.18 0.015 0.82 0.11 0.17 0.09 0.51

(yo)

Reference

47 47 47,153 47,154 47 47,154 45 103 45 45 155 45 45 156 156 156 29 29 29 155 157 47,158 47,158 159 159 159

4

a

d

U

F%

N a r c i s m incomparabilis Narcissus incomparabilis

Lycorine Lycorine

Nerine bowdenii

(MethylJ4C)methionine

Sprekeliu formosissima Narcissus ''Twink

~~-Serine-3-14C Sodium formate-14C Tyramine-l-14C

Sprekeliu formsissima Sprekelia formosissima Crinum erhescens

Narcissus "Deanna Durbin " Tyramine -2- 14C DL-Octopamine-1-14C

Narcissus incomparabilis Crinum erubescena

DL -Hydroxyphenylserine- 2 -14C

Crinum erubescena

Sodium cinnamate-3-14C Cinnamic acid-3-14C p-Hydroxycinnamic aoid-3-14C

Nerine bowdenii Narcissus pseudonarcissus Narcissus pseudonarcissus Nerine bowdenii Narcissus incomparabilis

Caffeic acid-3-14C Benzaldehyde-7-14C

Narcissus pseudonarcissus Spekelia formosissim

Ambelline Belladine Lycorine Tazettine Lycorine Norpluviine

0.00 0.18 0.37 0.023 0.42 0.095 0.01 0.01 0.01

155 155 155 157 47,158 47,158 157 47 47

Tazettine Tazettine Crinamine 6-Hydroxycrinamine Lycorine Lycorine Norpluviine

0.008 1.01 1.30 0.23 1.60 0.023 0.14

157 157 159 159 159 47 47

Lycorine Crinamine 6-Hydroxycrinamine Lycorine Crinamine 6-Hydroxycrinamine Lycorine

0.23 0.018 0.005 0.046 0.25 0.12 0.28

155 159 159 159 159 159 159

Lycorine Haemanthamine' Haemanthamine" Lycorine Haemanthamine' Lycorine' Heemanthamine Haeman thamine Tazettine

0.02

47 160, 160, 162 160, 160, 161 164 164

3.1

0.00 0.00 0.00

161 161 163 163

TABLE 111-continued Precursor

Plant

Protocatechuic aldehyde-sH Protocatechuic aldehyde-7-14C

Narcissus incomparabilis Narcissus incomparabilis

Protocatechuic acid-7-14C

Narcissus “ Deanna Durbin ”

p -Hydroxybenzaldehy de - 7-1% Isovanillin-U-3H

3-Hydroxy-4-(methoxy-l4C)N - (m-:thyl-l4C)benzylamine

Narcissus incomparabilis Narcissus “Deanna Durbin” Nerine bowdenii Narcissus “King Alfred ’’

Alkaloid Lycorine Haemanthaminen Lycorine” Lycorine Norpluviine Haemanthamine Lycorine Norpluviine Lycorine Galanthamine Haemanthamine

Incorporation

0.23

0.002 0.001

0.000

0.000 0.000 0.000 0.019 0.018

(yo)

Reference

155, 165 163 163 47 47 161 47 47 47 45 45

Percentage of incorporation ic;u these alkaloids was either not reported or quoted in figures that could not be converted to per cent of incorporation. I n all cases, acceptable incorporation is evident.

3 ?

s

U

F2

10.

THE AMARYLLIDACEAE ALKALOIDS

395

converted to tyrosine readily in the Amaryllidaceae, since radioactive alkaloids isolated from tracer experiments utilizing ~ ~ - 3 - p h e n y l a l a n ine-14C have little, if any, label in the C-6-C-2 fragment. Tyrosine in the proteins isolated from the phenylalanine feeding experiments also was not radioactive. The conversion of phenylalanine, a C-6-C-3 precursor, to the C-6-C-1 unit of the Amaryllidaceae alkaloids requires the formal loss of two carbon atoms from the side chain of the amino acid as well as the introduction of a t least two oxygenated substituents into the aromatic ring. The results shown in the latter part of Table 111emphasize the specificity of the C-6-C- 1 precursor. Benzaldehyde, p-hydroxybenzaldehyde, isovanillin, and protocatechuic acid are not incorporated to any appreciable extent into the alkaloids, while cinnamic, p-hydroxycinnamic and caffeic acids, protocatechuic aldehyde, and 3-hydroxy4-methoxy-~4C-W-methyl-14C-benzylamine readily become part of the C-6-C-1 unit. The negative incorporations must be interpreted with caution, since solubility aspects and transport of the radioactive precursors to the site of biosynthesis may be extremely important (45, 47, 166). The last compound cited in Table I11 was incorporated into galanthamine with no randomization (presumably via isovanillin), yet isovanillin was not utilized for alkaloid formation in either the Narcissus “Deanna Durbin” or in Nerine bowdenii (45, 47). Phenylalanine, an established precursor of the C-6-C-1 fragment of the alkaloids when injected into the leaves, flower stems, or bulbs, is not incorporated into alkaloids when introduced via root absorption from a hydroponic solution containing the radioactive amino acid (166). The feeding data cited in Table I11 suggest that tyrosine, a C-6-C-2 precursor, is degraded no further than to tyramine before incorporation into the alkaloids. I n controlled experiments, DLoctopamine (2-hydroxytyramine) is a far poorer precursor of crinamine and 6-hydroxycrinamine than tyramine itself (159). p-Hydroxybenzaldehyde, a possible derivative of either tyrosine or phenylalanine, is barely incorporated into Narcissus pseudonarcissus (161). The conversion of phenylalanine to a C-6-C-1 unit must include a process for the loss of two carbon atoms of the aromatic side chain as well as the introduction of oxygen in the aromatic ring. From previous biochemical studies two possible pathways seemed feasible for degradation to a C-6-C-1 unit : ( a ) phenylalanine+phenylserine-+benzaldehyde+protocatechuic aldehyde, or ( b ) phenylalanine+cinnamic acid+ caffeic acid-tprotocatechuic aldehyde. The negligible incorporation of benzaldehyde and phenylserine compared with protocatechuic aldehyde

396

W. C. WILDMAN

mitigates against pathway a. Phenylserine is metabolized by Narcissus spp. to form glycine, presumably by threonine aldolase cleavage of the substrate. All compounds listed in pathway b are good precursors of the Amaryllidaceae alkaloids. It appears unlikely that cinnamic acid is aminated to phenylalanine as an alternative in pathway b since phenylalanine in the plant protein was not radioactive in experiments utilizing radioactive cinnamic acid. The presence of phenylalanine deaminase in Narcissus has been detected. Tyramine and protocatechuic aldehyde are logical components for the synthesis of norbelladine (CXXVIII; R, RI,Rz, R3=H). This substance and various 0- and N-substituted derivatives were suggested as probable precursors of the Amaryllidaceae alkaloids. Barton and Cohen (167)proposed that compounds such as CCXXVIII could undergo oxidative phenyl-phenyl coupling in the plant to form the intermediate H

R0

CCXXVIII

CCXXVIII

I

1

o

d

R3

R3

ccxxx

CCXXIX

R3

CCXXXI

CCXXXII

Ri0

CCXXXIII

10.

THE AMARYLLIDACEAE ALKALOIDS

397

dienones CCXXIX and CCXXX. Three aromatic substituents are possible in structure CCXXX, since either para-para or ortho-para coupling may occur in the conversion of CCXXVIII to CCXXX. When R3 = H in CCXXIX, 1,6-addition of the amino group would lead to the lycorinetype nucleus (CCXXXI). I n CCXXX, when R 1 = H , narwedine (CCXXXII) results from 1,4-addition of the hydroxyl group to the conjugated ketone. If R 3 = H in CCXXX, 1,4-addition of the amino group provides the nucleus of the crinine type (CCXXXIII). Initial support for the phenyl-phenyl oxidative coupling theory came in the isolation of belladine (CCXXVIII; R , R1, Rz, R3=CH3) from several plant sources. Conclusive proof was derived from radioactive tracer studies with double- and triple-labeled norbelladine (CCXXVIII ; R, R1, Rz, R3 = H) and 0- and N-methyl derivatives. A list of the precursors fed is given in Table IV. The incorporation data and chemical degradations of the radioactive alkaloids support the theory of phenylphenyl oxidative coupling of a norbelladine-like precursor. The multiplelabeled norbelladine derivatives have been shown to be incorporated intact into the Amaryllidaceae alkaloids. The degree of 0- and N-methyl substitution in CCXXVIII plays an important role in the formation of the alkaloids. I n general, N-methylated derivatives of CCXXVIII are converted to galanthamine-type alkaloids but not to the lycorine- and crinine-type nuclei. This suggests that N-demethylation of either the alkaloids or their precursors is not a rapid process. It was observed that 0-methylnorbelladine (CCXXVIII ; R, Rz, R3 = H, R1= CH3) was not incorporated into galanthamine, although the 0,N-dimethyl derivative (CCXXVIII ; R, Rz = H, R1, R3 = CH3), N-methylnorbelladine (CCXXVIII ; R , R1,Rz = H, R3 = CH3), and norbelladine were incorporated a t a percentage close to that found for tyrosine (0.012 "/o). Although negative incorporation data must be used with caution, it seems likely that 0-methylation of norbelladine occurs after N-methylation. The 0,N-dimethylnorbelladine then is converted to galanthamine. 0-Methylnorbelladine, while not used in the synthesis of galanthamine, is a good precursor of haema.nthamine. This substance, labeled at the methoxyl group and a t C-1 with 14C, is incorporated into haemanthemine with no randomization of the labels. Essentially identical radioactivity ratios were found in the precursor and in the methylenedioxy and benzylic carbon atoms of the haemanthamine isolated from the feeding experiments. The radioactivity of the C-12 position of haemanthamine is explained readily from earlier biosynthetic experiments. The radioactive methylenedioxy group is derived from the 0I4CH3 group of the double-labeled norbelladine precursor. Experimental evidence for the conversion of the methoxyl group of

TABLE IV INCORPORATION OF NORBELLADINE AND DERIVATIVES INTO AMARTLLIDACEAE ALKALOIDS Precursor Norbelladine-lJ4C

Plant

Narcissus “Twink” Narcissus “King Alfred ”

Norbelladine-l,l’-14C

Nerine bowdenii

Bisdeoxynorbelladine-l’-14C

Narcissus “Twink”

Hydroxynorbelladine- 1‘-14C

Narcissus “Twink”

N (Methyl-14C)norbeUadine

Narcissus “King Alfred”

0-Methyl-N - (methyl-14C) norbelladine

Narcissus “King Alfred ”

0-(Methyl-l4C)-N-(methyl-I4C) norbelladine

Narcissus “King Alfred”

0-(Methyl-“%)-N - (methyl-14C) norbelladine-1-14C

Narcissus “King Alfred”

O-(Methyl-14C)norbelladine

Narcissus “ King Alfred ”

O-(Methyl-lW)norbelladine- 1-

Narcissus “King Alfred”

~

14c

Alkaloid Lycorine Norpluviine Haemanthamine Galanthamine Galanthine Haemanthamine Belladine Crinamine Lycorine Tazettine Haemanthamine Lycorine Norpluviine Galanthamine Galanthine Haemanthamine Galanthamine Galanthine Haemanthamine Galanthamine Galanthine Haemanthamine Galanthamine Galanthine Haemanthamine Galanthamine Galanthine‘ Haemanthamine Galanthamine Galanthine Haemanthamine

Incorporation 0.24 0.74 0.15

2.64 0.0009 0.07 0.00 0.00 0.0007 0.0017 0.18 0.00 0.00 0.14 0.00 0.00 0.14 0.00 0.00 0.018 0.00 0.00

0.00 0.036 0.00

1.00

W CD

(yo)

m Reference

168 168 153 46 46 46 169 169 169 170 170 170 170 45,46 45,46 45,$6 45, 46 45,46 45,46 45,171 45,171 45,171 171 171 171 45,172 45,172 45, 172 45,172 45,172 45,172

Percentage of incorporation into these alkaloids was either not reported or quoted in figures that could not be converted to per cent of iacorporation. I n all cases, acceptable incorporation is evident. a

3 c)

4

Fg

10.

THE AMARYLLIDACEAE ALKALOIDS

399

an 0-methoxyphenol t o a methylenedioxy group has been observed in several studies. 3-Hydroxy-4-(methoxy-~4C)-N-(methyl-~4C)benzylamine affords radioactive haemanthamine which contains all activity in the methylenedioxy group (45).N-Demethylation of the precursor, via either 3-hydroxy-4-methoxybenzylamine or isovanillin, probably has occurred prior t o incorporation. L-( Methyl-14C)methionine is incorporated by “Twink” daffodils into both lycorine and norpluviine, and the label resides almost exclusively in the methylenedioxy and methoxyl groups of the respective alkaloids. A cell-free enzyme system, isolated from Nerine bowdenii, converts norbelladine (in the presence of ( - )8-adenosyl-L-methionine t o 0-methylnorbelladine. Other potential C-1 precursors are not effective. The specificity of this plant enzyme was emphasized when an enzyme isolated from rat liver and known t o catalyze the methylation of catechols was found to give largely the isomer CCXXVIII (R, Rg, R3 = H, R1 =CH3) (173). The conversion of the o-methoxyphenol to the methylenedioxy group may occur late in the biosynthetic pathway. Tritiated norpluviine is converted t o tritiated lycorine by the “Deanna Durbin” daffodil. This transformation not only demonstrates the conversion of an 0methoxyphenol to the methylenedioxy group but also indicates that the C-2 hydroxyl group of lycorine is derived by allylic oxidation of either norpluviine or caranine. This late-stage hydroxylation was suspected when it was found that hydroxynorbelladine (CCXXVIII;R, R1, Rg, R3 = H ; OH instead of H ortho to Rg0) was incorporated into lycorine with extremely low efficiency. The experimental evidence cited earlier provided information about the nature of the amino acids and C-6-C-2-N-C-6-C-1 precursors utilized in alkaloid formation. Information concerning the discrete steps (starting with norbelladine) in the biosynthesis of the alkaloids is less definite. 0-Methylnorbelladine has been detected in the “Twink ” daffodil by isotopic dilution methods. This substance is not utilized in the biosynthesis of galanthamine, and the experimental evidence presented to date suggests that galanthamine is formed by the following N-dimethylnorbelsequence : norbelladine-tN-methylnorbelladine-+O, ladine-tgalanthamine. I n the lycorine- and crinine-type alkaloids, 0-methylation occurs in preference to N-methylation. 0-Methylnorbelladine then is converted to norpluviine and the other alkaloids of the lycorine type by coupling, subsequent hydroxylations, and formation of the methylenedioxy group. Similar steps also may occur in the crinine series. The biosynthesis of lycorenine- and tazettine-type alkaloids cannot be accommodated within the concept of the phenyl-phenyl oxidative

400

W. C. WILDMAN

coupling of a norbelladine derivative. While these alkaloids were originally thought to arise from coupling of suitable C-6-C-1 and C-6-C-2 fragments, it is likely that they are derived by molecular rearrangement of carbinol amines formed by benzylic hydroxylation. Such a process can be envisaged in the transformation of XLV to XLVI. It has been shown that haemanthamine (CXIIb) and haemanthidine (CXIIc) are precursors of tazettine in Sprekelia formosissima ( 174). Tritiated haemanthamine afforded radioactive haemanthidine and tazettine 3 days after feeding, and the radioactivity of the tazettine rose steadily over a 90-day growing period. Tritiated haemanthidine formed radioactive tazettine in S. formosissima, but the haemanthamine was found to be inactive. Tritiated tazettine was converted to haemanthamine and haemanthidine in negligible quantities. The montanine-type alkaloids probably are derived from a rearrangement of a haemanthamine-like precursor. However, haemanthamine is not a precursor of montanine or manthine in Haemanthus coccineus (164). Research over a period of seven years has provided an immense amount of information on the chemical nature of the precursors utilized by the Amaryllidaceae for alkaloid formation and the chemical processes involved. However, many fundamental questions concerning the role of the alkaloids in plant metabolism remain unanswered. Enzymes for the various transformations have not been purified or characterized. Alkaloid catabolism is a relatively unexplored research area. One paper has appeared which relates the quantitative estimation of various amino acids, both free and combined in the plant protein, with the period of plant development of the Narcissus “Golden Sceptre.” Phenylalanine and tyrosine are most prevalent during the periods of active growth, i.e., leaf and flower formation (175).Maximum alkaloid content was observed to occur during the dormant period. REFERENCES 1. H. A. Lloyd, H. M. Fales, P. F. Highet, W. J. A. Vanden Heuvel, and W. C . Wildman, J . Am. Chem. SOC.82, 3791 (1960). 2. K. Grade, 2. Chem. 1, 158 (1961). 3. F. Sandberg and K.-H. Michel, Lloydiu 26, 78 (1963). 4. H. Hauth and D. Stauffacher, Helv. Chirn. Actu 45, 1307 (1962). 5. Y. Inubushi, H. M. Fales, E. W. Warnhoff, and W. C. Wildman, J . Org. Chem. 25, 2153 (1960). 6. R. J. Highet, J . Org. Chem. 26, 4767 (1961). 7. J. A. Mills, J . Chem. Soc. 4976 (1952). 8. H.-G. Boit and W. Dopke, Ber. 92, 2578 (1959). 9. W. Dopke, Naturwiss. 50, 645 (1963). 10. H.-G. Boit and H. Ehmke, Nuturwiss. 46, 228 (1959). 11. H.-G. Boit and W. Dopke, Naturwiss.47, 159 (1960).

10.

THE AMARYLLIDACEAE ALKALOIDS

40 1

12. L. J. Dry, M. Poynton, M. E. Thompson, and F. L. Warren, J . Chem. SOC.4701 (1958). 13. H. M. Fales and W. C. Wildman, J . Org. Chem. 26, 881 (1961). 14. H. Hauth and D. Stauffacher, Helw. Chim. Acta 44, 491 (1961). 15. A. Goossen and F. L. Warren, J . Chem. SOC.1094 (1960). 16. H.-G. Boit and B. Mehlis, Naturwiss. 48, 603 (1961). 17. H. M. Fales, D. H. S. Horn, and W. C. Wildman, Chem. & Ind. (London)1415 (1959). 18. H.-G. Boit and W. Dopke, Naturwiss. 48, 406 (1961). 19. H. Hauth and D. Stauffacher, HeZw. Chim. Acta 47, 185 (1964). 20. W. Dopke, Arch. Pharm. 295, 868 (1962). 21. R. E. Lyle, E. A. Kielar, J. R. Crowder, H. M. Fdes, and W. C. Wildman, J . Am. Chem. SOC.82, 2620 (1960). 22. H.-G;Boit and W. Dopke, Naturwiss. 46, 475 (1959). 23. H.-G. Boit and W. Dopke, Naturwiss. 47, 498 (1960). 24. H.-G. Boit and W. Dopke, Naturwiss. 47, 109 (1960). 25. L. Bubeva-Ivanova and V. Ivanov, Tr. Nauchn.-Issled. Inst. Farm. 3, 70 (1961); C A 61, 14465h (1964). 26. A. P. Yakovleva, Zh. Obshch. Xhim. 33, 1691 (1963); CA 59, 13114h (1963). 27. H. M. Fales and W. C. Wildman, J . Org. Chem. 26, 1617 (1961). 28. J. Goosen, P. W. Jeffs, J. Graham, F. L. Warren, and W. G. Wright, J . Chem. SOC. 1088 (1960). 29. P. W. Jeffs, Proc. Chem. SOC.80 (1962). 30. H.-G. Boit and W. Dopke, Ber. 92, 2582 (1959). 31. W. Dopke, Arch. Pharm. 295, 920 (1962). 32. H.-G. Boit and W. Dopke, Naturwiss. 47, 470 (1960). 33. D. T. Bailey, Thesis, Iowa State University, Ames, Iowa (1967). 34. H.-G. Boit and W. Dopke, Naturwiss. 47, 323 (1960). 35. N. F. Proskurnina, Zh. Obshch. Khim. 33, 1689 (1963); CA 59, 11586g (1963). 36. All Union Scientific-Research Chemical-Pharmaceutical Institute, French Patent 1,310,209 (1962) ; CA 59, 3722g (1963). 37. A. Gheorghiu and E. Ionescu-Matiu, Ann. Pharm. Franc. 20, 531 (1962). 38. L. Bubeva-Ivanova and V. Ivanov, Tr. hrauchn.-IssZed. Inst. Farm. 3, 89 (1962); C A 61, 8128g (1964). 39. Shan-Hai Hung and Kuang-En Mas, Y a o Hsueh Hsueh Pao 11, 1 (1964). 40. S. Uyeo and Y. Yamamoto, Yakugaku Zasshi 85, 615 (1965). 41. W. Dopke and H. Dalmer, Naturwiss. 52, 60 (1965). 42. W. Dopke and H. Dalmer, Naturwiss. 52, 61 (1965). 43. W. Dopke, Naturwiss. 50, 354 (1963). 44. W. Dopke, Naturwiss. 50, 595 (1963). 45. D. H. R. Barton, G . W. Kirby, J. B. Taylor, and G. M. Thomas, J. Chem. SOC.4545 (1963). 46. D. H. R. Barton, G . W. Kirby, J. B. Taylor, and G. M. Thomas, Proc. Chem. SOC. 254 (1961). 47. A. R. Battersby, R. Binks, S. W. Breuer, H. M. Fales, W. C. Wildman, and R. J. Highet, J . Chem. SOC.1595 (1964). 48. W. Dopke, Naturwiss. 49, 469 (1962). 49. E. W. Warnhoff end W. C. Wildman, J . A m . Chem. SOC.82, 1472 (1960). 50. D. F. C. Garbutt, P. W. Jeffs, and F. L. Warren, J . Chem. SOC.5010 (1962). 51. 2. F. Ahmed, A. M. Rize, and F. M. Hamouda, Lloydiu 27, 115 (1964). 51a. S. Rangaswami and R. V. K. Rao, Tetrahedron Letters 4881 (1966).

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10. TEE

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83. H.-G. Boit and H. Ehmke, Be?. 90,67 (1967). 84. P.W. Jeffs and T. P. Toube, J. Ofg. Chem. 31, 189 (1966). 86. W. A. Hawksworth, P. W. Jeffs, B. K. Tidd, and J.P.Toube, J.Chem.50~.1991 (1966). 86. S. Ozeki, Yakugaku Zasshi 85,699 (1966);C A 83, 13336a (1966). 87. S. Ozeki, J. P h a m . Soc. Japan 85, 206 (1966). 88. P.W. Jeffs, personal communication (1966). 89. B. Mehlis, Ph.D. Thesis, Humboldt University, Berlin (1966). 90. B. Mehlis, Natumiss. 52, 33 (1966). 91. C.K. Briggs, P. F. Highet, R. J. Highet, and W. C. Wildman, J. Am. Chem. SOC.78, 2899 (1966). 91a. W. Dopke, M. Biernert, A. L. Burlingame, H. K. Schnoes, P. W. Jeffs, and D. S. Farrier, Tetrahedron Letters 461 (1967). 92. H.-G. Boit and H. Ehmke, Be?. 89, 2093 (1966). 93. T.Kitigawa, S. Uyeo, and N. Yokoyama, J. Chem. Soc. 3741 (1969). 94. S. Uyeo, T. Kitagawa, and Y. Yamamoto, Chem. & Phurm. B d l . (Tokyo) 12,408 (1964). 948. W. Dopke and M. Biernert, Phannazie 21, 323 (1966). 96. N.F.Proskurnina, Zh. Obsheh. Khim. 3a, 1686 (1963);C A 69,14036h (1963). 96. Kh. A. Abduezimov and S. Yu. Yunusov, Dokl. Akad. NaukSSSR 188,1316(1963); C A 60, 9324b (1964). 97. S. Yu. Yunusov,and Kh. A. Abduazimov, Dokl. Akad. Nauk Uz.S S R 44 (1963); Zh. Obshch. Khim. 27, 3367 (1967);C A 49, 1281b (1966). 98. Kh. A. Abduazimov, L. 6 . Smirnova, and S. Yu. Yunuaov, Dokl. A m . Nauk Uz. S S R 21,24 (1964). 99. Kh. A. Abduazimov, L. S. Smirnova, and S. Yu. Yunusov, Dokl. A m . Nauk Uz. S S R 20, 19 (1963);C A 60,10736b (1964). 100. S. Yu. Yunusov and Kh. A. Abduazimov, Zh. Obshch. Khim. 29, 1724 (1969). 101. L. S. Smirnova, Kh. A. Abduazimov, and S. Yu. Yunusov, Khim. Prirodn. Soedin., A M . Nauk Uz.S S R 322 (1966);C A 64,6161d (1966). 102. H.-Q. Boit, W. Dbpke, end W. Stender, Natunviss. 45, 262 (1968). Chem. Soc. 392 (1960);J . Chem. Soc. 806 103. D. H.R.Barton and G. W. Kirby, PTOC. (1962). 104. D. J. Williams and D. Rogers, Proc. Chem. Soc. 367 (1964). 106. H.-G. Boit, W. Dopke, and A. Beitner, Ber. 90,2197 (1967). 106. S. M. Laiho and H. M. Fales, J. A m . Chem. Soc. 86,4434 (1964). 107. G. W. Kirby and H. P. Tiwari, J . Chem. Soc. 4666 (1964). 108. L. Bubeva-Ivanova. Be?. 97,663 (1964). 109. L. Bubeva-Ivanova, Be?. 95, 1348 (1962). 110. J. Koizumi, S. Kobayashi, and S . Uyeo, Chem. & Pharm. Bull. (Tokyo) 12, 696 (1964). 111. H. A. Lloyd, E. A. Kielar, R. J. Highet, S. Uyeo, H. M. Fales, and W. C. Wildman, Tetrahdron Letters 106 (1961);J . 079. Chem. 27, 373 (1962). 112. W. C. Wildman, J . A m . Chem.Soc. 80, 2667 (1968). 113. H. Hauth and D. Stauffacher, Helu. Chim. Acta 46, 810 (1963). 114. K.-H. Michel and W. C. Wildman, unpublished research (1966). 116. H. M.Fales and W. C. Wildman, J . A m . Chem. Soc. 82, 197 (1960). 116. R.J. Highet and P. F. Highet, J. O?g. Chem. 80, 902 (1966). 117. A. L.Burlingeme, H. M. Fales, and R. J. Highet, J. A m . Chem. Soc. 86,4976 (1964). 118. P. Naegeli, E.W. Warnhoff, H. M. Fales, R. E. Lyle, and W. C. Wildman, J. Org. Chem. 28, 206 (1963).

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-CHAPTER 11-

COLCHICINE AND RELATED COMPOUNDS W . C. WILDMAN AND B . A . PURSEY Iowa State University. Ames. Iowa

I. Introduction

...................................................... .............................................. 111. Chemistry of Colchicine Alkaloids .................................... A. Synthesis of Colchicine Degradation Products ....................... B . Spectroscopy ................................................... C . Oxycolchicine .................................................. IV . Photoisomers ...................................................... A . j-and y.Lumicolchicine .......................................... B . a-Lumicolchicine ................................................ C. Lumiisocolchicines .............................................. D. Other Photoisomers ............................................. V . Minor Alkaloids .................................................... A . Cornigerine ..................................................... B . 3-Demethyldemecolcine .......................................... C. Substance CC-12 ................................................ D. Androcymbine .......................... .................... E . Melanthioidine ................................................. F. Kesselringine ................................................... G . Bulbocodine .................................................... H . Bechuanine .................................................... I . Alkaloids of Camptorrhiza stmmosa ................................ J . Alkaloids of Colchicum kesselringii ................................. K . Alkaloids of Colchicum cornigerum ................................. V I . Synthesis ......................................................... A . Total Syntheses ................................................. B . Syntheses of Desacetamidocolchicine ............................... ................................................. A . Biogenetic Schemes .............................................. B. Biosynthetic Experiments ........................................ .................................................... I1. Distribution in Nature

407 414 414 414 418 424 426 426 428 429 431 431 431 432 432 433 434 434 434 435 435 435 436 436 436 445 448 448 450 455

.

I Introduction Investigation of colchicine. the major alkaloid of Colchicum and related genera. and its congeners has attracted a great amount of interest for many years . The long-established use of colchicine in the 407

+P 0

TABLE I

00

DISTRIBUTION IN NATURE Substance -

Plant

Androcymbium melanthioides var. stricfa Baker Corms Seeds Leaves

Bulbocodium vernum L. (G. vernum Ker-Gawl) Corms and leaves Flowers Camptorrhiza stmmosa (Bak.) Oberm. Corms and seeds

Colchicine

C

B

F

Corms

Reference

3 -

0.07% 0.12y0

-

-

Substance I (0.002y0) Melanthioidine (0.O 1 yo)

-

-

Substance El (0.062%) Androcymbine (0.7%) Melanthioidine (0.093%)

*a

?

-

0.1% O.lfq0

*

*

*

* *

-

-

Bulbocodme Substance El

3 3

0.023%

*

-

-

Substance I (0.000370) Cornigerine Isocorydine (0.0004~0) Unknown substance (mp 192'-194") (0.0003y0) Isocorydine Strumosine (0.005~0) Umtaline

4 4 4 4 4 4 4

Substance C or El

3

*

-

Aerial parts

Colchicum alpinum Lam. et D.C.

Other

*

*

-

-

c.autumnale L? Seeds

0.3%

-

5

(loDllS

0.035%

Substances El, S

5

Flowers

C . byzantium Ker-Caw1 Corms Flowers C . cornigerum (Sweinf.) TLckh. et Drar. Corms

-

*

-

-

Old corms (Feb.)

-

New corms (May)

-

5

6 6

*

Seeds Corms (autumn)

New corms (Feb.)

-

1

1

d 0

Cornigerine (0.014%) Substance CC1 (CC4) (0.0008%) Substance CC2 (0.0009~o) Substance CC3 (0.003%) Substance CC6 (trace) Substance CC5 (O.O1yo) 3-Demethyl demecolcine (0.0003y0) Cornigerine (0.0033yo) Substance CC1 (0.0003~0) Substances CC2, CC3, CC6, CC9, CC16 Substance CC8 ( O . O O O l ~ o ) 3-Demethyl demecolcine (0.002%) Cornigerine (0.017~0) Substance CC8 (0.0003~0) Substance CCll (0.0003%) Substance CC8 (0.001%) Substance CClO (0.004%) Substance CCll (0.0003~0) Cornigerine (0.014%) Substance CC1 ( O . O O O l ~ o ) Substance CC2 (0.0001%) Substance CC8 ( O . O O O l ~ o ) Substances CC6, CCll

r 7 7 7 7

r

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

F

0

8 Q2

M

! i tl F

5

tl d

0

Ei

: 8rn

ip

0

CD

E

TABLE I-continued

0

Substance ~

~~

Plant

Colchicine

B

C

F

Other

Reference

C . cornigerum (Sweinf.) Tiickh. et Drar.

Seeds

-

Leaves

-

Stems

Flowers

C . kesseki??giiRgl. Corms ( ? )

-

-

*

Aerial parts

C . luteum Baker Corms

0.21-0.25% 0.26-0.27~0

Substance CC5 (0.001%) Substance CC12 ( 0 . 0 0 2 ~ 0 ) Substance CC13 Substance CC5 (0.003%) 3-Demethyl demecolcine (0.009yo) Substance CC8 Substance CC5 (0.001%) Substance CCl4 (O.OO1yo) Substance CC15 (0.0003%) Substance CC5 (0.002%) Substance CC15 (0.0002%)

1 1 1 1

Colchiceine Substances D, I, J Substance Kz-KI1 Kesselringine

8-1 1 8-1 1 8-1 1 8-1 I

Colchiceine

Seeds

-

I 1 1 1 1 1 1

12 13 14 12 13

td

?

C . maeedonicum KoHanin Seeds

15

0.4%

C . montanum L. Corms

*

C . ritchii R. Br.

*

*

Dipidax triquetra Baker ( D . rosea Laws.) Corms, seeds

*

-

*

-

Gloriosa simplex L. Seeds, corms

*

$

*

-

G . superba L.

* *

* *

-

Substances Gz, G3, G4

$

-

-

*

*

*

-

Corms

Corms Seeds

G . virescens L h d . Seeds, corms

Zphigenia bechuanica Baker Seeds

*

0.03%

*

Corms

0.2%

-

Aerial parts

0.006~0

*

Substance C or EI

3

Substance C or El

4

Substance B or cornigerine

3

c. c.

z 16 16 d 0

2

Cornigerine Bechuanine (0.017 yo) Unknown substance (0.009~o) Substance I Bechuanine (0.045%) Cornigerine Bechuanine (0.028y0) Unknown substance (mp 215"-220") (0.002%)

4

60

I+

c.

412 W. C. WILDMAN AND B. A. PURSEY

M . robusta Bge. Whole plant

*

0.17%

o.oo2~o

0.096%

Omithoglossurn glaucum Salisb. var. grandiflorum

corns 0. viride Drijand. (0. glaucum Salisb.) Corms Sandersonia aurantiaca Hook.

Corms

Colchiceine (0.003~0) Substance I (0.01%) Substance El (0.012%) Substance D (0.004%) Substances J, T,, S

18,19 18,19 18,19 18,19 18,19

*

*

*

-

*

*

*

-

2

*

*

*

-

2

The asterisk indicates the substance is present but a yield was not reported. Of Bulgarian arigin.

Substances I, OGG1, OGG2, OGG3

3

414

W. C. WILDMAN AND B. A. PURSEY

treatment of gout, the discovery of its antimitotic activity, and the chemical studies culminating in elucidation of the structure of this unusual molecule continue t o stimulate widespread investigations by chemists, biologists, and pharmacologists. Volume I1 of this series discussed in detail the biological aspects of colchicine. The structure and stereochemistry of colchicine and the constitution of the most common minor alkaloids were reviewed in Volume VI. Recent work on colchicine and related alkaloids has had two major foci : the total synthesis and the biosynthesis of colchicine. I n addition structures have been unambiguously determined for a- and ,8-lumicolchicine as well as for several other natural and photochemical compounds. Studies on the ORD-, NMR-, and mass-spectra of colchicine and related compounds have appeared that may be of diagnostic value to future investigations in the field. 11. Distribution in Nature

A large number of new species has been investigated since the completion of Volume VI. Increasing use of modern spectroscopic techniques in conjunction with alumina and paper chromatography has resulted in the characterization of many new minor components which would have escaped detection previously. Many nontroponoid alkaloids have been found using these modern assay methods. Colchicum cornigerum (Sweinf.) Tackh. et Drar., a species native to Egypt, has provided the only example thus far of a plant which contains colchicine-related compounds but no colchicine as such. Cornigerine, a close relative of colchicine, is the major alkaloid. The effect of seasonal factors on the quantity and composition ofthe alkaloid fraction in various parts of the plant has been reported (1).I n agreement with other studies of this nature, cornigerine is present in largest quantity in the corms during the spring. Unlike colchicine-containing plants, however, no cornigerine is found in the aerial parts of the plant. On the other hand, demecolcine-type compounds appear t o be largely absent from the corms, though present in the aerial parts. The results of recent isolation studies (through 1965) are summarized in Table I. A listing in this table implies that the substance in question has been either isolated and characterized or detected by standard paper chromatographic techniques. 111. Chemistry of Colchicine Alkaloids A. SYNTHESIS OF COLCHICINE DEGRADATION PRODUCTS With the completion of Volume VI of this series, a complete structure for colchicine, including stereochemistry, had been established. The

1 1.

COLCHICINE AND RELATED COMPOUNDS

415

basis for this formulation (particularly with regard t o the C ring) was in terms of properties and reactions closely analogous t o those of more simple tropolones, as well as the more definitive X-ray analysis. None of the work mentioned, however, had completely defined the positions of the carbonyl and methoxyl groups in ring C. I n a series of reductive degradations, Rapoport et al. (20-22) prepared I, 11,and I11 by unambiguous methods. The position of the nonreducible double bond in these compounds is in some doubt (see Volume VI, Chapter 8, and below).

I

I1

The synthesis of I by Loewenthal ( 2 3 )has provided firm evidence for the position of the carbonyl group of colchicine and therefore for structure IV. Pyrogallol trimethyl ether provided V via a series of condensation reactions. After homologation and treatment with polyphosphoric acid, V furnished VI. Selective catalytic reduction followed by dehydration gave VII. Reduction of the ketone by LiAl(0tBu)BHand subsequent selenium dioxide oxidation of the alcohol acetate furnished VIII ; catalytic hydrogenation and epimerization of the hydroxyl group via oxidation and reduction led to the formation of IX. Dehydration of IX gave X, the double bond of which could not be rearranged under conditions effective for analogous compounds. However, hydrolysis of X followed by oxidation afforded XI, which readily rearranged with p-toluenesulfonic acid in acetone (or hydrogen chloride in chloroform) to XII. The ethylene ketal of XI1 was identical with Rapoport’s degradation product (I,as ketal) by mixed melting point and IR-spectra. XI11 was also prepared by similar methods ( 2 4 ) .The synthesis of 111has been accomplished as part of a total synthesis (see Section VI).

416

w. c. WILDMAN AND

T

A

1

T %

0

x

8' 9

B. A. PURSEY

3c

U

H

s

B E

417

11. COLCHICINE A N D RELATED COMPOUNDS

XIV

XV

The UV-spectra of I, 11, and I11 (256 3 mp) violate Woodward's rules when compared with XIV (264 mp), if the double bond is at 12,12a. Several workers have concluded, however, that strain in a cycloheptadiene B ring would force one of the double bonds t o move to an exocyclic position (23-25). The hypsochromic shift in the UV-spectrum may be explained by steric interference to coplanarity, since XV (R=CH3, R' = H, Lax248 mp) and XV (R, R' = CH3, A,,,,, 251 mp) exhibit a lower maximum than X I V (23). Loewenthal, on the basis of conformational considerations, has concluded that XVI is better than XVII as a conformation for XII, due to the possibility of greater coplanarity in XVI (24).There is, however, no positive NMR-evidence for an olefinic proton in XII, though it was considered possible that the pertinent signal was masked by the aromatic proton resonance (24). The position of the nonreducible double bond in these hydrogenated derivatives of colchicine clearly remains ambiguous. Hexahydrocolchicine and hexahydrocornigerine also apparently show no olefinic proton in the NMR-spectrum and structures XVIII (R, R' = CH3) and XVIII (R, R' =-CH2-) have been assigned to these compounds (26). On the other hand, 111, with the double bond unambiguously at position 7a, 12a, has been synthesized and it differs from the authentic degradation product in the IR-fingerprint region (27). However, isomerization of the double bond with boron trifluoride to the 12, 12a position

XVI

XVII

bCH3

XMII

W.

418

C. WILDMAN AND B. A. PURSEY

gave a compound identical with authentic material. No NMR-data were given, but clearly both isomers contain the styrene chromophore (UVspectra).

B. SPECTROSCOPY 1. Optical Rotation and Optical Rotatory Dispersion Earlier work on the optical rotation behavior of colchicine at the sodium D line was discussed in Volume VI. As rotational data for various derivatives of colchicine accumulated, it became apparent that Leithe's rule, which correlates bases containing aromatic rings stereochemically by optical rotation shifts, is not generally followed; in fact, the shifts are often of opposite sign to those found with L-amino acids and Lphenethylamines (28). Several authors (29-31) have pointed out thah isocolchicine and its ring C derivatives have rotation values considerably TABLE I1 OPTICAL ROTATORY DISPERSION OF COLCHICINEDERIVATIVES' First effect

Second effect

Compound

h

[@I

Colchicine

370 318 357 303 370 318 370 312 392 310"

-12400 -20500 1-30200 -7950 +17300 -1 7000 439000 -9200 t-10350'

373 311 370 313

t-16000 -88500 -20700 +78000

Isocolchicine Demecolcine Isodemecolcine Colchicide

+17200

Hexahydrocolchicine P-Lumicolchicine y-Lumicolchicine

Data from Hrbek et UZ. ( 2 8 ) .

h 294 256 278 256 294 256 282 260 287 270 260 238 272 238 274 248

[@I +12000 +49000* f31400 +392006 +I1400 +401006 +35000 +59O0Ob +17600sh +204006 -35800 +24800 +I42000 -27O0Ob -140000 +11900b

' Extremum not obtained; the value is given for the lowest wavelength reached. Estimated.

11. COLCHICINE

419

AND RELATED COMPOUNDS

more negative than those of colchicine and its derivatives. Such optical rotation effects have not yet been explained. ORD-studies conducted on oolchicine derivatives, colchinols, and pand y-lumicolchicine (Table 11)have clarified some of the stereochemical aspects of these molecules (28). Colchinol (XIX) and its derivatives are essentially bridged and skewed biphenyls. They show a single strong negative Cotton effect a t 260 mp which implies an S-configuration (XX), also indicated in the X-ray analysis of colchicine (XXI).

XIX

xx

XXI

Both colchicine and isocolchicine exhibit double negative Cotton effects (330 and 280 mp). The effect a t 330 mp is probably related to the absorption of the tropolone ring, since it is absent in the colchinols. The Cotton effect a t 280 mp is considered to be due to the K band of the biaryl system (as in the colchinols) and the sign agrees with the one predicted on the basis of the chirality shown by X-ray analysis. The amplitude of the first effect (330 mp) is appreciably greater in the is0 series than in the normal one. The absolute configuration of the asymmetric center is considered to have only an indirect connection with the large Cotton effect in the 260-280 mp region. Colchicide (XXII) appears to have a single Cotton effect, but two overlapping effects are considered more probable. Hexahydrocolchicine (a cinnamylamine with skewed chromophore) exhibits a strong negative Cotton effect a t 250 mp. The p- and y-lumicolchicines (XXIII) are essentially arylcyclobutenes combined with a,p-unsaturated ketone

I

XXII

OCH3 XXIII

420

W. C. WILDMAN AND B. A. PURSEY

moieties. Each lumi derivative shows a large Cotton effect at 350 mp followed by an even larger one at 250 mp. The curves for /3- and ylumicolchicines are roughly enantiomeric ; this is presumably due to differences in interaction between the aromatic system and the unsaturated ketone group.

2. Nuclear Magnetic Resonance Recently NMR-analysis has contributed to the structural elucidation of colchicine-type compounds and also to the transformation products oxycolchicine and the lumicolchicines. Selected data are shown in Table 111, based partly on a comprehensive study of normal and isocolchicine derivatives (32). Certain diagnostic features emerge from a detailed comparison of the tropolone compounds. The aromatic and tropolone methoxyl protons appear as neighboring or overlapping singlets in the region of 3.9 ppm. The single aromatic proton (C-4) appears at about 6.55 ppm and is essentially independent of changes in the C ring or at C-7 (the same is true of the methoxyl protons), although there appears to be a slight trend to higher field in the is0 series. The proton at C-8 reflects the change from normal to is0 arrangement, as expected, and is also sensitive to changes at C-7. The effect due to changes at C-7is more marked in the is0 series. The protons at C-ll and (2-12 produce an AB TABLE lTI NUCLEARMAGNETIC RESONANCE or' COLCHICINEDERIVATIVES'

Normal Series Substituent at C-7 NHAc

NHAC NHAc NHz NH2 H H

C-10 Om3

N H Z SCH3 OCH3 SCH3 ocH3 SCH3

Resonance positions Hs

Hi1

Hiz

Jii-iz

7.74 7.73 7.66 7.66 7.33

6.89 6.87 6.92 6.90 6.94 7.12 6.93 7.15 6.82 7.08 6.78 7.00

7.43 7.43 7.38 7.37 7.16 7.33 7.38 7.37 7.20 7.22 7.20 7.21

12 11 10 11

7.60 7.55 7.77 7.62 7.35 7.30

11 11 10.5 10 11 11

Other

NAc 1.96 NAc 1-93,

Reference 33 34 32 26.35 35 32 32 32 32 32 32

421

11. COLCHICINE AND RELATED COMPOUNDS TABLE 111-continued Is0 Series Substituent at

Resonance positions

C-7

C-9

Hs

NHAc

om3

7-25 7.27 7.28

NHAc

SCX&

H NHz

om3 SCHj

7.42 6.78 8.23

HII(IZ) HIZ(II) 7.15 7.17 6.92 7.12 7.00 7.15 6.98

7.46 7.47 7.28 7.48 7.46 7.40 7.37

511-12

Other

Reference

32 35 35

13.5

NAc 2.06 NAc 2.00'

32 32 32

12.5 13 12.5

Colchiceines

Resonance positions Substituent at C-7 m

c

HE 7.65 7-66 7.66 7.58

NH% H

8.16 1.45

H11(12) Hiz(11, 7.66 7.63 7.23 7.42 7.17 7.37 6.93 7.57

7.38 7.32 7.54 7.72 7.48 7.68 7.38 7.32

511-12

Other

Reference

NAc 2.00

32 26 35

NAc 1.97*

35

10.5 11

12 11

32 32

Other cofnpounds Resonance positions Compound Comigerine

Cornigereine SubstanceCClZ

Oxycolcbicine

Ha

Hi1

7.64 7.60

6.89 7.28

511-iz 7.32 7.54

(")

("1

(7

7.38

6.98 7.07 6.01 6.00

7.79 7.98 7.46 7.45

5.53 5.49

11 11

5.4 5.4

Other

04Hz-0 O4H2-0 NAc 1.83 NAc 1.71'

6.01 6.01

Referenee

26 26 35 35 33 34

422

W. C . WILDMAN AND B. A. PURSEY TABLE 111-continued Lumicolchicines Resonance positions

Compound ,&Lumicolchicine

y-Lumicolchicine or-Lumicolchicine Isolumicolchicine

D-ring OCH3

C-8,C-12 bridge

3.68 3.63 3.47 3.76 3.02

4.09, 3.63 4.07, 3.63 4.03, 3.70

6.54

C=CH-OCHa

Other

6.63d 6.68d 6.74dd 6.70d 6.37s 6.35s 6.61s 6.66s

=CH =CH =CH =CH

Reference

33 36 36 36 37 6.37s' 38 6.35s' 39 6.40s' 38 6 . 6 4 ~ ~ 39

Expressed as 6 (ppm) relative to internal tetramethylsilane, in CDC13 at 60 mHz unless otherwise specified; J given in cps. I n dimethylformamide-d7. Not distinguishable. I n pyridine. ' Hydrate. 'Dried as a melt.

quartet, which shifts slightly with alterations in C-ring substituents and a t C-7. The coupling constant is slightly larger in the is0 series. If both normal and is0 modifications of a given colchicine compound are available, it is possible to differentiate between them. The AB- coupling constant for colchiceine-type compounds is intermediate between those for the isomeric methyl ethers but tends to be closer to those in the normal series. The lumicolchicines and oxycolchicine show some significant changes in their NMR-spectra (see Table 111),all of which can be clearly attributed to alterations in the tropolone moiety. For example, the typical AB quartet of colchicine is missing in the lumi derivatives, and in oxycolchicine this set of resonances has shifted somewhat together with a decrease in coupling constant. The C-ring methoxyl group signal moves upfield with respect t o the troponoid compounds in both the lumicolchicines and oxycolchicine, reflecting changes in its environment.

3. Mass Spectra A number of colchicine derivatives have been analyzed by mass spectroscopy under conditions which allowed clear fragmentation patterns t o be observed in the high mass region (40).

11.

423

COLCHICINE AND RELATED COMPOUNDS

I n the spectrum of N-acetylcolchinol methyl ether (XXIV), the molecular ion is the most abundant peak, followed in intensity by an ion of mass 312 (M-59). Other significant ions are a t m/e 297 and m/e 281. The processes thought to be responsible for these peaks are shown below. c

CH30 H 3

0

q

2

\

c

H

3

-

c

CH30

r

r

OH q + CH3-C=NH I

CH30 OCH3

OCH3

XXIV m/e 371

mle 312 /C€h

m/e 297

\mle 281

The spectra of N-acylated colchicine derivatives containing a tropolone ring show great similarities in fragmentation pattern. I n particular, the most intense peaks are those representing the successive loss of small fragments. Expulsion of CO appears to be a common process in colchicines, as well as in simple tropolones (41). The major high mass fragmentation processes of colchicine are considered to be as shown below.

1

OCH3 mle 399

1

- ACNH8

m/e 340

\

m/e 371

-COCIIs

m/e356

- co

d

m/e328

A general similarity to XXIV is observed in the region below m/e 312, which supports the scheme proposed. The spectrum of N-formyldesacei tylcolchicine also supports these assignments. The base peak is at m/e 312 (loss of CO and HCONH2) and there is a close correspondence with colchicine below m/e 312. Isocolchicine exhibits the same high mass peaks as colchicine but with some differences in intensity. 2-Demethyland 3-demethylcolchicine have almost identical high mass peaks,

424

W. C. WELDMAN AND B. A. PURSEY

uniformly shifted 14 mass units from the analogous peaks produced by colchicine. Colchiceine, on bhe other hand, exhibits striking differences in peak intensities when compared with colchicine. !be molecular ion and the M-CO peak are much more intense than in colchicine. The behavior parallels that of tropolone and its methyl ether (41).However, the M-87 peak (loss of AcNHz and CO) is somewhat reduced in intensity. All other high mass peaks are a t the same masses as 2- or 3-demethylcolchicine, providing further evidence for the suggested fragmentation processes. Demecolcine (XXV)has its base peak a t m/e 207 (M-164), shifting to m/e 208 with deuteration. Intense peaks a t this mass are also found in the spectra of desacetylcolchiceine and N-methyldesacetylcolchiceine but not in the spectrum of N-methyldemecolcine. Analogous base peaks a t m/e 193 are found in the spectra of 2- and 3-demethyl-N-methyldesacetylcolchiceine. From these data, it was inferred that (1) the ion concerned contains the aromatic ring but not the - 4 R ( R = H or CH3) groups, (2) one N-H is necessary for the fragmentation to occur, and (3) a hydrogen transfer is involved in this process. XXVI or XXVII is thought to be a possible ion resulting from this fragmentation.

cH30m ma cH30P30

CH30

NEfCH3

ma

CH3O

H

m 3 0

(=so

om3

xxv

XXM

XXVII

Neither 8- nor y-lumicolchicine shows the intense peak at M-28 characteristic of troponoid compounds. The base peaks z m at m/e 356 (M-43), with the loss of AcNHz also prominent. ! b e primary process appears to be the degradation of ring D by loss of CO and CH3.

C. OXYCOLCHICINE Treatment of colchicine with chromic acid furnishes oxycolchicine, which contains one extra oxygen and shows no loss of carbon. Early work on this compound was reviewed in Volume VI. !be absence of a troponoid UV-band, the ready conversion to colchicehe, the absence of hydroxyl absorption in the IR-spectrum, and the presence of a reactive carbonyl group all point to an ether bridge in ring C.

11.

COLCHICINE AND RELATED COMPOUNDS

XXXI

425

XXIX

Buchanan et al. have recently proposed XXVIII as the structure of oxycolchicine on the basis of chemical and NMR-evidence (33). Borohydride reduction of XXVIII gave XXIX, which showed only an amide band in the carbonyl region of the IR-spectrum. XXIX could be transformed into colchiceine by treatment with acid. Catalytic hydrogenation of oxycolchicine provided a hexahydro compound (XXX)which formed a monoacetate, indicating that the ether linkage was still intact. Compound XXVIII was reduced by lithium aluminum hydride to an amine

426

W. C. WILDMAN AND B. A. PURSEY

(XXXI) which absorbed 2 moles of hydrogen; X X X I was also shown to revert to colchiceine by treatment with potassium iodide in acetic acid. A comparison of the NMR-spectra of XXVIII and colchicine has provided further evidence for the structure proposed (33, 34). The pertinent data are shown in Table 111.The shift of HS and H12 to higher field indicates the loss of aromatic character. The reduction in coupling constant (511-12) and the abnormally low value of H11 in XXVIII were ascribed to the effect of the adjacent oxygen atoms. Further supporting data have been obtained by a detailed study of IR- and UV-spectra and polarography ( 3 4 ) .Mechanisms for the formation of XXVIII and its reconversion to colchiceine have been proposed (33).

IV. Photoisomers

A.

p- AND Y-LUMICOLCHICINE

When a solution of colchicine is exposed to light in the absence of air, three products are isolated in varying amounts, depending on the conditions : a-, p-, and y-lumicolchicine. One feature they all share is the absence of the long wavelength UV-band associated with the troponoid system. A discussion of earlier work on these photoisomers may be found in volume VI. /3-Lumicolchicine, the most plentiful isomer, was investigated extensively, culminating in the proposal by Gardner et ad. of X X I I I as its structure (42). Parallel reactions and similar spectra indicated that y-lumicolchicine was a stereoisomer of /I-lumicolchicine. Stereoformulas X X X I I and XXXIII were assigned to p- and y-lumicolchicine, respectively, by a study of hydrogen-bonding differences in the tetrahydro derivatives (reduction of one double bond and the carbonyl group). More recently Chapman et ad. have reinvestigated the structural problem using NMR-techniques (36).They point out that photoisomerization of tropolones has been shown to frequently involve more than simple alterations (43),so that XXXIV is not rigorously excluded by the cCH3OH

3

o

CH30

v

r

c

~

o

CH30

OCHa

XXXII

OCH3

XXXIII

o

11. COLCHICINE AND RELATED COMPOUNDS

427

earlier investigations as a possible structure for 8- and/or y-lumicolchicine. I n addition, the dihydro compounds (reduction of the carbonyl group) both show strong intramolecular hydrogen bonds in the UVspectrum, indicating the need of additional evidence for stereochemical assignments. The NMR-spectra of 8- and y-lumicolchicine reveal the presence of an intact B ring, an olefinic proton doublet, vinyl methyl ether protons, and signals in the 4 pprn region attributable to bridgehead hydrogen atoms. The pertinent data are included in Table 111. One bridgehead proton in 8-lumicolchicine which is masked in CDC13 was uncovered in pyridine by the upfield shift of the masking methoxyl protons. Double resonance saturation of the lower-field bridge proton collapsid the olefinic doublet to a singlet. Thus the nature of rings C and D was established. Further evidence was obtained by an examination of the homogeneous alcohols derived from sodium borohydride reduction of the respective photoisomers. Since the hydride ion would enter from the most accessible side, XXXV was deduced for the relative stereochemistry of that part of the alcohol molecules. The NMR-spectra of the two alcohols were very similar, except that the N-H resonance was anomalously low in the 8-alcohol [8.60 ppm, compared with 6.68 ppm (y-alcohol), 6.36 pprn (8-lumicolchicine), and 5.70 pprn (y-lumicolchicine)], suggesting the creation of a new intramolecular hydrogen bond. On extrapolation to infinite dilution, this resonance shifted much less than the corresponding one exhibited by the y-alcohol. This clearly indicated a strong NH-OH hydrogen bond, which is only possible if the OH and NH functions

8

cH30c53$NHAc CH30

OH OCH3 XXXIV

OCH3 XXXVI

OCHs

xxxv

bCHs XXXVII

428

W. C. WILDMAN AND B. A. PURSEY

involved are on the same side of the molecule. Therefore, the /3-alcohol is XXXVI and 8-lumicolchicine is XXXII. Further NMR-studies proved that the NH proton was the one involved in the hydrogen bond. By similar methods, the y-alcohol revealed intramolecular hydrogen bonding involving the hydroxyl proton, which does not allow a firm structure proposal because of the many possibilities for this type of hydrogen bond in the molecule. Compound XXXVII was considered perhaps more plausible than other possibilities. On this basis y-lumicolchicine can be formulated as XXXIII.

B.

a-LUMICOLCHICINE

Early work on a-lumicolchicine showed it to be different in character from the B- and y-isomers, although combustion analysis indicated that it too was an isomer of colchicine. There was no absorption of hydrogen under catalytic conditions and no reaction was observed with carbonyl reagents. It was also found that a-lumicolchicine, when heated t o its melting point or above 100" in solution, was converted to /?-lumicolchicine. Conversely, 8-lumicolchicine, when irradiated, formed alumicolchicine. This indicated that a simple reversible reaction was involved. On the basis of these and other observations, Schenck et al. proposed XXXVIII as the structure for a-lumicolchicine ( 4 4 ) .

XXXVIII

OCH3 XXXII

Further investigation by Chapman and co-workers using physical methods has revealed that a-lumicolchicine is a dimer of /I-lumicolchicine (37). UV- and IR-spectra showed the absence of an enol ether group and indicated the presence of only the styrene chromophore. The NMR-spectrum of a-lumicolchicine is similar to that of P-lumicolchicine except that ( 1 ) the vinyl proton observed in P-lumicolchicine is missing, (2) a-lumicolchicine exhibits one more aliphatic proton than the /3isomer, and (3) the methoxyl resonance a t 3.63 ppm in /?-lumicolchicine has shifted to unusually high field in a-lumicolchicine (3.02 ppm). This

11.

COLCHICINE AND RELATED COMPOUNDS

429

evidence indicated a dimer, and the abnormal chemical shift of the methoxyl group suggested diamagnetic shielding by an unsaturated group. Reduction of the vinyl ether of P-lumicolchicine by careful hydrogenation showed the methoxyl signal t o be in a normal position (3.40 ppm). The shielding effect disappeared when the carbonyl group was reduced. The diol produced is thermally more stable, and Rast determinations verified the presence of a dimer. It was concluded that the shielding group must be a carbonyl group on the other half of the molecule and that XXXIX is the only possible structure. Confirmation of XXXIX was obtained by partial reduction with sodium borohydride ; one methoxyl group appeared a t 3.19 ppm and the other a t 3.05 ppm. A study of the alcohols analogous t o those conducted on 8-lumicolchicine indicated hydrogen bonding as shown in XL.

CH30

,H..

N '

C. LUMIISOCOLCHICINES The photoisomerization of isocolchicine has been studied by Dauben and Cox (38)and Chapman et al. (39).I n aqueous solution one photoisomer, lumiisocolchicine, is isolated as a hydrate in 50 yoyield (39),but in methanol solution an additional compound (methanol adduct) has been found in smaller amounts (38). The IR-spectrum of lumiisocolchicine indicates the presence of a ketone group and two double bonds; the UV-absorption is very similar to 8- and y-lumicolchicine suggesting a styrene chromophore. The NMR-spectrum, however, reveals a different type of structure from the colchicine photoisomers. The pertinent data are shown in Table 111. I n addition t o the ubiquitous A and B ring

430

W. C. WILDMAN AND B. A. PURSEY

protons, there are two olefinic proton singlets and one resonance attributable to a bridgehead proton. Sodium borohydride reduction of the carbonyl group identified one of the olefinic protons as being involved in a structure of type XLI. The other was essentially unchanged in position. Acid hydrolysis of the alcohol gave a hydroxy ketone exhibiting a cyclopentanone carbonyl group in the IR-spectrum and a positive periodate test. Thus XLI could be expanded to XLII. The bridgehead proton in the alcohol was shown to be coupled both to H-C-OH and to the unchanged olefinic proton by double resonance studies (39). Further evidence for the nature of rings C and D was obtained by an examination of the products of hydrogenation and subsequent hydrolysis. Thus the structure of lumiisocolchicine was concluded to be XLIII. It would appear that production of the styryl system is an important factor in controlling the direction of the photoisomerization process in colchicine-type compounds (39).

c H 3 0 ~ N € € A c

v

0

XLII

XLI

XLIII

The methanol adduct produced by the photoisomerization of isocolchicine in methanol exhibited a styrene chromophore and a cyclopentanone carbonyl group (38); no olefinic protons were detectable in the NMR-spectrum. Catalytic hydrogenation resulted only in reduction of the carbonyl group; acid hydrolysis of the dihydro compound (with

ORI

0

XLIV

XLV

Ri a CeH1105 b CH3 c CH3

Rz

R3

R4

CH3 CH3 CH3

CH3 H CH3

AC AC CH3

11.

COLCRICINE AND RELATED COMPOUNDS

43 1

loss of methanol) produced a ketol which could be oxidized by copper acetate to an a-diketone. The diketone was shown to be identical with the one produced from y-lumicolchicine. These data lead t o the formulation of the methanol adduct as LXIV. Presumably this compound is formed from isocolchicine by 1,%addition of methanol followed by photoisomerization.

D. OTHERPHOTOISOMERS Lumi isomers have also been produced from other colchicine-type compounds. Colchicoside (the glycoside of 3-demethylcolchicine) has been shown to form /3- (XLVa) and y-lumi isomers in a 9 : 1 ratio ( 4 5 ) . Removal of the sugar moieties gave compounds identical with those derived by irradiation of 3-demethylcolchicine (substance C). Colchiceine isomerizes primarily to a p-lumi isomer (XLVb) which can be reversibIy transformed t o an a-isomer in a manner analogous t o that found for /3-lumicolchicine ( 4 6 ) . Demecolcine (substance I?) forms one photoisomer. lumidemecolcine (XLVc), which is unchanged by further irradiation (46). UV- a i d IR-spectra of XLVc indicate a structure analogous t o P-lumirolrhicint Lumidemecolcine has been reported to occur in C. autumnale (46). V. M~UOF Alkaloids

A. CORNIOERINE Cornigerine, CzlHzlNOs (mp 270": [u]; -57" in CHCl3), has been isolated in appreciable quantities from 6. cornigerum, (7') and in smaller amounts from Iphigenia spp. and Camptorrhiza strumosu ( 4 ) . Chemical and spectroscopic evidence showed the presence of a methoxylated tropolone ring and acetamido and methylenedioxy groups (26).Dilute acid hydrolysis gave cornigereine, whereas alkali provided a benzenoid compound, cornigeric acid. Permanganate oxidation of cornigerine yielded isocotarnic acid. Structure XLVI has been proposed. A close correspondence between the NMR-spectra of cornigerine, cornigereine, hexahydrocornigerine, and the analogous compounds derived from colchicine (see Table 111)suggests that cornigerine possesses a similar structure to colchicine. I n addition the mass spectrum shows the typical fragmentation pattern of N-acetyl colchicine derivatives in the high mass region with all peaks 16 mass units lower than colchicine. The functional groups in the A ring were assigned by analogy to colchicine.

432

W. C. WILDMAN AND B . A. PURSEY

OCH3

XLVIII

B.

3-DEMETHYLDEMECOLCINE

The seeds and aerial parts of C. cornigerum provide XLVII, CzoH23N05 (mp 220"-222"; [m]k2 -128" in CHC13) ( I ) . XLVII gives a positive Oberlin-Zeisel test, a negative ferric chloride reaction, and a yellow color with concentrated sulfuric acid. The UV- and IR-spectra show the presence of a tropolone ring. An IR-comparison (1 100-800 cm-1) of XLVII with substances C, El, and S suggested that the phenolic hydroxyl group of XLVII is in the same position as in substance C (3-demethylcolchicine). C. SUBSTANCE CC-12

The structure of substance CC-12, C ~ Z H ~ ~(mp N O 197"-199"; ~ C. cornigerum, has recently been determined (35).The UV- and IR-spectra, although similar to colchicine in most respects, exhibit slight shifts in the position of the tropolone bands from those normally found and reveal the presence of a n intramolecularly associated hydroxyl group. The NMR-spectrum of CC- 12 in CDC13 was inconclusive due to insolubility. However, comparison of CC-12 with colchicine, colchiceine, and isocolchicine in DCON(CD& (see Table 111)revealed very similar chemical shifts attributed to three [mID -45" in CHClS), a constituent of

433

11. COLCHICINE AND RELATED COMPOUNDS

aromatic methoxyl groups, an N-acetyl group, a tropolone methoxyl group, and protons a t positions 1, 8, 11, and 12. This implied that the extra hydroxyl group was in the B ring. Hydroxylation a t C-5 was not considered likely, because the C-4 aromatic proton showed only the usual chemical shifts on changing solvents. However, there was a marked shift of the N-acetyl resonance in comparison with the model compounds, leading to the proposal of XLVIII as the probable structure of CC-12. As added evidence for this formulation there were no methylene or methine protons visible in the usual region for these resonances. I n contrast to colclzicine the mass spectrum of XLVIII shows no molecular ion. The "parent" ion is M-AcNHZ (M'). The other high mass peaks representing M'-CH3, CO, CO + CH3, and CO + CH30 are analogous t o those found in other troponoid compounds.

D. ANDROCYMBINE Androcymbine (XLIX), CzlHzSN05 (mp 199"-201"; [ a ] g-260" in CHC13), was isolated from A . melanthioides (2, 47). The occurrence of XLIX along with tropolone compounds has been a key factor in unraveling the biosynthesis of colchicine alkaloids (see Section VII). The alkaloid shows UV-absorption a t ,A, 240 mp, log E = 4.21, and 277 mp, log ~ = 3 . 6 7 Strong . IR-absorption occurs a t 1665, 1635, and 1615 cm-1 (the 1665cm-1 banddisappears on treatment with NaBH4). These spectra

-CH3

CH30

6

XLIX

LI

-CH3

0 L

LIT

434

W. C. WILDMAN AND B. A. PURSEY

are characteristic of a cross-conjugated cyclohexadienone system together with an isolated aromatic chromophore. One tertiary N-methyl and one phenolic hydroxyl group were shown to be present by chemical methods. Oxidation of XLIX methyl ether provided 3,4,5-trimethoxyphthalic anhydride. NMR-data shed further light on the nature of the dienone system (47). I n addition to signals corresponding to three OCH3, one N-CH3, and one aromatic proton, there are two olefinic proton singlets (6.27and 6.83ppm). The absence of coupling indicated L as a partial structure. There are also about five protons (in unresolved signals) in positions expected for benzylic protons or those adjacent t o nitrogen. Treatment of O-methylandrocymbine with sodium and ammonia provided LI, whose structure has been proved by synthesis. The phenolic hydroxyl group is placed at position 2 in analogy with 2demethylcolchicine which is found also in the same plant. The stereochemistry is derived on the basis of a positive Cotton effect in the 265278 mp region and on the fact that XLIX and salutaridine (LII) have mirror-image ORD-curves.

E. MELANTHIOIDINE The corms and leaves of Androcymbium melanthioides contain a substance, C4&0N207 (mp 142"-144"; [a]","-63" in CHCl,; ha, 200 mp, log E = 4.36,and 283mp, log E = 3.34). Melanthioidinepossessesmethoxyl and N-methyl groups and gives a positive Dragendorff reaction but no color with concentrated sulfuric acid ( 2 ) .

F. KESSELRINBINE The basic fraction of the aerial parts of C. kesselringii yields a nontroponoid compound, C19H25N04 (mp 194"-196"; [a]$'2+75.2" in EtOH) (9).It has been found to contain a tertiary nitrogen, one O-methyl, one N-methyl, and a phenolic hydroxyl group.

G. BULBOCODINE A nontroponoid basic compound (mp 220"-222" subl.; [a]L3t-111" in CHC13) has been isolated from Bulbocodium vernum (3). Bulbocodine gives a weak yellow color with concentrated sulfuric acid. The IR-spectrum indicates the presence of a primary or secondary amine and a conjugated exocyclic ketone (1675cm-1).

11.

435

COLCHICINE AND RELATED COMPOUNDS

H. BECHUANINE The basic fraction of several Iphigenia spp. yields a nontroponoid compound, C ~ I H ~ ~(mp NO ~ 232"-235"; [a]&2+76" in CHC13) ( 4 ) . On the basis of IR- and UV-spectra, bechuanine is related to CC-1 (a constituent of C. cornigerum). It gives no color with concentrated sulfuric acid.

I. ALKALOIDS OF Camptorrhixa strumosa The basic fraction of C. strumosa has provided small amounts of three nontroponoid compounds (4). Isocorydine (mp 184"-187") gives no color with concentrated sulfuric acid. Umtaline (mp 234"-235") shows a gray-blue color with sulfuric acid. Strumosine seems to resemble CC-1 and also gives a gray-blue color with sulfuric acid.

J. ALKALOIDS OF Colchicum kesselringii A number of nontroponoid alkaloids have been isolated from the neutral and basic fractions of this ,plant (10). Physical constants are recorded in Table IV. Two of these compounds, K3 and K 4 , have been identified as LIII and LIV, respectively (11). TABLE IV NONTROPONOID COMPOUNDS FROG Colchicum kesselringii

Compound Fraction Neutral Neutral Neutral Basic Basic Basic Basic Basic Basic Basic

Empirical

Melting point

Hydrochloride melting point

Methiodide melting point

formula

("C)

("C)

("C)

226-228 255-251 238-240 224-226

144-146 193-197

232-234 214-276

241-249 -

239-241

232-234 248-250

261-263

-

278-280 253-254 241-248 2 65-2 68 245-241 249-251

436

W. C. WILDMAN AND

B. A. PURSEY

‘COOCHI LIV

K. ALKALOIDS OF Colchicum cornigerum By extensive alumina chromatography, a large number of minor alkaloids have been isolated from C. cornigerum (I, 7). The pertinent data are summarized in Table V. Substance CC-5 has been identified as N-methyldemecolcine by comparison with an authentic specimen.

VI. Synthesis

A. TOTALSYNTHESES Within the past few years numerous syntheses of colchicine (or its simple derivatives) and desacetamidocolchicine (which can readily be reconverted to colchicine) have been published. A wide variety of approaches have been employed, which in terms of the order of formation of rings A, B, and C may be summarized as ( 1 ) A+AB+ABC, and ( 2 ) A-tAC-tABC. The syntheses of van Tamelen, Eschenmoser, Woodward, and Martel are variations of the first approach, while the second route, in different modifications, has been utilized by Nakamura and Scott. Chemical ground has been broken in several of these syntheses, illustrating again the fact that new chemical ideas are often gained in the course of constructing complicated natural products. Most of the syntheses discussed below end with dl-colchiceine or dl-desacetylcolchiceine. Conversion of these compounds to natural colchicine was demonstrated during earlier work on the structure of colchicine (see Volume VI). The successful conversion of desacetamidocolchiceiiie to colchicine has prompted other workers to stop a t this commonly used relay point. Van Tamelen and co-workers (48) converted LV to LVI (2 isomers) via the addition of acrylonitrile to form LVII, followed by a Reformatsky reaction. The first step in this sequence represented the first successful

TABLE V

MINORALKALOIDS FROM COkh~CUT?tC O T n ' b p W n

Compound

Empirical formula

Melting point ("C)

123-125 CC-1 (CC-4)CzsH3iNOs cc-2 C Z Z H Z ~ - Z ~ N O G168-170 198-200 cc-3 CzoHzsN05 208-2 10 cc-5 178-181 CC-6 Cz3HmNOs 266-268 CC-8 215-217 cc-9 200-204 cc-10 251-253 cc-11 115-117 CC-13 182-185 CC-14 230-232 CC-15 250-254 CC-16 (I

In chloroform unless otherwise specified.

* Oberlin-Zeisel test. ' Dragendorff test. In methanol.

F F [EIDB

0-Zb

-14" +38" +155" -104" -115"d +268"

-

+308"

-

-

DC

+ + +

.-

+

-

+

+ +

Conc. HzS04 None Crimson to yellow Yellow Yellow

Eemarks IR-, UV-spectra like bechuanine 3-OCH3 N-Methyldemecolcine -NHAc by IR-spectrum

Violet-red Red Lumi compound by UV-spectrum Red to yellow-orange None None Crimson t o yellow-orange Crimson Similar to substance D Dark violet

EF

%M

U

438

W. C. WILDMAN AND B. A. PURSEY

alkylation of LV; the structure of LVI was rigorously proved by further reactions. Alkaline hydrolysis of LVI gave a diacid which, though inert to normal ring-closure techniques, could be cyclized with N,N-dicyclohexylcarbodiimide to two isomers of LVIII (R = H) which were converted to their methyl esters (LVIII; R = CH3). The major isomer of LVIII (R = CH3) could not be induced t o undergo an acyloin reaction with either sodium in xylene or sodium and liquid ammonia. However, the less plentiful isomer readily formed LIX with sodium and ammonia. Conformational arguments indicate that only the trans isomer of LVIII (LX) allows a close enough approach by the carbonyl groups for the cyclization t o proceed. Oxidation of the secondary hydroxyl group of LIX by copper acetate, followed by treatment with p-toluenesulfonic acid in benzene, converted L I X to an unsaturated diketone whose UV-spectrum indicated that it was mostly in the form of the enol (LXI). Treatment with N-bromosuccinimide in chloroform then gave desacetamidocolchiceine (LXII), identical with authentic material derived from colchicine. The methyl ether of LXII from natural sources was functionalized a t C-7 by N-bromosuccinimide. Reaction of the bromo compound thus formed with sodium azide, followed by catalytic reduction to the amine and hydrolysis with dilute acid, provided dl-trimethylcolchicinic acid (LXIII) identical with authentic material. Purpurogallin trimethyl ether (LXIV) was used as the starting material in the synthesis devised by Eschenmoser and co-workers (49).A series of selective reductive procedures transformed LXIV into LXV. Preparatively, the best method (50 yooverall yield) was catalytic hydrogenation, then lithium aluminum hydride reduction, followed by treatment with phosphoric acid. Treatment of LXV with methyl propiolate, 1 mole of potassium t-butoxide, and a catalytic amount of triethylamine provided the pyrone LXVI in 70 yoyield. Varying the conditions allowed the isolation of intermediates LXVII and LXVIII. The methyl ether of LXVI when heated with a-chloromethylmaleic anhydride gave LXIX, whose structure was assigned by NMR-analysis. Treatment of the diester of LXIX with potassium t-butoxide a t room temperature led to the formation of L X X (R = CH3). The essential step in this ring expansion is considered to be LXXI, followed by valence tautomerism of the resulting norcaradiene; LXX (R = H) was formed by partial hydrolysis of LXX (R = CH3). Several methods for producing a tropolone ring from LXX ( R = H ) were explored. The one ultimately selected involved hydroxylation of the 1 0 , l l-double bond with osmium tetroxide, followed by treatment with sodium bicarbonate in the presence of oxygen, which gave LXXII. Saponification anddecarboxylation then provided LXXIII.

V

0

t i

11.

t

COLCHICINE AND RELATED COMPOUNDS

t

t G 0

H

I4

5

439

440

0 ° C V

!I

x

&Po

t

W. C. WILDMAN A N D B. A. PURSEY

P

H

!I

3

!I

T

11. COLCRICINE A N D RELATED COMPOUNDS

f

441

442

W. C . WILDMAN AND B. A. PURSEY

Rearrangement to the proper orientation of the tropolone system was accomplished by reaction with p-toluenesulfonic acid in pyridine and then treatment with ammonia to form LXXIV, whose UV-spectrum was identical with that of colchicinamide. Hydrolysis converted LXXIV to desacetamidocolchiceine (LXII), identical with the authentic degradation product (mixed melting point and spectra). Compound LXII derived from colchicine was remethylated t o a mixture of normal and is0 ethers. The is0 modification was functionalized a t C-7 by treatment with N-bromosuccinimide. Metathesis with ammonia gave LXXV which was identical with dl-desacetylisocolchicinamide. Alkaline hydrolysis completed the synthesis of dl-desacetylcolchiceine (LXIII). The elegant synthesis by Woodward (50)is a complete departure from other approaches, since it begins with the construction of an auxiliary ring (representing carbon atoms 6, 7, 7a, 8, 12a, and the nitrogen atom of the future colchicine molecule) upon which the entire structure of colchicine is built. The nitrogen atom is masked in the stable isothiazole system until it is released in the final step. Simple isothiazoles were previously unknown. I n the course of this synthesis much was discovered about the chemistry of these interesting compounds. CH3

CNH2

-

CH3

NH2

-H 8

CHsOOC c1'

@

___f

C H 3 0 0 CI c . S

I

c1

LXXVI H CH3)p CH300C

He CH3)3 CH300C

-

C"3Q CH3OOC

c1

H

LXXVII

Reaction of methyl p-aminocrotonate (LXXVI) with thiophosgene under the catalysis of triethylamine led to the formation of LXXVII. A possible mechanism is shown above. Deuteration studies showed that C-5 has a considerable amount of anionic character, a property utilized later in the synthesis. Treatment of LXXVII with N-bromosuccinimide provided LXXVIII. Subsequent formation of the Wittig reagent with triphenylphosphine and reaction with 3,4,5-trimethoxybenzaldehyde gave LXXIX. The styrene double bond was selectively reduced with diimide and the carbomethoxy group transformed into an aldehyde

HOOC’. LXXVII

LXXVIII

LXXIX

LXXX

LXXXI

CH3O

cH30Fl CHsO

\

HOOCLXXXII

COOH

COOH

LXXXIII

OAc

LXXXVI

LXXXVII

COOCHI

LXXXIV

OH LXXXVIII

LXXXV

OH LXXXIX

444

W. C. WILDMAN AND B. A. PURSEY

group (LXXX) via lithium aluminum hydride reduction and manganese dioxide oxidation. Treatment of LXXX with the Wittig reagent, Ph3P=CHCH=CHCOOCH3, followed by saponification and iodinecatalyzed isomerization to the all-trans arrangement of double bonds furnished LXXXI, which was cyclized with perchloric acid to LXXXII. Selective reduction of the isolated double bond with diimide, metalation a t the reactive site of the isothiazole ring with o-lithiobiphenyl, followed by carboxylation, gave LXXXIII. Ring closure of the diester of LXXXIII to LXXXIV with sodium hydride was accomplished in 90 yo yield. Subsequent hydrolysis and decarboxylation to LXXXV completed the basic colchicine skeleton. Treatment of LXXXV with ethyl formate gave the C-10 hydroxymethylene derivative, which was converted to the thioketal LXXXVI by means of trimethylene-bis-p-toluenethiosulfonate. Mercuric acetate in aqueous acetic acid furnished a bright yellow a-diketone, which formed the enol acetate (LXXXVII) on treatment with acetic anhydride in pyridine. Alkaline treatment of LXXXVII in the presence of air gave the tropolone LXXXVIII. Reductive removal of the sulfur atom with Raney nickel, saturation of the carbon-nitrogen double bond, and acetylation provided dl-colchiceine (LXXXIX), identical with an authentic specimen. Nakamura and co-workers (51)devised a total synthesis of colchicine in which rings A and C are joined in the first step. The majority of the route then concerns the elaboration of ring B. Condensation of XC with XCI gave the coumarin XCII. The ally1 ether of XCII, when subjected t o the Cope rearrangement, double bond isomerization, and ozonolysis, provided the aldehyde XCIII. A malonic acid homologation of XCIII t o the aryl propionic acid followed by treatment with alkaline dimethyl sulfate furnished XCIV (R = H). Dieckmann ring closure of the diester (XCIV; R = CH3) and decarboxylation gave a conjugated ketone (XCV) whose oxime was reduced by lithium aluminum hydride to the cinnamyl amine (XCVI; R = H ) . The N-acetate (XCVI; R=COCH3) was not identical with Rapoport’s degradation product (111),but boron trifluoride treatment converted it to the isomer (XCVII ; R = COCHS), identical with the authentic compound (mixed melting point andspectra). The N-formyl compound (XCVII; R = CHO) was also prepared and was found to be identical with the degradation product prepared by Rapoport (20-22). Levorotatory XCVII (R = COCH3) derived from colchicine and synthetic (EZ-XLVII (R = COCH3) were converted to colchicinamide (XCVIII) by Nozoe’s method as shown, and thence to colchiceine and desacetyl colchiceine by known procedures. All of these products were identical in every respect with the authentic substances.

445

1 1. COLCHICINE AND RELATED COMPOUNDS

xc C

H

?H s

XCI

-

?CHs O

W

+ CHsO%

CHO

XCII

CHsO C H

s

O

p0-

CHsO COOR

XCIII

XCIV

xcv

I

NHz XCVI

XCVII

XCVIII

B. SYNTHESES OF DESACETAMIDOCOLCHICINE Martel and co-workers (52), by a series of condensation reactions, converted X C I X to C. Formylation of the double bond, condensation of the resulting unsaturated aldehyde with methyl cyanoacetate, followed by catalytic hydrogenation, saponification, decarboxylation, and reesterification provided CI. Desacetamidocolchicine (LXII), identical with an authentic specimen, was produced from C I by ring closure to CII, followed by benzoyl peroxide treatment to give CIII, alkaline hydrolysis to the enolic a-diketone, and subsequent N-bromosuccinimide treatment.

446

T'

t

G

V

x G x

V

P i

8

g

0 ° C

X p

0

p

T

t

mug

o " 0 ,

W. C. WILDMAN AND B. A. PURSEY

ya

rv 8

g@8o , V

H

G

11.

447

COLCHICINE AND RELATED COMPOUNDS

An interesting synthesis of desacetamidocolchicine based on the biogenetic theory of radical coupling (see Section VII) has recently been reported by Scott and co-workers (53). Purpurogallin (CIV) was converted by controlled treatment with alkaline peroxide to CV. Condensation of CV with 3;4,5-trimethoxyphenylacetaldehydeprovided CVI in 71 yoyield, which in turn gave a 78 yoyield of CVII by pyrolysis a t 270" with copper-bronze or quartz powder. Hydrogenation and demethylation to CVIII provided a suitable precursor for radical coupling experiments. The desired coupling product (CIX)was produced from authentic desacetamidocolchicine by controlled treatment with hydrobromic acid. Most of' the oxidants which were tried resulted in destruction of the HO HO HO

OH

0 CIV

0

cv

CVI

CVII

HO

H

0

o

q

o HO%

0

OH

CVIII

OH FeCls

CH3O

HO

=

c

H

3

:

0

OH

OH

CIX

q

LXII

448

W. C. WILDMAN A P D B . A. PURSEY

chromophore. Potassium ferricyanide in dilute alkaline solution converted both CIX and CVIII to CX, the structure of which was derived from spectral data. Control experiments indicated that the oxidative coupling of CVIII and CIX had occurred a t least to the extent of 25-30 yo. Eventually the coupling was successfully carried out in 4-5 yoyield in a two-phase system consisting of chloroform containing CVIII and acidic aqueous-alcoholic ferric chloride a t room temperature. Isolated by preparatory paper chromatography, the product proved to be identical with authentic CIX. Methylation of synthetic CIX provided crystalline LXII, also identical with the colchicine degradation product.

VII. Biosynthesis

A. BIOGENETIC SCHEMES The unusual structural features of the colchicine molecule have generated a great deal of interest in its mode of biosynthesis. A number Flavones

Ho2ma Hov'H HO

/

C-6 unit from Acetate

OH

Y unit

Colchicine

HO'

of biogenetic schemes were proposed prior t o tracer investigations based on analogies with the biogenesis of other types of compounds. HO

Phenylalanine

_t

HO

c-c-c

OH

H O % '-'-

CXI

OH

0

449

11. COLCHICINE AND RELATED COMPOUNDS 0

o

q\

I;

Prephenete

\

0

Shikimate

The Anet-Robinson scheme (54)was based on an analogy with flavone biogenesis. Phenylalanine was the starting point for both aryl moieties in Belleads scheme (55),via oxidative coupling of intermediate CXI.

@-

+

-

COOH

ro1

COOH HO

HO

HO

q

0

H OH

OH

0

J

HO

HO

--+ Colchicine

__j

OH

0

450

W. C, WILDMAN AND B. A. PURSEY

Wenkert (56) proposed that a shikimate-prephenate interaction was involved. Coupling of the two moieties could be envisioned to occur either as shown or a t a pretropolone stage. Since it has been shown that phenol oxidative coupling can take place under mild conditions, Scott (57) proposed the pathway shown below. The feasibility of this type of coupling reaction was demonstrated by the synthesis of desacetamidocolchicine using essentially this route (53)(see Section VI). B. BIOSYNTHETIC EXPERIMENTS The actual pathway used in the biosynthesis of colchicine was initially clarified by the tracer experiments of Leete (6,58-SO), Battersby (61-64), and co-workers. Both C. autumnale and C. byzantium were used in these studies, and similar trends in incorporation of various potential precursors were obtained by both groups. The incorporation data are shown in Table VI and the degradation schemes used to identify individual carbon atoms or groups of atoms are summarized in Fig. 1. Most of the biogenetic proposals for the elaboration of the A ring involved the use of phenylalanine or its biochemical equivalent. DLPhenylalanine-3-14C was fed (58) as a means of determining which of these possibilities was closer to the true situation. The colchicine activity from this experiment was found almost entirely at C-5, an observation which negates the first two schemes illustrated in Section VII, A. ~ ~ - P h e n y l a l a n i n e - 2 - (59, l ~ C62, 64) and ~~-phenylalanine-l-~4C (62, 64) were found to label specifically carbon atoms 6 and 7 , respectively, Sodium cinnamate-2- and 3-14C were also incorporated (62, 64, 65) specifically into carbons 6 and 5, respectively. The firm conclusion can be reached that the phenylalanine-cinnamic acid pathway is used in the elaboration of ring A and carbon atoms C-5, C-6, and (3-7. Similar results were found with demecolcine (6, 59). ~-Methionine-14CH3(6, 61) and other C-1 donors (see Table VI), as expected, were excellent sources of the O-methyl groups. The genesis of the tropolone ring was more problematic. Tracer studies on simple mold tropolones such as puberulic acid (CXII) (66)and stipitatic acid (CXIII) (67) have indicated that these compounds are a t least partly derived from acetate. However, sodium acetate-l-1% was found (6,61)to be incorporated entirely into the N-acetyl function of colchicine and not at all into demecolcine (6). I n analogy with the biosynthesis of the Amaryllidaceae alkaloids (see Chapter 10) in which phenylalanine and tyrosine account for different

C02(4a, 7a) HOOC (4s-713) HOAc, Colchiceine, Desacetylcolchiceine

/

Acid

CH30

II-

452

W. C. WILDMAN A N D B. A. PURSEY

units within the alkaloid, tyrosine-l-l4C, -2-14C, and -3-14C were fed to Colchicum plants (61-64). Tyrosine- l-14C was poorly incorporated and the label was found to be widely scattered. The results with tyrosine-214C seemed to indicate that the C-6-C-3 chain is degraded to C-6-C-1 and C-2 fragments before incorporation into the colchicine molecule. TABLE VI INCORPORATION OF RADIOACTIVE COMPOUNDS Compound fed

Compound isolated Incorporation

(yo)

Reference

Colchieum autumnale Sodium acetate-l-14C DL-Tyrosine-1-l4C n~-Tyrosine-2-l~c n~,-Tyrosine-3-~~C DL-Phenylalanine-l-14c ~~-Phenylalanine-2-~4C Sodium cinnamate-2-14C Sodium cinnamate-3-14C ~-Methionine-l4CH3 Benzoic acid - 7 - 14C Protocatechuic acid-7-14C Glycine-2-14C Sodium pyruvate - 2-14C Ornithine-2-14C Methanol-14C Sodium cinnamate-3-14C

Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine Colchicine

Sodium acetate-l-14C

Colchicine Demecolcine Colchicine Demecolcine Colchicine Colchicine Demecolcine Colchicine Demecolcine Colchicine Demecolcine Colchicine Demecolcine Colchicine Demecolcine Colchicine

0.13 -0.19 i 6 x 10-3 0.21-0.23 0.35-0.7 3.2 0.58 0.22 1.0 0.90 < 5 x 10-4 < 4 x 10-3

0.8 0.25 0.003 1.0 0.1

64 6.1 64 64 64 64 64 64

64 64 64 64 64 65

65 65

Colchicum byzantium

~~-Phenylalanine-3-l~C ~~-Phenylalanine-3-14C and p-hydroxybenzoic acid ~ ~ - P h e n y l a l a n i n e - 3 -and l~C protocatechuic acid ~~-Phenylalanine-3-14C and gallic acid Gallic acid-7-14C

0.01

0.08 0.10 0.06 0.06 0.07 0.02 0.03 0.02 0.015

-

6 59 58 59 59 59 59

-

0.95 0.37 0.8

6 60

11.

COLCHICINE AND RELATED COMPOUNDS

453

0 HO " O O o H

HOH oJ( \

bOOH CXII

COOH CXIII

Approximately 50 yo of the activity resided in the N-acetyl group, 1yo was found at C-6, and almost all of the remainingradioactivity was found in the phenanthrene (CXIV). C-9 was determined to be inactive. Tyrosine-3-14C showed a more specific incorporation into the tropolone ring. Eighty per cent of the activity was found a t C-12, 11yo in the N-acetyl group, and low levels of radioactivity were found in other parts of the molecule. Carbon atoms l a , 7, 7a, 9, and 12a were inactive. I n confirmation, Leete (60) found that the activity from feeding C X V resided entirely a t C-9. Other possible sources of C-6-C-1 units such as gallic acid (59)and protocatechuic acid ( 5 9 , 6 4 )led to essentially inactive colchicine. These results demonstrated that the aromatic ring and

x

CXVI

CXVII

CXIX

* Carbon 14

0 Tritium

Nitrogen 15

cxx

454

t

I

@ --- -_

0

s

8

:

W. C. WILDMAN AND B . A. PURSEY

11. COLCHICINE AND RELATED COMPOUNDS

455

benzyl carbon atom of tyrosine were involved in the genesis of the tropolone ring. An intermediate of the type CXVI was proposed (60, 6 4 ) ; oxidative coupling was postulated to occur prior to ring expansion. An important clue to the actual biosynthetic pathway was the discovery that androcymbine (CXVII ;R = H) occurs along with colchicinetype compounds in A . mezanthioides (2, 4 7 ) . The similarity of CXVII to CXVI was striking, as was the fact that CXVII (R = H) has the same absolute stereoehemistry as colchicine (47, 68). This suggested t h a t a 1-phenethylisoquinoline structure might be involved in the biosynthesis of colchicine. This hypothesis, as well as a detailed pathway to colchicine (see Fig. a), has been brilliantly demonstrated by Battersby and coworkers (68, 69) in recent tracer experiments. The incorporation (C. autumnale) of 0-methylandrocymbine (CXVII ; R = CH3, tritium label in the OCH3 a t carbon 2) and CXVIII (14C a t carbon 6) into coIchicine (15 and 10yoincorporation, respectively) with no randomization of label indicated the general correctness of the proposed scheme. Multiple labeling experiments with synthetic CXVIII have confirmed many details of the biosynthesis. CXIX was incorporated into colchicine with no change in tl;e 14C/15N ratio, proving that the nitrogen atom is retained from the isoquinoline stage. One aromatic tritium atom (but no methoxyl tritium) was lost in the incorporation of CXX, as required by the proposal. Further work (68)has demonstrated that (1)the benzylic carbon atom of CXXI (R = CH3) is stereospecifically hydroxylated, (2) the methylene adjacent to the nitrogen atom is lost, and (3) the N-methyl group is retained as far as demecolcine, all in accordance with the scheme. The final stages were elucidated by feeding radioactive demecolcine, desacetylcolchicine, and colchicine ; the forward pathway shown in Fig, 2 was indicated to be the predominant one. Labeled intermediates (14C) from CXXII to CXXIII were also incorporated to extents consistent with the sequence shown, whereas other possible compounds of the same type with different oxygenation and methylation patterns were not utilized in the formation of colchicine. The origin of the colchicine class of molecules thus falls into line with other types of alkaloids in a satisfying manner. A fortuitous combination of molecular circumstances appears to be responsible for the production of the unusual tropolone moiety from a more “normal” isoquinoline structure. REFERENCES 1. M. Saleh, S. El-Gangihi, A. El-Hamidi, and F. Santavf, Collection Czech. Chem. Commun. 28, 3413 (1963). 2. J. Hrbek, Jr. and F. Santavf, Collection Czech. Chem. Commun. 27, 255 (1962).

456

W. C. WILDMAN AND B . A. PURSEY

3. B. K. Mom, H. Potesklova, and F. Santavj., Planta Med. 10, 152 (1962). 4. J. L. Kaul, B. K. Moza, F. Santavj., and P. Urublovskj., Collection Czech. Chem. Commun. 29, 1689 (1964). 5. B. Avramova and V. Ivanov, Tr. Nauch-issled. Inst. Farm. 3, 75 and 81 (1961); CA 61, 8128 (1964). 6. E . Leete and P. E. Nemeth, J . Am. Chem. SOC. 83, 2192 (1961). 7. A. El-Hamidi and F. Santavjr, Collection Czech. Chem. Commun. 27, 2111 (1962). 8. A. S. Sadykov and M. K. Yusupov, Uzbek. Khim. Zhur., No. 2,38 (1960);C A 55,9788 (1961). 9. M. K. Yusupov and A. S. Sadykov, Uzbek. K h i m . Z h . No. 5, 49 (1961); C A 56, 8839 (1962). 10. M. K. Yusupov and A. S. Sadykov, Zh. Obshch. Khim. 34, 1672 (1964). 11. M. K. Yusupov and A. S. Sadykov, Zh. Obshch. Khim. 34, 1677 (1964). 12. I. A. Siddiqui, P a k i s t i n J . Forestry 10, 314 (1960); C A 55, 26372 (1961). 13. M. A. Wahid and Samiullah, P a k i s t a n J . Sci. I n d . Res. 3, 228 (1960); C A 58, 1301 (1963). 14. A. S. Sadykov and M. K. Yusupov, Zh. Prikl. Khim. 38, 222 (1965); C A 62, 12160 (1965). 15. B. D. Podolesov, Olasnik Hem. Drustva, Beograd 28, 461 (1964); C A 64, 8640 (1966). 16. M. Maturova, B. Lang, T. Reichstein, and F. Santavj., Planta Med. 7, 298 (1959). 17. P. N. Mehra and T. N. Khoshoo, J . Pharm. Pharmucol. 3, 486 (1951). 18. A. S. Sadykov and M. K. Yusupov, Dokl. Akad. N a u k Uz. SSR No. 5, 34 (1960); C A 56, 15830 (1962). 19. A. S. Sadykov and M. K. Yusupov, Nauchn. Tr., Tashkentsk. Qos. Univ. 203, 15 (1962); C A 59, 6451 (1963). 20. H. Rapoport, A. R. Williams, J. E. Campion, and D. E. Pack, J . Am. Chem. SOC. 76, 3693 (1954). 21. H. Rapoport and J. B. Lavigne, J . Am. Chem. SOC.77, 667 (1955). 22. H. Rapoport, J. E. Campion, and J. E. Gordon, J . Am. Chem. SOC. 77, 2389 (1955). 23. H. J. E. Loewentha1,J. Chem. SOC.1421 (1961). 24. H. J. E. Loewenthal and P. Rona, J . Chem. SOC. 1429 (1961). 25. E . J. Forbes, Chem. & I n d . (London) 192 (1956). 26. A. D. Cross, A. El-Hamidi, J. Hrbek, Jr., and F. Santavj., Collection Czech. Chem. Commun. 29, 1187 (1964). 27. G. Sunagawa, T. Nakamura, and J. Nakazawa, Chem. & Pharm. Bull. (Tokyo) 9, 81 (1961). 28. J. Hrbek, Jr., J. P. Jennings, W. Klyne, and F. Santavjr, Collection Czech. Chern. Commun. 29, 2822 (1964). 29. M. Sorkin, Helv. Chim. A h a 29, 246 (1946). 30. F. Santavj., Chem. Listy 46, 280 (1952). 31. R. M. Horowitz and G. E. Ullyot, J . Am. Chem. SOC. 74, 587 (1952). 32. V. Delaroff and P. Rathle, BUZZ.SOC. Chim. France 1621 (1965). 33. G. L. Buchanan, A. L. Porte, and J. K. Sutherland, Chem. & I n d . (London)859 (1962); G . L. Buehanan, A. McKillop, A. L. Porte, and J. K. Sutherland, Tetrahedron 20, 1449 (1964). 34. A. D. Cross, F. Santavj., and B. Trivedi, CollectiomCzech. Chem. Conznzun. 28, 3402 (1963). 35. A. D. Cross, A. El-Hamidi, L. Pijewska, and F. Santavj., Collection Czech. Chern. Commun. 31, 374 (1966). 36. 0. L. Chapman, H. G. Smith, and R. W. King, J . Am. Chem. SOC. 85, 803 (1963).

11. COLCHICINE AND RELATED COMPOUNDS

467

37. 0. L. Chapman and H. G. Smith, J . Am. Chem. SOC. 83, 3914 (1961); 0. L. Chapman, H. G. Smith, and R. W. King, ibid. 85, 806 (1963). 38. W. G. Dauben and D. A. Cox, J. Am. Chem. SOC. 85, 2130 (1963). 39. 0. L. Chapman, H. G. Smith, and P. A. Barks, J. Am. Chem. SOC.85, 3171 (1963). 40. J. M. Wilson, M. Ohashi, H. Budzikiewicz, F. Santavy, and C. Djerassi, Tetrahedron 19, 2225 (1963). 41. J. M. Wilson, M. Ohashi, H. Budzikiewicz, and C. Djerassi, Tetrahedron 19, 2247 (1963). 42. P. D. Gardner, R. L. Brandon, and G. F. Haynes, J . Am. Chem. SOC.79, 6334 (1957). 43. W. G. Dauben, K. Koch, 0. L. Chapman, and S. L. Smith, J . Am. Chem. SOC.83,1768 (1961). 44. G. 0. Schenck, H. J. Kuhn, and 0.-A. Neumiiller, Tetrahedron LettersNo. 1,12 (1961). 45. M. P. Bellet and D. Gerard, Ann. Phamn. Franc. 19, 587 (1961). 46. 0.-A. Neumiiller, H. J. Kuhn, G. 0. Schenck, and F. Santavjr, Ann. 679, 122 (1964). 47. A. R. Battersby end R. B. Herbert, Chem. Commun. 228 (1966). 48. E. E. van Tamelen, T. A. Spencer, Jr., D. S. Allen, Jr., and R. L. Orvis, J . Am. Chem. Soc. 81, 6341 (1959); Tetrahedron 14, 8 (1961). 49. J. Schreiber, W. Leimgruber, M. Pesaro, P. Schudel, and A. Eschenmoser, Angew. Chem. 71,637 (1959);J . Schreiber, W. Leimgruber, M. Pesaro, P. Schudel, T. Threlfall, and A. Eschenmoser, Helv. Chim. Acta 44, 540 (1961). 50. R. B. Woodward, Harvey Lectures 59, 31 (1963-1964). 51. T. Nakamura, Y. Murase, R. Hayashi, and Y. Endo, Chem. & Phamn. Bull. (Tokyo) 10, 281 (1962); G. Sunagawa, T. Nakamura, and J. Nakazawa, ibid. 291; T. Nekamura, ibid. 299. Prelim. commun. : T. Nakamura, Chem. d? Phamn. Bull. (Tokyo) 8, 843 (1960); G. Sunagawa, T. Nakamura, and J. Nakazawa, ibid. 9, 81 (1961). 52. J. Martel, E. Toromanoff, and C. Huynh, Compt. Rend. 258,243 (1964);J . Org. Chem. 30, 1752 (1965). 53. A. I. Scott, F. MoCapra, J. Nabney, D. W. Young, A. C. Day, A. J. Baker, and T. A. Davidson,J. Am. Chem.SOC. 83,3040 (1963);A. I. Scott, F. McCapra, R. L. Buchanan, A. C. Day, and D. W. Young, Tetrahedron 21, 3605 (1965). 54. Address by Sir R. Robinson, Nature 166, 924 (1950). 55. B. Belleau, Ezperientia 9, 178 (1953). 56. E. Wenkert, Ezperientia 15, 165 (1959). 57. A. I. Scott, Nature 186, 556 (1960). 58. E . Leete and P. E. Nemeth, J . Am. Chem. SOC. 82, 6055 (1960). 59. E. Leete, J. Am. Chem. SOC. 85, 3866 (1963). 60. E. Leete, Tetrahedron Letters 333 (1965). 61. A. R. Battersby and J. J. Reynolds, Proc. Chem. SOC. 346 (1960). 62. A. R. Battersby, R. Binks, and D. A. Yeowell, Proc. Chem. SOC. 86 (1964). 260 (1964). 63. A. R. Battersby and R. B. Herbert, Proc. Chem. SOC. 64. A. R. Battersby, R. Binks, J. J. Reynolds, and D. A. Yeowel1,J. Chem. SOC. 4257 (1964). 65. R. D. Hill and A. M. Unrau, Can. J . Chern. 43, 709 (1965). 66. J. H. Richards and L. D. Ferretti, Biochem. Biophys. Res. Commun. 2, 107 (1960). 67. R. Bentley, Biochim. Biophys. Acta 29, 666 (1958). 68. A. R. Battersby, Abstr. 4th Intern. S y m p . Chem. Nat. Prod., Stockholm, 1966 p. 117. Butterworth, London and Washington, D.C., 1966. 69. A. R. Battersby, R. B. Herbert, E. LcDonald, R. Ramage, and J. H. Clements, Chem. Commun. 603 (1966).

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-CHAPTER

12-

THE PYRIDINE ALKALOIDS W . A . AYER and T . E . HABGOOD University of Alberta. Edmonton. Canada

.

.................................................... ............................................. I11. The Alkaloids of Pomegranate Root ................................ IV. Lobelia and Sedurn Alkaloids ...................................... A . 8-Methylnorlobelol ............................................ B . 8.Methylnorlobelone ........................................... C. 8.Ethylnorlobelol.I ............................................ D. 8-Phenylnorlobelol-I .......................................... E . 8-Phenyllobelol-I ............................................. F. 8-Phenyllobelol ............................................... G . cis.8,l 0.Diethylnorlobelidione .................................. H . cis.8,l 0.Diethylnorlobelionol ................................... I . trans.3, 4. or 4,5.Dehydro.E.methyl.l 0.ethyllobelidiol .............. J . 8.Methyl.lO.ethyllobelidiol ..................................... K . cis.8,l 0.Diethyllobelionol ...................................... L . trans.3,4.Dehydro.8,l0.diethyllobelidiol .......................... M . 8,lO-Diethyllobelidiol . ......................................... N . 8-Methyl-10-phenyllobelidiol................................... 0. 8.Methyl.lO.phenyllobelionol . . . . . ............................. P . 8-Methyl-lO.phenyl.4, 5.dehydrolobelidiol ........................ Q . cis-8,10-Diphenyllobelionol . .................................... R . cis.8,l 0.Diphenyllobelidione .................................... S. Lobinaline ................................................... V . The Alkaloids of Hemlock ......................................... A . Coniine ...................................................... B . Conhydrine .................................................. C. Pseudoconhydrine ............................................ D . Coniceines ................................................... VI . The Tobacco Alkaloids ............................................ A . Nicotine ..................................................... B. Anabasine and Anatabine ...................................... C. Alkaloids of Tobacco Smoke .................................... VII . The Biogenesis of Nicotine, Anabasine, and Ricinine .................. A . Nicotine ..................................................... B . Anabasine ................................................... C. Ricinine ..................................................... I Introduction

I1. The Pepper Alkaloids

459

460 460 461 462 463 464 464 464 465 465 465 466 466 466 467 467 467 468 468 468 469 470 470 473 473 474 475 476 477 478 481 482 483 483 485 486

460

W. A. AYER A N D T. E. HABGOOD

. . . . . . . . .. . . . . . . .. . . . . . . , . . . . . IX. Gentianhe ...................................................... X. The Pinus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . XI. Alkaloids of Tripterygium wilfordii and E v o n y m w europaeus . . .. .. .. .. .. XII. Alkaloids of Adenocarpus spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII. Carpaine, Cassine, Prosopine, and Prosopinine. . .. .. . . .. . . . . . . . . . . .. . . XIV. The Alkaloids of Astrocasia phyllanthoides . . . . . . . . . . . . . . . . . .. .. . . . . .. XV. Nudiflorine . . . . . . . .. . . . . .. . . . . . . .. . . .. . . . . .. .. . . . . . . .. .. . . . . . . .. XVI. Homostachydrine . . , . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . .. . . . . . . XVII. Anibine . , . . . . . . . . . . . . . . , . . . . . . . . .. . . . . . . . . . . . . . . .. . . . . . . . . .. . . . . XVIII. Julocrotine . . . . . . . . . . . . . . . . . . . . . . . , .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. XIX. HaZfordia Alkaloids.. . . . . . . . . . . . . . I . . . . , . , . . . . . . . . . . . . . . . . . . . . . . . . XX. Monoterpenoid Alkaloids Containing a Pyridine or Piperidine Ring.. . . . . A. Actinidine . . . . . . . , . . . . . . . . , . . .. , . . . . . . . . . . . .. , . . . . . . . .. .. . . .. B. Skytanthine .................................................. C. Tecomanine and Tecostanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References .. .... .. .. . . .. .. . . . . .. . . . . .. .. . . .. .. .. . . .. .. .. .. .. .. .. VIII. Alkaloids of Withania somnqera Dunal

486 487 488 489 490 490 493 495 495 496 496 498 499 499 501 502 503

I. Introduction During the past. ten years many new pyridine alkaloids have been discovered and much work has been reported on some of the known alkaloids, especially with regard to relative and absolute stereochemistry. Much progress has been made in the study of the biogenesis of many of the alkaloids, although much remains to be done in this area. 11. The Pepper Alkaloids

The alkaloids of the roots of Piper longurn L., a plant which has found considerable use in the Ayurvedic system of medicine ( I ) ,have been the subject of recent investigations (1-3). Chatterjee and Dutta have isolated piperlongumine, C17H1905N (mp 124') (I),piperine (l),and piperlonguminine, C16H1903N (mp 166"-168") ( 2 )from P. Zongum. Piperlongumine, the major alkaloid, was shown to be N-(3,4,5-trimethoxycinnamoy1)3,4-dihydro-2-pyridone (1) and piperlonguminine the isobutylamide of piperic acid ( 2 ) .Atal and Banga (3) reported the isolation from the stems of P. Zongum of piplartine (mp 124'-125') which afforded 3,4,5trimethoxycinnamic acid on hydrolysis. Treatment of the acid chloride of the latter with piperidine gave a product having an RF value similar to that of piplartine and it was suggested that piplartine is the piperidide

12.

THE PYRIDINE ALKALOIDS

461

of 3,4,5-trimethoxycinnamicacid (3). However, Chatterjee and Dutta prepared this piperidide and found that it melts a t 101”-102” (1).From the similarity in melting points it would appear that piplartine may be identical with piperlongumine. 111. The Alkaloids of Pomegranate Root

It has now been clearly demonstrated that the pelletierine of Tanret and of Hess is not 3-(2-piperidyl)propanalbut is in fact identical with isopelletierine, (2-piperidyl)-2-propanone. Attempts to synthesize 3(2-piperidy1)propanal have without exception ended in failure (4,5). Derivatives of the aldehyde have been prepared but the free aldehyde itself undergoes rapid self-condensation ( 4 ) .Hess’s structure was based mainly on the observation ( 6 )that the oxime of the alkaloid, when treated with phosphorus pentachloride in phenetole, was transformed into a base, C8H1&2, assumed to be a nitrile since it was transformed by the action of alcoholic potassium hydroxide followed by alcoholic hydrogen chloride into a compound, CloH2oN02C1, having the same melting point as ethyl /?-(2-piperidyl)propionatehydrochloride. It has now been shown (7, 8) that the compound C8H14N2 is 2-methyl-l,3-diazabicyclo[4.3.0]2-nonene (I)formed by normal Beckman rearrangement of the ketoxime followed by cyclization to the amidine I. The structure of I has been confirmed by synthesis (7, 8).

As expected for a methyl ketone, hypobromite oxidation of N benzoylisopelletierine gives bromoform ( 9 ) . Attempts t o prepare the compound CloHzoNOzCl described by Hess have been unsuccessful (7,8).The procedure described by Hess (10)for the isolation of “pelletierine” from pomegranate root has been repeated (11) and a urethane different from synthetic 3-(2-piperidy1)propanal urethane but identical with synthetic (2-piperidyl)-2-propanone urethane was isolated. Gilman and Marion (12) examined a sample of 2-pelletierine sulfate prepared by C. Tanret in 1880. The IR-spectrum of the base showed carbonyl absorption a t 1710 cm-1 but no absorption due to an aldehyde C-H stretching vibration. The NMR-spectrum showed a three-proton

462

W. A. AYER A N D T. E. HABGOOD

methyl ketone band a t 7.97 7 and lacked a low field aldehydic proton. The Z-pelletierine obtained from Tanret’s sulfate was transformed into the N-cyano derivative which was identical (except for rotation) with the N-cyano compound obtained by the action of cyanogen bromide on synthetic dl-N-methylisopelletierine. I n view of the fact that pelletierine and isopelletierine are identical it has been proposed that the name isopelletierine be dropped and that the name pelletierine be used to represent (2-piperidyl)-2-propanone and N-methylpelletierine to represent the corresponding N-methyl compound (12). Tanret’s pelletierine is thus Z-pelletierine ; Tanret’s isopelletierine, Hess’s racemic isopelletierine, and Hess’s pelletierine are dZ-pelletierine. A detailed review of the chemistry of pelletierine has appeared (13). Z-Pelletierine has been shown to possess the R configuration (11)at the asymmetric center ( 1 4 ) . (-)-Sedridine, known to have the R configuration a t the asymmetric center in the piperidine ring, furnishes R-(- )-pelletierine when oxidized with chromic acid in aqueous acetic acid. ( + )-Sedridine gives S-(+ )-pelletierine on oxidation (14). The method of resolution of racemic pelletierine through salts with the 6,6’-dinitrophenyl-2,2‘-dicarboxylic acids (15 ) has been improved (16). The pH dependence of the synthesis of pelletierine from Al-piperideine and acetoacetic acid has been investigated ( I 7 , 1 8 ) .Pelletierine has been synthesized from cadaverine and acetoacetic acid in the presence of diamine oxidase (19). Pelletierine has recently been isolated from Duboisia myoporoides R.Br. ( Z O ) , Sedum acre L. (21), and Withania somnifera Dunal (22).

IV. Lobelia and Sedum Alkaloids The systematic nomenclature introduced (23)for the Lobelia alkaloids will be followed in this review. Under this system the alkaloids are numbered as shown in A and B. The basic name “lobeli-” is used to designate alkaloids of type A, and “lobel-” to designate alkaloids of type B. The nature of the oxygen functions at C-8 and C-10 is indicated by a suffix, “-01” for a hydroxyl

A

B

12. THE

PYRIDINE ALKALOIDS

463

group, < I -one” for a carbonyl function which becomes “-on-” for combined functions. The relative stereochemistry a t C-2 and C-6 in A is indicated by the prefix “cis-” or “trans-”. I n cases where there are different carbon groups on C-8 and C-10, the group with the smaller number of carbon atoms is placed on the left (C-S), except t h a t in the lobelionols the hydroxylated carbon must be designated C-8. Under lelobanidine-I this system IobeIine becomes cis-8,1O-diphenyllobelionol, and lobinine is trans-8-ethyl-10is cis-8-ethyl-10-phenyllobelidiol-I, phenyl-3,4-dehydrolobelionol. Since the lobelol-type compounds are closely related t o the Sedurn alkaloids; it seems convenient to treat the Lobelia and thesedurn alkaloids at the same time. The compounds will be discussed in terms of structures A and B proceeding in order of increasing carbon content.

A. 8-METHYLNORLOBELOL ( + )-8-Methylnorlobelol (sedridine) (111), CsH170N (mp 83”-84”; [ a ] g +29.3” in C~HSOH), has been isolated from&’.acre L. ( 2 4 ) .Racemic 8-methylnorlobelol (mp 74O-75”) can be prepared from ( + )-conhydrine (25) and also by lithium aluminum hydride reduction of (2-piperidyl)2-propanone (26).From the latter reaction the C-8 epimer, 8-methylnorlobelol-I (allosedridine) (mp 70”-71”) has also been obtained. Racemic 8-methylnorlobelol has been resolved by the use of N-acetyl-L-leucine (26) and the threoid structure 111 assigned to 8-methylnorlobelol on the basis of the interpretation of the NMR-spectrum of the oxazine IV (X=p-chlorophenyl) obtained by condensation with p-chlorobenzaldehyde ( 2 7 ) . Since ( - )-8-methylnorlobelol on oxidation affords R-( + )- pipecolic acid (27),the absolute configuration of which is known, naturally occurring ( + )-8-methylnorlobelol [( + )-sedridine] has the 2S,8S-configuration I11 (27). CH3

I

H-C-OH

I

HoH H-C-H

I11

I n a stereospecific synthesis of erythro-econiceine, pure threo-( + )-8methylnorlobelol (sedridine) was prepared by resolution of racemic

464

W. A. AYER AND T. E. HA-BGOOD

picolylmethylcarbinol with ( - )-dibenzoyltartaric acid, catalytic hydrogenation of the #-( + )-enantiomer (which resulted in a 9 : 1 mixture of threoid SS-(+ )-sedridjne and erythroid SR-( - )-allosedridine), and crystallization of the threoid N-acetylleucinate salt (28).

B. 8-METHYLNORLOBELONE See pelletierine, Section 111.

c. 8-ETHYLNORLOBELOL-1 (+)-8-Ethylnorlobelol-I (V), CgH190H (mp 87"; [a]2.5 +22.3" in CzHsOH), isolated from L. injata L. (23, 29), forms a hydrochloride (mp 135"), a hydrobromide (mp 115°-1160), a picrate (mp 116"-117°), a chloroaurate (mp l26"-127"), and a phenylthiourea derivative (mp 126"-127"). On chromic acid oxidation, 8-ethylnorlobelone (hydrochloride, mp 157")was formed. Condensation of dl-piperideine and propionylacetic acid followed by reduction gave two racemates. These were

H VI

V

separated and resolved into optical antipodes, one of which was identical with ( + )-8-ethylnorlobelol-I, to which the 2R,8S configuration has been assigned (23).

D. 8-PHENYLNORLOBELOL-I

+

( + )-8-Phenylnorlobelol-I [( )-norallosedamine] (VI), C13H190N (mp 102"-103°; [m]i3 +49.3" in C~HSOH),isolated from L. injata (23, 30), forms an acid oxalate (mp 184O), a hydrochloride (mp 133"), and a chloraurate (mp 142"-143"). Methylation gave noncrystalline ( - )-8-phenyllobelol-I (chloroaurate, mp 179"-180"). dl-Piperideine condensed with benzoylacetic acid followed by reduction gave two racemates, norsedamine and norallosedamine. Norallosedamine, resolved by means of G,B'-dinitrodiphenic acid, gave a dextrorotatory enantiomer

12. THE

PYRIDINE ALKALOIDS

465

identical with ( + )-8-phenylnorlobelol-I t o which the configuration 28,8R was assigned (31).

E. 8-PHENYLLOBELOL-I ( - )-8-Phenyllobelol-I [( - )-allosedamine] (VII), C14H21OH (mp 81"; [ c L ] ~-18.6" ~ . ~ in CzHSOH), has been isolated from L. inJEata (23, 29) and forms a hydrochloride (mp 118"-119") and a chloroaurate (mp 181"). ~t-Picoline and benzaldehyde on condensation, methylation, and reduction gave two racemates, sedamine and allosedamine, which were resolved into their respective optical antipodes by dibenzoyltartaric acid (26).The levorotatory antipode of allosedamine was identical with ( - )-8-phenyllobelol-I (32). ( - )-8-Phenyllobelol-I has been related t o

VII

( - )-N-methylpipecolic acid (25, 32) and has been assigned the 2S,8R configuration (31).

F. 8-PHENYLLOBELOL

X.

( - )-8-Phenyllobelol [( - )-sedamine] (mp 89") has been isolated from acre (24)and has been assigned the 2X,8S configuration (32).

G.

cis-8,10-DIETHYLNoRLoBELIDIoNE

From the petroleum ether-soluble bases of L. syphilitica L., cis-8,lOdiethylnorlobelidione (VIII), C I ~ H ~ ~ (hydrochloride, NO~ mp 183"184'), was isolated (33). On methylation it gave cis-8,10-diethyllobelidione.

VIII

IX

466

W.A. AYER A N D T. E. HABGOOD

H.

CiS-8,10-DIETHYLNORLOBELIONOL

cis-8,10-Diethylnorlobelionol(IX), C13H25N02 (hydrochloride, mp 183"-184", depressed when.mixed with the hydrochloride of diethylnorlobelidione), occurs in L. syphilitica (33).On oxidation it gave the dione

VIII.

I. t?%nS-3,4- O r 4,5-DEHYDRO-8-METHYL-1O-ETHYLLOBELIDIOL ( - )-trans-3,4- or 4,5-Dehydro-8-methyl-l0-ethyllobelidiol(X), C13H25N02 (hydrochloride, mp 120"; - 110" in CzHsOH), from L. syphilitica ( 3 4 ) ,ga,ve on hydrogenation followed by oxidation %methyl10-ethyllobeljdione (23).

CHsCHOHCHaANACH2CHOHCH&H3

I

CH3 X

J.

8-METHYL-10-ETHYLLOBELIDIOL

An optically inactive minor alkaloid, C13H2702N (chloroplatinate, mp 217"-218" decomp. ; chloroaurate, mp 104"-105"; picrate, mp 133"-134"), isolated from L. inJata (23),was assigned structure XI on the basis of its oxidation by chromic acid t o 8-methyl-10-ethyllobeli-

0

CH3CHOHCHz

CHgCHOHCHzCHs

I

CH3 XI

CH3CH&HOHCHz

CHzCOCHzCH3

I

dione, identical with that prepared by condensation of glutardialdehyde, methylamine, propionylacetic acid, and acetoacetic acid.

12. THE

467

PYRIDINE ALKALOIDS

K. ~ ~ ~ - ~ , ~ ~ - D I E T H Y L L O B E L I O N O L ( - )-cis-8-lO-Diethyllobelionol(XII), C14H27N02 (hydrochloride, mp 120°-1210), from L. syphilitica (33), on oxidation gave cis-8,lOdiethyllobelidione.

L. trans-3,4-DEHYDRO-8,10-DIETHYLLOBELIDIOL ( - )-trans-3,4-Dehydro-8,10-diethyllobelidiol (XIII),

C14H27N02

([a]","-114" in C2HSOH; hydrochloride, mp 128"; perchlorate, mp 123";

reineckate, mp 101°-1020), occurs in L. syphilitica (33). The position of the double bond was established by oxidation to the unsaturated lobelidione, which was oxidized to a dicarboxylic acid by means of permanganate-periodate. The methiodide of the dicarboxylic acid by Hofmann degradation followed by hydrogenation of the methine and saponification yielded 6-propionylpropionic acid. Catalytic hydrogenation of trans-3,4-dehydro-8,10-diet8hyllobelidiol followed by chromic acid oxiidentical with that synthesized dation gave cis-8,1O-diethyllobelidione, from glutardialdehyde, methylamine, and propionylacetic acid (23).

0-

CHsCHzCHOHCHz

CHzCHOHCHzCHa

!Ha

XI11

CH3CHzCHOHCHz

CHaCHOHCHaCHa dH3 XIV

M. 8 , 10-DIETHYLLOBELIDIOL Structure XIV has been assigned to another optically inactive minor alkaloid, C14H2902N2, from L. injlata (23), which formed a chloroplatinate (mp 203"-204" decornp.), a chloroaurate (mp 118"-119"), and a picrate (mp 138"). Chromic acid oxidation of 8,lO-diethyllobelidiol gave 8,lO-diethyllobelidione which was synthesized from glutardialdehyde, methylamine, and propionylacetic acid. Lithium aluminum hydride reduction of the dione gave a diol identical with XIV.

468

W. A. AYER AND T. E. HABGOOD

N. 8-METHYL-10-PHENYLLOBELIDIOL ( + )-8-Methyl-l0-phenyllobelidiol(XV),C17H2702N ([m]? +3" in CzH50H; hydrochloride, mp 91"-92"; chloroaurate, mp 170°), has been isolated from L. inJEata (23) and from S. acre (35). It has been assigned structure XV on the basis of its oxidation to racemic 8-methyl-10-

CH3CHOHCH2

0

CH~CHOHCBHS

I

CH3

xv

CHzCOCeH5

CH 3CH 0HCHz

I

CH3 XVI

phenyllobelidione, which has been synthesized from glutardialdehyde, methylamine, benzoylacetic acid, and acetoacetic acid.

0.

8-METHYL-10-PHENYLLOBELIONOL

8-Methyl-10-phenyllobelionol (sedinone) (XVI), C17H25N02 (mp 93"; hydrochloride, mp 175") occurs in S. acre (36).

P.

8-METHYL-10-PHENYL-4,5-DEHYDROLOBELIDIOL

( - ) - trans - 8 - Methyl - 10 - phenyl - 4,s- dehydrolobelidiolfsedinine), C17H25N02, isolated from S. ucre (35) (mp 121"; [ c Y ] ~-105" in CH30H), has been assigned structure XVII on the basis of IR- and NMR-data ( 3 6 , 3 7 ) .On hydrogenation XVII gave the dihydro compound, 8-methyl10-phenyllobelidiol, enantiomeric with that isolated from L. i n j a t a (23). Chromic acid oxidation of the dihydro compound (dihydrosedinine) gave

I

CH3 XVII

I

CH3 XVIII

12. THE PYRIDINE ALKALOIDS

469

a mixture of two racemic diketones, one of which was identical with synthetic %methyl- 10-phenyllobelidione. The position of the double bond was established (37) by oxidation of trans-8-methyl-lO-phenyl-4,5dehydrolobelidiol to the diketone, ozonolysis of which followed by treatment with peracetic acid gave an aminodicarboxylic acid. Hofmann degradation and hydrogenation resulted in /3-benzoylpropionic acid which can arise only from structure XVII. The assignment of the trans configuration was made on the basis of comparison of the molecular rotation differences of salts of trans-8-rnethyl-lO-phenyl-4,5-dehydrolobelidiol and its dihydro compound (sedinine-dihydrosedinine)with and dihydro those of trans-8-ethyl-l0-phenyl-4,5-dehydrolobelidiol compound (lobinanidine-dihydrolobinanidine) and cis-8-ethyl-10phenyl-4,5-dehydrolobelidioland dihydro compound (isolobinanidinedihydroisolobinanidine) .

&.

CiS-8,10-DIPHENYLLOBELIONOL

The mutarotation of optically active 8,lO-diphenyllobelionol (lobeline) (XVIII) has been studied (38, 39). Both (+)-cis- and (+)-trans-8,10diphenyllobelionol undergo mutarotation. The rate of mutarotation of ( - )-cis-8,1O-diphenyllobelionol is increased in hydrophilic solvents and in the presence of hydroxyl ion. Hygrine and pelletierine show similar mutarotation. Compounds lacking the carbonyl a t C-10 do not undergo mutarotation. The configuration of racemic 8,1O-diphenyllobelionol was determined as (2R,6X,8R) (2X,6R,8X) (40) by removal of the phenacyl side chain and correlation of the product with 8-phenyllobelol. Racemic XVIII was treated with benzyl bromide and the N-benzylmethobromide converted to the des base by treatment with sodium hydroxide. Ozonolysis followed by catalytic hydrogenation gave a product identical with racemic 8-phenyllobelol, the configuration of which is known to be (2R,8R) (28,88). Attempts to remove the side chain of natural ( - )-cis-8,10-diphenyllobelionol failed ( 4 1 ) . However, its configuration was established as 2X,6R,8S on the basis of conversion of O-acetyl-(- )-phenyllobelol by condensation of its immonium salt, prepared by mercuric acetate oxidation, with benzoylacetic acid followed by hydrolysis to ( - )-cis-8,$0dip henyllobelionol. cis-8,lO-Diphenyllobelionol has been shown to be the product obtained by catalytic hydrogenation or electroreduction of cis-8,lO-diphenyllobelidione (lobelanine). Reduction with aluminum isopropoxide gave an (42). unidentified isomer of cis-8,lO-diphenyllobelionol

470

W. A. AYER AND T. E. HABGOOD

R. cis-8,10-DIPHENYLLOBELIDIONE cis-8,lO-Diphenyllobelidione(lobelanine) was synthesized (43) by condensation of hepta-l,6-diyne with 2 moles of ethylmagnesium bromide followed by benzaldehyde. The 1,9-diphenylnona-2,7-diyne-ly9diol was oxidized by chromic acid to the dione, reduced under controlled conditions t o &,cis-1 ,9-diphenylnona-2,7-diene-1,9-dione, which on condensation with methylamine gave cis-8,lO-diphenyllobelidione (mp 97'-98').

S. LOBINALINE Lobinaline, the major alkaloid of L. cardinalis L., was first isolated by Manske in 1938 (44).Althoughnot widely distributed in the genus Lobelia, lobinaline has been detected in L. elonguta Small (45). The molecular formula assigned by Manske (44), C28H380N2, was later recognized to be that of a monohydrate and modified to C2sH3sN2 (46). Recently, Robison and co-workers (47)have shown that lobinaline is represented by structure XIXa. Lobinaline, after recrystallization from hexane and sublimation, melts a t 108"-110" ( [ a ] g+38' in chloroform) and on the basis of analytical and mass spectral data has the molecular formula C27H34N2. The presence of the two mono-substituted benzene rings and the N-methyl group was revealed by NMR-measurements. The presence of the 6-substituted 2,3,4,5-tetrahydropyridine was deduced from the observation that lobinaline (XIXa), which shows strong absorption at 1665 cm-1 in the IR-spectrum but does not show N-H absorption or olefinic protons in the NMR-spectrum, readily forms a mono-N-acetyl derivative (XXa) which does show an olefinic proton in the NMRspectrum. Furthermore, treatment of lobinaline with selenium dioxide which N Z from , its spectroscopic furnished a dehydrolobinaline," C ~ ~ H ~ O properties clearly contained an a-substituted pyridine ring. ((

XIXa; R = CHa XIXb; R = H

XXa; R = CHI XXb; R=CN

47 1

12. THE PYRIDINE ALKALOIDS

The key reaction in the determination of the structure of lobinaline was the dehydrogenation of desmethyllobinaline (XIXb) to give compounds XXI and XXII. Treatment of acetyllobinaline (XXa) with cyanogen bromide and hydrolysis of the resulting cyanamide XXb

XXI

XXIII

XXII

XXIV

gave desmethyllobinaline (XIXb). Compound XXI contained two alkyl pyridine rings as well as two mono-substituted benzene rings. Oxidation of XXI with potassium permanganate gave picolinic and quinolinic acids as well as benzoic acid, revealing the substitution pattern of the pyridine rings. The structure of compound XXII, 5,7-diphenyl-6-(2pyridyl)quinoline, which was deduced mainly from a consideration of its UV- and NMR-spectra as well as its supposed relationship to compound XXI, was firmly established by synthesis. Base-catalyzed condensation of 2-phenacylpyridine with benzalacetone followed by dehydration of the resulting carbinol furnished 3,5-diphenyl-4-(2pyridyl)-cyclohex-2-enone (XXIII). The ketone XXIII was transformed to the azine and dehydrogenated and hydrogenolyzed to the aniline XXIV, which when subjected to Skraup quinoline synthesis gave the dehydrogenation product XXII. The relative stereochemistry of lobinaline as depicted in XIXa was established (48) by means of a stereochemically controlled synthesis of " dehydrolobinaline " (XXVa), the product obtained in the selenium dioxide oxidation mentioned previously. trans,trans-3,5-Diphenyl-4-(2-pyridyl)cyclohexanone (49) was transformed to its pyrrolidine enamine (XXVI) which was then cyanoethylated and hydrolyzed to the ketonitrile XXVII. Hydrogenation of XXVII over palladium-charcoal in ethanol in the presence of a small

472

W.A. A Y E R A N D T. E. H A B G O O D

,

R XXVa; R = CHs

XXVI

XXVII

XXVb; R = H

R XXVIIIa; R = H XXVIIIb ; R = CH3

XXIX

xxx

amount of aqueous ammonia furnished the cis-decahydroquinoline XXVIIIa. Methylation of XXVIIIa afforded XXVIIIb ,which was not identical with “dehydrolobinaline.” However, when the ketonitrile XXVII was hydrogenated in the presence of a large amount of anhydrous ammonia the desired trans isomer, XXVb, was obtained. Methylation of XXVb furnished dl-dehydrolobinaline (XXVa). It is believed that the first reduction proceeds via the imine XXIX which is hydrogenated from the “topside” to yield XXVIIIa, whereas in the presence of excess anhydrous ammonia the first step is reductive amination of the carbonyl group to give XXX, which then undergoes reductive cyclization to give XXVb. Further confirmation of the lobinaline structure has been presented by Clugston et al. (50) who carried out a detailed mass spectrometric analysis of lobinaline, its derivatives, and its Hofmann degradation products. Among the latter was the base XXXI, prepared by exhaustive methylation of N-methyldihydrolobinaline. Biosynthetic studies indicate that lobinaline is formed in the plant from phenylalanine and lysine (51). Two alkaloids isolated from L. syphilitica appear to be related to (mp 192”-194”), optically lobinaline (52). Syphilobine-A, CZ~HZZNZOZ inactive, is a highly unsaturated base containing two methoxyl groups for which structure XXXII has been suggested on the basis of its spectral properties and on biogenetic grounds. Syphilobine-F, C28HZ6Nz03 (mp 222”-223”; [aID-1 .64” in pyridine), contains one hydroxyl group more than syphilobine-A which, from the UV-spectrum, appears to be part of a 3-hydroxypyridine system. Structure XXIII has been advanced

12.

THE PYRIDINE ALKALOIDS

473

XXXI

OCHa XXXIII

XXXIV

for syphilobine-F. Dehydrogenation of the methyl ether of syphilobine-F proceeds with the loss of 2 molecules of hydrogen to give an amorphous compound formulated as XXXIV. The presence of at least six other alkaloids in L. syphilitica was demonstrated by thin-lhyer chromatography (52).

V. The Alkaloids of Hemlock A color test utilizing isatin for piperidine and pyrrolidine alkaloids containing the structural unit -NH-CHz-CHzhas been described (53).Coniine and conhydrine give a positive test but pseudoconhydrine, which lacks the above feature, does not. The Conium alkaloids have been separated by gas-liquid chromatography (54). A. CONIINE

A new synthesis of coniine has been reported (55). 2-Cyanopyridine with ethyl magnesium bromide gave 2-propionylpyridine which was transformed to coniine by Wolff-Kishner reduction followed by catalytic hydrogenation. Clemmensen reduction of the 2-propionylpyridine gave

474

W.

A.

AYER AND T. E. HABGOOD

2-(1 -hydroxypropyl)pyridine which on catalytic hydrogenation gave a mixture of diastereoisomers from which racemic conhydrine could be separated by fractional crystallization. The biosynthesis of the hemlock alkaloids has been studied using 1%-labeled compounds (56) and the results indicate that coniine and conhydrine are formed by way of an eight-carbon polyketo acid chain (XXXV) derived by linear condensation of four acetate units and not from lysine as previously believed (57). The scheme suggested (56) involves condensation of XXXV with ammonia to give the intermediate XXXVI which on reduction and dehydration could give y-coniceine (XXXVII). Evidence that y-coniceine may play a central role in the biosynthesis of the hemlock alkaloids has been presented (58).Reduction of y-coniceine would lead to coniine (XXXVIII) while allylic oxidation and then reduction could lead to conhydrine(XXX1X).

HOOCh

c xxxv

&

-

O

b

OCH

H

a

-%

CHs

XXXVII

XXXVI

XXXVIII

XXXIX

B. CONHYDRINE The work of Hill (59) and Sicher and Tichy (60) has proved the erythro configuration for conhydrine. Racemic conhydrine was degraded by the method of Spath and Adler (61) involving a double Hofmann degradation (Volume I, p. 220) and the resulting epoxide (XL) was hydrolyzed to the corresponding diol which on hydrogenation furnished erythro-octane-3,4-diol, an authentic sample of which was obtained by cis-hydroxylation of cis-oct-3-ene. Since the formation of erythrooctane-3,4-diol from conhydrine involves two inversions, conhydrine must also have the erythro configuration. Conhydrine had previously been degraded t o ( - )-pipecolic acid (62),the absolution configuration of which is known to beS (63),thus the 2S,l'R configuration XLI represents the absolute configuration of conhydrine.

475

12. THE PYRIDINE ALKALOIDS

if. XLI

XL

It has been shown (64) that rearrangement of 2-n-propylpyridine N-oxide with acetic anhydride followed by hydrolysis yields 2-( 1'hydroxypropy1)pyridine as well as a small amount of 5-hydroxy2-propylpyridine. Reduction of the former gives conhydrine, while reduction of the latter gives pseudoconhydrine. C. PSEUDOCONHYDRINE The S configuration a t C-2 in pseudoconhydrine (XLII) has been shown by oxidation to ( + )-P-norleucine (XLIII) (65), the absolute configuration of which was established by synthesis from S-norvaline (XLIV). This configuration also followed from the fact that dehydration of pseudoconhydrine followed by hydrogenation gives d-coniine (66), while conhydrine, which on oxidation gives S-( - )-pipecolic acid, yields 1-coniine when the hydroxyl is removed reductively (67). By establishing the absolute stereochemistry a t C-5, Hill (68) was able to complete the stereochemical assignment for pseudoconhydrine. Earlier, Spath and his co-workers (66)converted pseudoconhydrine to a series of compounds containing only the C-5 asymmetric carbon. Hofmann degradation of pseudoconhydrine, followed by catalytic hydrogenation (XLV). A of the resulting olefin, yielded d-dimethylamino-1-octanol-2 second Hofmann gave l-octene-1,2-oxide (XLVI). Hill (68) prepared dl-octene-l,2-oxide by perbenzoic acid oxidation of I-octene. Treatment COOH HO H-Q.HAcH3 H

XLII

XLIII

XLIV

XLVI

476

W. A. AYER AND T. 1.HABOOOD

with dimethylamine gave dl-dimethylamino-1-octanol-2, which was resolved using I-dibenzoyltartaric acid to give pure E-dimethylamino- 1octanol-2. Hofmann elimination gave pure d-octene-l,2-oxide which on reduction with lithium aluminum hydride gave d-octan-2-01, known t o have the (8)configuration. Since none of the reactions mentioned affect the stereochemistry a t the asymmetric center, pseudoconhydrine must possess the ( 8 )configuration a t C-5 and its relative and absolute stereochemistry is as represented by XLII. The relative stereochemistry deduced in this way has been confirmed by an X-ray diffraction study of pseudoconhydrine hydrobromide (69).

D. CONICEINES y-Coniceine, the major alkaloid of C . maculatum in the vegetative state (70), and the only naturally occurring coniceine, has now been (XLVII), shown (71, 7 2 ) to be 2-n-propyl-3,4,5,6-tetrahydropyridine not 2-n-propyl- 1,4,5,6-tetrahydropyridine (XLVIII) as previously assumed. The IR-spectrum of y-coniceine shows little or no N--R absorption but does show a moderately intense band a t 1660 cm-1 characteristic of a C-N bond. The NMR-spectrum shows no absorption below 7 6.0, which rules out the presence of an olefinic proton and strongly supports structure XLVIII. The absence of an active hydrogen in y-coniceine has also been demonstrated ( 7 1 ) . Buchel and Korte (72) have developed a new synthesis of y-coniceine which involves basecatalyzed condensation of N-butyryl-2-piperidone with ethyl butyrate 0

I

c-0 I

Pr XLVII

XLVIII

XLIX

to give XLIX. Acid hydrolysis of XLIX is accompanied by decarboxylation and ring closure to y-coniceine (XLVII). A general method for the preparation of 2-substituted Al-piperideines, including y-coniceine, has been developed (73).This involves the treatment of the 2-alkylpiperidine with N-chlorosuccinimide in ether and dehydrochlorination of the resulting N-chloropiperidine with potassium hydroxide in ethanol.

477

12. THE PYRIDINE ALKALOIDS

Two new syntheses of 8-coniceine fL)have been reported. I n one (741, 1-methyl-2-pyrrolidone and 4-methoxybutylmagnesium bromide yield the dihydropyrrole L I which is reduced to the pyrrolidine, converted t o the-bromo compound, cyclized, and the resulting methobromide thermally decomposed to give S-coniceine (L).

m 0

L

LI

0

LII

I n the other synthesis ( 7 5 ) , the Leuckart reaction on y-ketosuberic acid gave /3-( 6-oxopiperidy1)propionic acid which on heating yielded LII. Lithium aluminum hydride reduction of L I I gave koniceine (L). A stereospecific synthesis of racemic erythro-r-coniceine (LIII) has been achieved (28). The nitrogen in ( )-8-methylnorlobelol [( 5 )sedridine] (LIV; R = H) was protected as the tert-butoxycarbonyl derivative and the hydroxyl group was then mesylated. Removal of the N protecting group followed by thermally induced cyclization of LIV (R = methanesulfonyl) gave E-coniceine methanesulfonate. Since sedridine has the threo configuration and since an inversion very likely occurs a t carbon 2 of the side chain during ring closure, the E-coniceine obtained should be the erythro form LIII.

+

& 3

&

LIV

CH3

LIII

VI. The Tobacco Alkaloids Recent intensive interest in the physiological effects of habitual smoking has resulted in the publication of thorough reviews of the chemistry of tobacco constituents (76, 77). The chemistry of nicotine and related alkaloids including biosynthetic aspects has been surveyed (78) and the chemistry of pyrolysis products of tobacco alkaloids in smoke has been reviewed (79). Nicotine has been found in Sempervivum arachnoideum L. (80),in Erytkoxylum coca Lam. (81),in Duboisia myoporoides R.Br. grown on

478

W. A. AYER AND T. E. HABGOOD

the Acacia Plateau, South Queensland (82), and in D. hopwoodii (F. Muell) F. Muell (83).Nicotine does not occur in Sedum acre (35).Nornicotine has been found in Duboisia hopwoodii (83) and in Salpiglossis sinuata (84). The IR-spectra of 41 tobacco alkaloids and related compounds have been tabulated (85). Nornicotine, nicotine, myosmine, nicotyrine, anabasine, anatabine, and dihydronicotyrine were separated from an extract of tobacco alkaloids by countercurrent partition (86). Thinlayer chromatography has been used to separate nicotine, nornicotine, anabasine, and nicotyrine (87).The use of gas chromatography to separate tobacco alkaloids has been studied. The retention times of 1 1 tobacco alkaloids on polyethylene glycol columns has been reported (88)and the effect of the column packing on the retention times of pyridine bases has been described (89). Mixtures containing pyrrolidine, piperidine, pyridine, and various alkylated pyridines have been separated using programed temperature control (90).

A. NICOTINE Many new syntheses of nicotine have been described. Ethyl nicotinate condensed with ethyl acetate gave ethyl nicotinoylacetate which with ethyl bromoacetate gave diethyl nicotinoylsuccinate (LIV). LIV was hydrolyzed to the acid which was converted to the ethyl ester oxime (LV). Hydrogenation gave the amino ester (LVI) which on being heated gave dl-des-N-methylcotinone (LVII). Lithium aluminum hydride reduction followed by methylation gave dl-nicotine (91).

LIV

LVI

LV

LVII

Ethyl nicotinate heated with 3-benzylidenepropylamine gave the amide (LVIII) which with phosphorus oxychloride gave 2-(3-pyridyl)3-benzylidene- 1 -pyrroline (LIX). LIX was reduced with sodium

12. THE PYRIDINE

479

ALKALOIDS

borohydride to LX, the benzoyl derivative of which was ozonized to l-benzoyl-2-(3-pyridyl)-3-pyrrolidinone(LXI). The tosylhydrazone derivative of LXI when treated with sodium alkoxide gave L X I I which was catalytically . hydrogenated to N-benzoylnornicotjne from which dl-nicotine was obtained by hydrolysis and methylation (92).

LVIII

LIX

LX

0

LXI

LXII

3-Bromopyridine with butyllithium and 1-methyl-2-pyrrolidone gave N-methylmyosmine which when heated with formic acid and fused potassium forrnate gave dl-nicotine (9’3).

CHs

LXIII

LXIV

An acyl-lactone rearrangement has been utilized in synthesizing nicotine (94),myosmine ( 9 4 ) ,and N-methylanabasine (95).Ethyl nicotinate and 1-methyl-2-pyrrolidone treated with potassium in dry ether gave 3-nicotinoyl-1-methyl-2-pyrrolidone (LXIII). L X I I I was hydrolyzed with acid to LXIV which on hydrogenation gave dl-nicotine.

r(co-c? / \

(yJ N’

LXV

LXVI

480

W. A. AYER A N D T. 1.HABGOOD

Ethyl nicotinate and 1-nicotinoyl-2-pyrrolidone with sodium hydride gave 1,3-dinicotinoyl-2-pyrrolidone (LXV) which was hydrolyzed with acid to myosmine (LXVI) (94). Similarly, ethyl nicotinoate with 1-methyl-%piperidone gave dl-N-methylanabasine (95).' Ethyl nicotinoylacetate with formaldehyde and diethyl acetamidomalonate gave LXVII which on being treated with dilute hydrobromic acid followed by saponification gave LXVIII from which myosmine and nicotine were prepared (96).

LXVII

LXVIII

The racemization of 1-nicotine by heating in acid solution has been studied (97). Various salts of nicotine with aromatic acids have been prepared (98),

4,

J.

0

0 LXIX

LXX

LXXI

The N-oxides of nicotine have been prepared (99, 100). I n 10% hydrogen peroxide, nicotine gives the 1'-oxide (LXIX).I n 30 yohydrogen peroxide or with perlauric acid, the 1,l'-dioxide (LXX) is formed which on reduction with sulfur dioxide gives the 1-oxide (LXXI). The rearrangements of the 1'-oxide have been studied (88).

Dehydrogenation of nicotine over palladium a t 280" (99) gave a mixture of iiicotyrine and L X X I I which on Hofmann degradation gave LXXIII. L X X I I I was also prepared by treating dihydrometanicotine with methyl iodide.

48 1

12. THE PYRIDINE ALKALOIDS

B. ANABASINE AND ANATABINE The absolute configuration of anabasine has been determined (101). Anebasine methiodide was oxidized with potassium ferricyanide to N,N’-dimethylanabasone (LXXIV) which was further oxidized by chromic acid to ( - )-N-methylpipecolic acid. Since the configuration of N-methylpipecolinic a,cid is known to be LXXV (102), the absolute configuration of natural ( - )-anabasine must be (2S)-2-(3-pyridy1)piperidine (LXXVI). The configurations of ( - )-anatabine and ( - )-Nmethylanatabine must also be 2X.

CHs LXXIV

I

COOH

CHs LXXV

LXXVI

The reactions of anabasine have been studied for many years by Russian chemists. Hydrogenation of 1-anabasine with Raney nickel in aqueous suspension gives dl-a$’-dipiperidyl ; in alkaline suspension the product is 1-a$’-dipiperidyl (103). With hydrogen peroxide in acetic acid a t 60”N-methylanabasine gives the N,N’-dioxide which is reduced by sulfur dioxide to the py-N-oxide, in a manner analogous to nicotine, Reduction of the N,N’-dioxide with zinc and hydrochloric acid gives back N-methylanabasine (104). The reactions of anabasine have been described with chlorine (105), bromine (106),carbon monoxide (lor),and ketene (108).The reaction of N-methylanabasine-N-oxideor -dioxide with metliylmagnesium iodide has been described (109).

LXXVII

Anabasine with ethylene oxide gave N-(2-hydroxyethyl)anabasine, and with propylene oxide, N-(2-hydroxypropyl)anabasine. N-(2Chloroethy1)anabasine heated with potassium hydroxide was reported (LXXVII) (110). to yield /l-(a-quinuclidy1)pyridine

482

W. A . AYER A N D T. E. HABGOOD

An interesting synthesis of dl-anatabine has been reported (111).The bis-carbamate of 3-formylpyridine (LXXVIII) when heated with butadiene in acetic acid in the presence of boron trifluoride gave l-ethoxycarbonyl-1,2,3,6-tetrahydro-2,3'-bipyridine(LXXX ; R = COOEt) presumably via a Diels-Alder addition to the intermediate LXXIX. Hydrolysis of LXXX (R = COOEt) gave dl-anatabine (LXXX; R = H) and LiAlH4 reduction gave dl-N-methylanatabine (LXXX ; R = CH3). NHCOOEt

S & OCH- [QC7 j I

"HCOOEt

LXXVIII

COOEt

LXXIX

R

N'

LXXX

C. ALKALOIDS OF TOBACCO SMOKE Gas chromatography has been an invaluable aid in the analysis of tobacco smoke, resolution being most complete on a polypropylene glycol column (112).Nicotine makes up 90 yoor more of the total alkaloids of Burley tobacco smoke ; myosmine, nornicotine, anabasine, anatabine, 2,3'-dipyridyl, and cotinine were also identified (113).Nicotyrine, metanicotine, N-methylnicotinamide, and nornicotyrine were absent. The presence of methyl 3-pyridyl ketone and ethyl 3-pyridyl ketone was shown to depend on the growth and the history of the tobacco prior to smoking (114). When nicotine was vaporized by flask distillation into a stream of helium passing through a horizontal unpacked silica tube above 600°, equivalent amounts of myosmine and 3-vinylpyridine were produced, as well as small amounts of pyridine, 3-picoline, 3-ethylpyridine, metanicotine, benzonitrile, 3-cyanopyridine, naphthalene, 3-(buta1,3-dienyl)pyridine, quinoline, nicotine, isoquinoline, nornicotyrine, 1,T-diazaindene, and two unknown compounds. Nornicotine, nicotyrine, N-methylmyosmine, nicotinamide, and nicotinic acid were not detected (115). Nicotine pyrolyzed in a stream of nitrogen a t 500"-800" produced as major products myosmine, 3-vinylpyridine, and 3-cyanopyridine, along with nornicotine, pyridine, 3-picoline, 3-ethylpyridine, pyrrole, quinoline, isoquinoline, and 3,2'-dipyridyl (116). When nicotine was pyrolyzed in a vertical reactor packed with quartz or activated alumina, myosmine was the major product (117).The pyrolysis of nornicotine has also been studied (118).

12. THE PYRIDINE ALKALOIDS

483

VII. The Biogenesis of Nicotine, Anabasine, and Ricinine

A. NICOTINE At the time of the last review (Volume VI, p. 128) it had been shown that the methyl group of nicotine has its origin in methionine, betaine or choline, that ornithine is a n efficient precursor of the pyrrolidine ring, and that nicotinic acid gives rise t o the pyridine ring, the carboxyl group being lost at some stage in the biosynthesis. Further work has served to confirm and extend these findings. Degradative schemes have been developed which allow the isolation of each carbon atom of nicotinic acid (119-121). When nicotinic acid-2-3H, -43H, and -5-3H were administered to sterile root cultures of N . tabacurn, the labeled atoms were retained in the nicotine isolated, but when nicotinic-6-3H was supplied, most of the label was lost (122).Since R-hydroxynicotinic acid-lsN is not converted into nicotine, a 6-pyridone is probably not an intermediate ( 1 2 2 ) .When nicotinic acid-2,3,7-14Cwas administered it was found that all the activity was present a t C-2 and (2-3 (121),consistent with the view that the pyrrolidine ring is attached to nicotinic acid a t position 3 where decarboxylation occurs. Quinolinic acid, which is a precursor of nicotinic acid in corn and castor bean plants (123),is an efficient precursor of the pyridine ring in nicotine (121). Acetate-2-14C, propionate-2-14C7and glycerol- 173-14Care incorporated into the pyridine ring of nicotine, acetate and propionate contributing to C-2 and C-3, and glycerol to C-4, C-5, and C-6 (124). Glycerol-2-14C gave nicotine mainly labeled a t C-5, while with glycerol- 1-14Cor glycerol1,3-14Cthe label was distributed between C-4 and C-6 (121, 125). Both acetate-2-14C and succiiiate-2,3-14C contribute equally to C-2 and C-3 (126), a result consistent with the hypothesis that succinate, derived from acetate in the Krebs cycle, is the source of C-2 and C-3 of the pyridine ring. It has also been demonstrated that positions 2 and 3 of the pyridine ring of anabasiiie are formed from the methylene carbons of succinate (127) and that glycerol serves as a precursor for C-4 ,C-5, and C-6 (119). Aspartic acid-3-14C)when administered to N . rustica, gave radioactive nicotine in which 63 "/b of the activity was in the pyridine ring, about half of it at C-3 (128).This result has been rationalized by postulating that the aspartic acid is metabolized by way of the Krebs cycle to succinic acid, which is then reconverted to aspartic acid which would have the radioactivity equally distributed between C-2 and C-3 (129).A tentative scheme (129) for the biosynthesis of nicotinic acid that accommodates the results discussed involves the condensation of aspartic acid (LXXXI), available from succinic acid via oxaloacetic acid, with glyceraldehyde

484

W. A. AYER AND T. E. HABOOOD

%phosphate (LXXXII) to give the hydroxy acjd LXXXIII which on dehydration and dehydrogenation gives quinolinic acid (LXXXIV). Decarboxylation of LXXXIV then gives nicotinic acid. Much work has been reported on the origin of the pyrrolidine ring in nicotine. Ornithine-2-14C (130, 131) and glutamic acid-2-14C (132, 133) are incorporated into the pyrrolidine ring, positions 2' and 5' bearing equal activity. Putrescine-l,4-14C gives a similar result (133). These results were interpreted to mean that ornithine is an immediate precursor of the pyrrolidine ring of nicotine and that glutamate, derived by the tricarboxylic acid cycle, is related to ornithine via the intermediacy of 0

II

CHzCOOH I

p H CHOH

I

@ 0-CHz LXXXI

HzN

-

OH

H

o

/"? COOH

I

OH

COOH

~

~

acoo COOH

H

LXXXII

LXXXIII

LXXXIV

glutamic semialdehyde (LXXXV).Cyclization of glutamic semialdehyde to Al-pyrroline-5-carboxylicacid (LXXXVI) and decarboxylation to a symmetrical anion (LXXXVII)would lead t o dl-pyrroline (LXXXVIII) in which the label is symmetrically distributed (132, 133). When A l pyrroline-5-carboxylic acid-5-14C (LXXXVI) is supplied to intact tobacco plants equal activity is found a t C-2' and (2-5' in the nicotine

LXXXV

LXXXVI

Q - - - Q *- * Q * LXXXVII

LXXXVIII

(134).Further support for this hypothesis was obtained from the results of feeding various labeled tricarboxylic acid cycle intermediates to tobacco plants and root cultures (135,136). I n contradiction to the scheme shown is the finding (137) that the source of the nitrogen of the pyrrolidine ring of nicotine is the &amino group of ornithine, not the a-amino group as required above. No nitrogen from ornithine-2-14C-a-15N was incorporated by a sterile root culture of N , tabacum; ornithine-2-14C-6-15Nresulted in a specific incorporation of

12.

485

THE PYRIDINE ALKALOIDS

15N one half that of 14C. These results were explained by postulating that tobacco roots contain an ornithine-a-transaminase which catalyzes the formation of a-keto-6-aminovaleric acid from ornithine, resulting in loss of 15N from the a-labeled compound. Transformation of the aketo-6-aminovaleric acid to Al-pyrroline via ornithine, putrescine, and 4-aminobutanal would account for the observed result (137). Exposure of N . glutinosa to 14CO2 resulted in a labeling pattern in the pyrrolidine ring which is not consistent with the symmetrical jntermediate hypothesis (138, 139). C-2' and C-5' were found to be equally labeled, but the activity a t C-3' was much lower than predicted on the basis of a symmetrical intermediate. Although there appears to be little doubt that ornithine is incorporated into nicotine via a symmetrical intermediate, the work with 14CO2 raises the question as to whether this may be a minor or aberrant pathway to nicotine in the plant (139).

B. ANABASINE It has been established that nicotinic acid is the precursor of the pyridine ring in anabasine (140)and that carbons 2 and 3 are derived from the methylene carbons of succinate (127).It has also been shown that glycerol serves as a precursor for C-4, C-5, and C-6 (119).Lysine serves as the precursor of the piperidine ring of anabasine (140, l a l ) , C-2 of lysine becoming C-2' of anabasine. Tracer experiments with lysine-2-14C labeled with 15N on the a- or €-nitrogen indicate that the piperidine nitrogen is derived from the €-amino group (142).The mechanism by which nicotinic acid is incorporated into nicotine must involve C-6 since nicotinic acid-6-3s was incorporated with loss of the label, whereas nicotinic acid-2-3H was incorporated with retention of the label (140).A

xc

LXXXIX

XCI

I(

XCII

XCIII

XCIV

486

W. A. AYER AND T. E. HABOOOD

plausible mechanism (129)for the biosynthesis of anabasine involves the transformation of lysine (LXXXIX) into the a-keto acid XC, cyclization of XC to Al-piperideine-2-carboxylicacid (XCI) and decarboxylation t o Al-piperideine,. Condensation of 1,B-dihydronicotinic acid (XCII) with Al-piperideine t o give the intermediate XCIII followed by decarboxylation with loss of hydride from C-6 would lead to anabasine (XCIV). Provided the hydride lost from C-6 is the original hydrogen of nicotinic acid, this scheme accounts for the tracer results obtained to date. C. RICININE Nicotinic acid is also a biogenetic precursor of ricinine (XCV) (143). By the use of tritiated nicotinic acid-7-14C and tritiated nicotinamide in 9CH3

I CH3

xcv which the amide nitrogen was labeled with 15N it was shown that the pyridine ring and the amide group are incorporated as a unit (144). Quinolinic acid is also incorporated efficiently into ricinine (123). Succinic acid-2,3-14Cwas incorporated into the pyridone ring (145))the activity being located mainly a t C-2 and C-3 (146).Most of the activity in ricinine obtained from young Ricinus plants fed succinate-l,4-14C was located on the nitrile carbon (147). Glycerol-l-14C produced a high level of activity a t C-4 and C-6, whereas glycerol-2-14C produced a high level of activity a t C-5 (148).The results obtained when labeled aspartic acid was incorporated into ricinine indicate that it is incorporated via the tricarboxylic acid cycle rather than directly as aspartic acid (149, 150).Nicotinic acid mononucleotide, nicotinic acid adenine dinucleotide, and nicotinamide adenine dinucleotide have been shown to give rise to the pyridone ring of ricinine in R. comnaunis (151).

VIII. Alkaloids of Withania sornnifera D u a l , I - I ~ ~ y c o r v u ~ u., il member of the Solanaceae, has been shown t o contain choline, tropine, pseudotropine, 3a-tigloyloxytropane, O U / I O I L . L p

12.

THE PYRIDINE ALKALOIDS

487

cuscohygrine, dl-pelletierine, and two new alkaloids, anaferine and anahygrine (152). Anaferine (153), C13H24NzO (bp 55"/0.01 mm; dihydrochloride, mp 222.P-223.5" ; dipicrate, mp 184"-185" decomp. ; distyphnate, mp 229'-231'), is optically inactive, shows NH and carbonyl absorption in the IR-spectrum, and forms a neutral diacetyl derivative. The NMR-spectrum indicates 6 protons adjacent to nitrogen (7.08 T), 4 protons CL to the carbonyl (7.65 T ) , and 12 ring protons not adjacent to nitrogen. These data were interpreted in terms of structure XCVI for anaferine which was confirmed by synthesis (153).Two equivalents of %picolyllithium were condensed with ethyl chloroformate and the resulting ketone was hydrogenated. The mixture of alcohols thus obtained was oxidized t o a mixture of isomers XCVI, one of which was identical with anaferine.

XCVI

XCVII

Anahygrine (154), C13Hz40N2 (bp 106'/0.2 mm ; dihydrochloride, mp 216'-217.5"; dipicrate, mp 173O~174.5')has been shown to have structure XCVII. Condensation of picolyllithium with ethyl l-methyl-2pyrrylacetate followed by reduction of the product yielded anahygrine (XCVII). N-Methyl-2-hydroxypyrrolidine, Al-piperideine, and acetone dicarboxylic acid a t pH 12 also gave anahygrine as well as small quantities of anaferine, cuscohygrine, pelletierine, and hygrine (155).

IX. Gentianine Gentianine (XCVIII), which has been isolated from Gentiana species and from Ixanthus viscosus (156),Pragraea fragrans (157), and Anthocleista procera (158),has been shown to be an artifact and not present as such in the plant (159).By the use of 15NH40H it was shown that the nitrogen of the gentianine isolated was derived from the ammonia used in the isolation procedure (160). Swertiamarin (XCIX) from Swertia japonica and gentiopicrin (C) from Gentiana species are both converted into gentianine under very mild conditions (161, 162). Enicostemma littorale Bl., from which gentianine had been isolated by ammonia treatment, has been shown to contain swertiamarin (163).

488

W. A . AYER AND T. E. HABGOOD

N ‘

XCVIII

XCIX

C

CI

Gentianidine, CgH902N (mp 1 2 8 O - 1 3 O o ) , has been isolated from Gentiana macrophylla and assigned structure C I on the basis of its oxidation to pyridine-2,4,5-tricarboxylic acid (berberonic acid) and its synthesis from 4,5-dimethylnicotinic acid and formaldehyde (164). Several alkaloids besides gentianine have been isolated from Gentiana species indigenous to Bulgaria (165).These again may be artifacts since ammonium hydroxide was used in the isolation procedure.

X. The Pinus Alkaloids The complete stereochemistry of pinidine (CII) has been elucidated (166).The relative configuration of the 2,6-alkyl substituents was shown by conversion of the propenyl group into a methyl group. Pinidine was benzoylated and oxidized to ( + )-N-benzoyl-6-methylpipecolic acid

CHz

H

I

I

CHzCeHs

CBH5

GI1

CIII

CIV

CHzCeH5

cv which was reduced to the N-benzyl alcohol with LiAIH4 and this was then converted to the chloromethyl compound CIII. Reduction of CIII gave a mixture of N-benzyl-cis-2,6-dimethylpiperidine and N-benzyl-2methylazacycloheptane (CIV), both probably formed by reduction of the intermediate ethylene immonium ion CV. An alternate preparation of the 2,6-dimethylpiperidine which circumvented the formation of CIV

12.

THE PYRIDINE ALKALOIDS

489

was also described (166). The optically inactive N-benzyl-cis-2,6dimethylpiperidine was identical with an authentic sample prepared from 2,6-lutidine. Interesting additional evidence for the stereochemistry of the N-benzyl-cis-2,6-dimethylpiperidine was provided by a comparison of its NMR-spectrum'with that of the corresponding trans compound (167).Because of the lack of a plane of symmetry in the trans compound, the methylene protons of the N-benzyl group are stereochemically and magnetically nonequivalent and thus may give rise to an AB type spectrum, whereas the methylene protons in the cis compound should give rise to an A2 singlet. In agreement with this, N-benzyl-trans-2,6dimethylpiperidine showed an AB quartet centered at 6.377 for the methylene protons. The benzyl methylene protons of the cis compound gave rise to a sharp singlet at 6.30 T . The geometry about the double bond was shown to be trans by the presence of a band in the IR-spectra of pinidine and its derivatives a t 970 cm-1 and by the 18 cps coupling between the olefinic protons in the NMR-spectrum. The absolute configuration was determined by hydrogenation of N-methylpinidine methiodide to give ( + )-2-dimethylaminononane which was enantiomeric with synthetic S ( - )-2-dimethylaminononane prepared from S-( + )-2-nonanol. Pinidine is thus 2-@)-methyl6-(22)-(2-trans-propenyl)-piperidine (CII).

XI. Alkaloids of Tripterygium wilfordii Hook and Evonymus europaeus L. Nonane has been obtained from wilfordic acid and hydroxywilfordic acid by the technique of hydrogenolytic gas chromatography (168).This result, coupled with a study of the NMR-spectra of wilfordic acid and hydroxywilfordic acid, has lead to a revision of the structures of these acids to CVI and CVII respectively. COOH

COOH CH3

I

CH2-CH2-C-COOH

l

CH(CHa)CH(CH8)COtH

x

CVI; X = H C V I I ; X =O H

CVIII

Seeds of Evonyrnus europaeus were found to contain a t least twelve alkaloids (169).The major constituent, evonine, C36H43-45N017, contains five acetyl groups and has two active hydrogens. On acid hydrolysis formaldehyde is obtained. LiAlH4 reduction of evonine gives a basic

490

W. A. AYER AND T. E. HABQOOD

diol, CllH17N02, which has the UV-spectrum of a pyridine and shows strong OH absorption in the IR-spectrum. Saponification of evonine gave a dibasic acid, evoninic acid, CllH13N04 (mp 127"-133" decomp.; dimethyl ester, bp 950-100"/0.05 mm), isomeric with wilfordic acid. Structure CVIII was proposed for evoninic acid mainly on the basis of the mass spectrum and NMR spectrum of the basic diol and its diacetyl derivative. The dimethyl ester of evoninic acid on ozonolysis gives ( - ) -a& -dimethylsuccinic anhydride.

XII. Alkaloids of Adenocarpus spp. Santiaguine (CIX) was synthesized by heating isotripiperideine with a-truxillyl chloride ( 170). Methylation of santiaguine followed by acid hydrolysis gives tetrahydro-N-methylanabasine(CX) (171). Details of the syntheses of ammodendrine and orensine have been published (172). Isoorensine has been shown to be a stereoisomer, not a structural isomer, of orensine (173).Condensation of isotripiperideine with phenylpropiolyl chloride followed by hydrolysis and partial hydrogenation gave the cis-cinnamoyl isomer (CXI), identical with isoorensine. Orensine is the trans isomer.

0-9 .H

NI

co

cx

CO

CIX

CXI

XIII. Carpaine, Cassine, Prosopine, and Prosopinine The mass spectrum of carpaine shows the molecular weight to be 478, and therefore carpaine must exist as the dimer C28H50N204 (CXII)

12, THE

491

PYRIDINE ALKALOIDS

with a 26-membered ring (174). Since the hydroxyl group in methyl carpamate is strongly intramolecularly hydrogen-bonded to the nitrogen and since the methyl group and the alkyl side chain have been shown

$-B

CXIII H CXII

(175) to be cis to one another methyl carpamate must have the all-cis configuration CXIII (176).The absolute stereochemistry of carpaine has been established as that shown in CXII by degradation to (R)-(- ) - 3 tetradecanol, also prepared from (R)-1,2-epoxybutane which was reduced to (A')-( + )-2-butanol of known absolute configuration (177). Evidence has been presented t o the effect that pseudocarpaine, the minor alkaloid of Carica papaya, differs from carpaine (CXII) only in the stereochemistry of one of the methyl groups (178). Cassia excelsa Shrad. contains cassine, C I ~ H ~ ~(mp N O57"-58.5' ~ ; [a]'$' -0.6'; hydrochloride, mp 173"-175"; hydronitrate, mp 116'117') (179),which has been shown to possess structure CXIV (180,181). IR- and NMR-data indicated a secondary hydroxyl, a secondary C-methyl, and a methyl ketone (confirmed by positive iodoform test). Dehydrogenation furnished optically inactive dehydrocassine (CXV), which showed the characteristic UV-spectrum of a 3-hydroxypyridine.

H&'* H o ' * ~ I. s ( C H z ) ~ ~ C O C H 3 H

cxv

CXTV

bH3 CXVI

492

W.A. AYER A N D T. E. HABGOOD

The NMR-spectrum of CXV. showed an aromatic methyl group and indicated a 2,3,6-substitution pattern. Wolff-Kishner reduction of dehydrocassine followed by nitric acid oxidation gave lauric acid, proving the unbranched nature of the side chain. N-Methylcassine was transformed to the ketone CXVI by Wolff-Kishner reduction followed by chromic acid oxidation. The oxime of ketone CXVI underwent a second-order Beckmann rearrangement giving, after hydrolysis, acetaldehyde, which shows that the hydroxyl group in cassine is vicinal to the C-methyl group (179, 180). The all-cis configuration for cassine (CXIV) was indicated by the fact that the hydroxyl group is, as in methyl carpamate, strongly intramolecularly hydrogen-bonded to the nitrogen (179). This was confirmed and the absolute stereochemistry of cassine established by direction correlation with carpaine (181). Compound CXVII, prepared from carpaine, was homologated and CXVIII was condensed with ethyl acetoacetate and hydrolyzed.

CXVII; n = 8 CXVIII; n = 9

CXIX

cxx The product (CXIX) was identical with N-methylcassine except that the rotations were opposite, indicating that cassine (CXIV) has the mirror-image relationship to carpaine. Carnavoline, C18H37N02 (mp 66.7"-67.2"), isolated along with cassine from Cassia carnaval Spreg., is the diol (CXX) resulting from the reduction of the carbonyl group in cassine (182).Sodium borohydride reduction of cassine gives carnavoline. From Prosopis africana Taub., which has been used in Africa as a remedy for toothache and other ailments, two alkaloids related to carpaine and cassine have been isolated (183).Prosopine (CXXI; R = H, OH), C18H37N03 (mp 126")has three hydroxyl groups and a secondary amino group. Prosopinine (CXXII ; R = 0), C18H35N03 (mp 95"), has two hydroxyls, a secondary amino group, and a keto group.

12.

493

THE PYRIDINE ALKALOIDS

Hen(

HOCH2 H o ~ H ( C H 2 ) ~ ~ C R C H ~HOCHz CXXI

H

CHa)&RCH&H3

CXXII

Oppenauer oxidation of prosopine (CXXI ; R = H, OH) gave prosopinone (CXXI; R = O ) (mp 90") which is isomeric with prosopinine. Both prosopinone and prosopinine on Wolff-Kishner reduction gave desoxoprosopinine (CXXI ; R = H, H). The presence of a piperidine ring in both prosopine and prosopinine, indicated by formation of a 3hydroxypyridine on dehydrogenation, was confirmed by mass spectral data which also served to locate the lateral side chain and the hydroxymethyl group at positions 2 and 6. The location of the secondary hydroxyl at position 3 was shown by formation of the monobenzylidene derivative CXXIII from desoxoprosopinine and benzaldehyde. Oxidation of prosopine with periodic acid gave prosopinamide (CXXIV)by cleavage of the two C-C bonds between the amino group and the hydroxyl groups, elimination of the hydroxymethyl as formaldehyde, and recyclization. CsHs-HC

I " Hz ~ ( C H H Z ) ~ I C H ~

I HO/IN/j(CH2)10CHOHCHs CHO

CXXIII

CXXIV

Formation of lauric acid on chromic acid oxidation of the amide corresponding to desoxoprosopinine indicated an unbranched side chain. The positions of the substituents in the side chain were confirmed by the NMR-spectra of prosopine and prosopinine and by the mass spectra of the ethylene ketal derivatives of prosopinine and prosopinone. Although the stereochemistry has not yet been established, it is probably all-cis, comparable with cassine (183).

XIV. The Alkaloids of Astrocasia phyllanthoides Two closely related alkaloids, astrocasine (CXXV) and astrophylline (CXXVI), have been isolated from Astrocasia phyllanthoides, a member of the Euphorbiaceae (184, 185). Astrocasine, CzoH26NzO (mp 171"172"; ["ID -270" in ethanol), forms a hydroperchlorate (mp 149"-151") and a methiodide (mp 227"-228") (184).Its IR-spectrum (1645, 1610, 1597 and 1570 cm-I), UV-spectrum (A,, 263 mp, log E 4.09), and

494

W.A. AYER A N D T. E. HABGOOD

NMR-spectrum (4 aromatic protons, 2 olefinic protons as doublets at 2.92 and 3.57 r , J =12 cps) indicate a nearly planar cis-cinnamoyl N dialkylated lactam as in CXXV. Permanganate oxidation of astrocasine gave phthalic, phthalonic, oxalic, malonic, succinic, and glutaric acids. Catalytic hydrogenation gave dihydroastrocasine which had simple aromatic absorption in the UV-spectrum while LiAlH4 reduction gave the desoxy compound which shows styrene-type absorption. The methiodide of dihydroastrocasine underwent Hofmann degradation to the methine CXXVII which on osmium tetroxide-sodium periodate oxidation gave a neutral aldehyde, C15H17NO2 (CXXVIII), readily oxidized by silver oxide to the corresponding acid. The mass spectra of both astrocasine and dihydroastrocasine had the most intense peak a t m/e 98 due t o an N-methylpiperidine fragment. Astrophylline (CXXVI), C19HzsNzO (bp 115"/0.001 mm), forms a hydroperchlorate (mp 172"-174") and a monopicrate (mp 146"-148" decomp.) (185).Acid hydrolysis gives trans-cinnamic acid and ( + )-a$dipiperidyl. Although trans-cinnamic acid was obtained in the hydrolysis, the UV-spectrum (A,, 254 mp, log E 4.05) and NMR-spectrum ( 2 olefinic protons a t 3.36 and 3.99 7, J = 12 cps) showed that a cis-cinnamoyl system is present in the original alkaloid. Astrophylline is completely isomerized to the trans-isomer by heating a t 220" for 12 hours. To determine which nitrogen carried the cinnamoyl group, ( - )N-methylanabasine was hydrogenated and the mixture of epimers was reacted with trans-cinnamoyl chloride. The mixture of amides was separated by chromatography. One of the amides was the enantiomorph of trans-Nmethylastrophylline, prepared by N-methylation of the alkaloid followed

cxxv

3 %

q CXXVI

CHO CXXVII

CXXVIII

12.

496

THE PYRIDINE ALKALOIDS

by thermal isomerization, thus confirming structure CXXVI for astrophylline. It may be noted that astrophylline is a dihydroisoorensine. Since the absolute stereochemistry of ( + )-a,P-dipiperidyl is known (186),structure CXXVI represents the absolute configuration of astrophylline.

XV. Nudiflorine Leaves of Trewia nudijlora L., a member of the Euphorbiaceae, were found t d contain a cyanopyridone alkaloid nudiflorine (CXXIX), C7HsNz0 (mp 161°),reniiniscent of the pyridone alkaloid riciniiie (XCV) (187, 188). Hydrolysis of nudiflorine gives nudifloric acid (CXXX). Treatment of coumalic acid methyl ester (CXXXI) with ammonia N

C

H

n

N

I

CH3 CXXIX

O

O

O

C

n

N

I

flcN

M e O O c n O

0

N'

I

0

CH3

CH3

cxxx

0

CXXXI

CXXXII

followed by hydrolysis gave 6-oxonicotinic acid which on N-methylation yielded l-methyl-2-pyridone-5-carboxylic acid (CXXX), identical with the acid derived from nudiflorine. Nudifloric acid was transformed into nudiflorine in the usual manner. Nudiflorine was also prepared by oxidation of 3-cyanopyridine methosulfate with potassium ferricyanide. I n this case nudiflorine (CXXIX) was the minor product, the isomeric ricinidine (CXXXII) being formed in lapger amounts (188). XVI. Homostachydrine Stachydrine from Medicago sativa (L.) Grimm was found to be contaminated with homostachydrine, C ~ H I ~ O which ~ N , was isolated as the hydrochloride (mp 216"-217" decomp.; [.In -13.3' in ethanol) by chromatography of crude stachydrine hydrochloride on cellulose powder (189).The structure CXXXIII was proven by methylation of the silver

/\

Me Me CXXXIII

496

W. A. AYER A N D T. E. HABOOOD

salt of ( - )-pipecolic acid to give ( - )-homost,achydrinehydrochloride identical with natural material (190, 191).

XVII. Anibine The South American rosewood, A n i b a duclcei Kostermans and Aniba rosaodora Ducke, family Lauraceae, contains an alkaloid, anibine, C11HgN03 (mp 179"-180" ; picrate, mp 199"-201" ; hydrochloride, mp 205"-230" decomp. ; methiodide, mp 233"-236") shown to have structure CXXXIV (192). Saponification of anibine with potassium hydroxide

cxxxv

CXXXIV

CXXXVI

results in formation of the dipotassium salt CXXXV which on acidification spontaneously decarboxylates to give the known 1- (3'-pyridyl)butane-l,3-dione (CXXXVI). This transformation, together with a consideration of the functionality of anibine, led to structure CXXXIV for the alkaloid. The synthesis of anibine was achieved (193)by condensation of 3-acetylpyridine with the 2,4-dichlorophenyl diester of benzylmalonic acid t o give 3-benzyl-4-hydroxy-6-(3'-pyridyl)-t~-pyronewhich Methylation of was debenzylated t o Li-hydroxy-6-(3'-pyridyl)-a-pyrone. the latter compound with diazomethane gave anibine.

XVIII. Julocrotine I n 1925 Anastasi reported (194)the isolation of a crystalline alkaloid, jujocrotine (mp 105") from Julocroton montevidensis Klotzsch (family Euphorbiaceae) and assigned to it the formula C19HZGN203. Djerassi and co-workers have reexamined this plant (195)and isolated a substance (mp 108"-109"; ["ID -9" in chloroform), which is presumably the sameas

12.

NHCOCH(CHs)CH&Ha 00

I

497

THE PYRIDINE ALKALOIDS

0

NHCHzCH(CHa)CHzCH3

I

CHzCHzCeHs

CHzCHzC6Hs CXXXVII

CXXXVIII

Anastasi's julocrotine. Analytical results were more in accord with the formula C18H24N203. On the basis of results which are summarized briefly below, structure CXXXVII has been assigned to julocrotine. The compound is nonbasic and fails to form salts. It shows IR-absorption bands a t 3413, 1736, 1686, and 1503 cm-1 characteristic of an glutarimide and a secondary amide and it shows simple aromatic absorption in the UV-spectrum. On hydrogenation julocrotine takes up 3 moles of hydrogen to give a hexahydro compound which no longer shows aromatic absorption. LiAlH4 reduction gives the diamine CXXXVIII, ClaH30N2 (dipicrate, mp 186'-187"). The loss of the three oxygen atoms with the simultaneous generation of two basic nitrogens is in accord with the presence of both an amide and an imide in julocrotine. Hofmann degradation of the methiodide of CXXgVIII gave styrene and the base CXXXIX. Acid hydrolysis of julocrotine gave ( + )-a-methylbutyric acid, ,8-phenylethylamine, and L-( + )-glutamic acid, which together NHCOCH(CHa)CH&H3

NHCOCH(CH3)CH&H3

HN I CHzCHzC6H5

I

CXLI

CXLII

CXLIII

498

W. A. AYER AND T. E. HABGOOD

account, for all the atoms of julocrotine. Alkaline hydrolysis of julocrotine brought about opening of the imide and led to two isomeric acids, C18H26N204, julocrotic acid-A and julocrotic acid-B, formulated as CXL and CXLI, respectively. Confirmation of structure CXXXVII was obtained by synthesis of julocrotic acid-A (CXL) via the amide CXLII. Hydrolysis of synthetic CXLII was accompanied by rearrangement (arrows, CXLIII) and gave, after ring opening, julocrotic acid-A (CXL).

XIX. Halfordia Alkaloids The principal alkaloid of the bark of Halfordia scleroxyla is a quaternary base, CzoH2304Nz+, isolated as the picrate (mp 143" or 198") which may be converted into the perchlorate (mp 148" or 206")and the chloride (mp 210" decomp.) by anion exchange. Pyrolysis of the chloride, N methylhalfordinium chloride (CXLIV), gave the corresponding free base, halfordine (CXLV) (mp 163"-164") as well as the dehydration product, halfordinone (CXLVI) (mp 132"-133") and the phenolic base, halfordinol (CXLVII) (mp 255"-256"). Halfordine, halfordinone, and halfordinol were also found among the tertiary bases isolated from the plant (196, 197).

CH3 CXLIV

CXLV; R = -CH2-CHOH-C(OH)(CH3)2 CXLVI; R = --CH~-CO-CH(CH~)Z CXLVII; R = H

Acid hydrolysis of halfordine (CXLV) gave halfordinol (CXLVII) as well as acetone, 1-hydroxy-3-methyl-2-butanone, and isopropanol. This, coupled with the finding that periodate oxidation of halfordine gives acetone and an unstable nitrogen-containing aldehyde, served to establish the structure of the side chain. Oxidation of O-methylhalfordinol gave anisic acid and nicotinamide, accounting for the two nitrogen atoms and all the carbon atoms except one. This carbon atom was located when it was found that vigorous catalytic hydrogenation of halfordinol (CXLVII) methochloride gave the amide CXLVIII, the structure of which was verified by synthesis. I n order to account for the lack of carbonyl absorption in halfordine and halfordinol and at the

12.

499

THE PYRIDINE ALKALOIDS

same time to account for the formation of the amide CXLVIII the incorporation of an oxazole ring was required. Further evidence for the structures proposed was obtained by a study of the NMR-spectra of the alkaloids (197) and by a comparison of the mass spectrum of halfordin01 with that of 2,5-diphenyloxazole (198).

e NH-

CH2

I bH3

CXLVIII

XX. Monoterpenoid Alkaloids Containing a Pyridine or Piperidine Ring I n the past few years several pyridine and piperidine alkaloids of obvious terpenoid origin have been encountered and will be reviewed here. Since many of the sesquiterpenoid alkaloids have been reviewed elsewhere in this treatise (Volume I X , Chapter 10)they have not been included.

A. ACTINIDINE Actinidine, C ~ O H (bp ~ ~ 100"-103"/9 N mm ; [aID -7.2" in chloroform ; picrste, mp 143'), has been isolated from Actinidia polygama Miq. (199). Both actinidine (CXLIX) and nietatabilactone (dihydronepetalactone) (CL), isolated from the same plant, have an excitatory effect on cats. Actinidine shows the spectral properties and color tests expected of a

(AQ

i"v

CH3 CXLIX

C

H

CH3 CL

q

CH3 CLI

substituted pyridine and on permanganate oxidation gives 5-methylpyridine-3,4-dicarboxylicacid and the tertiary alcohol CLI. Treatment of actinidine N-oxide with hot acetic anhydride gave the acetoxy compound CLlI which was hydrolyzed and oxidized to a ketone, indicating

W. A. AYER AND T. E. HABQOOD

500

the attachment of a methylene group a t the 7-position of the pyridine ring. Structure CXLIX for actinidine was confirmed by synthesis from nepetalinic acid .iniide (CLIII) (199). Treatment of CLIII with phosphorus pentachloride gave the dichloro compound CLIV which on

‘Ip

r^’cB,

(y+ c1

AcO

CH3 CLII

CH3

CH3

CLIII

CLIV

reduction in the presence of palladium-charcoal gave actinidine. In another synthesis (ZOO)of actinidine, ethyl ~-(3-methyl-2-oxocyclopenty1)propionate was transformed to the cyanohydrin and dehydrated to the isomers CLV which on hydrolysis yielded the dihydroxypyridine

iy,

()/+

COOEt

0

OH

CH3 CLV

g

CH3 CLVI

CLVII

CLVI. Treatment of CLVI with phosphorus oxychloride gave CLIV. dl-Actinidine obtained by hydrogenation of CLIV was resolved by means of dibenzoyl-1-tartaric acid. The absolute configuration a t C-7 in actinidine has been established (201) by synthesis of d-actinidine, the enantiomorph of the natural product, from ( + )-pulegone (CLVII). Methyl pulegenate (CLVIII), derived from ( + )-pulegone, was subjected to ozonolysis and the resulting ketone was condensed with ethyl cyanoacetate and then methylated to give CLIX. Hydrolysis of CLIX gave optically active CLVI. Transformation of CLVI to CLIV as before and hydrogenation gave d-actini-

&

$CH3

COOCH3

COOEt CH3

CLVIII

CLIX

CLX

12.

501

THE PYRIDINE ALKALOIDS

dine, showing that natural 1-actinidine has the absolute configuration shown in CLX. A quaternary alkaloid isolated (202) from the roots of Valeriana oficinalis L. as the chloride, ClsHzzNOCl (mp 201"-203" decomp.; [a],, +50.5" in methanol) has been shown to be N-/3-(p-hydroxypheny1)ethylactinidinium chloride (CLXI). Pyrolysis of CLXI gives I-actinidine (CLX) hydrochloride and, according to mass spectral evidence, phydroxystyrene. CH3 I

CH3

bH3

CLXII

CLXI

B. SKYTANTHINE The structure CLXII was proposed almost simultaneously by two groups (203, 204) for the alkaloid obtained from the Chilean Skytanthus acutus Meyen, a member of the Apocynaceae. Skytanthine, CllHzlN (bp 54"/1.5 mm (203),62Oll.5 mm (204);[a],,+42" in chloroform),forms a picrate (mp 135"-136"), a picrolonate (mp 210°-218"), and a niethiodide (mp 296"-298"). Dehydrogenation gives a 3,4-disubstituted pyridine ClOHlSN which was shown to be identical with racemic actinidine (CXLIX). Skytanthine methiodide underwent Hofmann degradation to give a basic methine (CLXIII) ozonolysis of whichgave formaldehyde

$:(CH3)2

e R N ( C H d z

2)3: :% 2

CHI CLXIII

CH3 CLXIV

CLXV

and the ketone CLXIV. The ketone gave iodoform when treated with hypoiodite. Oxidation of CLXIV with peroxytrifluoroacetic acid gave an acetate (CLXV; R = A c ) which was saponified t o the alcohol (CLXV; R = OH) and oxidized with Jones's reagent t o the ketone which showed typical cyclopentanone absorption (1745 em-1) in the IR-spectrum (203). Skytanthine has been shown to be a mixture of three diastereoisomers, E - , /3-, and 6-skytanthine (205,206).The t ~ - ,p-, y , and ti-nepetalinicacids

502

W. A. AYER AND T. E. HABOOOD

(stereoisomers of structure CLXVI) of known relative and absolute stereochemistry were reduced to diols, tosylated, and condensed with methylamine to give a - , p-, y , and a-skytanthine (CLXVII a , CLXVII p, etc.) (205).The picrate of natural skytanthine proved to be identical with P-skytanthine (CLXVII p). Gas chromatographic analysis of the

CLXVI

CLXVII a

CLXVII

p

bases regenerated from the mother liquors of skytanthine picrate revealed the presence of a-skytanthine (CLXVII a ) a,nd a-skytanthine (CLXVII 6) as well as P-skytanthine.

CLXVII y

CLXVII 6

CLXVIII

Two minor alkaloids have been isolated from S. acutus (207).Deliydroskytanthine, C11H1gN (picrate, mp 127"),has a methyl group located on a fully substituted double bond and gives &skytanthine (CLXVII 6) on hydrogenation. Dehydroskytanthine must be one of the double bond isomers CLXVIII. The NMR-spectrum of the second minor alkaloid, a hydroxyskytanthine C11H21NO (mp 93"), reveals the presence of the

v

groupings CH-CH3, CH3-C-OH, and N-CH3. Since the alcohol gives dehydroskytanthine (CLXVIII) on dehydration, i t must bcl one of the two possible methyl carbinols. It has been shown that mevalonic acid is a biogenetic precursor of skytanthine (208,209).

C. TECOMANINE AND TECOSTANINE Two alkaloids having the actinidine skeleton, tecomanine and tecostanine, have been isolated from Tecoma stans Juss. Tecomanine (210), C11H17NO (bp 125"/0.1 mm; ["ID -175" in chloroform), forms a picrate (mp 179.5"-180.5") and a methiodide (mp 240"-242" decomp,). The UV-spectrum (ymax226 mp, log E 4.10) and the IR-spectrum (1700,1620

12.

o

q

-

C

H

CH3 CLXIX

s

503

THE PYRIDINE ALKALOIDS

@-':€I3

&-C& CHzOH

CHzOH CLXX

CH3

CLXXI

cm-1) indicate an a$-unsaturated cylopentenone. The NMR-spectrum reveals the presence of one olefinic proton, an N-methyl group, and two secondary C-methyl groups. On catalytic hydrogenation over palladiumcharcoal in ethanol, dihydrotecomanine, which shows cyclopentanone absorption of 1740 cm-l, is formed. Catalytic hydrogenation of tecomanine over platinum in acetic acid gave a mixture of saturated ketones which were reduced by the Huang-Minlon method to a mixture of three bases which on dehydrogenation gave dl-actinidine (CXLIX). Tecomanine is therefore CLXIX. Huang-Minlon reduction of dihydrotecomanine gave a base (picrate, mp 152"-153") which must be one of the eight possible stereoisomers of skytanthine but which is not identical with any of the four synthetic skytanthines CLXVII. Tecostanine (ZU),CilHzlNO (mp 82"; 0 2'; methiodide, mp 245"),is inert to hydrogenation. Its NMR-spectrum shows the presence of an N-methyl, a secondary C-methyl group, and a primary alcohol. Tecostanine was converted to desoxytecostanine (picrate, mp 143") via the tosylate and hydride reduction. Desoxytecostanine gave dl-actinidine (CXLIX) on dehydrogenation ;thus tecostanine must be either CLXX or CLXXI. Mass spectral evidence indicates that the hydroxymeth yl group is attached to the piperidine ring and hence structure CLXX is preferred for the alkaloid. Desoxytecostanine must be a stereoisomer of skytanthine but it is not identical with any of the skytanthines CLXVII or with the desoxy base prepared from dihydrotecomanine. REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10.

A. Chatterjee and C. P. Dutta, Sci. Cult. (Cnlcutta) 29, 568 (1963). A. Chatterjee and C. P. Dutta, Tetrahedron Letters 1797 (1966). C. K. Atal and 8. S. Banga, Current Sci. ( I n d i a )32, 354 (1963); C A 59,15329(1963). J. P. Wibaut and M. I. Hirschel, Rec. Truw. Chim. 75, 225 (1956) (and references cited therein). M. Ohta and Y. Isowa, Nippon Kagnku Zasshi 80, 688 (1959); C A 55, 3635 (1961). K. Hess and A. Eichel, Ber. 50, 1192 (1917). R. L. Augustine, J. Am. Chem. Soc. 81, 4664 (1959). S. Kuwata, Bull. Chem. SOC. J a p a n 33, 1672 (1960). P. I. Mortimer, AustralianJ. Chem. 11, 82 (1958). H. Hess and A. Eichel, Ber. 50, 1386 (1917).

504

W. A. AYER AND T. E. HABGOOD

S. Kuwata, Bull. Chem. SOC.Jnpan 33, 1668 (1960). R. E. Gilman and L. Marion, Bull. Soc.Chim. France 1993 (1961). G. Drillien and C. Viel, Bull. SOC. Chim. France 2393 (1963). H. C. Beyerman and L. Maat, Rec. Trav. Chim. 82, 1033 (1963). F. Galinovsky, G. Bianchetti, and 0. Vogl, Monatsh. 84, 1221 (1953). H. C. Beyerman and L. Maat, Rec. Trav.Chim. 84, 385 (1965). C. Schopf, F. Braun, K. Burkhardt, G. Dummer, and H. Muller, Ann. 626, 123 (1959). 18. J. H. Wisse, H. de Klonia, and B. J. Visser, Rec. Traw. Chim. 83, 1265 (1964). 19. H. Tuppy and M. S. Faltaous, Monatsh. 91, 167 (1960). 3967 (1957). 20. P. I. Mortimer and S. Wilkinson, J . Chem. SOC. 21. B. Franck, Ber. 91, 2803 (1958). 22. K. L. Khanna, A. E. Schwarting, and J. M. Bobbitt, J . Pharm. Sci. 51,1194 (1962). 23. C. Schopf, T. Kauffmann, P. Berth, W. Bundschuh, G. Dummer, H. Fett, G . Habermehl, E. Wieters, and W. Wiist, Ann. 608, 88 (1957). 24. B. Franck, Angew. Chem. 70, 269 (1958). 25. H. C. Beyerman, J. Eenshuistra, and W. Eveleens, Rec. Trav.Chim. 76, 416 (1957). 26. H. C. Beyerman, J. Eenshuistra, W. Eveleens, and A. Zweistra, Rec. Trav. Chim. 78, 43 (1959). 27. H. C. Beyerman, L. Maat, A. Van Veen, A. Zweistra, and W. von Philipsborn, Rec. Trav.Chim. 84, 1367 (1965). 28. G. Fodor and G. A. Cooke, Tetrahedron Suppl. 8, Part I, 113 (1966). 29. H. Wieland and M. Ishimasa, Ann. 491, 14 (1931). 30. H. Wieland, W. Koschara, E. Dane, J. Renz, W. Schwaree, and W. Linde, Ann. 540, 103 (1939). 31. C. Schopf, W. Bundschuh, G. Dummer, T. Kauffmann, and R. Kress, Ann. 628, 101 ( 1959). 32. C. Schopf, G. Dummer, W. Wust, and R. Rausch, Ann. 626 134 (1959). 33. R. Tschesche, K. Kometani, F. Kowitz, and G. Snatzke, Ber. 94, 3327 (1961). 34. R. Lukei, J. Kloubek, K. Blhha, and J. KovhZ, Collection Czech. Chem. Commun. 22, 286 (1957). 35. B. Franck, Ber. 91, 2803 (1958). 36. €3. Franck, Ber. 92, 1001 (1959). 37. B. Franck, Ber. 93, 2360 (1960). 38. F. Horak, Chem. Zvesti 17,795 (1963); CA 60, 9099 (1964). 39. A. Ebnother, Helw. Chim. Acta 41, 386 (1958). 40. C. Schopf and E. Schenkenberger, Ann. 682, 206 (1965). 41. C. Schopf, E. Muller, and E. Schenkenberger, Ann. 687, 241 (1965). 42. D. Bellus, 0. Liska, and .F. Horak, Chem. Zwesti 18, 90 (1964); CA 61, 1903 (1964). 43. W. Parker, R. A. Raphael, and D. I. Wilkinson, J . Chem. SOC.2433 (1959). 44. R. H. F. Manske, Can. J . Res. B16, 445 (1938). 45. M. G. Chaubal, R. M. Baxter, and G . C. Walker, J . Pharm. Sci. 51, 885 (1962). 46. F. Kaczmarek and E. Steinegger, Pharm. Acta Helv. 33, 852 (1958). 47. M. M. Robison, W. G. Pierson, L. Dorfman, B. F. Lambert, and R. A. Luces, J . Org. Chem. 31, 3206 (1966); Prelim. commun., Tetrahedron Letters 1513 (1964). 48. M. M. Robison, B. F. Lambert,, L. Dorfman, and W. G. Pierson, J. Org. Chem. 31, 3220 (1966). 49. M. M. Robison, W. G. Pierson, L. Dorfman, and B. F. Lambert, J. Org. Chem. 31, 3213 (1966). 50. D. M. Clugston, D. B. MacLean, and R. H. F. Manske, Can. J . Chem. 45,39 (1967). 11. 12. 13. 14. 15. 16. 17.

12. THE

PYRIDINE ALKALOIDS

505

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207. C. G. Casinovi, F. Delle Monache, G. Grandolini, G. B. Marini-Bettolo, and H. H. Appel, Chem. & Ind. (London)984 (1963). 208. C. G. Casinovi, G. Giovanni-Sermanni, and 0. B. Marini-Bettolo, Gazz. Chim. Ital. 94, 1356 (1964). 209. M. A. Luchetti, Ann. 1st SuperSanita 1, 563 (1965); CA 65, 9349 (1966). 210. G. Jones, H. M. Fales, and W. C. Wildman, Tetrahedron Letters 397 (1963). 211. Y. Hammouda, M. Plat, and J. Le Men, Bull. Sac. Chim. France 2802 (1963). ADDENDUM The following pertinent papers have appeared since the time of writing of this chapter and are included here in order to bring the bibliography to date as of November, 1967. Kh. A. Aslanov, S. Z. Mukhamedzhanov, and A. S. Sadykov, “Chemical Studies of Anabasis aphylla seeds.” Nauchn. Tr., Tashkentsk. Gas. Univ. 286, 71 (1966); CA 67, 73730 (1967). H. Auda, H. R. Juneja, E. J. Eisenbraun, G. R. Waller, W. R. Kays, and H. H. Appel, ‘‘ Biosynthesis of methylcyclopentane monoterpenoids. I. Skytanthus Alkaloids.” J . Am. Chem. Sac. 89, 2476 (1967). G. W. K. Cavil1 and A. Zeitlin, “Synthesis of D-( +)-tecostidine and related actinidine derivatives.” Australian J . Chem. 20, 349 (1967). J. Cuzin, “Alkaloid-like compounds in tobacco smoke.” Abhandl. Deut. Akad. Wiss. Berlin, KZ. Chem., Geol. Biol. 141 (1966); CA 66, 92491 (1967). M. Dymicky and R. L. Stedman, “Composition studies on tobacco. XXV. Moieties in a high-molecular-weight smoke pigment : alkaloids and a silicone.”Phytochemistry 6,1025 (1967). M. M. El-Olemy and A. E. Schwarting, “Simulated biosynthesis of some pyrrolidine and piperidine alkaloids of Withania somnifera.” Abhandl. Deut. Akad. Wiss. Berlin, K1. Chem., Geol. Biol. 137 (1966); CA 66, 85902 (1967). J. W. Fairbairn, “Variations in the alkaloidal pattern in developing fruits of Conium maculatum and Papaver somniferum.” Abhandl. Deut. Akad. Wiss. Berlin, Kl. Chem., Geol. Biol. 141 (1966); C A 66, 83045 (1967). J. Fleeker and R. U. Byerrum, “Incorporation of glyceraldehyde into the pyridone ring of nicotine.” J . Biol. Chem. 242, 3042 (1967). E. Leete, “Alkaloid biosynthesis.” Ann. Rev. Plant Physiol. 18, 179 (1967). E. Leete and N. A. Chaudhury, “Biosynthesis of the hemlock alkaloids. 11.The conversion of y-coniceine to coniine and ybconhydrine.” Phytochemistry 6, 219 (1967). M. Pa. Lovkova, “Biosynthesis of nicotine.” Izv. Akad. Nauk SSSR, Ser. Biol. 413 (1967); CA 67, 29832 (1967). T. M. Jackanicz and R. U. Byerrum, “Incorporation of aspartate and malate into the pyridine ring of nicotine.” J . Biol. Chem. 241, 1296 (1966). Y. Kaburaki, S. Mizusaki, and E. Tamaki, “y-Methylaminobutyraldehyde,a new intermediate in nicotine biosynthesis.” Arch. Biochem. Biophys. 117, 677 (1966). T. Kisaki and E. Tamaki, “Phytochemical studies on tobacco alkaloids. X. Degradation of tobacco alkaloids and their optical rotatory changes in tobacco plants.” Phytochemistry 5 , 293 (1966). G. Neurath and M. Duenger, “N-Nitroso compounds from tobacco alkaloids.” Be&. Tabakforsch. 3, 339 (1966); CA 67, 64605 (1967). G. J. H. Rall, T. M. Smalberger, H. L. de Waal, and R. R. Arndt, “Dimeric piperidine alkaloids from Azima tetracantha Lam. : Azimine, azcarpine, and carpaine.” Tetrahedron Letters 3465 (1967).

510

W. A. AYER AND T. E. HABGOOD

H. Rapoport, “Biosynthesis of the pyridine and piperidine alkaloids. The tobacco alkaloids.” Abhnndl. Deut. Akad. Wiss. Berlin, K l . Chem., Geol. Biol. 111 (1966); C A 66, 73203 (1967). M. F. Roberts, B. T. Cromwell, and D. E . Webster, “Occurrence of Z-(Z-propenyl)A 1-piperideine in the leaves of pomegranate (Punica granatum).” Phytochemistry 6, 711 (1967). H. B. Schroeter, “Enzymic synthesis of tobacco alkaloids.” Abhandl. Deut. Akod. Wiss. Berlitb, K l . Chern., Geol. Biol. 157 (1966); C A 66, 83181 (1967). H. B. Schroeter and D. Neumann, “N-Methylornithine as precursor of the pyrrolidine ring in Nicotine.” Tetrahedron Letters 1279 (1966). H. Smogrovicova, 0. Spetkova, and A. Jindra, “Biochemistry of Lobelia alkaloids. ” Abhandl. Deut. Akad. Wiss. Berlin, K1. Chem., Geol. Biol. 147 (1966); C A 66, 83123 (1967) T. C. Tso, “Biochemical studies on tobacco alkaloids. VII. Biosynthesis of alkaloids Phytochemistry 5, 287 (1966). triply labeled with 14C, 3H, and 15”’. K. S. Yang, R. Triplett, K. S. Klos, and G. R. Waller, “Chemical synthesis of 1% labeled ricinine and biosynthesis of ricinine in Ricinus cornrnunis.” Proc. Oklahoma Acad. Sci. 46, 142 (1966); C A 67,41082 (1967). D. Yoshida and T. Mitake, “Agmatine and N-carbamylputrescine as intermediates in the formation of nicotine by tobacco plants.” Plant Cell Physiol. (Tokyo) 7,301 (1966); C A 65, 17382 (1966).

AUTHOR IM)EX Numbers in parentheses are reference numbers and indicate that an author’s work is referred to, although his name is not cited in the text. Numbers in italics show the page on which the complete reference is listed. Albright, J. D., 15(37), 35, 182(55), 186 A Abduazimov, Kh. A., 319(54, 55, 56, 57, Ali, M. S., 15(87), 35 58, 60, 61), 320(61), 334(82), 346(56, Aliev, Ya. Yu.;481(107), 506 96, 97, 98, 99, 100, 101), 347(96), 382 Allayarov, Kh. A., 319(58, 60), 386(60), 402 (61), 386(60), 402, 403 Abdurahman, N., 207(8), 226(8), 228(8), Allen,D. S., Jr., 436(48), 457 Alves, A. C . , 9(19), 34 303 Abdurakhimova, N., 25(138), 38, 112(43, Alworth, W. L., 485(138), 507 44), 113(44), 114(58), 115(58), 122, Amai, R. L. S., 45(6), 47(6), 54(6), 70, 86 123, 151(30), 162(30), 165(30), 186, (32), 98 Amarasingham, R. D., 251 (79a), 306 241 (76a), 306 Aminuddin, M., 29(172), 39 Abdusrtlamov, B., 10(23), 34 Abdusamatov, A., 319(57, 61), 320(61), Amjad Ali, M., 15(37), 35 Anastasi, G., 496(194), 508 382(61), 402 Abraham, D. J., 18(67), 25(135), 36, 38, Anderson, E. L., 174(45), 186 59(58), 65(58), 7 I , 101(24a), 120(24a, Anet, F. A. L., 27(168), 39, 66(65), 7 2 Ang, S. K., 50(26a), 70 84,88), l 2 1 , 1 2 3 , 1 2 4 , 2 3 0 ( 7 2 d ) , 305 Achenbach, H., 9(19), 20(89, 90, 91), 23 Antonaccio, L. D., 16(55a), 17(62), 18(55a), 35, 36, 45(9), 70, 210(28), (114, 116), 34, 37, 52(29), 59(29), 71, 213(28), 303 126(3), 127(3), 128(9), 129(9), 142, 143, 206(4, 6) 208(19d, 61a), 210(4, Aono, A., 326(72), 402 31, 79), 213(6,49), 215(19d), 228(19d, Aplin, R. T., 373(141), 404 61a), 246(4, 79), 247(31, 79), 252(4), Appel, H. H., 501(205), 502(205,207), 508, 509 254(4, 791, 279(6, 49), 292(6), 294(6), Archer, D. A., 398(170), 405 303, 304, 305, 306 Acton, E. M., 279(90), 306 Arigoni,D., 2,4(2), 33,45(4), 70, 79(4), 97, Adityachaudhury, N., 221 (Ma), 305 126(2), 142 Adler, E., 474, 505 Armstrong, J. G., 105(26), 121, 230(72a), Aguayo, B. J., 212(40), 304 305 Aguilar-Santos, G., 23(115), 24(115, 121), Arndt,R.R., 17(59a, 61), 27(170),31(170), 25(157, 158), 37, 38, 39, 80(13), 97 36, 39, 147(10), 150(10), 185, 212(34, Agurell, St., 318(52), 319(52), 402 42), 214(42), 215(34, 42), 269(34), Agwada, V., 18(65), 25(65), 36, 96(52), 97 270(34), 304, 509, (53), 98, 211(85), 213(85), 215(98), Arojan,A. A., 481(101), 506 265(85), 268(85), 295(85), 296(85), Asher, J. D. M., 134(28), 143, 148(21),186 302 (85,98), 306 Aslanov, Kh. A., 10(23), 34, 481(110) 506, Ahmad, U. U., 15(37), 35 509 Ahmed,Z. F., 318(51), 319(51), 386(51), Atal, C. K., 460(3), 461(3), 487(152), 503, 401 507 Alashev, F. D., 481 (104), 506 Atta-ur-Rahman, 230(72e), 305 511.

512

AUTHOR INDEX

Auda, H., 509 Augustine, R. L., 461 (7), 503 Autrey, R. L., 184(67),187 Avramova, B., 409(5), 456 Awad, A. T., 14(36a), 35 Azim-ul-Mulk, S., 29(172), 39 Ayer, W. A., 16(58), 36, 210(35), 211(35), 260(35), 304

B Baarschers, W. H., 27(170), 31(170), 39 Bailey, A. S., 66(65), 7 2 Bailey, D. T., 315(33), 401 Baker, A. J., 447(53), 450(53), 457 Balasubrahmanyan, S. N., 482(118), 506 Balasubramanian, M., 12 (30a), 34 BalenoviE, K., 475 (65), 505 Balikdjian, M., 56(38), 7 1 Ban, Y., 146(1), 171(41, 42), 178(48), 179 (49, 49a), 182, 185, 186, 222(67), 305 Banga, S. S., 460(3), 461(3), 503 Barks, P. A., 422 (39),429 (39), 430 (39), 457 Barnes, A. J., Jr., 25 (149), 39, 100(17), 101(17), 106 (30), 107(30),121, 122 Bartlett, M. F., 19(74, 75), 20(74), 36, 45(6), 46(22), 47(6), 50(26c), 54(6), 56(26c), 59(46, 62), 65(46), 70, 71, 72, 83(25), 86(25, 32), 98, 127(7), 130(7), 135(33), 142, 143, 190(3), 204 Barton, D. H. R., 316(45, 46), 348(103), 350(103), 351 (103), 392(45, 103), 394 (45), 395(45), 396, 398(45, 46, 171, 172), 399(45), 401, 403, 405 Barton, J. E. D., 128(8), 143, 207(7), 225 (7), 226(7, 69), 303, 305 Battersby,A. R., 1(1),2, 4, 15(37),19(81), 26(161), 33(3a), 33, 34, 35, 36, 39, 45 (4), 53(35), 70,71,79(2,3), 97,121 (go), 124, 126(2), 142, 194(5), 204, 255(80, 82), 256(SZ), 257(82), 258(80, 82), 259(82), 260(82), 306, 317(47), 392 (47, 153, 154, 156, 158), 393(47, 158), 394(47), 395(47), 398(153, 168, 169, 170), 401, 404, 405, 433(47), 434(47), 450, 452(61, 62, 63, 64), 453 (64), 455 (47, 64, 68, 69), 457 Bauer, S., 130(14), 143 Baxter, R. M., 470(45), 504

Bayha, C., 222, 223 (68), 305 Beak, P., 45(6), 47 (6), 54(6), 70,86(32), 98 Beal, J. L., 14(36a), 19(71), 24(118), 35, 36, 38, 52(28), 58(28), 71, 80(9, 12), 83(12), 92(9), 95(9), 97, 120(87), 124 Beckett,A. H., 29(173), 30(176, 177, 178), 39, 40, 148(19, 19a), 151(19), 162(19, 19a), 184(64, 65, 66), 185, 187 Bedwell, D. R., 100(13), 107(13), 121, 139 (45), 143 Beitner, A., 350(105), 403 Belikov, A. S., 16(50), 35, 131(16), 143 Belleau, B., 449, 457 Bellet, M. P., 431 (45), 457 Bellus, D., 469(42), 504 Benington, F., 323(69), 324(69), 402 Benoin, P. R., 16(56b), 36, 183(58), 187, 214(55d), 215(55d), 305 Bentley, R., 450(67), 457 Bergoeing, R., 23(105), 37, 159(26), 186 Bernauer, K., 8(83), 20(82a, 83), 36, 37, 206(1), 209(1, 26), 215(26), 223(26), 235(26), 242(1), 244(77), 303, 306 Beroza, M., 489 (168), 507 Berth, P., 462(23), 464(23), 465(23), 466 (23), 467 (23), 468(23), 504 Besch, E., 200(13), 204 Beugelmans, R., 25(137), 38, 52(31), 71, 73(1), 74(1), 7 7 , 112(45), 122 Bevan, C. W. L., 19(77), 36, 136(36), 143 Beyerman, H. C., 462(14, 16), 463(25, 26, 27), 465 (25, 26), 476 (71), 504, 508 Bhacca, N., 288(94), 306 Bhakuni, D. S., 15(37),35 Bianchetti, G., 462 (15), 504 Bianchi, E., 501 (206), 508 Biemann, K., 9(19), 16(44, 47), 17(63), 20(89,90,91),23(111),26(164), 34,35, 36, 37, 39, 47(23, 24), 48(23), 50 (23, 24), 58(43), 61 (43), 65(43), 70, 71, 94 (48), 98, 102(8, 9), 116(65, 66), 121, 123, 126(3), 127(3), 128(9), 129(9), 142, 143, 196(8), 197(8, l l ) , 198(11), 199 (ll),204, 206(3,3a, 4, 6), 208(66), 209(23, 29), 210(4, 29, 31, 79), 213 (6, 49), 214(52), 215(29, 66), 221(66), 230(3, 72), 233 (23, 29), 235 (23), 236,

AUTHOR INDEX 237(73), 246(4, 79), 247(31, 79), 248 (31), 249 (29), 250(29), 251 (79a), 252 (a), 254(4, 79), 270(23), 279(6, 49, 52), 292(6), 294(6), 303, 304, 305,

D b

513

Bon, R. D., 11(24), 34 Bonati, A., 46(22), 7 0 Booth, H., 379 (146), 404 Bose, A. K., 23(117), 25(139, 145), 38, 39,

B\\’%,i%\\% \?I\, 3%

\Q%\Y&\,

Biernert, M., 339(91a), 345(94a), 385(94a), 112(47), 121, 134(27), 137(39), 143, 403 209(21, 22), 231(22), 233(21, 22), Biglino, G., 478(86), 505 303 Binks, R., 2(3a),4(3a), 33(3a), 34,317(47), Bosley, J., 26(164), 39 392(47, 154), 393(47), 394(47), 395 Botyos, G., 127(6), 142 (47), 398(168, 170), 401, 404, 405, 450 Bouquet, A., 487 (159), 507 (62, 64), 452 (62,64), 453 (64), 455 (64), Boyer, N. E., 480(100), 506 457 Bozjanov, B., 119(80a), 123, 183(62), Bisset, N. G., 26(164, 165, 166), 39 187 Bite, P., 46(22), 70 Bradshev, C. K., 171(43), 186 BlBha, K., 25(142), 38, 109(37), 110(37), Braekman, J. C., 56 (38), 7 1 122, 132(24), 143, 207(9a), 208(11), Brandon, R. L., 426(42), 457 210(9a), 220(11), 221(11), 303, 466 Brauchli, P., 27(170), 31(170), 39 (34), 481 (101, 102), 504, 506 Braun, F., 462(17), 490(172), 495(186), Blomster, R. N., 18(67),25(134, 135, 136), 504,508 36, 38, 52(32a), 59(57, 58), 65(58), Bressler, H., 495 (186), 508 67(32a), 71, lOl(23, 24a), 102(4), Breuer, S. W., 317(47), 392(47, 158), 393 120(23, 24a, 81, 82, 84, 85, 88), 121, (47, 158), 394(47), 395(47), 398(168, 123, 124, 212(42b), 230(72d), 304, 169, 170), 401, 404, 405 Briggs, C. K., 339(91), 345(91), 403 305 Blossey, E. C., 16(52), 17(52), 35, 212(40), Bright, A., 80(8), 97, 501 (205), 502(205), 304 508 Bobbitt, J. M., 462 (22), 487 (152, 153, 154), Bringi, N. V., 45(6), 47(6), 54(6), 70, 86 504, 507 (32), 98, 137(39), 143 Boder, G . B., 106(29), 122 Brissolese, J. Aguayo, 16(52), 17(52), 35, Bodiei, S. E., 483(123), 486(123), 506 113(52), 119(80), 122, 123 Bodmer, F., 15(41), 20(92), 35, 37, 67(71), Britten, A. Z., 285(91), 306 72, 129(11), 143, 206(5), 213(5), Brown,C.L., 321(64),331(64,78),333(78), 292(5), 294(5), 295(5), 303 338(78), 402 Boekelheide, V., 200(14), 204 Brown, K. S., Jr., 16(52, 56a), 17(52, 60), 35, 36, 211(36, 37), 212(40), 213(50), Boit, H.-G.,3,4(10), 14(10), 3 4 , 3 0 9 ( 8 , lo), 310(11, 16), 311(11, 18, 22), 312(11, 219(37), 260(36), 261(36), 263(37), 18, 22, 23), 313(18, 23, 24), 314(24, 265(37), 279(37, 50), 304 30, 32), 315(32, 34), 317(24, 32), 318 Brown, R. T., 2(3), 4(3), 25(143), 33, 39, 45(4), 70, 79(2, 3), 84(28), 97, 98, 106 (10, 24), 320(18), 322(8, 24), 332(24), (31), 107(31), 122, 126(2), 142, 148 333(8,24), 335(83), 340(92), 347(102), (15), 149(15), 150(15), 152(15), 185 349(24), 350(105), 360(32), 363(11, 18, 23, 30, 32, 122, 123), 364(24, 32), (76), 185, 187, 227(69b, 69c), 230(70), 365(18, 22), 370(92), 373(23, 32), 375 305 (24), 381(23, 24, 92), 384(11, 16, 24), Brown, S. H., 17(59a), 36, 212(34), 215 (34), 269(34), 270(34), 304 385(10, 24, 30), 386(16, 22), 400, 401, 403, 404 Brown, W. W., 25(134), 38, 59(57), 71, Bombardelli, E., 46(22), 70 120(82),123 Bommer, P., 47(23), 48(23), 50(23), 70, Bubeva-Ivanova, L., 313(25), 315(38),351 102(8), 116(66), 121, 123 (108, log), 352(109), 401, 403

514

AUTHOR INDEX

Buchanan,G.L.,420(33), 421(33),422(33), 425, 426 (33), 456 Buchanan, R. L., 447(53), 450(53), 457 Buckley, J. P., 18(67), 36, 101(24a), 120 (24a), 121 Budzikiewicz, H., 18(66), 20(86), 25(146), 27(170), 28(171), 31(170), 36, 37, 39, 42(11), 45(9), 47(11), 52(11), 70, 75 (6), 76(6), 77, 96(51), 97(54), 98, 113 (52), 116(61), 118(77),- 119(80), 120 (61), 122, 123, 131(17, 20), 143, 151 (31), 162(31), 164(31), 186, 213(46), 219(63), 233(63), 237(75, 76), 239 (76), 241(75, 76), 285(92), 288(94), 295(46), 296(46), 302(46, 97), 304, 305, 306, 373(141), 404, 422(40), 423 (41), 424(41), 457 Buchel, K. H., 476(72), 479(95), 480(95), 505, 506 Buchi, G., 88(35), 89(38), 93(45), 94(45), 95(45), 98, 102(7, 9), 120(86), 121, 123,230 (727, 305 Bukreeva, E. V., 117(74), 123 Bu’Lock, J. D., 3(9), 34 Bundschuh, W., 462(23), 464(23), 465 (23, 31), 466(23), 467(23), 468(23), 504 Burkhardt, K., 462(17), 504 Burlingame, A. L., 47(23, 24), 48(23), 50 (23,24), 58(43), 61(43), 65(43), 70, 71, 116(65, 66), 123, 339(91a), 358(117), 403 Burnell, R. H., 16(56b, 58), 36, 183(58), 187, 260(35), 211(35), 213(55e), 214 (55d), 215(55d, Me), 260(35), 279 (55e), 304, 305 Burnett, J. P., Jr., 105(26), 121 Butsugan.Y., 499(199),500(199,200,201), 508 Buzas, A., 15(38), 35 Bycroft, B. W., 8(78), 17(59), 19(78), 20 (93), 36, 37, 105(11), 121, 137(38), 143,207(59), 208(19b), 209(19b), 211 (59), 212(38), 217(19b, 59, 60, 61), 218(19b, 59), 219(59, 60, e l ) , 244(59), 245(19b, 601, 269(38), 270(59), 303, 304, 305 Byerrum, R. U., 483(124, 125, 126, 128), 484(131, 132, 135), 496(191), 506, 507, 509

Byrne, J. C., 19(81), 36, 255(80, 82), 256 (82), 257(82), 258(80, 82), 259(82), 260(82), 306 Byuskyulev, B., 118(76a, 76b), 123

C Camerman, A., 85(29), 98, 207(58), 218 (58), 219(58), 220(58), 305 Cemerman, N., 85(29, 30), 98, 105(12), 121, 207(56, 57, 58), 218(58), 219(58), 220(58), 305 Cammarato, L. V., 102 (4), 121 Campello, J., 16(52), 17(52), 35, 212(40), 304 Campion, J. E., 415(20, 22), 444(20, 22), 456 Carlson, R. M., 383(151), 404 Carrazzoni, E. P., 16(52), 17(52, 59a), 35, 36, 212(34, 40), 215(34), 270(34), 304 Casa, D. D., 213(55e), 215(55e), 279(55e), 305 Casanova, C., 487 (156), 507 Casinovi, C. G., 26(166), 39, 501 (204, 206), 502(207, 208), 508, 509 Cassady, J. M., 19(69), 23(69), 36, 80(22), 83(22), 98 Cava, M. P., 14(36a), 19(71, 72, 73), 23 (113), 24(118), 35, 36, 37, 38, 52(28), 58(28), 59(55), 65(45), 71, 80(9, 12), 83(12), 91(39), 92(9), 94(46), 95(9), 97, 98, 120(87), I24 Cavill, G. W. K., 509 Cekan, Z., 208(14,17), 303 Cereghetti, M., 25 (l46), 39, 237 (76), 239 (76), 241 (76), 306 Ceriotti, G., 387 (152), 404 Eervinka, O., 479(93), 505 Cetenko, W. A., 183(59), 187 Chan,K. C., 31(183), 40, 151(33, 33a), 162 (33, 332-4, I86 Chan, T. H., 488(166), 489(166, 167), 507 Chapman, O.L., 57(39), 71,422(36,37,39), 426 (36,43), 428(37), 429,430(39), 456, 45 7 Charean, N., 23(105), 37 Chatterjee, A,, 13(33), 15(41, 42), 16(43, 44, 45, 47), 19(79), 35, 36, 146(6, 7), 150(6, 7), 185, 209(23, 29), 210(29), 214(52), 215(29), 221(66a), 233(23,

AUTHOR INDEX 29), 235(23), 249(29), 250(29), 270 (23), 279(52), 303, 304, 305, 460(1, 2), 461 (l),495 (187, 188),503, 508 Chatterjee, B. G., 137(39), 143 Chaubal, M. G., 470(45), 504 Chaudhury, N. A., 509 Chaveau, N., 159(26), 186 Chiavarelli, S., 66(66), 7 2 Chow, Y. L., 487(157), 507 Christman, D. R., 483(120, 122), 484(136), 485(140), 506, 507 Clements, J. H., 455(69), 457 Clugston, D. M., 472, 504 Coffen, D. L., 89(38), 98 Cohen, T., 396, 405 Coke, J. L., 491(177, 181), 492(181), 508 Collera, O., 80(11),81 (ll),97 Combes, G., 21(99), 37, 184(69), 187 Comes, R. A., 182(54), 186 Cone, N. J., 25(151), 39, 58(51, 52), 7 1 , 84(27), 86(27), 98, 102(3, 9), 121, 226 (69a), 230(72, 72c), 305 Cooke, G. A., 464(28), 477(28), 504 Corral, R. A., 17(64), 36, 42(7), 45(7), 52(7), 53(7), 70, 214(51a), 215(51a), 304, 496 (195), 508 Cox,D. A., 422(38), 429, 430(38), 457 Craig, J. C., 478(88), 480(88), 505 Cretney, W. J., 228(69d), 305 Crews, 0. P., 279(90), 306 Cromwell, B. T., 476 (70), 505, 510 Cross, A. D., 417(26), 420(26, 34, 351, 421(26, 34, 35), 426(34), 431(26), 432 (35), 456 Crow, W. D., 498(196, 197), 499(197, 198), 508 Crowder, J. R., 311(21), 317(21), 360(21), 361(21), 363(21), 365(21), 401 Cruickshank, P. A., 74(4), 77 Culvenor, C. C. J., 11(24), 34 Cuzin, J., 509

D D’Adamo, A., 483 (122), 506 Dalev, P., 24(132), 38, 117(72), 123 Dalmer, H., 316(41, 42), 321(42), 322(42), 325 (41), 352 (42), 401 Damratoski, D., 102(4), 121 Dane, E., 464(30), 504

515

Das, B. C., 16(44, 47), 24(126), 27(169), 35, 38, 39, 59(60), 67(60), 72, 112 (48), 122, 208(54, 65b), 209(23, 29), 210(29), 215(29, 55a), 221(54, 65b), 233(23,29), 235(23), 249(29j, 250(29), 270(23), 303, 304, 305, 492(183), 493 (183), 508 Das, K. G., 23(117), 25(145), 38, 39, 108 (33a), 121, 209(21, 22), 231(22), 233 (21, 22), 303 Dastoor, N. J., 16(54a), 35, 215(55c), 279 (55c), 305 Dauben, W. G., 422(38), 426(43), 429, 430 (38), 457 Dave, K. G., 169(38), 174(38), 186 Davidson, T. A., 447 (53), 450 (53), 457 Dawson, R. F., 483(120, 122), 484(136), 485 (140), 506, 507 Day, A. C., 447(53), 450(53), 457 Deb, A., 19(79), 36 Defay, N., 25(155), 39, 53(37), 56(37), 57 (37), 59(37), 71 de Klonia, H., 462(18), 504 Delaroff, V.,, 420(32), 421 (32), 456 Delle Monache, F., 501 (206), 502(207), 508,509 Demanczyk, M., 22(102), 37, 48(20), 53 ( Z O ) , 54(20), 7 0 Denayer-Tournay, M., 25 (155), 39, 53 (36), 57(36), 59(36), 60(36), 65(36), 71 de Neys, R., 25(155), 39, 53(37), 56(37), 57(37), 59(37), 71 Denolin-Dewaersegger, L., 57 (40), 71 Deulofeu, V., 27(170), 31(170), 39, 212 (41), 304 Devi, V., 319(53), 402 Devissaguet, J. P., 25(152), 39 de Weal, H. L., 509 Dewey, L. J., 484(131), 507 Deyrup, J. A., 58(51), 7 1 , 1 9 4 , 2 0 4 Dezelic, M., 480(98), 506 Dickel, D. F., 83(25), 86(25), 98 Dieterich, D., 480 (96), 506 Diszler, E., 46(22), 7 0 Djerassi, C., 8(53), 16(14, 52, 53, 53a, 54, 55), 17(52, 5313, 59a, 60, 61, 62), 18 (68), 20(85), 24(124, I%), 25(146), 27 (170), 28(171), 31(170), 33(14), 34, 35, 36 37, 39, 42(11), 45(9), 47(11), 52 (11, 32), 70, 71, 75(6), 76(6), 77, 96

516

AUTHOR INDEX

(51), 97(54), 98, 113(52), 116(61), 118 (77), 119(80), 120(61), 122, 123, 131 (17, 20), 143, 147(10), 148(20), 150 (lo), 151(20, 31), 155(20, 23), 158 (23), 162(31), 164(31), 185, 186, 206 (2), 208(12), 211(12, 37), 212(2, 12, 34, 39, 40, 42), 213(12, 43, 46), 214 (2, 12, 42, 51, 53), 215(12, 34,42, 55b), 219(37, 63), 228(12), 229(12), 233 (63), 237(75, 76), 239(76), 241(75, 76), 260(12), 263(37), 265(37),269(12, 34), 270(12, 34), 271(2, 12, 39), 273(43, 87), 276 (43), 278 (43), 279 (37, 51), 285(2, 53, 92), 295(46), 296(46), 302 (46, 97), 303, 304, 305, 306, 373(141), 404, 422(40), 423(41), 424(41), 457, 496 (192, 195), 501 (203), 508 Dopke, H., 324(70), 402 Dopke, W., 25(140), 38, 309(8,9), 310(11), 311(11, 18, 20,22), 312(11, 18, 20,22, 23), 313(18, 20, 23, 24), 314(24, 30, 31, 32), 315(32, 34), 316(9, 41, 42, 43, 44), 317(24, 32, 48), 318(24), 320 (18, 44, 62), 321(42, 43), 322(8, 24, 42), 323(9), 325(31, 41), 332(24), 333(8, 9, 24, 79), 337(31), 339(91a), 345(94a), 347(102), 349(24), 350(105), 352(42), 354(48), 360(32, 48), 363 (11, 18, 20, 23, 30, 31, 32, 48), 364 (24, 32, 125), 365(18, 22), 373(20, 23, 32), 375(24), 381(23, 24), 384(11, 24, 48), 385(24, 30, 43, 44, 94a), 386(22, 62), 400(175), 400, 401, 402, 403, 404, 405 Dolby, L. J., 41(3), 50(26b), 70, 74(3), 77, 135(32), 143 Doleji, L., 25(142), 38, 101(25), 109(37), 110(37), 121, 122, 208(11), 220(11), 221(11), 303 Dolfini, J. E., 131(14a), 143 Dominguez, J., 490(170, 171), 508 Dorfman, L., 470(47), 471(48,49), 504 Douglas, B., 19(71, 72), 23(113, 113a), 36, 37, 52(28), 58(28, 50, 54), 59(50, 55, 56), 65(45, 54), 67(54, 56), 71, 80(9), 92(9), 94(46), 95(9), 97, 98, 120(87), 124, 174(45), 186, 302(99), 306 Draus, F. J., 101(23), 120(23), 121, 212 (42b), 304 Drillien, G., 462 (13), 504

Dry, L. J., 310(12), 384(12), 401 Duarte, A. P., 16(52), 17(52, 59a), 35, 36, 212(34,40), 215(34), 269(34),270(34), 304 Dubois, J., 56(38), 71 Dubravkova, L., 109(40),122,208(15), 220 (15), 303 Dudek, G. O., 65(45), 71, 94, (46) 98 Duenger, M., 509 Duffield, A. M., 373(141), 404 Dugan, J. J., 208(65a), 221(65a), 246(78), 254(78), 305, 306 Dummer, G., 462(17, 23), 464(23), 465(23, 31, 32), 466(23), 467(23), 468(23), 504 Durham,L. J., 16(14,56), 17(56),24(124), 33(14), 34, 35, 38, 45(9), 70, 96(51), 98, 116(61), 120(61), 123, 131(17), 143, 155(23), 158(23), 160(27), 186, 210(33), 213(46), 214(51), 219(63), 233 (63), 237 (75, 76), 241 (75, 76), 254(33), 255(33), 273(87), 279(51), 288 (94), 295 (46), 296 (46), 302 (46), 304, 305, 306 Dutschevska, H., 117(72), 123 Dutta, C. P., 460 (1, 2), 461 (l),503 Dwyer, J. D., 99(2), 121 Dymicky, M., 509

E Ebnother, A., 469(39), 504 Edwards, 0. E., 113(50), 122 Eenshuistra, J., 463 (25, 26), 465 (25, 26), 504 Egli, C., 50(26a), 70 Egnell, C., 15(38), 35 Ehmke, H., 309(10), 318(10), 335(83), 340 (92), 363(123), 370(92), 381(92), 386 (lo), 400, 403, 404 Eichel, A., 461 (6, lo), 503 Eilertsen, R., 183(60), 187 Eisenbraun, E. J., 501 (205), 502(205), 508, 509 Eisner, A., 482(117), 506 El-Gangihi, S., 409(1), 410(1), 414(1), 432 (l),436 (l),455 El-Hamidi, A., 409(1, 7), 410(1), 414(1), 417(26), 420(26, 35), 421(26, 35), 431 (7, 26), 432 (1, 35), 436 (1, 7), 455, 456 El-Olemy, M. M., 487 (155), 507, 509

AUTHOR INDEX Emerson, T. R., 146(3), 185 Endo, Y., 444(51), 457 Englert, G., 8(83), 20(82a, 83), 36, 37, 206 (l),209(1, 26), 215(26), 233(26), 235 (26), 242 (l),303 . Ensfellnw, L., 475(66), 505 Ernest, I., 169(39a), 186 Eschenmoser, A., 438(49), 457 Essery, J. M., 486(148), 507 Evelleens, W., 463(25, 26), 465(25, 26), 504

F Fairbairn, J. W., 473(54), 474(58),505,509 Falco, M., 24(126), 38, 52(30), 65(30), 7 1 , 110(42), 112(42), 122 Pales, H. M., 308(1), 309(5), 310(13, 17), 311(17, 21), 313(5, 17, 27), 317(21, 47), 323(66), 330(66), 331(66), 350 (106), 354(111), 355(115), 356(5), 358 (115, 117), 359(115, 118), 360(21, 118), 361(21), 362, (120, 121), 363 (21, 124), 364(124), 365(21), 370(17), 371 (115), 374(27), 375(27), 378(5), 379 (115, 147), 385 (5), 392 (47, 153, 156), 393(47), 394(47), 395(47), 398 (153, 168, 169), 399(173), 400(174), 400, 401, 402, 403, 404, 405, 502(210), 509 Falshaw, C. P., 100(14), 121, 209(20a), 230 (ZOa), 303 Faltaous, M. S., 462(19), 504 Farnsworth, N. R., 18(67), 25(134, 135, 136), 36, 38, 52(32a), 59(57, 58), 65 (58), 67(32a), 71, lOl(23, 24a), 102 (4, 5), 120(23, 24a, 81, 82, 84, 85, 88), 121, 123, 124, 212(42b), 230(72d), 304, 305 Farrier, D. S., 339(91a), 403 Fehlhaber, H. W., 472(52), 473(52), 505 Fehlmann, M., 200(15), 204 Feinstein, A. I . , 392(159), 393(159), 395 (159), 404 Fejer-Kossey, O., 478(87), 505 Fellion, E., 24(126), 38, 52(30), 65(30), 71, 110(42), 112(42), 122, 215(55a), 304

51 7

Ferrari, C., 16(51), 35, 211 (61b), 215(6lb), 228 (61b), 305 Ferreira, J. M., Filho, 16(55, 56, 56a), 17(56, 59a), 35, 36, 210(33), 211(36), 212(34), 215, 254(33), 255(33), 260 (36), 261(36), 269(34), 270(34), 304 Ferreira, M. A., 9(19), 34, 102(6), 121 Ferretti, L. D., 450(66), 457 Fett, H., 462(23), 464(23), 465(23), 466 (23), 467(23), 468(23), 504 Figueiredo, A. de A., 16(56a), 36, 211 (36), 260(36), 261 (36), 304 Fikenscher, L. N., 477(81), 505 Finch, N., 113(52), 119(79, 80), 122, 123, 146(3), 174(4), lS0(4), 185 Fischer, A. G., 392(155), 393(155, 161), 394(155,161, 165), 395(161, 166), 404, 405 Fish, F., 25(159), 39, 52(34), 71, 80(18), 92(18), 97 Fleeker, J., 483 (125), 506, 509 Flores, S. E., 16(52), 17(52, 59a), 35, 36, 212(34, 40), 215(34), 237(75, 76), 241 (75, 76), 269(34), 270(34), 304, 306 Floss, H. G., 487(160), 507 Fodor, G., 464(28), 477(28), 504 Fonzes, L., 21(99), 37, 184(69), 187 Foote, C., 368(131), 379(131), 404 Forbes, E. J., 417(25), 456 Franck, B., 462(21), 463(24), 465(24), 468(35, 36, 37), 469(37), 478(35), 504 Francois, P., 1(l),33 Frei, E., 111, 105(26), 121 Frey, A. J., 48(25), 70 Friedlin, L. Kh., 481 (107), 506 Friedman, A. R., 483(119, 127), 485(119, 127), 506 Friedrich, G., 475(67), 505 Frigot, P., 477(80), 505 Fritsch, G., 320 (62), 386 (62), 402 Fritz, H., 23(112), 37, 95(49), 98, 138(41), 139(41), 140(41), 143, 200(13), 202 (16), 203(17), 204 Fu, F. Y., 488(164), 507 Fuganti, C., 387(152), 404 Fujino, A., 499(199), 500(199, 200, 201), 508 Fukuda, D. S., 230(72b), 305

518

AUTHOR INDEX

Fukumoto, K., 2(5), 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142 Funke, P., 25(145), 39, 108(33a), 122, 209 (21, 22), 231(22), 233(21, 22), 303 Fylypiw, W. M., 18(67), 36, 101(24a), 120 (24a), 121

Goh, J.,22(101), 37,42(19),47(19),52(19), 53 (19), 70 Gol’dfarb, Ya. L., 481 (104), 506 Goldman, L., 15(37), 35, 182(55), 186 Goldman, N. L., 478(88), 480(88), 505 Gonzalez Gonzalez, A., 487 (156), 507 Goodman, L., 279(90), 306 Goosen, J., 313(28), 401 Goossen, A., 310(15), 401 G Gordon, J. E., 415(22), 444(22), 456 Galeffi, C., 26(166), 39 Gornian, A. A., 16(54a), 18(65), 26(65), Galinovsky, F., 462 (15), 504 35, 36, 96(52), 97(53), 98, 211(85), Ganguli, G., 214(52), 221(66a), 279(52), 213(85), 215(55c, 98), 237(74a), 245 304,305 (74a), 265(85), 268(85), 279(55c), 295 Garbarino, J. A., 501 (204, 206), 508 (85), 296(85), 302(85, 98), 305, 306 Garbutt, D. F. C., 318(50), 343(50), 344 Gorman, M., 25(136, 147, 148), 38, 39, 47 (50), 401 (24), 50(24), 52(32a), 58(48, 49, 51), Garcia, F., 80(11), 81(11), 97 65(49), 67(32a, 49), 70, 71, 84(27), 86 Gardner, P. D., 426(42), 457 (27), 92(42, 43), 98, 100(22), 101(18), Gamier-Gosset, J.,24(126, 127), 38,52(30), 102(9), 105(26, 28), 106(29, 30), 107 59(60), 65(30), 67(60), 71, 72, 110 (22, 28, 30), 116(65), 120(28, 83, 85, (42), 112(42, 48), 122 89), 121, 122, 123, 124, 139(44), 143, Gaskell, A. J., 212(39a), 271 (39a), 304 148(14), 150(14), 185, 226, 230(72, Gemenden, C. W., 8(39, 40), 15(39,40,41), 72b), 237(75), 241(75), 305, 306 22(102), 35, 37, 48(20), 53(20), 54 Gosset, J., 111(49), 122 (20), 67(69, 70, 71), 69(70), 70, 72, Gosset-Garnier, J., 111(49), 122 119(79), 123, 146(4), 177(4), 180(4), Gottlieb, 0. R., 496(192), 508 Goutarel, R., 23(105), 37, 73(2), 77,87(34), 185,213(44), 288(44), 304 Gerard, D., 431 (454, 457 98, 118(76), 123, 159(26), 186, 492 Gheorghiu, A., 315 (37), 401 (183), 493(183), 508 Gholson, R. K., 483(121, 123), 486(123, Govindachari, T. R., 16(46), 19(80), 23 151), 5d6, 507 (117), 35, 36, 38, 80(21), 83(21), 98, Ghosal, S., 11(25), 34 146(5), 150(5), 185, 208(84), 306, 475 Ghosh-Oastidar, P. P., 15(37), 35 (64), 487(163), 491(175, 172:, ,505 Gilbert, B., 16(14, 52, 53a, 54, 55, 55a, 56), 507, 508 17(52, 53a, 56, 62), 18(55a), 33(14), Grade, K., 308, 400 34, 35, 36, 45(9), 52(32), ro, 71, 113 Graham, J., 313(28), 401 (52), 119(80), 122, 123, 160(27), 186, Grandolini, G., 502(207), 509 206(2), 210 (28, 33), 212(2, 34, 39, Grdinic, M., 200(14), 204 40), 213(28), 214(2), 215(34), 254 Gregory, B., 1 ( l ) , 33 (33), 255(33), 269(34), 270(34), 271 Gregory, H., 19(81), 36, 255 (80, 82), 256 (2, 39), 273(87), 285(2), 303, 304, (82), 257(82), 258(80, 82), 259(82), 260(82), 306 306 Gilbert, F. B., 17(59a), 36 Griffith, T., 483(124, 126, 128), 484(135), Gilbertson, T. J., 484(137), 485(137, 142), 506,507 507 Grob, K., 478(90), 505 Groeger, D., 9(15), 10(22), 25(144), 33 Gilman, R. E., 461, 462 (12), 504 Giovanni-Sermanni, G., 502 (208), 509 (14a), 34, 39, 100(14), 102(6), 121, 209(20a), 230(20a), 303 Goeggel, H., 2(2), 4(2), 33, 45(4), 70, 79 Gros, E. G., 484(137), 485(137, 142), 507 (4), 97, 126(2), 142

AUTHOR INDEX Grossert, J. S., 26(163), 39, 196(8, 9), 197 (8, I l ) , 198(11), 199(11), 204 Grundon, M. F., 476(73), 505 Guggisberg, A., 19(80): 27(167), 36, 39, 194(4), 204, 208(84), 237(74a), 245 (74a), 255(81), 256(81), 257(81), 258 (81), 305, 306 Guillen-Escalante, N., 45 (8), 7 0 Guise, G. B., 23(109, 110), 25(110), 37, 80(14), 81(14), 83(14), 84(14), 92(14), 97, 213(95), 306 Gupta, R. N., 472(51), 505 Gurevich, H., 113(51), 122

519

Haynes, H. F., 127(5),142 Hegnauer, R., 3 (7), 34 Heimer, N. E., 331(78), 333(78), 338(78), 402 Hellman, K. P., 483 (124), 506 Hellmann, H., 480(96), 483(124), 128), 506 Henderson, L. M., 486(144, 145, 147), 507 Hendrickson, J. B., 368(131), 379(131), 404 Herbert, R. B., 433(47), 434(47), 450(63), 452 (63), 455 (47, 69), 457 Herran, J., 80(11), 81(11), 97 Hess, H. G., 461, 474(57), 505 Hess, K., 461 (6), 503 H Hesse, M., 3, 4(12), 8(39, 40, 78), l4(12), Haack, E., 15(37), 35 15(39, 40, 41), 18(65), 19(76, 78), 20 Habermel, E., 462(23), 464(23), 465(23), (76, 88, 92), 25(65), 26(162), 27(167), 466 (23), 467 (23), 468 (23), 504 31(182), 34, 35, 36, 37, 39, 40, 52(33), Hadwiger, L. A., 483(123), 486(123, 151), 67(69, 70, 71), 69(70), 71, 72, 82(6), 507 96(52), 97(53), 97, 98, 119(80a),123, Haglid, F., 169(38), 174(38), 186 129(11), 135(30, 31), 136(34, 37), 137 Hagwitz, R. D., 373 (140), 404 (37, 38), 243, 147(8), 148(22), 150(8), Haines, P. G., 482(117), 506 183(56, 62, 63), 185, 186, 187, 190(1), Hall, E. S., 2(5), 4(5), 34, 45(4), 70, 79 191(1), 193(1), 194(4), 199(12), 204, (4), 97, 126(2), 142 206(5), 208(65a), 209(30, 30a), 211 Hammouda, Y., 503(211), 509 (85), 213(5, 44, 85), 214(30, 30a), Hamoda, Y., 326(72), 402 215(30, 30a, 98), 221(65a), 255(81), Hamouda, F. M., 318(51), 319(51), 386 256 (81), 257(81), 258(81), 265(85), (51), 401 268 (85), 285(93), 288(44), 291(93), Hanson, J. R., 2 ( 5 ) , 4(5), 34, 45(4), 70, 292(5), 294(5), 295(5, 85), 296(85), 79(4), 97, 126(2), 142 302 (85, 98), 303, 304, 305, 306 HanuB, V., 25(142), 38, 109(37), 101(25), Highet, P. F., 308(1), 339(91), 345(91), 110(37), 121, 122, 208(11), 220(11), 358(116), 364(126), 372(139), 379 221 ( I l ) , 303 (145), 381(126), 400, 403, 404, 491 Happert, C. A., 484(134), 507 (180), 492 (180), 508 Hargrove, W. W., 102(9), 105(27), 121, Highet, R. J., 309(6), 312(6), 315(6), 317 230(72), 305 (47), 319(6), 345(91), 354(111), 358 Harley-Mason, J., 128(8), 143, 207(7), (116, 117), 364(126), 372(139), 381 225(7), 226(7, 69, 69e), 230(72e), (126), 382(6), 383(6), 392(47), 393 (47), 394(47), 395(47), 398(169), 400, 303, 305 Harris, D. R., 19(77), 36, 136(36), 143 401, 403, 404, 405, 491 (179, 180), 492 Hart, N. K., 31 (181), 40 (179, 180), 508 Hauth, H., 309(4), 310(4, 141, 311(19), Hilinski, I. M., 102(5),121 354(14, 113), 362(4), 363(14), 381(19), Hill, R. D., 450(65), 452(65), 457 382(19), 384(14), 385(4, 14, 19), 400, Hill, R: K., 327, 328(75), 383(151), 402, 404,474,475),488(166),489(166,167), 401, 403 Hawksworth, W. A., 336(85), 403 505, 507 Hagashi, R., 444(51), 457 Hirose, T., 370(136), 379(136), 404 Habee., G. F., 426(42), 457 Hirschel, M. I., 461 (4), 503

520

AUTHOR INDEX

Hodgkin, J. H., 498(196, 197), 499(197, 198),508 Hodson, H. F., 194(5),204 Hoffmannova, J., 208(17),303 Hofmann, A., 48(25),70 Holker, J. S. E., 147(11),185 Holubek, J., 3, 4(12a), 14(12a), 34, 134 (27),143 Honti, K., 169(37),181 (51),186 Hootele, C., 18(68),36, 80(7,20),97, 98 Horak, F., 469(38, 42),504 Horn, D. H. S., 310(17),311(17), 313(17), 370(17),401 Horowitz, R . M., 418(31), 456 Hoshaku, H., 482(116), 506 Hrbek, J., Jr., 408(2),411(2),412(2), 413 (Z), 417(26),418(28),419(28),420(26),

421(26),431(26),433(2),434(2),455 (2),455, 456 Hsiu-Chu Hsu, I., 146(4), 177(4), 180(4), 185 Hsu, I. H., 119(79),123 Huang, H.-I., 13(32),35 Huckstep, L. L., 25(151),39,230(72c),305 Hurzeler, H., 15(41), 35, 67(71), 72, 213 (44),288(44),304 Huffman, J. W., 91(40),98 Hugo, J. M., 26(163), 39, 196(8, 9), 197 (8), 204 Humber, L. E., 323,402 Hung,S.-H., 315(39),316(39),386(39),401 Hunt, M. E., 42(5),45(5), 7 0 Huynh, C., 445(52),457

I Iacobucci, G. A., 12(30),34 Ibuka, T., 321 (64a),402 Iida, M., 478(85),505 Ikeda, T., 370(137),404 Inoue, I., 182,186, 222(67), 305 Inubushi, Y . , 309(5),313(5), 356(5), 378 (5),385(5),400 Ionescu-Matiu, E., 315(37),401 Iris, H., 321(64a), 361 (119),367(127, 130), 370(135,136),379(136,144), 402, 404 Isametova, A. I., 481(log),506 Ishimasa, M.,464(29),465(29),504 Isowa, Y., 461(5), 503 Ito, A., 367(127),404

Ivanov, V., 14(36),35, 313(25), 315(38), 401, 409(5), 456 Ivashchenko, S. P., 16(50),35,131(16),143 Iyer, R.S . , 137(39), 143

J Jackanicz, T. M., 509 Jackson, A., 271 (86b), 306 Jaeggi, K. A., 87(33),98 Jaggi, H., 66(67),7 2 Jakovljevic, I. M., lO2(6),121 Janda, M., 477(75),505 Janot, M.-M., 1(1), 20(85,86,87),24(126, 127), 25(137, 146), 28(171), 33, 37, 38, 39, 42(10, ll),47(10, Il), 52(11, 31),59(60,63,64),66(64),67(60),7 0 , 71, 72, 73(1,2), 74(1), 75(5), 76(6), 77, 87(34), 98, 111(49), 112(45, 48), 116(61), 118(76), 120(6l), 122, 123, 131(17, 20), 143, 150(25), 151(31), 159(25), 162(31), 164(31), 186, 195

(7),204,219(63),233(63),237(75,76), 239(76), 241 (75, 76), 285(92), 305, 306, 487(159),507 Jansen, C . J., 230(72a), 305 Jarboe, C. H., 482(115),506 Jaret, R.S., ZZ(lOO), 37, 148(13), 183(57), 185,187 Jeffrey, G. A., 302(99), 306 Jeffs, P. W., 313(28,29),318(50),336(84, 85), 338(88), 339(91a), 343(50), 344

(50), 345(88), 370(29), 373(140), 392 (29),401, 403, 404 Jennings, J. P., 418(28),419(28),456

Jindra, A., 510 Johns, S. R., 9(17), 12(28), 13(31), 27 (170a). 31(180, 181), 34, 35, 39, 40,

151(36), 166(36), 183(61), 185(75), 186, 187, 486(149),507 Johnson. A. W., 480(99), 506 Johnson, I. S., 105(26),106(29),107(30), 121, 122, 148(14), 150(14), 185, 230 (72a),305 Johnson, L. F., 501(203),508 Johnstone, R.A. W., 477(76), 505 Jones, G., 502(210),509 Jordan, W., 20(84),37, 148(18), 151(18), 155(18), 185, 213(47), 215(47), 279 (47),304

AUTHOR INDEX

Joshi,B. S., 15(41),23(117),35,38,67(71), 72, 80(21), 83(21), 98, 213(44), 288 (44), 304 Joson,L.M., 24(121), 38,80(13), 97 Joule, J. A., 8(53), 16(14, 52, 53, 53a, 54), 17(52, 53a), 33(14), 34, 35, 52(32), 71, 206(2), 212(2, 3, 9, 39a, 40, 53), 214(2), 271(2, 39, 39a, 86b), 273(87), 285(2, 53), 303, 304, 306, 327(75), 328 (75), 402, 489(166), 507 Juby, P. F., 486(146, 148), 507 Juneja, H. R., 509

K KablicovQ, Z., 132(24), 143 Kaburaki, Y., 509 Kackac, B., 169(39a), i86 Kaczmarek, F., 470(46), 504 Kahovec, L., 373(143), 378(143), 404 Kaisin, M., 56(38), 71 Kamikawa, T., 487 (162), 507 Kamiya, T., 91 (40), 98 Kan, C., 28(171), 39, 75(5, 6), 76(6), 77 Kanaoko, Y., 222(67), 305 Kapil, R. S., 2 ( 3 ) ~4(3), 15(37), 33, 35, 79(2), 97, 121(90), 124, 126(2), 142 Kaplan, M., 226(69e), 305 Karimov, M., 481(110), 506 Karlstrom, K . I. C., 483(120), 506 Karns, T. K . B., 482(111), 506 Karrer, P., 19(76), 20(76), 26(162), 27 (167), 36, 39, 136(34), 143, 190(1), 191(1), 194(4, 6), 199(12), 204, 285 (93), 291 (93), 306 Kaschnitz, R., 9(18), 19(18), 34, 131(15), 143, 151(35), 165 (35), 186, 213(48), 214(48), 215(48), 221 (66a), 279(48), 290(48), 304, 305 Kasymov, Sh. Z., 24(129, 132), 38, 114 (56, 57), 115(56, 57), 122 151(29), 162 (29), 165(29), 184(74), 186, 187 Kato, A., 321 (64a), 402 Kauffmann, T., 462 (23), 464 (23), 465 (23, 31), 466 (23), 467 (23), 468 (23), 504 Kaul, J. K., 25 (139), 38

521

Kaul, J . L . , 4 2 ( 1 2 , 13), 46(12, 13), 70, 112 (46, 47), 122, 408(4), 411(4), 412(4), 431(4), 435(4), 456 KavkovB, K., 208(14), 303 Kays, W. R., 509 Kerigan, A., 85(30), 98, 207(56), 305 Kernweisz, P., 100(21), 120(21), 121, 137 (40), 139(40), 143, 212(42c), 304 Kerr, A., 146(4), 177(4), 180(4), 185 Kessel, J. W., 24(122), 38, 81(14a), 84 ( 1 4 4 , 97 Khaleque, K . A., 29 (172), 39 Khamidkhodzhaev, S. A., 319(59), 402 Khan, N. H., 15(37), 35 Khan, Z. M., 20(88), 37, 52(33), 71, 135 (30), 143, 148(22), 186, 209(30, 30a), 214(30, 30a), 215(30, 30a), 304 Khanna, K . L., 462(22), 487(152), 504, 507 Kholy, I. El., 131(18), 143 Khoshoo, T. N., 412(17), 456 Khuong-Huu, Q., 492, (183),493 (183), 508 Kiang, A. K., 22(101, 102), 37, 42(19), 47 (19), 48(20), 52(19), 53(19, 20), 54(20, 27), 59(27), 70,136(35), l43,251(79a), 306 Keilar, E. A., 311(21), 317(21), 354(111), 360(21), 361(21), 363(21), 365(21), 401, 403 Kihara, Y., 333(80), 402 K i n g , F . E . , 379(146), 404, 474(63), 505 King, R. W., 57(39), 71, 373(142), 404, 422(36, 37), 426(36), 428(37), 456, 457 King,T. J., 474(63), 480(99), 505, 506 Kinstle, T. H., 321 (64), 331 (64), 402 Kirby, G. W., 316(45, 46), 348(103), 350 (103), 351(103, 107), 392(45,103), 394 (45), 395(45), 398(45, 46, 171, 172), 399(45), 401, 403, 405 Kirkpatrick, J. L., 58 (54), 65 (54), 67 (54), 71, 174(45), 186, 302(99), 306 Kiryukhin, V. K., 481 (105, 106), 506 Kisaki, T., 480 (97), 506, 509 Kishi, T., 8(39, 40), 15(39, 40), 35, 67(69, 70), 69(70), 72 Kitagawa, M., 16(56), 17(56), 35, 210(33), 254(33), 255(33), 304 Kitagawa, T., 342(93), 343(94), 370(93), 403 Kitayama, U., 370(136), 379(136), 404

522

AUTHOR INDEX

Kloclen, D., 472(52), 473(52), 505 Klos, K. S., 510 Kloubek, J., 466(34), 481(102), 504, 506 Klyne, W . , 105(11), 121, 146(3), 185, 207 (59), 211(59), 217(59, 61), 218(59), 219(59, 61), 244(59), 270(59), 305, 418(28), 419(28), 456 Knight, J. A., 2(3), 4(3), 33, 45(4), 70, 79 (3), 97, 126(2),142 Kobashi, Y., 478 (89), 482 (116), 505,506 Kobayashi, M., 327 (73), 402 Kobayashi, S., 352(110), 403 Koch, K., 426(43), 457 Koch, M., 27(169), 39, 487(159), 507 Kocsis, K., 89(38), 98 Koizumi, J., 352 (110), 403 Kometani, K., 465(33), 466(33), 467 (33), 504 Kompis, I., 25(142), 38, 109(34, 35, 36, 38), 110(35,36), 122, 130(14), 131(19, 23), 132(23), 143, 184(72), 187, 208 (10, 13, 15, 19c), 214(52), 215(19c, 22a), 220(13, 15, 65), 221(13, 65), 233 (22a), 279(52), 303, 304, 305 Kondo, H., 323(67), 402 Koo, W.-Y., 11 (24a), 34 Koop, H., 495(186), 508 Koretskaya, N. I., 114(71), 123 Korobko, V. G., 291 (96), 306 Korte, F., 476(72), 479(94, 95), 480(94, 95), 505, 506 Koschara, W., 464(30), 504 Kotera, K., 321 (64a),323(67), 326(72),327 (73, 74), 328(74), 329(76), 402 KovBI, J., 466(34), 481(101, 102), 504, 506 Kowitz, F., 465(33), 466(33), 467(33), 504 Koyama, H., 200(15), 204, 321(65), 326 ( 6 5 ) ,335(65), 402 Krampl, V., 484(134), 507 Kreibich, K., 490(172), 508 Krekel, A., 203(17), 204 Kress, R., 465(31), 504 Kubota, T., 487(161, l62), 507 Kuchenkova, M. A., 24(131), 38, 42(15), 70, 113(53, 54, 55), 114(53, 54, 55), 122 Kuehne, M. E., 61(44), 71, 133(25), 143, 222, 223(68), 305

Kuffner, F., 475(66), 505 Kuhn, H., 477(79), 505 Kuhn, H. J., 428(44), 431, (46), 457 Kump, C., 20(97), 21(95), 37, 127(4), 136 (37), 137(37), 142, 143, 209(27), 210 (32), 241(27), 246(32, 78), 247(32), 254(78), 303, 304, 306 Kump, W. G., 19(80), 20(96), 21(96), 36, 37, 128(10), 143, 190(2), 204, 209 (19a), 215(19a), 303 Kumra, S. K., 16(48), 35 Kunesch, N., 97(54), 98, 208(54, 65b), 221 (54, 65b), 302(97), 304, 305, 306 Kupchan, S . M., 19(69), 23(69), 36, 80 (8, 22), 83 (22), 97, 98 Kuriyama, K., 326 (72), 402 Kutney, J. P., 25(143), 39, 84(28), 85(29, 30), 98, 106(31), 107(31), 121, 148 (15), 149(15), 150(15), 152(15), 185, 206(8), 207(56, 58), 218(58), 219(58), 220 (58, 64), 226 (8), 227 (69b, 69c), 22S(S, 69d), 230(70), 303, 305, 501 (203), 508 Kuwata, S., 461 (8, I l ) , 503, 504 Kuzmanov, B., 488(165), 507

L Laiho, S. M., 350(106), 403 Lambert, B. F., 50(26c), 56(26c), 70, 470 (47), 471 (48, 49), 504 Lamberton, J. A,, 9(17), 12(28), 13(31), 27(170a), 31(180, 181), 34, 35, 39, 40, 151(36), 166(36), 183(61), 185 (75), 186, 187 Lamberts, B. L., 484(131, 132), 507 Lang, B., 411(16), 456 Lathwilliere, P., 24( 120), 38 Laursen, P., 10(21), 34 Lavie, D., 487(158), 507 Lavigne, J. B., 415(21), 444(21), 456 Lawrie, W., 2(3a), 4(3a), 33(3a), 34 Lawton, R. G., 50(26b), 70 Leary, J. D., 487(152, 154), 507 Ledouble, G., 20(86, 87), 37, 59(63, 64), 66(64), 72, 150(25), 159(25), 186 Lee, C . M . , 29(173), 30(176, 177, 178), 39,

523

AUTHOR INDEX 40, 148(19), 151(19), 162(19), 184 (64, 65, 66), 185, 187 Lee,H.,22(101), 37,42(19),47(19), 52(19), 53 (19), 70 Leete,E., 2,4(4), 34, 79(2), 97,409(6), 450, 452(6, 58, 59, 60), 453(59), 455(60), 456, 457, 474(56), 483(119, 127, 129), $84(130, 133, 137), 485(119, 127, 137, 141, 142), 486(129, 143), 505, 506, 507, 509 Legrand, M., 184(73), 187 Leicht, C., 131(22), 143 Leimgruber, W., 438(49), 457 Leitz, F. H. B., 486(143), 507 Lemay, R., 42(11), 47(11), 52(11), 70, 112 (45), 122, 131(20), 143, 151(31), 162 (311, 164(31),186 Le Men, J., 2, 19(74), 20(74, 85, 86, 87), 24(120, 126, 127), 25(137, 146, 156), 27(169), 28(171), 34, 36, 37, 38, 39, 41(1), 42(10, ll), 45(1), 47(10, l l ) , 52(11, 30, 31), 59(60, 63, 64), 65(30), 66(64), 67(60), 70, 71, 72, 73(1), 74 (11, 75(5, 6), 76(6), 77, 79(1), 82(1), 92(42), 96(l), 97, 98, 108(41), 110 (42), 111(49), 112(42, 45, 48), 113 (41), 116(61), 120(61, 83), 122, 123, 125(1), 126(1), 131(17, 20), 142, 143, 150(25), 151(31), 159(25), 162(31), 164(31), 186, 207(9), 219(63), 233 (63), 237(75, 76), 239(76), 241(75, 76), 285(92), 303, 305, 306, 487(159), 503(211), 507, 509 Leonard, N. J., 66(66), 72 Le Quesne, P., 207(8), 226(8), 228(8, 69d), 303, 305 Leung, A. Y., 14(35), 35 Levisalles, J., 1( l ) ,33 LBvy, J., 19(74), 20(74, 85, 86, 87), 24 (120), 36, 37, 38, 59(63, 64), 66(64), 72, 111(49), 122, 150(25), 159(25), 186, 285(92), 306 Lhoest, G., 25(155), 39, 53(37), 56(37), 57 (37), 59(37), 71 Li, M.-T. 13(32), 35 Liang, H.-T., 488(164), 507 Libiseller, R., 489 ( l e g ) , 507 Liebman, A. A., 485(138, 139), 507 Liljgren, P. R., 171(40), 181 (40), 186 Linde, H. H. A., 20(82), 36, 208(19),

210(19),213(19),215(19),249(19), 250 (19), 252(19), 303 Linde, W., 464(30), 504 Ling, N. C., 17(59a), 36, 212(34), 215(34), 269(34), 270(34), 304 Lipscomb, W. N., 25(150), 39, 85(31), 98, 105(10), 121, 219(62), 230(62), 305, 476 (69), 505 Liska, O., 469(42), 504 Lloyd, H. A., 308(1), 354(111), 400, 403, 493(184, 185), 494(185), 508 Loder, J. W., 19(70), 36, 279(88), 306 Loffler, K., 475(67), 505 Loeffler, L. J., 327(75), 328(75), 402 Loew, P., 2(2), 4(2), 33, 45(4), 70, 79(4), 97, 126(2), 142 Loh, S. K., 22(102), 37, 48(20), 53(20), 54(20), 70 Lomonosov, M. V., 291 (96), 306 Lou, V., 11 (24a), 34 Loub, W. D., 25(134, 136), 38, 52(32a), 59 (57), 67(32a), 71, 120(81, 82, 85), 123 Lovkova, M. Ya., 509 Lowenthal, H. J. E., 415(24), 417(23, 24), 456 Lucas, R. A., 470(47), 504 Luces, J., 490(171), 508 Luchetti, M. A,, 502(209), 509 Luke& R., 466(34), 477(74, 75), 479(93), 481 (101, 102), 504, 505, 506 Lyapunova, P. N., 25(141), 38 Lyle, R. E., 311(21), 317(21), 359(118), 360(21, 118), 361(21), 363(21), 365 (21), 401, 403 Lythgoe, D., 492 (182), 508

M Ma, J. C. N., 372(139), 404 Maat, L., 462(14, 16), 463(27), 504 McCaldin, D. J., 473(53), 505 McCarpa, F., 2(5), 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142, 447(53), 450 (53), 457 McCormick, A., 80(20), 98 McDonald, E., 455(69), 457 McKague, B., 288(69d), 305 McKillop, A., 420(33), 421 (33), 422(33), 425(33), 426(33), 456

524

AUTHOR INDEX

Macko, E., 23(113a), 37, 58(50), 59(50), 71, 80(8), 97 MacLean, D. B., 472(50), 504 McMurray, W. J., 47(23), 48(23), 50(23), 70,102(8), l l 6 ( 6 6 ) , 121, 123,.206(3a), 303 McPhail, A. T., 26(160), 39 Maeno, S., 179(49a), 186 Maguo, F. S., 25(158), 39 Major, R. T., 131 (18), I 4 3 Majumdar, D. N., 119(78),123 Majumdar,P.L., 16(44,45), 35,146(7), 150 (7), 185, 209 (23, 29), 210(29), 215(29), 233(23,29), 249 (29), 250(29), 270(23), 303, 304 Malikov, V. M., 24(128), 38, 114(60), 115 (60), 123, 184(68), 187, 209(20b), 231 (20b), 303 Malinowski, E. R., 134(27), 143 Mallett, G. E., 230(72b), 305 Maloney, E. M., 120(84), 123 Manh, D. D., 131(17), 143 Mann, J., 399(173), 405 Manning, R. E., 88(35), 93(45), 94(45), 95(45), 98, 102(7, 9), 121, 230(72), 305 Manske, R. H. F., 470,472(50), 504 Marco, M. N., 45(8), 70 Marekov, N., 488(165), 507 Marini-Belloto, G. B., 26( 166), 39,501 (204, 206), 502 (207, 208), 508, 509 Marion, L., 18(51), 35, 113(50), 122, 211 (61b), 215(61b), 228(61b), 305, 461, 462(12), 486(146, 148, 149), 495(189), 496 (190), 504, 507, 508 Markey, S., 17(63), 36, 208(66), 215(66), 221 (66), 305 Marshak, M. L., 19(77), 36, 136(36), 143 Martel, J., 445, 457 Martello. R. E., 101 (23), 120(23),121,212 (42b), 304 Martin, J. A., 2(3), 4(3), 33, 45(4), 70, 79(3), 97, 126(2), 142 Martin, R. H., 18(68), 25(155), 36, 39, 53 (36, 37), 56(37, 38), 57(36, 37, 40), 59 (36, 37), 60(36), 65(36), 71, 80(7, 20), 97, 98 Mary, N. Y., 478(88), 480(88), 505 Mas, K.-E., 315(39), 316(39), 386(39), 401

Masamune, S., 50(26a), 70 Matsubara, Y., 480(97), 506 Matsumoto, N., 12(26), 34 Maturova, M., 411 (l6), 456 Medina, J. D., 16(56b, 58), 36, 183(58), 187, 210(35), 211(35), 214(55d), 215 (55d), 260(35), 304, 305 Meer, W. A., 102(4), 121 Mehlis, B., 310(16), 338(89), 339(89, go), 384(16), 386(16), 401,403 Mehra, P. N., 412(17), 456 Meisel, H., 25 (140), 38 Mendelli, R., 31 (182), 40 Mendez, M. R., 490(170), 508 Menefee, B. S., 482(114), 506 Merchant, J. R., 15(37), 35 Merkel, W., 490(173), 508 Merlini, L., 31(182), 40, 147(8), 150(8), 183(56, 63), 185, 186, 187 Meyer, H., 202(16), 203(17), 204 Michel, K.-H., 308(3), 309(3), 318(3), 333(81), 355(3, 114), 356(3, 8, 14), 357(114), 382(3), 384(3), 400, 402, 403 Miet, C., 25(152, 154), 39, 80(16), 92(16), 95(16), 97 Miller, J. A., 392(157), 393(157), 404 Miller, R., 102(3), 121 Mills, H. H . , 19(77), 36, 136(36),143 Mills, J. A., 320(7), 326, 400 Minami, S., 367(128, 129), 404 Miranda, E. C., 17(59a), 36, 212(34), 215(34), 269(34), 270(34), 304 Mitake, T., 510 Mitscher, L. A., 182(55), 186 Mizoguchi, T., 479(92), 505 Mizukami, S., 327(73), 330(77), 342(77), 402 Mizusaki, S., 509 Mohandas, J., 23(117), 38, 80(10), 97 Mokrf, J., 25(142), 38, 109(34, 35, 36, 38, 40), 110 (35, 36), 122, 130(14), 131(19, 21, 23), 132(23), 143, 208(10, 13, 15, 19c), 214(52), 215(19c), 220(13, 15, 65), 221(13, 65), 279(52), 303, 304, 305 Mollov, N., 24(132), 38, 117(72), 123, 488 (165), 507 Molodozhnikov, M. M., 16(50), 35, 131 (16), 143

525

AUTHOR INDEX Moncrief, J. W., 25(150), 39, 85(31), 98, 105(10), 121, 219(62), 230(62), 305 Mondelli, R., 147(8), 150(8), 183(56, 63), 185, 186, 187, 387(152), 404 Money, T., 2(5), 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142 Monseur, X., 492 (183), 493 (183), 508 Monteiro, H. J., 24(124), 16(14), 27(170), 31(170), 33(14), 34, 38, 39, 155(23), 158(23),186, 214(51, 86), 273(86, 87), 279(51, 86), 304, 306 Monti, S. A., 93(45), 94(45), 95(45), 98, 102 (7), 121 Mooberry, 5. B., 369(134), 379(134), 404 Moore, B. P., 58(54), 65(54), 67(54), 7 1 Mootoo, B. S., 2(5), 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142 Morimoto, H., 12(26), 34 Morin, R. D., 323(69), 324(69), 402 Morrison, G. C., 183(59), 187 Mors, W. B., 496(192), 508 Morsingh, F., 31(183), 40, 151(33, 33a), 162(33, 33a), 184(72), 186, 187 Mortimer, P. I., 461(9), 462(20), 478(82, 83), 503, 504, 505 Mosher, C . W . , 279(90), 306 Mothes, K., 3(8), 33(8), 34 Mothes, U., 487(160), 507 Mowdood, S. K., 24 (118), 38, 80 (12), 83 (12), 97 Mom, B. K., 25(145), 39, lOl(19, 20, 24, 25), 108(19, 33a), 121,122, 209(18,20, 21, 22), 230(18, 20), 231(20, 22), 233(21, 22), 303, 408(3, 4), 411(3, 4), 412(3, 4), 413(3), 431(4), 434(3), 435 (4), 456 Mudd, S. H., 399(173), 405 Muller, E., 469(41), 504 Muller, H., 26(162), 39, 199(12), 204, 462 (17), 504 Mukhamedzhanov, S. Z., 509 Mukherjee, B., 11(25), 15(42), 34, 35 Mukherjee, K . S., 13(33), 35 Mukherjee, R., 495(187, 188), 508 Mundy, B . P., 485(139), 507 Murai, F., 499(199), 500(199, 200, 201), 508 Murase, Y., 444(51), 457

Murphy, C.F., 372(138), 373(141,142), 379 (138), 381(149), 382(150), 404 Muxfeldt, H., 369 (134), 379 (134), 404 Myiano, M., 177(47), 186

N Nabney, J., 447(53), 450(53), 457 Naegeli,.P., 359(118), 360(118), 403 Nagai, M., 222(67), 305 Nagarajan, K., 19(80), 36, 208(84), 255 (81), 256(81), 257(81), 258(81), 306, 491 (178), 508 Nair, M. D., 113 (50), 122 Nakagawa, Y., 16(52), 17(52), 35, 212(40), 304, 312(64a), 326(71), 402 Nakamura, T., 417(27), 444, 456, 457 Nakano, T., 496(195), 508 Nakatsu, K., 67(68), 72 Nakatsuka, N., 50(26a), 70 Naknyama, Y.,,478 (85), 505 Nakazawa, J., 417(27), 444(51), 456, 457 Narasi
52 6

AUTHOR INDEX

Kordman, C. E., l6(48), 35, 67(68), 72 Sorkina, S., 113(51), 122 Sormatov, M., 319(55), 334(82), 402

0 Occolowitz, J., 196(8), 197(8, l l ) , 198(11), 199(11), 204 Occolowitz, J.L., 9 (17), 26 (164), 27 (1704, 34, 39, 151 (36), 166 (36), 183(61), 185 (75), 186,187 Ognyanov,I., 24(132, 133), 38, 117(72, 73, 75), 118(73, 75, 76a, 76b, 77), 119 (SOa), 120(73), 223, 150(24), 151(32), 159(24, 24a), 160(24), 161(24, 24a), 162(24a, 32), 163(32), 183(62), 184 (70), 186, 187, 215(22a), 233(22a), 303

Ohashi, M., 8(53), 16(53, 53a, 54), 17 (53a), 35, 52(32), 71, 206(2), 212(2, 39), 214(2, 53), 271(2, 39), 285(2, 53), 303, 304, 422(40), 423(41), 424(41), 457

Ohta, M., 461 (5), 503 Oishi, T., 178(48), 179(49, 49a), 186, 222 (67), 305 Oki, M., 66(66), 72 Oliver, A. T., 100(13), 107(13), 121, 139 (45), 1 4 3 Olivier, L., 19(74), 20(74, 85, 87), 24(120), 36, 37, 38, 59(63), 72, 285(92), 306 Ondetti, M. A., 212(41), 304 Openshaw, H. T., 174(45a), 186 Orazi, 0. O., 17(64), 36, 42(7), 45(7), 52 (7), 53(7), 70, 214(51a), 215(51a), 304,496 (195), 508 Orazkuliev, I. K., 10(20), 34 Orekhoff, A. P., 113(51), 122 Orvis, R. L., 436(48), 457 Oshio, H., 12(26), 34 Otroshchenko, 0. S., 10(20), 34, 481 (103, 105, 106, log), 506 Ozeki, S., 320(63), 334(63), 336(86, 87), 337(86), 385(87), 4 0 2 , 4 0 3 Owellen, R. J., 16(52, 55), 17(52), 35, 212 (40), 304

P Pack, D. E., 415(20), 444(20), 456 Paes Leme, L. A., 16(55a, 56), 17(56),

18(55a), 35, 210(28, 33), 213(28), 254(33), 255(33), 303, 304 Psi, B. R., 16(46), 19(80), 35, 36, 146(5), 150(5), 185 Pailer, M., 477(78), 489(169), 505, 507 Pakrashi, S. C., 15(37), 35 Palmer, K. H., 17(59b), 36, 215(25), 303 Papariello, G. J., 22(102), 37, 48(20), 53 (20), 54(20), 70 Pappas, N. A., 482(114), 506 Paris, R. R., 477 (SO), 505 Parker, W., 470(43), 504 Parry, G. V., 2(3a), 4(3a), 33(3a), 34 Pascard-Billy, C., 164(34),186 Paszek, L. E., 23(106), 37, 45(5), 70 Patel, M. B., 19(77), 20(93, 96), 21(94, 96), 23(103), 24(119), 25(154), 36, 37, 38, 39, 42(14), 70, 80(15, 16), 81 (15), 83(16), 92(16), 95(16), 97, 136 (36, 37), 137(37), 143, 208(19b), 209 (19a, 19b), 214(55),215(19a), 216(55), 217(19b), 218(19b), 245(19b), 303, 304

Pattabhiraman, T. R., 9(16), 34 Paul, B., 119(78), 1 2 3 Paul, H. G., 14(35), 35 Peeher, J., 18(68), 25(155), 36, 39, 53 (36, 37), 56(37, 38), 57(36, 37), 59 (36, 37), 60(36), 65(36), 71, 80(7, 20), 97, 98 Pereheron, F., 84 (26), 87 (34), 93 (26), 98 Pereazmador, M. C., 80(11), 81(11), 97 Pereira, N. A., 45(9), Y O Pesaro, M., 438(49), 457 Phillips, G. T., 2(5), 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142 Phillipson, J. D., 29(173), 30(174, 175, 176, 177, 178), 39, 40, 148(19, 19a), 151(19), 162(19, 19a), 184(66), 185, 187

Pichon, M., 99(1), 113(1), 121 Piers, E., 84(28), 85(29), 98, 207(8, 58), 218(58), 219(58), 220(58, 64), 226 (8), 227(69b, 69c), 228(8, 69d), 230 (70), 303, 305 Pierson, W. G., 470(47), 471(48, 49), 504 Pijewska, L., 420(35), 421 (35), 432(35), 456 Pillay, P. P., 23(117), 38 Pinar, J . M . , 17(59), 36

527

AUTHOR INDEX

Pinar, M., 17(59), 36, 212(37a, 38), 269 (37a, 38), 270(37a), 304 Piozzi, F., 387 (152), 404 Plant, S. G. P., 95(50), 98 Plat, M., 18(66), 25(146), 27(169), 36, 39, 42(11), 47(11), 52(11), 70, 96(51), 97 '(54), 98, 112(45), 116(61), 120(61), 122, 123, 131(17, 20), 143, 151(31), 162(31), 164(31), 186, 213(46), 215 (55a), 219(63), 233(63), 237(75, 76), 239 (76), 241 (75, 76), 295 (46), 296 (46), 302(46, 97), 304, 305, 306, 487 (159), 503(211), 507, 509 Plimmer, J. R., 477(76), 505 Plunkett, A. O., 2(3), 4(3), 33, 45(4), 70, 79(2, 3), 97, 126(2), 142 Pobedimova, E. G., 113(52a), 122 Podolesov, B. D., 411(15), 456 Poisson, J., 18(66), 23(103, 104, 105, 106, 107), 24(119), 251152, 153, 154), 36, 37, 38, 39, 42(14), 70, 80(15, 16), 81 (15), 83(16), 92(16), 95(16), 96(51), 97(54), 97, 98, 118(76), 123, 151(28), 159(26), 162(28), 164(28), 184(71, 72, 73), 186, 208(54, 65b), 213(46), 214 (55), 216(55), 221 (54, 65b), 295(46), 296 (46), 302 (46, 97), 304, 305, 306 PongrAcz-Sterk, L., 46(22), 70 Popelak, A., 15(37), 35 Popli, S. P., 15(37), 19(81),35, 36, 255(80, 82), 256 (82), 257 (82), 258 (80, 82), 259 (82), 260(82), 306 Popov, S., 488(165), 507 Porte, A. L., 420(33), 421(33), 422(33), 425(33), 426(33), 456 Potesklova, H., 408(3), 411 (3), 412(3), 413(3), 434(3), 456 Potier, P., 1(1), 25(137), 28(171), 33, 38, 39, 52(31), 71, 73(1), 74(1), 75(5, 6), 76(6), 77, 112(45),122 Potts, K. T., 171(40), 181(40), 186 Pousset, J. L., 23(103, 104, lo?'), 37, 42 (14), 70, 151(28), 162(28), 164(28), 184(71, 72, 73), 186, 187 Poynton, M., 310(12), 384(12), 401 Prasad, K. B., 473(55), 505 Prein, N., 113(51), 122 Prelog, V., 73(2), 77 Preobrazhenskii, N. A., 291 (96), 306 Price, J. R., 127(5), 142

Prins, D. A., 58(42, 43), 61(42, 43), 65 (43), 71, 83(24), 87(33), 98, 139(43), 143 Prista, L. N., 9(19), 34, 102(6), 121 Proskurnina, N. F., 315(35), 346(95), 384 (35), 401, 403 Puisieux, F. 25(152, 153, 154), 39, 80(16), 83(16), 92(16), 95(16), 97 Putschevska, H., 24 (132), 38 Pyuskyulev, B., 24(132), 38, 117(75), 118(75), 119(80a), 123, 150(24), 159 (24, 24a), 160(24), 161(24, 24a), 162 (24a), 183(62), 184(70), 186, 187, 215 (22a), 233(22a), 303

Q Qaisuddin, M., 52(34), 71 Quadrat-i-Khuda, M., 29(172), 39 Quan, P. M., 482 (11l), 506 Quin, L. D., 477(77), 482(111, 112, 113, 114, 118), 505, 506 Quirin, F., 25(156), 39, 80(17), 92(17), 97 Quirin, M., 25(156), 39, 59(63), 72, 80(17), 92(17), 97

R Rae, I. D., 302(99), 306 Raffauf, R. F., 19(71, 72), 23(113, 113rt), 36, 37, 52 (28), 58 (28, 50), 59 (50, 55), 71, 80(9), 92(9), 95(9), 97, 120(87), 124, 147(11), 185 Rajappa, S., 19(80), 36,475(64), 505 Rall, G. J. H., 509 Ramage, R., 455(69), 457 Ramiah, N., 23(117), 38, 80(10), 97 Ramstad, E., 11(24a), 34 Rangaswami, G., 12(30a), 34 Rangaswami, S., 318(51a), 344(51a), 401 Rao, C. B. S., 91 (40), 98 Rao, K. V., 59(59), 7 1 Rao,R. V. K., 318(51a), 319(53), 344(51a), 401, 402 Raphael, R . A., 470(43), 504 Rapoport, H., 415(20, 21, 22), 444, 456, 485(138, 139), 507, 510 Rasmussen, M., 23(110), 25(110), 37, 80

528

AUTHOR INDEX

(14), 81(14), 83(14), 84(14), 92(14), 97 Rathle, P., 420(32), 421(32), 456 Ratle, G., 492 (183), 493 (183), 508 Ratnagiriswaran, A. N., 58(53), 71 Rausch, R., 465(32), 504 Ray, A. B., 15(42), 16(43, 44, 45, 47), .35, 146(6, 7), 150(6, 7), 185, 209 (23, 29), 210(29), 215(29), 233(23), 249 (29), 250(29), 270(23), 303, 304 Raymond-Hamet, 30(179), 40 Raymond-Hamet, M., 147(9), 150(9), 185 Rees, A. H., 19(77), 36, 136(36), 143 Reichstein, T., 411 (l6), 456 Relyveld, P., 16(57), 36, 148(20a), 151 (20a), 158(20a), 186, 212(24), 213 (24, 45), 214(24), 215(24), 260(84a), 269(24), 303, 306 Renner, U., 18(65), 23(112), 25(65), 36, 37, 58(41, 42, 43), 61(41, 42, 43), 65 (43), 66(67), 71, 72, 83(24), 87(33), 94(47), 95(49), 96(52), 98, 100(21), 120(21), 121, 134(29), 137(40), 138 (41, 42), 139(40, 41, 42, 43), 140(41, 42), 142(42), 143, 208(65a), 211 (85), 212(42c), 213(85), 221(65a), 265(85), 268(85), 295(85), 296(85), 302(85), 304, 305, 306 Renz, J, 464(30), 504 Rettig, A,, 487(160), 507 Reynolds, B. E., 476(73), 505 Reynolds, J. J., 450(61, 64), 452(61, 64), 453 (64), 455(64), 457 Rhodes, R. E., 230(72d), 306 Ribas, I., 490(170, I71), 508 Ribeiro, O., 23(113, 113a), 37, 58(50), 59 (50, 55), 7 1 Rice, W. Y., Jr., 491(177, 181), 492(181), 508 Richards, J. H., 450(66), 457 Richey, J. M., 146, 159, 185 Richie, E., 213(95), 306 R i n d , M. M., 197(10), 204 Ritchie, E., 23(109, 110), 25(110), 37, 80(14), 81(14), 83(14), 84(14), 92 (14~97 Rize, A. M., 318(51), 319(51), 386(51), 401 Robb, W. E., 137(39), 143 Roberts, M. F., 510

Robertson, A. V., 496 (190), 508 Robertson, J. M., 134(28), 143, 148(21), 186 Robinson, B., 12(29), 34 Robinson, R., 66 (65), 72, 95 (50), 98 Robinson, Sir R., 449(54), 457 Robison, M. M., 470, 471 (48, 49), 504 Rogers, D., 349(104), 403 Roller, P., 17(59a), 36, 212(34), 215(34, 55b), 269 (34), 270 (34), 304 Romanova, I. B., 481 (107), 506 Rona, P., 415(24), 417(24), 456 Root, M. A,, 92(43), 98 Roque, A. S., 102(6), I 2 1 Rosenberger, M., 19(72), 36, 302(99), 306 Rosene, C. J., 482(115), 506 Rosenkranz, H. J., 127(6), 142 Ross, W. J., 147(11), 185 Rother, A., 487(152, 153, 154), 507 Row, L. R., 185(76), 187 Rowson, J. M., 20(96), 21(94, 96), 23(103), 25(153), 37, 39, 42(14), 70, 80(16), 83(16), 92(16), 95(16), 97, 136(37), 137(37), 143, 209(19a), 215(19a), 303 Ruveda, E. A., 12(30), 34

S Sabolotnaya, E. S., 131 (16), 143 Sadykov, A. S., lO(20, 23), 34, 410(8, 9, 10, 11, 14), 413(18, 19), 434(9), 435 (10, l l ) , 456, 481(103), 105, 106, 109 110), 506, 509 Saito, K., 478(85), 505 Sakai, S.-I., 41(3), 70, 74(3), 77, 135(32), 143 Sakan, T . , 330(76a), 402, 499(199), 500 (199, 200, 201), 508 Saksena, A. K., 23(117), 38, 80(21), 83 98

Saleh, M., 409(1), 410(1), 414(1), 432(1), 436(1), 455 Salgar, S. S., 15 (37), 35 Salt, M. L., 485 (140), 507 Samiullah, W., 410(13), 456 Sanchez, L., W. E., 16(56a), 36, 211(36), 213(50), 260(36), 261 (36), 279(50), 304 Sandberg, F., 308(3), 309(3), 318(3, 52),

AUTHOR INDEX

319(52), 333(81), 355(3), 356(3, 81), 382(3), 384(3), 400, 402 Sandoval, A., 80(11), 81(11), 97 Santavf,F., 408(2, 3,4), 409(1,7), 410(1), 411(2,3,4, 16),412(2, 3,4),413(2, 3), 414(1), 417(26), 418(28, 30), 419(28), 420(26, 34, 35), 421(26, 34, 35), 422 (40), 426(34), 431(4, 7, 26, 46), 432 (1, 35), 433(2), 434(2, 3), 435(4), 436 (1, 7), 455(2), 455, 456, 457 Santos, A. C., 23(115), 24(115, 121), 25 (157, 158), 37, 38, 39, 80(13), 97 Sapiro, M. L., 197 (lo), 204 Sarkar, S. K., 50(26a), 7 0 Sathe, S. S., 23(117), 38, 80(21), 83(21), 98, 487(163), 507 Sato, T., 321(65), 326(65), 335(65), 402 Sato, Y., 222(67), 305 Savitri, T. S., 16(46), 35, 146(5), 150(5), 185 Schenck, G. O., 428,431 (46), 457 Schenkenberger, E., 469(40, 41), 504 Scheuer, P. J., 9(16), 20(84), 34, 37, 148 (18), 151(18), 155(18), 185, 213(47), 215(47), 279(47), 304 Schisdt, U., 474(57), 505 Schlittler, E., 45(6), 47(6), 54(6), 70, 86 (3% 98 Schmadel, E., 495(186), 508 Schmid, H., 8(39, 40, 78), 15(39, 40, 41), 16(54a), 17(59), 18(65), 19(76, 78, SO), 20(76, 88, 92, 93, 96, 97), 21(95, 96), 25(65), 26(162), 27(167), 35, 36, 37, 39, 52(33), 67(69, 70, 71), 69(70), 71, 72, 96(52), 97(53), 98, 105(11), 121, 127(4, 6), 128(10), 129(11), 135(30, 31), 136(34, 37), 137(37, 38), 142, 143, 148(22), 186, 190(1, 2), 191(1), 193 ( l ) , 194(4, 6), 199(12), 204, 206(5), 207(59), 208(19b, 65a, 84), 209(19a, 19b, 27, 30a), 210(32), 211(59, 85), 212(37a, 38), 213(5, 44, 85), 214(30, 30a), 215(19a, 30a, 55c, 98), 217(19b, 59, 60, 61), 218(19b, 59), 219(59, 60, 61), 221 (65a), 337, 241 (27), 244(59), 245(19b, 60, 74a), 246(32, 78), 247 (32), 254(78), 255(81), 256(81), 257 (81), 258(81), 265(85), 268(85), 269 (37a, 38), 270(37a, 59), 279(55c), 285 (93), 288(44), 291 (93), 292(5), 294(5),

529

295 (5, 85), 296(85), 302(85, 98), 303, 304, 305, 306 Schneider, R. S., 369(134), 379(134), 404 Schnoes, H. K., 23(111), 37, 214(52), 236, 237(73), 279(52), 304, 305, 339(91a), 403 Schopf, C., 462(17, 23), 464(23), 465(23, 31, 32), 466(23), 467(23), 468(23), 469(40, 41), 490(172, 173), 495(186), 504, 508 Schreiber, J., 438(49), 457 Schroter, H. B., 478(84), 505, 510 Schubert,B. G., 3,4(11), 14(11), 34 Schudel, P., 438(49), 457 Schulze-Steinen, H. J., 479(94), 480(94), 506 Schumann, D., 19(76), 20(76, 93), 36, 37, 105(11), 121, 136(34), 143, 190 (l),191(1), 193(1), 204, 208(19b), 209 (19b), 217(19b, 60, 61), 218(19b), 219 (60, 61), 245(19b, 60), 285(93), 291 (93), 303, 305, 306 Schwarting, A. E., 462(22), 487(152, 153, 154, m i ) , 504, $07, 509 Schwarze, W., 464(30), 504 Scott, A. I., 2, 4(5), 34, 45(4), 70, 79(4), 97, 126(2), 142, 447, 450(53), 457 Scullard, P. W., 184(67), 187 Seaton, J. C., 113(50), 122 Seay, D., 102(6), 121 SefEoviE, P., 109(40), 122, 130(14), 131 (19), 143 Seibl, J., 17(59), 20(97), 21 (95), 25(155), 36, 37, 39, 53(37), 56(37), 57(37), 59 (37), 71, 127(4), 142, 209(27), 210(32, 38), 241(27), 246(32), 247(32), 269 (38), 303, 304 Seo, M., 171 (41, 42), 186 SepEovi6, P., 208(15), 220(15), 303 Shaffer, R. W., 102(6), 121 Shamma, M., 21(98), 22(100), 23(98, 105), 25(142), 37, 38, 45(21), 70, 89(37), 98, 109(35), 110(35), 118(67a), 122, 123, I31(21), 143, 146, 148(12, 13), 159(26), 183(57), 184(70, 72), 185, 186, 187, 208(13), 220(13), 221(13), 271 (86a), 303, 306, 501 (203), 508 Shannon, J. S., 499(198), 508 Shapiro, T. A., 291 (96), 306

530

AUTHOR INDEX

Sharlrey, A. G., Jr., 25(135), 38, 59(58), 65(58), 71, 120(84, 88), 123, 124 Shavel, J., Jr., 177(46), 182(54), 183(59, 60), 186, 187 Shaw, S . C., 473(55), 505 Sheehan, J. C., 74(4), 77 Shellard, E. J., 29(173), 30(174, 175, 176, 177, 178), 39, 40, 148(19, 19a), 151 (19), 162(19, 19a), 185, 473(54), 505 Shine, R. J., 21(98), 22(100), 23(98), 25 (142), 37, 38, 109(35), 110(35), 118 (76a), 122, 123, 148(12, 13), 183(57), 184(70, 72), 185, 187, 208(13), 220 (13), 221(13), 271 (86a), 303, 306 Shiro, M., 321 (65), 326(65), 335(65), 402 Shoolery, J. N., 501 (203), 508 Shoop, E. C., 19(72), 36 Sicher, J., 474, 491 (176), 505, 508 Siddiqui, I. A., 410(12), 456 Siddiqui, S., 15(37),35 Siegfried, K. J., 484(130), 507 Sim, G. A., 26(160), 39, 134(28), 143, 146 (4), 148(21), 177(4), 180(4), 185, 186 Simpson, P . J., 106(29), 122 Sioumis, A. A., 12(28), 34 Sklar, R., 19(75), 36, 45(6), 47(6), 54(6), 59(62), 70, 72, 86(32), 98, 190(3), 204 Smalberger, T. M . , 509 Smidt, J., 476(71), 505 Smirnova, L. S., 319 (56), 346 (56, 98, 99), 402, 403 Smith, A. F., 19(75), 36, 59(62), 72, 190 (3), 204 Smith, A. H., 14(35), 35 Smith, E., 22(100), 37, 148(13), 183(57), 185,187 Smith, G. F., 136(35), 143, 285(91), 306 Smith, G. L., 368(132, 133), 379(133), 404 Smith, H. G., 422(36, 37, 39), 426(36), 428 (37), 429 (39), 430 (39), 456, 457 Smith, L. W., 11(24), 34 Smith, S. L., 426(43), 457 Smogrovicova, H., 510 Snatzke, G., 465 (33), 466 (33), 467 (33), 504 Solt, M. L., 483(122), 506 Sonnet, P. E., 89(38), 98 Sorkin, M., 418(29), 456

Soyster, H. E., 89(37), 98, 131(21), 143 Spiith, E., 373(143), 378(143), 404, 474, 475(66), 505 Sparatore, F., 12(27), 34 Spencer, H., 1(l),33 Spencer, T. A., Jr., 436(48), 457 Spenser, I. D., 472(51), 505 Spetkova, O., 510 Spiteller, G., 9(18), 18(68), 19(18, 76), 20 (76), 25(155), 34, 36, 39, 48(26), 53 (36), 57(36), 59(36), 60(36), 65(36), 70, 71, 80(7), 97, 107(32), 118(76b), 121, 123, 131(15), 136(34), 143, 148 (17), 150(17), 151(35), 153(17), 159 (24a), 161(24a), 162(24a), 165(35), 185, 186, 190(1), 191(1), 193(1), 204, 208(19c), 213(48), 214(48), 215(19c, 22a, 48), 221(66a), 223(22a), 279(48), 285(91, 93), 288(48), 291(93), 303, 304, 305, 306, 491 (174), 508 Spiteller-Friedmann. M., 18(68), 19(76), 20(76), 25(155), 36, 39, 48(26), 53 (36), 57(36), 59(36), 60(36), 65(36), 70, 71, 80(7), 97, 107(32), 121, 136 (34), 143, 148(17), 150(17), 153(17), 185, 190(1), 191(1), 193(1), 204, 221 (66a), 285(93), 291(93), 305, 306, 491 (174), 508 Springler, H., 15(37),35 Staba, E. J . , 10(21), 34 Starmer, G. A., 80(19), 97 Stauffacher, D., 309(4), 310(4, 14), 311 (19), 354(14, 113), 362(4), 363(14), 381(19), 382(19), 384(14), 385(4, 14, IS), 400, 401, 403 Stedman, R. L., 509 Steinegger, E., 470(46), 504 Stender, W., 347 (102), 403 Stenlake, J. B., 52(34), 71 Sticzay, T., 184(72), 187 Stillwell, R. N . , 279(89), 306 Stimac, N., 475(65), 505 Stoichevich, M. E., 17(64), 36, 42(7), 45 (7), 52(7), 53(7), 70, 214(51a), 215 (51a), 304 Stoll, W. G., 139(43), 143 Stolle, K., 25(144), 39, 100(14), 102(6), 121, 209(20a), 230(20a), 303 Stork, G., 131 (14a), 143

AUTHOR INDEX

Strouf, O., 3, 4(12a), 14(12a), 25(142), 34, 38, 109(37, 39), 110(37), 122, 134 (26, 27), 143, 208(11, 14, 16, 17), 220 (1I), 221 (ll),303 Suhadolnik, R. J., 392(155), 393(155, 160, 161, 162, 163), 394(155, 161, 163, 165), 395(161, 166), 404, 405 Sunagawa, G., 417 (27), 444(51), 456,457 Sutherland, J. K., 420(33), 421(33), 422 (33), 425(33), 426(33), 456 Suwal, P. N., 474(58), 505 Suzui, A,, 499(199), 500(199, 200, 201), 508 Svetkin, Yu. V., 481(108), 506 Svoboda, G. H., 25(148, 149), 39, 58(47), 59(61), 71, 72, 92(42, 43), 98, 100 (13, 15, 16, l?), lOl(17, 18), 106(30), 107(13, 16, 30), lZO(83, 89), 121, 122, 123, 124, 139(45), 143, 148(14), 150 (14), 185, 212(42a), 304 Swan, G. A., 182(53), 186 Swan,R. J., 105(11), 121, 146(3),185,207 (59), 211(59), 217(59, 61), 218(59), 219(59, 61), 244(59), 270(59), 305 Sweeney, J., 25(147), 39, 58(49), 65(49), 67(49), 71, 105(28), 107(28), 120(28), 121 Szabo, A. G., 19(72), 36, 302(99), 306 Szab6, L., 181(51), 186 Szantay, Cs., 169(37), 181(50, 51, 52), 186

T Tabata, T., 85 (30), 98, 207 (56), 305 Takagi, S., 323(67), 402 Takamatsu, H., 367 (128), 404 Takeda, K., 323(67), 327(73), 402 Talalaj, S., 473(54), 505 Talapatra, S. K., 14(36a), 15(41), 19(71, 72, 73), 23(113), 35, 36, 37, 52(28), 58(28), 59(55), 65(45), 71, 80(9), 92 (9), 94(46), 95(9), 97, 98, 120(87), 124 Tamaki, E., 480(97), 506, 509 Tantivatana, P., 29(173), 39, 148(19a), 162(19a), 185 Taylor, E. C., 480(100), 506 Taylor, J. B., 2(3), 4(3), 33, 79(2), 97, 126(2), 142, 316(45, 46), 392(45),

531

394(45), 395(45), 398(45, 46, 171, 172), 399(45), 401, 405 Taylor, W. C., 23(109, 110), 25(110), 37, 80(14), S l ( l 4 ) , 83(14), 84(14), 92(14), 97, 213(95), 306 Taylor, W. I., 2(5a), 8(39, 40), 15(39, 40, 41), 19(74, 75, 76), 20(74, 76), 22 (102), 23(106), 24(123), 34, 35, 36, 37, 38, 4 l ( l , 2), 42(5), 45(1, 5, 6), 46(22), 47(6), 48(20, 25), 50(26c), 53(20), 54(2, 6, 20), 56(26c), 59 (46, 62), 65(46), 67(69, 70, 71), 69 (70), 70, 71, 72, 73(2), 77, 79(1), 82 (1, 23), 83(25), 86(25, 32), 88(36), 96(1), 97, 98, 108(41), 113(41, 52), 119(79, SO), 122, 123, 125(1), 126(1), 127(7), 129(12), 130(7), 135(33), 136 (34), 142, 143, 146(3, a), 147(9), 150 (9), 177(4), 180(4), 185, 190(1, 3), 191 (l),193(1), 204, 207(9), 213(44), 285 (93), 288(44), 291 (93), 303, 304, 306, 323 (67), 370(137), 402, 404 Taylor-Smith, R., 487(158), 507 Telang, S. A., 19(69), 23(69), 36, 80(22), 83 (22), 98 Terashima, M., 222(67), 305 Terashima, V., 500(201), 508 Thomas, B. R., 323(67), 402 Thomas, D. W., 20(91), 37, 94(48), 98, 128(9), 129(9), 143, 206(6), 210(79), 213(6), 246(79), 247(79), 251 (79a), 254(79), 279(6), 292(6), 294(6), 303, 306 Thomas, G. M., 316(45, 46), 392(45), 394 (45), 395(45), 398(45, 46, 171), 399 (45), 401, 405 Thomas, J., 80(19), 97 Thomas, P. R., 182(53), 186 Thomas, R., 79(5), 97 Thompson, M. E., 310(12), 384(12), 401 Threlfall, T., 438(49), 457 Tibayan, L. L., 23(115), 24(115), 37 Tichy, M., 474, 491 (176), 505, 508 Tidd, B. K., 366 (85), 403 Tiwari, H. P., 351(107), 403 Toke, L., 169(37), 181(50,51,52), 186 Tokuyama, T., 330(76a), 402 Tolkachev, 0.N., 291 (96), 306 Tomczyk, H., 16(49), 35 Tomita, M., 367 (128), 404

532

AUTHOR INDEX

Tomita, Y . ,487(161), 507 Tomlinson, M., 95(50), 98 Tonev, Iv., 14(36), 35 Tori, K., 326(72), 402 Toromanoff, E., 445(52), 457 Torssell, K., 323(68), 402, 501(202), 508 Toubs,T. P., 336(84, 85), 403 Trager, W. F., 184(64, 65, 66), 187 Trenkfrog, B., 478(91), 505 Triplett, R., 510 Trivedi, B., 420(34), 421 (34), 426(34), 456 TrojLnek, J., 25(139, 142, 145), 38, 39, 42(12, 13), 46(12, 13), 75, lOl(19, 20, 24, 25), 108(19, 33a), 109(37, 39), 110(37), 112(46, 47), 121, 122, 132 (24), 134(26, 27), 143, 207(9a), 208 (11, 14, 16, 17), 209(18, 20, 21, 22), 210(9a), 220(11), 221, 230(18, 20), 231 (20, 22), 303 Trotter, J., 85(29, 30), 98, 105(12), 121, 207(56, 57, 58), 218(58), 219(58), 220 (58), 305 Trumbull, E., 486(148), 507 Trust, R. H., 25(148), 39, 92(42), 98, 101 (18), 120(83), 121, 123 Tschesche, R., 465(33), 466(33), 467(33), 472(52), 473(52), 504, 505 Tso, T. C., 510 Tsuda, Y . , 323(67), 370(135, 137), 379 (144), 381 (148), 402, 404 Tsukamoto, K., 323(67), 402 Tuppy, H:, 462(19), 504 Turner, J. C., 1(1),33 Turner, J. R., 480(99), 506 Tyler, V. E., Jr., 9(15), 10(22), 34

U Ubaev, Kh., ll4(69, 70), I23 Ubaev, U., 113(55), 114(55), 122 Ueda, N., 330(76a), 402 Ueda, S., 2, 4(4), 34 Ullyot, G. E., 418(31), 456 Umans, A. J., 171(43), 186 Ulshafer, P. R., 23(106), 37, 42 (51,45 (5), 70 Unrau, A. M., 450(65), 452(65), 457 Urublovskj., P., 408(4), 411(4), 412(4), 431 (a), 435(4), 456 Utebaev, M. U., 481 (log), 506

Utkin, L. M., ll4(71), 123 Uyeo, S., 316(40), 321(64a), 323(67), 326 (TI), 342(93, 94), 347(40), 352(110), 354(111), 367(127, 128, 129, 130), 370 (93, 135, 136, 137), 379(136, 144), 381 (148), 401, 402, 403, 404

V Van Binst, G., 57(40), 71 Vanden Heuvel, W. J. A,, 308(1), 400 van der Kerk, G. J. M., 107(33), 122, 148 (16), 149(16), 150(16), 152(16), 185 van der Meulen, T. H., 107(33), 122, 148 (16), 149(16), 150(16), 152(16), 185 van Leeuwen, M., 476(71), 505 Van Meta, J. C., 15(37), 35 van Tamelen, E. E., 50(26b), 70, 172(44), 177(47), 186, 436, 457 van Veen, A,, 463(27), 476(71), 504, 505 Venkatachalam, K., 58(53), 7 1 Verengo, M. J., 492(182), 508 Verkey, E. J., 23(117), 38 Vesslj., Z., 477(74), 505 Vetter, W., 8(39, 83), 15(39), 20(82a, 83), 35, 36, 37, 67(70), 69(70), 72, 135 (31), 143, 206(1), 209(1, 26), 215(26), 233(26), 235(26), 242(1), 303 Viel, C., 462 (13), 504 Visser, B. J., 462(18), 504 Viswanathan, N., 19(80), 23(117), 36, 38, 80(21), 83(21), 98, 146(5), 150(5), 185, 487(163), 491(178), 507, 508 Vlattas, I., 207(8), 226(8), 228(8), 303 Vog1, O., 462(15), 504 von Klemperer, M. E., 26(163), 39, 196 (91,204 von Philipsborn, W., 19(76), 20(76), 36, 136(34), 143, 190(1), 191(1), 193(1), 204, 255(81), 256(81), 257(81), 258 (81), 285(93), 291 (93), 306, 463(27), 504 von Strandtmann, M., 183(60), 187 Vorbrueggen, H., 45(9), 70

w Wade E., 478(85), 505 Wahid, M. A., 410(13), 456

AUTHOR INDEX

Wahlberg, K., 501 (202), 508 Wakhloo, J. K., 14(34), 35 Walker, E. F., Jr., 45(21), 70 Walker, G. C . , 470(45), 504 Waller, G. R., 483(121, 123), 486(123, 144, 145, 147, 150, 151), 506, 507, 509, 510 Walls, F., 80(11), 81(11), 97 Walser, A., 24(124, 125), 38, 148(20), 151 (20), 155(20, 23), 158(23), 185, 186, 208, (12), 211(12), 212(12), 213(12, 43), 214(12, 51), 215(12), 228(12), 229(12), 260(12), 269(12), 270(12), 271 (12), 273(43), 276(43), 278(43), 279(51), 303, 304 Walter, W. G., 487(152), 507 Wan, A. S. C., 22(101), 37, 42(19), 47(19), 52(19), 53(19), 53(19), 54(27), 59 (27), 70,487(157), 507 Warnhoff, E. W., 309(5), 313(5), 317(49), 356(5), 359(118), 360(118), 363(49), 378(5), 385(5), 400, 401, 403 Warren, F. L., 26(163), 39, 196(8, 9), 197(8, l l ) , 198(11), 199(11), 204, 310 (12, 15), 313(28), 318(50), 343(50), 344 (50), 384 (12), 401 Warwick, R., 474(63), 505 Waser, P., 26(162), 39, 199(12),204 Watanabe, M., 482(116), 506 Webster, B. R., 2(3a), 4(3a), 33(3a), 34 Webster, D. E., 510 Wei, C . H., 23 (108), 37 Weisbach, J. A,, 19(71, 72), 23(113, 113a), 36, 37, 52(28), 58(28, 50, 54), 59(50, 55, 56), 65(45, 54), 67(54, 56), 71, 80 (9), 92(9), 94(46), 95(9), 97, 98, 120 (87), 124, 174, 186, 302(99), 306 Weiss, J. A., 118(76a), 123, 184(70), 187, 271 (86a), 306 Wenkert, E., 33(13), 34, 45(6), 47(6), 54 (6), 70, 86(32), 98, 130(13), 131(22), 137(39), 143, 169(39), 174, 186, 236 (74), 305, 373(140), 404, 450, 457 Werblood, H. M., 50(26c), 56(26c), 7 0 Werner, G., 495(186), 508 Whalley, W. B., 147(11),185 Whitlock, H. W., Jr., 368(132, 133), 379 (133), 404 Whittaker, N., 174(45a),186 Wibaut, J. P., 461 (4), 503

533

Wickberg, B., 130(13), 131(22), 143, 169 (39), 186 Wiehler, G., 495 (189), 508 Wieland, H., 464(29, 30), 465(29), 504 Wieland, T., 200(13), 202(16), 204 Wieters, E., 462 (23), 464(23), 465(23), 466(23), 467(23), 504 Wildman, W. C., 308(1), 309(5), 310(13, 17), 311(17, 21), 313(5, 17, 27), 317 (21, 47, 49), 321 (64), 323(66), 330(66), 331(84, 66, 78), 333(78), 338(78), 339(91), 345(91), 354(111, 112), 355 (114, 115), 356(5, 114), 357(114), 358 (115), 359(115, 118), 360(21, 118), 361(21, 119, 120, 121), 363(21, 49, 124), 364(124), 365(21), 370(17), 371 (115), 372(138), 373(141, 142), 374 (27), 375(27), 378(5), 379(115, 138, 145, 147), 381(149), 382(150), 385 (5), 392(47, 153, 154, 156, 158), 393 (47, 158, 164), 394(47), 395(47), 398 (153, 168, 169, 170), 400(164, 174), 400, 401, $02, 403, 404, 405, 602 (210), 509 Wilkins, C. K., Jr., 91 (39), 98 Wilkinson, D. I., 470(43), 504 Wilkinson, S., 462(20), 478(83), 504, 505 Willaman, J. J., 3, 4(11), 14(11),34 Williams, A. R., 415(20), 444(20), 456 Williams, D. H., 118(77), 123 Williams, D. J., 349 (104), 403 Williams, K. R., 174(45), 186 Willis, C. R., 302(99), 306 Willstlitter, R., 474(62), 505 Wilson, J. M., 45(9), 70, 113(52), 116(61), 119(80), 120(61), 122, 123, 131(17), 143, 219(63), 233(63), 237(75, 7G), 241 (75,76), 305,306,422 (40),423 (41), 424(41), 457 Winkler, W., 93 (44), 98 Winternitz, F., 21(99), 37, 184(69), 187 Wisse, J. H., 462 (18), 504 Witkop, B., 17(63), 36, 208(66), 215(66), 221 (66), 305 Wolf, A. P., 483(122), 506 Wolf, L., 478(88), 480(88), 505 Woodward, C. F., 482 (117), 506 Woodward, R. B., 442, 457 Wright, I. G., 2(5), 4(5), 34, 79(4), 97, 126(2), 142, 172(44), 186

534

AUTHOR INDEX

Wright, W. G., 313(28), 401 Wust, W., 462(23), 464(23), 465(23, 32), 466 (23), 467 (23), 504 Wu, P. L., 484(135), 507

Y Yajlma, H., 323(67), 370(137), 402, 404 Yakovleva, A. P., 313(26), 401 Yamamoto, Y., 316(40), 343(94), 347(40), 401,403 Yamasaki, K., 478(85), 505 Yamasaki, M., 79(2), 97 Yanai, H. S., 476(69), 505 Yanaihara, N., 323 (67), 402 Yang, K . S., 483(121), 486(150, 151), 506, 507, 510 Yardley, J. P., 177(47), 186 Yassi, J., 492 (183), 493 (183), 508 Yasunari, Y., 50(26a), 70 Yates, K . C., 128(8),143,226(69), 305 Yates, P., 19(72), 36, 302(99), 306 Yeoh,G.B., 31(183),40, 151(33, 33a,) 162 (33, 33a), 186 Yeowell, D. A., 26(161), 39, 53(35), 71, 450(62, 64), 452(62, 64), 453(64), 455 (64), 457 Yim, N. C., 174(45),186 Yokoyama, N., 342(93), 370(93), 403 Yonemitsu, O., 146(1),185,222(67), 305 Yoshida, D., 510 Yoshimura, N., 368(131), 379(131), 404 Yoshitake, A., 367 (127, 130), 370(136), 379(136), 404 Young, D. W., 447(53), 450(53), 457 Young, R. L., 74(4), 77 Yu, T. C., 488 (164), 507 Yuldashev, P. Kh, 24(128, 129, 130, 131, 132), 25(138), 38, 42(15, 16, 17, 18),

47(17, 18), 70, 112(43, 44), 113(44, 53, 54, 55), 114(53, 54, 55, 56, 57, 58, 60, 62, 63, 64, 67, 68, 69, 70), 115(56, 57, 58, 59, 60), 116(62, 63, 64), 122, 123, 151(29, 30), 162(29, 30), 165 (29, 30), 184(68, 74), 186, 187, 209 (ZOb), 231 (ZOb), 241 (76a), 303, 306 Yunusov, S. Yu., 24(128, 129, 130, 131, 132), 25(138), 38, 42(15, 16, 17, 18), 47(17, 18), 70, 112(43, 44), 113(44, 53, 54, 55), 114(53, 54, 55, 56, 57, 58, 60, 62, 63, 64, 67, 68, 69, 70), 115(56, 57, 58, 59, 60), 116(62, 63, 64), 122, 123, 151(29, 30), 162(29, 30), 165(29, 30), 184(68, 74), 186, 187, 209(20b), 231(20b), 241(76a), 303, 306, 319 (54, 55, 56, 57, 58, 60, 61), 320(61), 334(82), 346(56, 96, 97, 98, 99, 100, 101), 347(96), 382(61), 386(60), 402, 403 Yusupov, M. K., 410(8, 9, 10, 11, 14), 413 (18, 19), 434(9), 435(10, ll),456

Z Zabolotnaya,E. S., 16(50),35,117(74), 123 Zacharias, D. E., 302(99), 306 Zachystalova, D., 109(39), 122 208(16), 303 Zeitlin, A., 509 Zetler, G., 92(41), 98 Ziegler, E., 492 (193), 508 Ziegler, F. E., 89(38), 98 Zinnes, H., 177(46), 182(54), 186 Zulalian, J., 392(155), 393(155, 160, 161, 163), 394(155, 161, 163, 165), 395 (161, 166), 404, 405 Zvorykina, V. K., 481 (104), 506 Zweistra, A., 463(26, 27), 465(26), 504 Zymalkowski, F., 478(91), 505

SUBJECT INDEX A Abelmoschus esculentus, 12 Abrus precatorius, I 1 Acacia acuminata, 1 1 Acacia cardiophylla, 1 1 Acacia confusa, 1 1 Acacia cultiformis, 11 Acacia floribunda, 1 1 Acacia longifolia, 1 I .Acacia maidenii, 1 1 Acacia podalyriaefolia, I 1 Acacia pruinosa, 1 1 Acacia vestita, 1 1 Aceraceae, 9 Acer rubrum, 9 Acer saccharinum, 9 20-Acetoxytabersonine, 233 N-Acetylaspidospermatidine, 2 1 1 N-Acetylaspidospermidine, 208 Acetylcaranine, 309 0-Acetylcinchonamine, 73 Acetyllobinaline, 47 1 I-Acetyllycorine, 3 1 1, 32 I 0-Acetylmacranthine, 3 11 Acetylnerbowdine, 3 10, 354 0-Acetylvallesamine, 2 13 Actinidia polygama, 299 Actinidine, 499, 501, 503 Adina cordifolia, 27, 185 Adina rubrostipulata, 27 Aestivine, 315, 384 Affinine, 59, 62, 81 Affinisine, 52 Ajmalicine, 81, 119, 120 Ajmalidine, 50 Ajmaline, 42, 44, 46, 48, 50 Akuammicine, 100, 114 Akuammidine, 119 Alangiaceae, 2, 15 Alangium salviifolium, 15 Alangium lamarckii, 15 Albomaculine, 335 Alchornea floribunda, 25 Alchornea hirtella, 25 Allosedamine, 465

Alloyohimbanone, 182 Alstonia actinophylla, I5 Alstonia angustiloba, 15 Alstonia congensis, I 5 Alstonia constricta, 15 Alstonia giletti, 15 Alstonia macrophylla, 15, 67 Alstonia neriifolia, 15 Alstonia muelleriana, 15, 67 Alstonia scholaris, 15 Alstonia somersetensis, 15 Alstonia spatulata, 15 Alstonia spectabilis, 16 Alstonia venenata, 16, 146, 150, 215, 235, 249 Alstonia verticillosa, 16 Alstonia villosa, 16, 67 Alstoniline, 171 Alstophylline, 8, 44, 67 Amanitaceae, 9 Amanita citrina, 9 Amanita mappa, 9 Amanita muscaria, 9 Amanita pantherina, 9 Amanita porphyria, 9 Amanita tomentella, 9 Amaranthaceae, 9 Amaryllidine, 309, 322 Amaryllis belladonna, 309 Amaryllis parkeri, 309, 332 Amaryllisine, 357 Ambelline, 309, 358, 393 Ammocalline, 100 Ammocharis coranica, 3 10, 362 Ammodendrine, 490 Ammorosine, 100 Amsonia angustifolia, 16 Amsonia elliptica, I6 Amsonia salicifolia, 131 Amsonia tabernaemontana, 16, 13 1 Anabasine, 478, 48 1,483 Anacardiaceae, 9, 166 Anaferine, 487 Anahygrine, 487 Ananas sativus, 9

535

536

SUBJECT INDEX

Anatabine, 478, 48 1 Aniba rosaeodora, 496 Aniba duckei, 496 Anibine, 496 Andocymbine, 408, 433 Androcymbium melanthioides, 408, 455 Annapowine, 3 14, 360 Annonaceae, 2, 15 Anthocleista procera, 487 Antirhine, 183 Antirrhoea putaminosa, 27, 183 Apocynaceae, 2, 9, 15 Apovincamine, 108 Apoyohimbine, 169 Apparicine, 147, 2 12, 27 1 Araceae, 9 Arariba rubra, 13 Arthrophytum leptocladum, 10 Arundo donax, 1 1 Asclepiadaceae, 9 Aspergillus, 33 Aspidexcelsine, 2 13 Aspexeine, 151, 158, 213 Aspidoalbidine, 260 Aspidoalbine, 2 19 Aspidocarpine, 2 19 Aspidodasycarpine, 8, 206, 214, 280 Aspidofendlerine, 2 I 1, 260 Aspidofractinine, 209, 236, 244 Aspidolimidine, 2 18, 260 Aspidolimine, 2 19 Aspidosperma album, 16, 215 Aspidosperma auriculatum, 16 Aspidosperma austraie, 16, 2 15 Aspidosperma carapanauba, 16 Aspidosperma chakensis, 16 Aspidosperma compactinervium, 16 Aspidosperma cylindrocarpon, 16 Aspidosperma dasycarpon, 16, 2 15 Aspidosperma discolor, 16, 2 16 Aspidosperma dispersum, 16, 213, 215 Aspidosperma duckei, 16, 215, 252 Aspidosperma eburneum, 16, 2 15 Aspidosperma exaltum, 16, 215, 261 Aspidosperma excelsum, 16, 151, 183, 215 Aspidosperma fendleri, 16, 2 15 Aspidosperma gomezianum, 17, 21 5 Aspidosperma hilarianum, 17 Aspidosperma laxgorum, 17, 215

Aspidosperma limae, 17, 215, 270 Aspidosperma longipetiolatum, 17 Aspidosperma macrocarpon, 17, 215, 252 Aspidosperma marcgravianum, 17, 2 15 Aspidosperma megalocarpon, 17, 2 15 Aspidosperma multiforum, 17, 2 15 Aspidosperma neblinae, 17, 2 15 Aspidosperma nigricans, 17, 2 15 Aspidosperma nitidum, 17, 2 16 Aspidosperma oblongum, 17, 107, 148, 215 Aspidosperma obscurinervum, 17, 2 15 Aspidosperma olivaceum, 17, 2 15 Aspidosperma parvifolium, I7 Aspidosperma peroba, 17 Aspidosperma polyneuron, 9, 17 Aspidosperma populifolium, I7 Aspidosperma pyricollum, 17, 147, 150, 215 Aspidosperma pyrifolium, 17 Aspidosperma quebracho blanco, 17, 2 15, 228 Aspidosperma quirandy, 17 Aspidosperma refractum, 17 Aspidosperma rigidum, 17, 2 15 Aspidosperma sandwithianum, 17 Aspidosperma sessilgorum, 17 Aspidosperma spegazzini, 17, 45, 2 I5 Aspidosperma spruceanum, 17 Aspidosperma subincanum, 17, 216 Aspidosperma tomentosum, 17, 2 15 Aspidosperma triternatum, 17 Aspidosperma ulei, 18 Aspidosperma vargasii, 2 16 Aspidosperma verbascifolium, 18, 2 15 Aspidospermatine, 217 Aspidospermidine, 2 17, 2 19 Aspidospermine, 2 18, 2 19 Astrocasia phyllanthoides, 460, 493 Astrocasine, 493 Astrophylline, 493 Aulamine, 313, 322

B Banisteria caapi, 12 Banisteriopsis inebrians, 12 Bechuanine, 41 1, 435 Belladine, 31 I , 382, 391, 393 Beninine, 97, 21 1, 265, 299

SUBJECT INDEX

Bignoniaceae, 9 Bodamine, 3 17 Bowdensine, 3 17, 360 Bromeliaceae, 9 Brunsdonna tubergenii, 3 10 Bmnsdonnine, 3 10, 384 Brunsvigia cooperi, 3 10 Brunsvigine, 3 10, 384 Bulbocodine, 408, 434 Bulbocodium vernum, 408 Buphacetine, 310, 384 Buphanamine, 310, 361 Buphane disticha, 3 I0 Buphanicine, 3 10 Buphanidrine, 310, 353, 362 Buphanisine, 310, 353, 362 Burnamincine, 59

C Cabi paraensis, 12 Caffaeoschizine, I39 Calebassine, 200 Callichilia barteri, 18, 97, 215 Callichilia stenosepala, 18 Callichilia subsessilis, 18 Calkhiline, 93, 302 Calligonium 'alatum, 10 Calligonium caput-medusae, 10 Calligonium eripodum, 10 Calligonium macrocarpum, 10 Calligonium minimum, 10 Calycanthaceae, 9 Calycanthine, 4 Calycanthus Joridus, 9 Calycanthus glaucus, 9 Calycanthus occidentalis, 9 Camptorrhiza strumosa, 408, 435 Candimine, 314, 337 Canthine, 125 Caranine, 309, 327, 392 Campanaubine, 113 1-Carbomethoxy-P-carboline, 2 13, 279 Carex brevicollis, 10 Carica papaya, 10, 49 1 Caricaceae, 10 Carnavoline, 492 Carpaine, 490 Carpodinus umbellatus, 19

537

Cascarilla oblongifolia, 29 Cassia carnaval, 492 Cassia excelsa, 49 1 Cassine, 490 Cassinopsis ilicifolia, 27 Cathalanceine, 120 Catharanthine, 84, 92 Catharanthus lanceus, 18, 99, 119, 216 Catharanthus pusillus, 18, 99, I20 Catharanthus roseus, 18, 120, 215 Carharanthus tricolophyllus, 18 Catharine, 230 Catharosine, 101, 209, 230 Cathindine, 100, 107 Cavincidine, 100 Cavincine, 100, 107 Cerbera oppositifofia, 20 Charpentiera obovata, 9 Chenopodiaceae, 10 Chimonanthine, 4 Chimonanthus fragrans, 9 Chlidanthine, 3 I3 Cinchona calisaya, 28 Cinchona caloptera, 28 Cinchona carabayensis, 28 Cinchona condaminea, 28 Cinchona cordifotia, 28 Cinchona corymbosa, 28 Cinchona erythrantha, 28 Cinchona erythroderma, 28 Cinchona hasskarliana, 28 Cinchona lanceolata, 28 Cinchona lancifolia, 28 Cinchona ledgeriana, 28, 74 Cinchona lucumaefolia, 28 Cinchona macrocalyx, 28 Cinchona micrantha, 28 Cinchona nitida, 28 Cinchona oblongifolia, 29 Cinchona oficinalis, 29 Cinchona ovata, 29 Cinchona pahundiana, 29 Cinchona pelletieriana, 29 Cinchona pitayensis, 29 Cinchona pubescens, 29 Cinchona robusta, 29 Cinchona rosulenta, 29 Cinchona scrobiculata, 29 Cinchona succiruba, 29

538

SUBJECT INDEX

Cinchona tucujensis, 29 Cinchonamine, 73 Cinchonidine, 75 Cinchonine, 75 Cinchophyllamine, 74 Citrus aurantium, 13 Cleavamine, 85 Clivatine, 3 10 Clivia miniata, 3 10 Clivimine, 3 10, 338 Clivonine, 3 10, 338 Coccinine, 3 13, 375 Colchiceine, 410 Colchicide, 4 18 Colchicine, 414, 418, 436, 450 Colchicoside, 43 1 Colchicum alpinum, 408 Colchicum autumnale, 409 Colchicum byzantium, 409 Colchicum cornigerum, 409 Colchicum kesselringii, 4 10, 435 Colchicum luteum, 4 10 Colchicum macedonicum, 41 1 Colchicum monianurn, 4 1 1 Colchicum ritchii, 4 1 1 Condifoline, 2 1 I Conduramine, 92 Conhydrine, 474 Coniceine, 476 Coniine, 473 Conoduramine, 95 Conodurine, 95 Conoflorine, 22 1 Conopharyngia durissima, 18, 139, 2 I6 Conopharyngia hutstii, 18 , 1 39, 2 16 Conopharyngia jollyana, 18, 8 1 Conopharyngia longiflora, 2 16 Conopharyngia pachysiphon, 8 1, 2 15 Conopharyngine, 80 Convolvulaceae, 10, 33 Coprinaceae, 10 Coprinus micaceous, 10 Coranicine, 3 10, 385 Cordifoline, 185 Cornigereine, 42 1 Cornigerine, 408, 42 1, 43 1 Coronaridine, 80, 84, 92, 226 Coruscine, 3 10 Corymine, 136

Corynanthe macroceras, 29 Corynanthe paniculata, 29 Corynanthe yohimbe, 29 Corynantheidol, 174 Corynantheidine, 174 Corynantheine, 106, 172 Corynoxine, 185 Coutarea latipora, 29 Crinalbine, 3 12, 362 Crinamidine, 3 10, 353, 362 Crinamine, 310, 353, 370, 389 Crinine, 3 10, 352, 364, 369 Crinum erubescens, 3 I0 Crinum jimbriatulum, 3 1 1 Crinum Iaurentii, 3 11 Crinuum macrantherum, 3 1 1 Crinum moorei, 3 1 1 Crinum powellii, 3 1 1 Crinum zeyfanicum, 3 13 Cripaline, 3 12, 365 Crispamine, 384 Criwelline, 31 1, 370, 381 Cryptolepine, 4 Crypiolepis sanguinolenta, 9 Cryptolepis triangularis, 9 Curarine, 202 Cuscohygrine, 487 Cylindrocarpidine, 2 19 Cylindrocarpine, 2 19 Cyperaceae, 10

D Dasycarpidol, 2 12 Dasycarpidone, 212, 27 1 N-Deacetylaspidospermine, 2 19, 222 0,O-Deacetylbowdensine, 360 Deacetylvindoline, 209 Deacetylvindorosine, 230 1,2-Dehydroaspidospermine, 208, 2 19 3,4-Dehydro-8,1O-diethyllobelidiol, 467 3,4- or 4 3 - Dehydro- 8-methyl- 10-ethyllobelidiol, 466 Dehydroskytanthine, 502 19-Dehydroyohimbine, 147, 150, 2 14 Demecolcine, 4 18, 43 I Demethoxypalosine, 219 17-Demethoxyquebrachamine, 2 19 Demethylaspidospermine, 147, 2 19

539

SUBJECT INDEX

3-Demethyldemecolcine, 409, 432 Demethylhomolycorine, 3 I8 0-Demethypalosine, 208, 228 10,l 1-Deoxopleiocarpine, 247 2 I-Deoxyajmaline, 46 2 I-Deoxyisoajmaline, 46 Deoxyperaksine, 54 Desacetamidocolchicine, 43 6, 445 Desacetylcolcheine, 436 Deserpidine, 183 Des-N-methyldasycarpidone, 2 12 Des-N-methyluleine,-2 I 1 Desmodium pulchellum, 1 1 Diaboline, I95 0,O-Diacetylmacranthine, 3 11, 385 Dichotamine, 2 19 Dictyolama incanescens, 13 Dictyolama vandeltianum, 13 8,lO-Diethyllobelidiol, 467 8,lO-Diethyllobelionol, 467 8,IO-Diethylnorlobelidione,465 8,IO-Diethylnorlobelianol,466 2,16-Dihydroakummicine, 196 Dihydroambelline, 3 17 Dihydrocinchonamine, 7 3 Dihydrocleavarnine, 228 Dihydrocorynantheine, 174 Dihydrocrinine, 367 2,14-Dihydrogambirtanine,147, 150, 183 Dihydrogentianine, I74 Dihydrohaemanthamine, 3 11 Dihydrohaemanthidine, 373 2,7-Dihydromavacurine, I93 Dihydroneblinane, 265 Dihydronicotyrine, 478 Dihydroobscurinervidine, 2 1 1 , 263 Dihydroobscurinervine, 2 1 1, 263 2,7-Dihydropleiocarpamine,193 2,7-Dihydropleiocarpaminol,193 Dihydrositsirikine, 106, 148, 150 Dihydrotoxiferine-I, 200 Dihydrovittatine, 367 Dilleniaceae, 10 Dioclea bicolor, 11 Dioclea lasiocarpa, I 1 Dioclea macrocarpa, 11 Dioclea reflexa, 11 Dioclea violacea, 11 10,22-Dioxokopsane, 210

10,l I-Dioxypleiocarpine, 2 10 8, I 0-Diphenyllobelidione, 470 8,IO-DiphenyIlobelionol,469 Dipidax triquetra, 41 I Dipidax rosea, 41 1 cu,P-Dipiperidyl, 494 Diplorrhyncus condylocarpon, I8 Distichamine, 3 10, 385 Duboisia hopwoodii, 478 Duboisia myoporoides, 462, 477 Draconiomelum mangiferum, 9, 15 1, 166 Dregamine, 58, 63

E Eburnamenine, 292 Eburnamine, 108, 125, 226 Eburnarnonine, 108, 129 Echitamine, 8 Echitovenidine, 209, 233 Echitovenine, 209, 233 Eleagnaceae, 10 Eleagnus angustifoh, 10 Eleagnus horiensis, 10 Eleagnus orientalis, 10 Eleagnus spinosa, 10 Ellipticine, 279 Elwesine, 3 13 Enanfia pilosa, 15 Enantia polycarpa, 15 Enicosremma littorale, 487 Epialloyohimbane, 169 Epibuphanisine, 3 10, 362 Epicrinine, 310, 369 3-Epidasycarpidone, 2 12 Epigalanthamine, 3 16 Epiherbaceine, 1 18 Epikopsanol, 210 Epimeloscine, 209, 242 3-Epiravanine, 159 Epipleiocarpamine, 190 Epipleiocarpinine, 247 3-Epiuleine, 2 12 16-Epivincamine, 108, 13 1 19-Epivoacangarine, 83 19-Epivoacorine, 92, 95 19-Epivoacristine, 80, 83, 95 Epoxykopsinine, 249 Ereine, 114

540 Erectine, 1 15 Erinicine, 136 Erinine, 136 Ervamine, I 14, I 16, 209 Ervatamia coronaria, 18, 23 Ervatamia dichotoma, 19, 8 1 Ervatamia divaricata, 19 Ervine, 184 Erythrina abyssinica, I 1 Erythrina acanthocarpa, 11 Erythrina americana, 1 I Erythrina berteroana, 11 Erythrina carnea, 11 Erythrina cosfaricensis, 1 1 Erythrina cristagalli, 1 1 Erythrina dominguezii, 11 Erythrina excelsa, 1 I Erythrina falcata, I 1 Erythrina ~7abelliformis,I 1 Erythrina folkersii, 1 1 Erythrina fusca, 11 Erythrina glauca, 11 Erythrina griesbachii, 11 Erythrina herbacea, 1 I Erythrina hypaphorus, 11 Erythrina indica, 12 Erythrina macrophylla, 1 1 Erythrina orophila, 12 Erythrina pallida, I2 Erythrina poeppigiana, 12 Erythrina rubrinerva, 12 Erythrina sandwicensis, 12 Erythrina senegalensis, 12 Erythrina subumbrans, 12 Erythrina tholloniana, 12 Erythrina variegata, 12 Erythrina velutina, 12 Erythroxylum coca, 477 8-Ethylnorlobelol, 464 Euphorbiaceae, 2, 10, 25 Evodia alata, 13 Evodia rutaecarpa, 13 Evodiarnine, 4 Evonine, 489 Evoninic Acid, 490 Euonymus europaeus, 460,489 Excavatia coccinea, 19 Excelsinine, 183

SUBJECT INDEX

F Falcatine, 323 Fendleridine, 2 10 Fendlerine, 21 1 Fiancine, 3 11, 373 Flavopereirine, 18 1 Flexarnine, 3 17, 364 Flexine, 3 17 Flexinine, 313, 353 Fluorocarparnine, 2 14, 285 Fluorocurine, 189, 285 Fragraea fragrans, 487 Fruticosarnine, 255 Fruticosine, 255

G Gabonine, 83 Gabunia eglandulosa, 19 Gabunia odoratissima, 19, 81, 120 Gabunine, 92, 95 Galanthamine, 309, 348, 389, 392 Galanthine, 309, 330 Galanthus elwesii, 3 13 Galanthus nivalis, 3 13, 352 Galanthus woronovii, 3 13 Garnbirine, 183 Garnbirtanine, 147, 150, 183 Geissospermum sericeum, 19 Geissospermum laeve, 19 Geissospermum vellosii, 19, 23 Gelsernine, 8 <>elsemiurnelegans, 26 Gefsemium sempervirens, 26 Gentiana macrophylla, 488 Gentiana species, 487 Gentianidine, 488 Gentianine, 487 Gentiopicrin, 487 Girgensohnia diptera, 10 Gloriosa simplex, 4 11 Gloriosa superba, 4 1 1 Gloriosa virescens, 4 1 1 Golceptine, 323 Goleptine, 3 16, 323 Gonioma kamassi, 9, 19, 131, 151,215,279 Gossypium herbaceurn, 12 Gossypium hirsutum, 12

SUBJECT INDEX

Gramineae, I 1 Gamine, 4 Grewia salviiyolia, 15

H Habranthus braychyandrus, 3 14 Haemanthamine, 3 I I , 353,370,389,393 Haemanthidine, 3 13, 353, 390 Haemanthus coccineus, 400 Haemanthus kaiherinae, 3 13 Haemanthus rnultiflorus, 3 13 Haemanthus natalensis, 3 13 Haemanthus tigrinus, 3 13 Haemultine, 309, 373 Haljordia scleroxyla, 498 Halfordine, 498 Halfordinol, 498 Halfordinone, 498 Hammada leptoclada, 10 Haemadictyon amazonicum, 9 Haplocidine, 2 19 Haplocine, 2 19 Haplophytine, 302 Haplophyton cimicidum, 19, 215 Hedanthera barteri, 215 Henningsarnine, 196 Henningsoline, 196 Herbaceine, 116, 150, 159, 160 Herbaine, 118, 150, 159, 160 Herbaline, 117, 151, 162, 185 Herbine, 119 Hervine, 183 Hexahydrocolchicine, 4 18 Heyneanine, 80, 83 Hippacine, 385 Hipparnine, 3 14, 325 Hippandrine, 3 14, 385 Hippauline, 314, 385 Hippawine, 3 14, 373 Hippeastrine, 309, 340 Hippeastrum auliculum, 3 I3 Hippeastrum brachyandrum, 3 14 Hippeastrum candidum, 3 14 Hippeastrum hybrids, 3 14 Hippomane mancinella, 10 Hirsutine, 148, 151 Hodgkinsonia frutescens, 13

541

Homolycorine, 3 15, 340 Homoneblinine, 2 I I Homosempervirine, 17 1 Homostachydrine, 495 Hordenine, 3 18, 382 Hordeum vulgare, 7 1 Hortia arborea, 13 Hortia braziliana, 13 Huntabrine, 2 14 Hunteria corymbosa, 19 Hunteria eburnea, 19, 134, 190, 2 15 Hunteria umbellata, 19, 136 Hunteriamine, 134 Hunterburnine, 135 Huntrabrine, 135 6-Hydroxycrinamine, 3 10,370,392 6(or 7)-Hydroxykopsinine, 209, 249 20-Hydroxykopsinine, 209 1 I-Hydroxynorfluorocurine, 114 1 I-Hydroxyvittatine, 355 Hydroxywilfordic Acid, 489 Hymenocallis americana, 3 15 Hymenocallis festalis, 3 15 Hymenocallis harrisiana, 3 15

I Ibogaine, 89 Ibogaline, 92 Ibogamine, 80, 83, 88 Iboluteine, 81, 83 Iboxygaine, 80 Icacinaceae, 2, 27 Indolo[2,3-~pyridocolline,15 1, 21 3 lphigenia bechuanica, 41 1 lphigenia indica, 412 Iphigenia oliveri, 4 12 Iphigenia pallida, 412 lpomoea violacea, 10 Isoajmaline, 46 Ismine, 312, 382 lsmene species, 3 15 Isocinchophyllamine, 74 Isocolchicine, 4 18 Isocorydine, 408, 435 Isocorymine, 136 Isodemocolcine, 418 Isoeburnamine, 13I

542

SUBJECT INDEX

Isokopsine, 258 Isolumicolchicine, 422 lsomitraphylline, 177 Isopelletierine, 461 Isopteropodine, 15 1, 162 Isoreserpiline, I59 lsosandwicine, 42 Isoschizogaline, I39 Isoschizogarnine, 139 Isositsirikine, 107, 150, 148 Isotuboflavine, 126, 213, 279 Isovenenatine, 146, 150 Isovoacangine, 80 Isovoacarpine, 60 Isovoacristine, 80, 83 Isovobasine, 61 Ixanthus viscosus, 487

J Jonquilline, 3 16, 325 Julocrotine, 496 Julocroton montevidensis, 496

K Kesselringine, 4 10, 434 Kisantine, 81, 82 Kopsaporine, 25 I Kopsia albtfibra, 19 Kopsia arborea, 19 Kopsia ftavida, I9 Kopsia fruticosa, I9 Kopsia longiJlora, 19 Kopsia pruniformis, 19 Kopsia singaporensis, 19 Kopsane, 254 Kopsanol, 210 Kopsanone, 210, 254 Kopsine, 245 As-Kopsinene, 249 Kopsingine, 25 1 Kopsinine, 114 Kopsinoline, 2 10 Krelagine, 3 12, 373 Krepowine, 3 12 Krigeine, 3 18, 344 Krigenarnine, 3 18, 343 Krornantine, 260

L Ladenbergia hexandra, 147 Lanceine, 1 19 Lauraceae, 1 1 Leguminosae, 1 I Lens esculenta, 12 Leptactina densipom, 13 Lespedeza bicolor, 12 Leucojum aestivum, 3 15 Leurocristine, 85, 105 Leurosidine, 105, 230 Leurosine, 105, 120 Leurosivine, 100 Limapodine, 2 19 Limaspermine, 2 19 Limatine, 212, 269 Limatinine, 212 Littonia modesta, 4 12 Lobelia cardinalis, 470 Lobelia elongata, 470 Lobelia inflata, 464 Lobelia syphilitica, 465 Lobinaline, 470 Lochnera lancea, 19 Lochnera pusilla, 18, I9 Lochnera rosea, 19, 215 Lochnericine, 107, 209, 219, 231 Lochnerinine, 107, 120, 209, 219, 23 Lochnervine, 100 Lochrovicine, 10 1 Lochrovidine, 101 Lochrovine, 101 Loganiaceae, 2, 12, 26 a-Lumicolchicine, 422, 428 P-Lumicolehicine, 41 8, 426 7-Lumicolchicine, 41 8 Lumidemicolcine, 43 1 Lumiisocolchicine, 429 Lupinus albus, 12 Lupinus angustifolius, 12 Lupinus luteus, 12 Lupinus polyphyllus, 1 2 Lycopersicum esculentum, 14 Lycorarnine, 3 12 a-Lycorane, 329 P-Lycorane, 328 Lycorenine, 309, 334, 340 Lycorine, 309, 325, 388,392

543

SUBJECT INDEX

Lycoris aurea, 3 I5 Lycoris radiata, 3 16 Lycoris squamigera, 3 16

M Maandrosine, 100 Macoubea guianensis, 20 Macranthine, 3 1 1, 385 Macralstronine, 67 Macroline, 44, 68 Macronine, 3 I 1, 38 1 Macusine-B, 52 Macusine-C, 53 Magnarcine, 3 13 Majdine, 111, 112, 151, 162 Majoridine, 42, 46, 1 12 Majorine, I12 Majovine, 1 12 Malphighiaceae, L Malvaceae, 12 Manthidine, 385 Manthine, 3 13, 3 5 Maritidine, 356 Masonine, 3 13, 345 Mavacurine, 136, 189, 285 Medicago sativa, 495 Melanthioidine, 408, 434 Melodinus australis, 20, 2 13, 2 14, 249 Melodinus scandens, 20, 215, 242 Meloscandine, 209, 244 Meloscine, 206, 209, 242 Meratia praecox, 9 Merendera bulbocodium, 4 12 Merendera persica, 4 12 Merendera robusta, 4 13 16-Methoxycatharosine, 209 10-Methoxycorynanthine, 2 14 Methoxyellipticine, 279 Methoxygeissoschizine, 15 1, 158 7-Methoxyharman, 75 I I-Methoxylimatine, 2 12 1 I-Methoxylimatinine, 2 12 16-Methoxyminovincine, 2 19 9-Methoxyolivacine, 2 13 17-Methoxyquebrachamine, 208 I I-Methoxysitsirikine, 1 I9 0-Methylandrocymbine, 455 N-Methylaspidosperrnidine, 208

I -Methyl-3-carboxy-p-carboline, 2 13 8-Methyl- 10-ethyllobelidiol, 466 0-Methynorbelladine, 3 17, 382 8-Methylnorlobelol, 463 8-Methylnorlobelone, 464 8-Methyl- 10-phenyldehydrolobelidiol,468 8-Methyl- 10-phenyllobelidiol, 468 8-Methyl- 1O-phenyllobelionol, 468 Methypseudolycorine, 309, 330 N-Methylquebachamine, 208 Mimosa hostilis, 12 Miniatine, 310, 385 Minoriceine, 109 Minoricine, 109, 233 Minovine, 108 Minovincine, 120, 219, 233, 236 Minovincinine, 219, 233 Mitragyna africana, 29 Mitragyna citiata, 29 Mitragyna diversifolia, 29 Mitragyna hirsuta, 29, I5 1 Mitragyna inermis, 29 Mitragyna javanica, 29, 150 Mitragyna macrophylla, 29 Mitragyna parvipora, 30 Mitragyna rotundifolia, 30 Mitragyna rubrostiputacea, 27, 30 Mitragyna speciosa, 30, 15 1 Mitragyna stipulosa, 30 Mitrajavine, 150, 159 Mitraphylline, 100, 177 Montanine, 81, 84, 313, 375 Mostuea buchholzii, 26 Mostuea stimulans, 26 Mucuna pruriens, I2 Musaceae, 12 Musa sapientum, 12 Musa paradisica, 12 Myosmine, 478

N Narcidassine, 383 Narciprimine, 383 Narcissidine, 312, 33 1 Narcissus incomparabilis, 383 Narcissus jonquilla, 3 16 Narcissus poeticus, 3 16 Narcissus pseudonarcissus, 3 I6

5 44

SUBJECT INDEX

Nartazine, 3 13,332 Narwedine, 3 13 Nauclea formosana, 30 Neblinine, 21 I , 219,261 Neflexine, 312,333 Neoreserpiline, 160 Nerbowdine, 3 10,353 Narifline, 3 18,385 Nerine bowdenii, 3 17 Nerine crispa, 3 17 Nerine j e x u o s a , 3 17 Nerine krigei, 3 18 Nerine undulata, 3 18 Nerinine, 3 15,335 Nerispine, 3 18,332 Neronine, 3 18,344 Nerundine, 318,385 Neruscine, 3 12,345 Nervobscurine, 214,279 Newbouldia laevis, 9 Nicotine, 477,478,483 Nicotoine, 483 Nicotyrine, 478 Nivalidine, 352 Nivaline, 3 15,345 Norallosedarnine, 464 Norbelladine, 398 Noriluorocurarine, 1 14,199 Norisotubiflavine, 126 Norisotuboflavine, 213,279 Normavacurine, 190 Norneronine, 3 18 Nornicotine, 478 Norpluviine, 3 14,332,392 Nudiflorine, 495

0 Obscurinervidine, 2I 1, 219 Obscurinervine, 21 1, 219, 261 Ochropamine, 5 8 , 65 Ochropine, 58, 65 Ochrosandwine, 148,151,154,213 Ochrosia elliptica, 20 Ochrosia glomerata, 20 Ochrosia moorei, 20 Ochrosia oppositifolia, 20 Ochrosia poweri, 20 Ochrosia sandwicensis, 20,15 I , 215

Oduline, 345 Olivacine, 279 Orchipeda foetida, 97 Orensine, 490 Ornithoglossum glaucum, 413 Ornithoglossum viride, 413 Ourouparia africana, 30 Ourouparia formosana, 30 Ourouparia gambir, 30 Ourouparia guianensis, 30 Ourouparia rhynchophylla, 30 Ouroparine, 147,150 2I-Oxoaspidcalbine, 21 1 10-Oxocylindrocarpidine, 208,228 10-Oxoepikopsanol, 2 10 10-Oxokopsanol, 210 Afi-8-Oxokopsinene, 210,251 21-Oxo-O-methylaspidoalbine, 21 1 Oxycolchicine, 421, 424 Oxygambirtanine, 146,150, 183

P Pachysiphine, 81,214 Palosine, 219 Panaeolus acuminatus, 10 Panaeolus campanulatus, I0 Panaeolus foenescii, 10 Panaeolus fontinalis, 10 Panaeolus gracilis, 10 Panaeolus semiovatus, 10 Panaeolus solidipes, 10 Panaeolus sphinctrinris, I0 Panaeolus subalteatus, 10 Panaeolus texensis, 10 Pancratine, 3 18 Pancratium arabicum, 3 18 Pancratium longiflorum, 3 I8 Pancratium maritimum, 3 18, 355 Pancratium sickenbergii, 3 18 Pancratium tortifolium, 3 19 Pancratium tortuosum, 3 19 Pancratium trijorum, 3 19 Parkacine, 309,332 Parkarnine, 309,333 Passifloraceae, 13 Passiflora actinea, 13 Passiflora alata, 13 PassiJora alba, 13

SUBJECT INDEX

Passipora bryonioides, 13 Passifora capsularis, I3 Passiflora edulis, 13 Passij¶ora eichleriana, I 3 PassiJlora foetida, 13 Passiflora incarnata, 13 Passifora quadrangularis, I3 Passijora ruberosa, 13 Pausinystalia macroceras, 29, 30 Pausinystalia trillesii, 30 Pausinystalia yohimbe, 29, 30, 107, 148 Paynantheine, 148, 15 1 Peganum harmala, 14 Pelletierine, 46 1, 487 Penarcine, 347 Pentaceras australis, I3 Perakine, 44, 54 Peraksine, 44, 52, 54 Pericalline, 100, 120, 139 Pericyclivine, 52, 63, 119, 120 Periformyline, 59, 62, 65, 119 Periline, 59 Perimivine, 101, 120 Perividine, 59, 107 Perivindine, 100 Perivindoline, 105 Perivine, 58, 63, 65, 107, 119 Perosine, 58 Persea gratissima, 1 I Peschiera aflnis, 20, 23 Petalostylis labicheoides, I 1 Petomine, 309 Phalaris arundinacca, 1 I Phalaris tuberosa, 1 1 8-Phenyllobelol, 465 8-Phenylnorlobelol, 464 Physostigma cylindrospermum, 12 Physostigma venenosum, 12 Picralima klaineana, 20 Picralima nitida, 20, 150 Picralima umbellata, 19, 20 Picraline, 280 Picraphylline, 59, 150 Picrasma ailanthoides, 13 Picrasma crenata, 13 Pinidine, 488 Pipecolic, 496 Piperine, 460 Piperlongumine, 460

545

Piperlonguminine, 460 Piper longum, 460 Piplartine, 460 Piptadenia colubrina, 12 Piptadenia excelsa, 12 Piptadenia falcata, 12 Piptadenia macrocarpa, 12 Piptadenia peregrina, 12 Pleiocarpa flavescens, 20 Pleiocarpa mutica, 9, 20, 126, 135, 148, 190, 215, 247, 252 Pleiocarpa pycnantha, 9, 2 1, 126, 2 15 Pleiocarpa tubicina, 9, 20, 126, 215 Pleiocarpamine, 136, 189, 285 Pleiocarpaminol, 190 Pleiocarpine, 247 Pleiocarpinilam, 254 Pleiocarpinine, 244, 254, 292 Pleiocarpolinine, 2 10 Pleiomutine, 206, 213, 292 Pleiomutinone, 292 Plumaria durissima, I8 Pluviine, 3 14, 330 Poetamine, 316, 321, 385 Poetaminine, 3 16 Poetaricine, 3 16, 385 Pogonopus tubulosus, 3 1 Polyadoa umbellata, 19 Polygalaceae, 13 Polygala tenuifolia, 13 Polygonaceae, 10 Polyneuridine, 52, I16 Pouteria sp., 3 1 Powellamine, 3 11, 365 Powellidine, 3 12, 386 Precondylocarpine, 2 12, 270 Prestonia amazonica, 9 Prosopine, 490 Prosopinine, 490 Prosopsis africana, 492 Prosopsis juliflora, 12 Prunus domestica, 13 Pseudocarpaine, 49 1 Pseudocinchona africana, 3 1 Pseudocinchona mayumbensis, 3 1 Pseudoconhydrine, 475 Pseudokopsinine, 114, 241 Pseudolycorine, 3 10 Pseudotropine, 486

546

SUBJECT INDEX

Psilocybe atrobrunnea, 14 Psilocybe aztecorum, 14 Psilocybe baeocystis, 14 Psilocybe caerulescens, 14 Psilocybe caevulipes, 14 Psilocybe cyanescens, 14 PsiLocybe mexicana, 14 Psilocybe semperviva, 14 Psilocybe stricticeps, 14 Psilocybe zapotecorum, 14 Pteropodine, 15 1, 162 Pubescine, 1 12 Pusiline, 120 Pusilinine, 120 Pyrifolidine, 2 19

Q Quebrachamine, 115, 116, 218, 220, 224 Quebrachidine, 47, 116 Quinidine, 75 Quinine, 75

R Radiatine, 3 16, 347 Raujemidine, 183 Raumitorine, I59 Rauvanine, 159 Rauvoxine, 151, 162 Rauvoxinine, 15 I , 162 Rauwolfia aBnis, 2 1 Rauwolfia amsoniaefolia, 21 Rauwolfia bahiensis, 2 I RauwolJa beddomei, 2 I Rauwolfia boliviana, 21 Rauwolfia caflra, 21 RauwolJa cambodiana, 2 1 Rauwolfia canescens, 21 Rauwolfia chinensis, 21 Rauwolfia cubana, 2 1 Rauwolfia cummunsii, 2 1 Rauwolfia decurva, 2 1 Rauwo/fia degeneri, 2 1 Rauwolfia densijora, 21 Rauwoljia discolor, 2 1 Rauwolfia fruticosa, 2 I Rauwolfia grandifora, 2 1 Rauwolfia heterophylla, 2 1

Rauwolfia hirsuta, 21 Rauwolfia indecora, 2 1 Rauwolfia inebrians, 2 1 Rauwolfia javanica, 2 I Rauwolfia lamarckii, 2 1 Rauwolfia ligustrina, 2 1 Rauwolfia littoralis, 2 1 Rauwolfia longeacuminata, 21 Rauwolfia longifolia, 2 1 Rauwolfia macrocarpa, 22 Rauwotfia macrophylla, 22 Rauwolfia mannii, 22 Rauwolfia mattfeldiana, 22 Rauwolfia mauiensis, 22 RauwolJa micrantha, 22 Rauwolfia mombasiana, 22 Rauwolfia nana, 22 Rauwoljia natalensis, 22 Rauwolfia nitida, 22 Rauwolfia obscura, 22 Rauwolfia paraensis, 22 Rauwolfa pentaphylla, 22 Rauwolfia perakensis, 22, 47 Rauwolfia rosea, 22 Rauwolfia salicifolia, 2 2 Rauwolfia sandwicensis, 22 Rauwoifia sarapiquensis, 22 Rauwolfia sclrueli, 22 Rauwolfia sellowii, 22 Rauwolfia semperjorens, 22 Rauwolfia serpentina, 23 Rauwolfia sprucei, 23 Rauwolfia sumatrana, 23 RauwolJa fernifolia, 23 Rauwolfia tetraphylla, 23 Rauwolfia verticillata, 23 RauwolJa viridis, 23 Rauwolfia vomitoria, 23, 45, 151 Rauwolfia welwitschii, 23 Rauwolfia yunnanensis, 23 Rejoua aurantiaca, 8 I , 2 I5 Remijia pedunculata, 3 I Remijia purdieana, 3 1 Reserpiline, 159 Reserpinine, I 13, 1 I7 Rhazya stricta, 215 Rhazidine, 208, 221 Rhizopus, 33 Rhodophiala bifida, 355

SUBJECT INDEX

Rhynchophyllol, 177 Ricinidine, 495 Ricinine, 483, 485 Rindline, 196 Rosaceae, 13 Rovidine, 100 Rubiaceae, 2, 13, 27 Rulodine, 386 Rupicoline, 8 1, 83 Rutaceae, 13

S Salpiglossis sinuata, 478 Sandersonia aurantiaca, 4 I3 Sandicine, 42 Santiaguine, 490 Sapotaceae, 2, 31 Sarpagine, 5 1, 93 Schizogaline, 139 Schizogamine, 139 Schizoluteine, 139 Schizophylline, 139 Schizozygine, 137, 139 a-Schizozygol, 139 P-Schizozygol, 139 Schizozygia cafleoides, 120, 137, 216 Sedamine, 465 Sedridine, 463 Sedum acre, 462 Sempervivum arachnoideum, 477 Sickenbergine, 3 18, 386 Sickingia rubra, 13 Simurabaceae, 13 Sitsirikine, 106, 148, 150 Skytanthine, 501 Skytanthus acutus, 501 Solanaceae, 14 Soianum melongena, 14 Solanum nigrum, 14 Speciogynine, 148, 15I Speciophylline, I5 I , 162 Spegazzinidine, 2 19 Sprekelia formosissima, 3 19, 400 Squamigerine, 316, 386 Stachydrine, 495 Stemmadenia donnell-smithii, 8 1 Stemmadenia obovata, 81 Stemmadenia tomentosa, 8 1 Stemmadenine, 8 1

Stephagine parvifolia, 29 Sternbergia lutea, 3 19 Strictamhe, 214, 279 Strophariaceae, 14 Stropharia cubensis, 14 Strumosine, 408, 435 Strychnos aculeata, 26 Strychnos amazonica, 26 Strychnos chlorantha, 26, 199 Strychnos cinnamomifolia, 26 Strychnos colubrina, 26 Strychnos diaboti, 26 Strychnos divaricans, 26 Strychnos freesii, 26 Strychnos gaultheriana, 26 Strychnos guianensis, 26 Strychnos henningsii, 26, 196 Strychnos holstii, 26 Strychnos icaja, 26 Strychnos ignatii, 26 Strychnos kipapa, 26 Strychnos lanceolaris, 27 Strychnos ligustrina, 27 Strychnos lucida, 27 Strychnos macrophylla, 27 Strychnos malaccensis, 27 Strychnos melinoniana, 12, 27 Strychnos mitscherlichii, 27 Strychnos nux-vomica, 27, 194 Strychnos psilosperma, 27 Strychnos quaqua, 27 Strychnos rheedei, 27 Strychnos rubiginosa, 27 Strychnos smilacina, 27 Strychnos solimoesana, 27 Strychnos splendens, 27 Strychnos subcordata, 27 Strychnos tieute, 27 Strychnos tomentosa, 27 Strychnos toxifera, 27 Strychnos trinervis, 27 Suisenine, 333 Swertia japonica, 487 Sw ertiamann, 48 7 Symplocarpus foetidus, 9 Symplocaceae, 14 Symplocos racemosa, 14 Syphdobine- A, 472 Syphilobine-F, 472

5 47

548

SUBJECT INDEX

T Tabernaemontana affnis, 23 Tabernaemontana alba, 23, 8 1 Tabernaemontana amygdalifolia, 23, 2 IS Tabernaemontana australis, 23 Tabernaemontana citrifolia, 23 Tubernuemontuna coronaria, 18, 23 Tabernaemontana dichotoma, 8 1 Tabernaemontana entartica, 8 1 Tabernaemontana fuchsiaefolia, 23 Tabernaemontana globosa, 25 Tabernaemontana heyneana, 23, 8 1 Tabernaemontana holstii, 18 Tabernaemontana jollyana, 18 Tabernaemontana laevis, 19, 23 Tabernaemontana laurifolia, 24, 81 Tabernaemontana mucronata, 24 Tabernaemontana oppositifolia, 24 Tabernaemontana pachysiphon, 24, 8 I , 21s Tabernaemontana pandacaqui, 24, 8 1 Tabernaemontana psychotrifolia, 24 Tabernaemontana rupicola, 24,8 1 Tabernaernontanine, 5 8 , 63 Tabernanthe iboga, 24 Tabernanthine, 80 Tabernoschizine, 139 Tabersonine, 8 1, 2 19, 263 Tazettine, 3 1 1 , 378, 390, 392 Tecomanine, 502 Tecoma stuns, SO2 Tecostanine, SO2 Tetrahydroalstonine, I 19 Tetraphyllicine, 42 Tetraphyllinine, 184 3a-Tigloyloxytropane, 486 Tonduzia longifolia, 24 Toxiferine-I, 200 Trewia nudiJlora, 495 Triptetygium wilfordii, 460, 489 Trispheridine, 3 19, 386 Trispherine, 3 19 Tropine, 486 Tubispacine, 364 Tubispathine, 320 Tuboflavine, 126 Tuboxenine, 209, 237

U Uleine, 147, 271 Ultracurine A, 202 Ultracurine B, 202 Umtaline, 408, 435 Uncaria bernaysii, 3 I Uncaria ferreu, 3 1 Uncaria gambir, 31, 147, 150, 183 Uncaria kawakami, 3 1 Uncaria pieropoda, 3 1 , 15 1 Uncaria rhynchophylla, 3 1 Uncaria tomentosa, 3 1 Undulatine, 3 10, 353 Ungerine, 3 15 Ungernia minor, 3 19 Lingernia severtzovii, 3 19 Ungernia tadshikorum, 3 19 Ungernia trisphaera, 3 19 Ungernia victoris, 3 19 Ungiminetine, 3 19, 333 Unsevine, 319, 345 Urceoline, 3 14, 348 Urminine, 309, 348 Urticaceae, 14 Urtica dioica, 14

V Valeriana offcinalis, 50 1 Vallesamine, 2 13, 273 Vallesiachotamine, 148, 15 I , 155, 214,279 Vallesia dichotoma, 24, 151, 214, 218, 269, 273 Vallesia glabra, 24 Vallopurhe, 320, 386 Vallota purpurea, 320 Velbanamine, 103 Vellosimine, 48, 52, 110, 112 Venalstonidine, 2 10, 249 Venalstonine, 210,249 Venenatine, 146, 150 Venoxidine, 146, 150 Villalstonine, 2 13 Vinaphamine, 101 Vinaspine, 100 Vinca diformis, 24, 99, 110 Vincu erecta, 24, 99, 113, 151, 184

549

SUBJECT INDEX

Vinca herbaceae, 24, 99, 116, 150, 183, 216, 233 Vinca lancea, 18, 25 Vinca major, 25, 99, 110, 151 Vinca minor, 25, 99, 108, 131, 215 Vinca pubescens, 25, 99, 1 13 Vinca pusilla, 18, 25 Vinca rosea, 18, 25, 82, 99, 150, 215, 231 Vincadiffine, 59, 65, 67, 110, 112 Vincadifforrnine, 108, 114, 219, 230, 233 Vincadine, 208 Vincaherbine, 1 17 Vincaherbinine, I 17 Vincaleukoblastine, 89, 102 Vincamajine, 42, 11 I Vincamajoreine, 42, 47, 112 Vincamidine, 214 Vincamine, 129, 13 1 Vincaminine, 134 Vincaminoreine, 208, 220 Vincaminorine, 109, 208, 220 Vincanidine, 114 Vincanine, 1I4 Vincanorine, 108 Vincanovine, 112 Vincarine, 42, 47, 114, 116 Vincathicine, 100 Vincine, 114, 134 Vincinine, 134 Vincolidine, 10 1 Vincoline, 101 Vindoline, 120, 219, 230 Vindolinine, 237 Vindorosine, 101, 120, 209, 230 Vineridine, 113, 114, 151, 162, 184 Vinerine, 113, 114, 151, 162, 184 Vinervine, 113, 114 Vinine, 112 Vinosidine, 100 Vinrosidine, 230 Vittatine, 316, 353, 364 Voacafrine, 59 Voacamidine, 92, 94 Voacamine, 92, 93 Voacangarine, 8 1 Voacangine, 80, 88, 92 Voacaline, 44 Voacanga africana, 25, 215 Voacanga bracteata, 25, 8 1

Voacanga chalotiana, 25, 56 Voacanga cumingiana, 97 Voacanga dregei, 25 Voacanga globosa, 25, 81, 97 Voacanga megacarpa, 25 Voacanga obanensis, 8 1 Voacanga papuana, 25, 8 1 Voacanga schweinfurthii, 25, 8 1 Voacanga rhousarsii, 25 Voacanga zenkeri, 8 1 Voacarpine, 53,57,59,65 Voachalotine, 56 Voacoline, 53, 56 Voacorine, 92 Voacristine, 80, 92 Voacryptine, 93 Voaluteine, 81, 83 Voamonine, 53, 57, 59 Voaphylline, 208, 22 1 Vobasine, 58, 61, 65, 94 Vobtusine, 95, 213, 295 Vomilenine, 54

w Wilfordic Acid, 489 Wieland-Gumlich Aldehyde, 194 Withania somnifera, 460, 462, 486

X Xylopia polycarpa, 15

Y Yohirnbane, 171 Yohimbanone, 182 Yohimbine, 119, 147, 166 p-Yohimbine, 147, 166

Z Zanthoxyllum budrunga, 13 Zanthoxylum oxyphyllum, 13 Zanthoxylum rhetsa, 13 Zanthoxylum suberosum, 13 Zephyranthes candida, 320 Zephyranthes tubispatha, 320 Zephyranthine, 320, 334 Zygophyllaceae, 14 Zygophyllum elephantiasis, 14 Zygophyllum fabago, 14

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