Alkaloids: Chemistry and Pharmacology, Volume 9

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THE ALKALOIDS Chemistry and Physiology

VOLUME I X

This Page Intentionaiiy Laft Blank

THE ALKALOIDS Chemistry and Physiology Edited by

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

VOLUME IX

1967

ACADEMIC PRESS

NEW YORK

*

LONDON

COPYRIGHT 0 1967, B Y ACADEMIC P R E S S INC. ALL RIGHTS RESERVED. NO PART O F THIS BOOK MAY BE REPRODUCED IN ANY FORM, BY PHOTOSTAT, MICROFILM, OR ANY OTHER MEANS, WITHOUT WRITTEN PERMISSION FROM THE PUBLISHERS.

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

United K i n g d o m E d i t i o n published by ACADEMIC PRESS INC. (LONDON) LTD. Berkeley Square House, London W . l

LIBRARY OF CONGRESSCATALOG CARD NUMBER: 50-5522

PRINTED I N THE UNITED STATES O F AMERICA

LIST OF CONTRIBUTORS Numbers in parentheses indicate the page on which the author’s contributions begin.

FERDINAKD BOHLMANN, Organisch-Chemisches Institut der Technischen Universitiit, Berlin, Germany (175)

V. ERN$, Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague, Czechoslovakia (305) M. CURCUMELLI-RODOSTAMO, UniRoyal(66) Limited, Research Laboratories, Guelph, Ontario, Canada (133)

0. E. EDWARDS, National Research Council, Ottawa, Canada (545) G. FODOR, Department of Chemistry, Universitb Laval, Quebec, Canada (269)

T. R. GOVINDACHARI, CIBA Research Centre, Goregaon, Bombay, India (517) GERHARD HABERMEHL, Institut fur Organische Chemie, Technische Hochschule, Darmstadt, Germany (427) RICHARD K. HILL,Department of Chemistry, Princeton University, Princeton, New Jersey (483)

P. W. JEFFS,Duke University, Durham, North Carolina (41) MARSHALL KULKA,UniRoyal (66) Limited, Research Laboratories, Guelph, Ontario, Canada (133) G. LETTENBAUER, Research Department, C.F. Boehringer & Soehne GmbH, Mannheim, Germany (467)

H. T. OPENSHAW, The Wellcome Research Laboratories, Beckenham, Kent, England (223) A. POPELAK, Research Department, C.F. Boehringer & Soehne GmbH, Mannheim, Germany (467) E . RITCHIE, Department of Organic Chemistry, University of Sydney, Sydney, Australia (529) DIETER SCHUMANN, Organisch-Chemisches Institut der Universitat, Berlin, Germany (175)

Technischen

MAURICE SHAMMA. Department of Chemistry. The Pennsylvania State University, University Park, Pennsylvania (1) V

vi

LIST O F CONTRIBUTORS

F. SORM,Institute of Organic Chemistry and Biochemistry, Czechoslovak Academy of Science, Prague, Czechoslovakia (305)

JAROSLAV S T A N ~Charles K, University, Praha, Czechoslovakia (117) W. C. TAYLOR,Department of Organic Chemistry, University of Sydney, Sydney, Australia (529)

J. T. W R ~ B E L Department , of Chemistry, University of Warsaw, Warsaw, Poland (441)

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 for the first time 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 t o make another effort to bring this important field of chemistry into review once more. We have abandoned all attempts a t the orderly arrangement of chapters, either chemically or botanically. Each of the fifteen chapters in the present volume work is designed to bring the named subjects up t o date. I n order to keep the volume t o reasonable dimensions repetition of material from previous volumes is limited to the minimum consistent with clarity. This volume and the projected Volume X can therefore be regarded as periodical reviews. Volumes beyond X 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

vii

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CONTENTS LIST

O F CONTRIBUTORS

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

PREFACE .............................................................. CONTENTSOF PREVIOUS VOLUMES. ......................................... Chapter 1.

V

vii xv

The Aporphine Alkaloids

MAURICE SHAXMA I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. New Aporphine Alkaloids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Newly Clarified Stru ....... IV. Occurence of Known ........................... V. Two Aporphines of Unknown Structures from CoryduZis gortschukovii. . . . . . VI. Syntheses through Phenolic Oxidative Coupling ...................... VII. Reductions with Sodium in Liquid Ammonia.. ........................ VIII. The N-Demethylation of Quaternary Aporphines. . . . . . . . . . . . IX. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X. Addendum: Additional New Aporphines ................. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 2.

2 2 11 17 18 18 23 27

37

The Protoberberine Alkaloids

P. W. JEFFS I. Introduction

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

41 43 43 74 82 85

87 VII. Synthesis . . . 91 V I I I . Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1X. Table of Physical Constants of Protoberberine Alkaloids and Their Deriva102 tives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X. Addendum ............. 110 110 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 3.

Phthalidcisoyuinoline Alkaloids

JAROSLAV STANBK

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Shihunine ................. 111. Constitutio .... ... IV. Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Discovery, Isolation, and ................. Vl. Physiology and Pharmacology ................. References ..... ................. ix

117 117

120 122 123

CONTENTS

X

Chapter 4 . Bisbenzylisoquinoline and Related Alkaloids

M . CURCUMELLI-RODOSTAMO and MARSHALLKULKA I. I1. I11 IV . V. VI .

.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............. Alkaloids Containing One Diphenyl Ether Linkage ...................... Alkaloids Containing Two Diphenyl Ether Linkages . . . . . . . . . . . . Alkaloids Containing Three Diphenyl Ether Linkages . ............. Trisisobutylisoquinoline Alkaloids Melanthioidine (A Bisphenethyliso References ........

134 138 148 163 167 169 170

Chapter 5. Lupine Alkaloids

FERDINAND BOHLMANN and DIETERSCHUMANN I. I1. I11. IV V. VI . VII .

.

Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Properties ................................................ Bicyclic Alkaloids . . . . . . . . . . . . . . . . . Tricyclic Alkaloids ................................................ Tetracyclic Alkaloids: Sparteine Group ...... ............ ... Tetracyclic Alkaloids: Matrine Group ................................ Ormosia Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References .. ................................ . . . . . . . . . . . . . . . . .

176 176 184 188 191 208 213 213

Chapter 6 . Quinoline Alkaloids Other Than Those of Cinchona

H . T . OPENSHAW I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........................... I1. Simple Quinolines and Quinolones . . . . . . I11. Furoquinoline and Related Alkaloids .................................. IV Alkaloids of Lunusia amara and Bnlfourodendron riedelianum . . . . . . . . . . . . V Alkaloids of Oriza japonica .................... VI Alkaloids of Haplophyllum Species .................................... VII Alkaloids of Platydesma campanulata ..................... VIII . Alkaloids of Macrorungia longistrobus . . . . . . . . ........................ I X . Biogenesis .................................. References ........................................................

. . . .

223 224 226 236 250 252 25G 257 259 263

Chapter 7 . The Tropane Alkaloids G. FODOR I. I1. I11. IV . V VI . VII . VIII .

.

Introduction . . . . . . . . . . . . . . . ........................ ..... Structural Elucidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Absolute Configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Total Syntheses . . . . . . The Stereochemistry of Fragmentation of the Tropanes including Mass Spectrometry . . . . . . . . . . . . Biogenesis and Biogenetic Interconversion of the Tropanes . . . . . . . . . . . . . . Pharmacologically Active Synthetic Tropanium Salts . . . . . . . . . . . . . . . . . . References ........................................................

269 270 277 280 285 290 295 300 300

xi

CONTENTS

Chapter 8. Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae V.

ERN+

and F.

SORX

........... I. Introduction . . . . . . . . . . . . . . 11. Alkaloids of Apo 111. Alkaloids of Buxa,ceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I V . Biogenetic Notes References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 9.

305 307 376 417 419

The Steroid Alkaloids: The Salainandra Group GERHARD HABE~MEHL

IV. Biosynthesis . . . . V. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . References . . . . . . . .

427 427 429 436 438 439

Chapter 10. Nuphar Alkaloids

J. T. W R ~ B E L

I. Occurrence and History.. . . .. .. .. .. .. . . .. .. .. .. .. .. .. . . .. .. .. .. .. . . 11. Nupharidine and Deoxynupharidine . . . . . . . 111. Nupharamine ..................................

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

. . . . . . . . . .. . . . . V. Nuphamine . . . . . . . . VI. Neothiobinupharidine . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . , . . . . . . . . . . . . . . . . . . . . . .. . .

VIII. Castoramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

Chapter 11.

44 1 444 454 460 461 461 463 463 464

The Mesembrine Alkaloids

A. POPELAK and G. LETTENBAUER

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Occurrence and General History. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Chemistry of the Alkaloids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .

467 467 469 48 1

Chapter 12. The Erythrina Alkaloids RICHARDK. HILL

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . 11. Synthesis of Degradation and Rearrangement Products. . . . . . . . . . . . . . . . . . 111. Sterochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Total Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Biosynthesis ....................................................

483 486 497 505 512

xii

CONTENTS

VI. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . VII. Addendum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . , . . . . . . . .

Chapter 13.

513 514 514

Tylophora Alkaloids

T. R . GOVIXDACHARI

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

Chapter 14.

517 5 18 525 526 527 527 528

The Galbulirnimn Alkaloids

E. RITCHIEand W. C. TAYLOR I. The Family Himantandraceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. The Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. The Himbacine Group.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. The Structure of Himbosine.. . . .. . . .. . . . . . . . . .. . . .. . . . . . . . . . . . . .. . . References . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I

Chapter 15.

529 530 533 542 543

The Stemona Alkaloids

0. E. EDWARDS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Tuberostemonine . . . . . 111. Isotuberostemonine . . . . . . . . . . . . . . . IV. Tuberostemonine-A . . . References . . . . . . . . . . . . . . . Author Index

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

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

545 545 550 550 550

553

579

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 NELSON J . 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. . . . . .

. . .

. . . . .

. . . . .

. . . . .

. . .

1 15 91 107 165 271 375

Contents of Volume I I 8. The Morphine Alkaloids I BY H . L . HOLMES . . . . . . . . 1 8 . The Morphine Alkaloids I1 BY H . L .HOLMES A N D (IN PART) GILBERT STORK 161

9. 10. 11. 12. 13. 14. 15.

Sinomenine BY H . L . HOLMES . . . . . . . . . . . Colchicine BY J . W . COOKAND J . D . LOUDON . . . . . . . Alkaloids of the Amaryllidaceae BY J . W . COOKAND J . D . LOUDON. Acridine Alkaloids BY J . R . PRICE . . . . . . . . . . The Indole Alkaloids BY LEOMARION . . . . . . . . . The Erythrina Alkaloids BY LEOMARION . . . . . . . . The Strychnos Alkaloids Part I1 BY H . L . HOLRIES . . . . .

. .

219 261 . 331 . 353 . 369 . 499 . 513

Contents of Volume I I I 16. The Chemistry of the Cinchona Alkaloids BY RICHARD B . TURNERA N D R . B . WOODWARD. . . . . . . . . . . . . . . 1 17. Quinoline Alkaloids, Other than Those of Cinchona BY H . T . OPENSHAW 65 18. The Quinazoline Alkaloids B Y H . T . OPENSHAW . . . . . . . 101 19. Lupin Alkaloids BY NELSONJ . LEONARD . . . . . . . . . 119 20 . The Imidazolo Alkaloids BY A . R . BATTERSBY AND H . T . OPENSHAW . 201 21 . The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOG AND 0. JEGER . . . . . . . . . . . . . . . . . . 247 22 . P-Phenethylamines BY L .RETI . . . . . . . . . . . 313 23 . Ephreda Bases BY L . RETI . . . . . . . . . . . . . 339 24 . The Ipecac Alkaloids BY MAURICE-MARIE JANOT . . . . . . . 363

Contents of Volume I V 25 . The Biosynthesis of Isoquinolines BY R . H . F . MANSKE . . . . . 26 . Simple Isoquinoline Alkaloids BY L . RETI . . . . . . . . . 27 . Cactus Alkaloids BY L . RETr . . . . . . . . . . . . . 28 . The Renzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . 29 . The Protoberberine Alkaloids BY R . H . F. MANSKEA N D WALTERR . ASHFORD

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

30 . The Aporphiiie Alkaloids BY H . H . I? . MANSKE. 31 . The Protopine Alkaloids BY R . H . F. MANSKE.

...

Xlll

. . . . . . .

1 7

23 29 77

119 147

xiv

CONTENTS O F PREVIOUS VOLUMES

CHAPTER STANEXASD R . H . F . 32 . Phthalideisoquinoline Alkaloids BY JAROSLAV MANSKE . . . . . . . . . . . . . . . . . . 33. Bisbenzylisoquinoline Alkaloids B Y MARSHALLKULKA . . . . . 34. The Cularine Alkaloids BY R . H . F . MASSXE . . . . . . . . 35. m-Naphthaphenanthridine Alkaloids BY R . H . F . JIASSKE . . . . . . . . . . . . 36 . The Erythrophleum Alkaloids BY G. DALMA . . . . 37. The Aconitum and Delphinium Alkaloids BY E . S . STERS

1G7

199 249 233 2f15 273

Contents of Volume V Narcotics and Analgesics BY HUGOKRUEGER. . . . . Cardioactive Alkaloids BY E . L . MCCAWLEY . . . . . Respiratory Stimulants BY MARCELJ . DALLEMAGNE . . . . . . . . . . . . Antimalarials BY L . H . SCHMIDT 42 . Uterine Stimulants BY A . K . REYNOLDS . . . . P . CARNEY 43. Alkaloids as Local Anesthetics BY THOXAS . . . . . . . . 44 . Pressor Alkaloids BY K . K . CHEN 45 . Mydriatic Alkaloids BY H . R . ING . . . . . . . . 46 . Curare-like Effects BY L . E . CRAIG . . . . . . . . 47 . The Lycopodium Alkaloids BY R . H . F. MANSKE . . . . .NSKE . 48 . Minor Alkaloids of Unknown Structure BY R . H . F . MA 38. 39. 40 . 41.

. . . .

.

.

. . .

. . .

. . . . . .

. . .

. . . . . . . . .

1 59 109 141 163 21 1 229 243 265 295 301

Contents of Volume V I Alkaloids in the Plant BY K . MOTHES . . . . . . The Pyrrolidine Alkaloids BY LEOMARION. . . . . Senecio Alkaloids BY NELSONJ . LEONARD. . . . . . . . . . The Pyridine Alkaloids BY LEOMARION 5 . The Tropane Alkaloids BY G . FODOR . . . . . . . . . 6. The Strychnos Alkaloids BY J . B . HENDRICXSON 7. The Morphine Alkaloids BY GILBERTSTORK . . . . 8. Colchicine and Related Compounds BY W . C. WILDXAN . 9 . Alkaloids of the Amaryllidaceae BY W . C . WILDMAN. . 1. 2. 3. 4.

. . . . .

. . . . .

. . . . .

. . . . .

. . . .

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

1 31 35 123 145 179 219 247 289

Contents of Volume V I I 1 The Indole Alkaloids BY J . E . SAXTON. . . . . . . . . . The Erythrina Alkaloids B Y V . BOEXELHEIDE . . . . . . . . 201 Quinoline Alkaloids. Other than Those of Cinchona BY H . T . OFENSHAW229 The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . 247 Lupin Alkaloids BY NELSON J . LEONARD . . . . . . . . . 253 Steroid Alkaloids: The Holarrhena Group BY 0 . JEGER A N D V . PRELOG 319 Steroid Alkaloids: The Solanum Group BY V . PHELnC- A N D 0 . JEGER . 343 Steroid Alkaloids: Veratrum Group BY 0. JEGER AND V . PRELOG . . 363 The Ipecac Alkaloids BY R . H . F . NANSKE. . . . . . . . . 419 Isoquinoline Alkaloids BY R . H . F . MANSKE . . . . . . . . 423 Phthalideisoquinoline Alkaloids BY JAROSLAV STANEX . . . . . 433 Bisbenzylisoquinoline Alkaloids BY MARSHALLKULKA . . . . . 439 22 . The Diterpenoid Alkaloids from Aconitum, Delphinium, and Garrya Species B Y E. S. STERN . . . . . . . . . . . . . . 473 23. The Lycopodium Alkaloids BY R . H . F . BIANSKE . . . . . . . 505 . . . . 509 24 . Minor Alkaloids of Unknown Structure BY R . H . F . MANSKE

10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20 . 21.

CONTENTS O F PREVIOUS VOLUMES

xv

Contents of Volume V I I I CHAPTER 1 . The Simple Bases BY J . E . SAXTON. . . . . . . . . . . 1 2 . Alkaloids of the Calabar Bean BY E . COXWORTH . . . . . . . 27 3 . The Carboline Alkaloids BY R . H . F . MANSKE . . . . . . . . 47 4 . The Qumazolinocarbolks BY R . H . F . MANSKE . . . . . . . 55 3 . Alkaloids of Ilfztragyna and Ouroupnria Species BY J . E . SAXTON . . 59 6 . Alkaloids of Gelsemium Species BY J . E . SAXTON. . . . . . . 93 7 . Alkaloids of Picralima nitida BY J . E . SAXTON . . . . . . . 119 8 . Alkaloids of Alstonia Species BY J . E . SAXTON . . . . . . . 159 9 . The Iboga and Voacnnga Alkaloids BY W . I . TAYLOR . . . . . 203 10 The Chemistry of the 2.2 '.Indolylquinuclidine Alkaloids BY W . I . TAYLOR238 1 1 . The Pentnceras and the Eburriamine (Hunteria)-Vicarnine Alkaloids by W I. TAYLOR . . . . . . . . . . . . . . . 250 12. The Vinca Alkaloids BY W . I . TAYLOR. . . . . . . . . . 272 13 . Rouwolfia Alkaloids with Special Reference t o the Chemistry of Reserpine BY E . SCHLITTLER. . . . . . . . . . . . . . . 287 14. The Alkaloids of Aspidosperma, Diplorrhyncus, Ropsia, 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 eirnicidum 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 . MANSKE . . . 694 21 . The Ergot Alkaloids BY A. STOLLAND A. HOFMANN . . . . . . 726 22. The Ajmaline-Sarpagine Alkaloids BY W . I . TAYLOR. . . . . . 789

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1-

THE APORPHINE ALKALOIDS MAURICESHAMMA Department of Chemistry, T h e Pennsylvunia State University, University Pa rk, Pennsylvaiiia

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. S e w Aporphine Alkaloids. . . . . ................................ A. Neolitsine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Launobine . . . .. . .. . . D. Mecambroline (Isofugapa,vine, Isofungipavine) . E. l,lO-Dihydroxy-2-methoxyaporphine ... . . . . . . .. . .. . .. .. . . .. . .. . ...

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

G. Asimilobine

I. Guatterine.. . . . . . .

2 2 2 3 3 i)

6 7 7 8 9 11 11

C. Isoboldine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Laurelliptine. E. Itogersine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12 13 14 15 16

......................... ......... ....... IV. Occurrence of Known Aporphines in Plan ....................... V. Two Aporphines of Unknown Structures from Corydnlis gortschakovii. . . . . . VI. Syntheses through Phenolic Oxidative Coupling. . VII. Reductions Reductions with with Sodium Sodium in in Liquid Liquid Ammonia. Ammonia. ........ . . . . . . . . . . . . . . . . . . . . . VII. VIII. The N-Demethylation of Quaternary Aporphines. IT;. Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. UV-Spectra . . . . .... ........... ....... B. NMR-Spectra NMR-Spcctra .. . . . . . . . . . . . . . . . B. C. Absolute Absolute Configuration Configura C. and Optical Rotatory Dispersion. . . . . . . . . . . . . . X. Addendum Addendum:: Additional Additional S e w Aporphines phiries .. .... .. .... ...... . . . . . . ... .. .. .. ........ . . . . . . . X. __........ ndigerine . . . . . . . _.

D. E. F. G. H.

A'-Methylcorydinium Cation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thaliporphine . . . . . . . ....................... Preocoteine . . . .. . . . . Catalpifoline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cassythidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I. LV-Met.hylactinoda.phnine .. .. .. .. .. .. .. .. _ _ .. .. .. .. .. .. .. .. .. .. .. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

-16 18 18 18 18 18 23 23

26 27 27 27 27 27 30 30 30 30 30 32 32 33 34 34

35 35 37 37

2

MAURICE SHdN.13IA

I. Introduction

A variety of new developments have occurred in the area of aporphine alkaloids since the last complete review on the subject appeared ( I ) . Twenty new aporphines have been isolated from natural sources and characterized; these are 12'-methylactinodaphnine, X-methylcorydinium cation, nandigerine, N-methylnandigerine, ovigerine, Xmethylovigerine, hernovine, catalpifoline, thaliporphine, sparsiflorine, asimilobine, 1,1O-dihydroxy-2-methoxyaporphine, neolitsine, guatterine, caaverine, cassyfiline, preocoteine, cassythidine, launobine, and mecambroline. The structures of a number of tetrasubstituted aporphines, including glaucentrine, the quaternary Fagara tinguassoiba alkaloid, laurelliptine, and rogersine, have been clarified. Studies on the NMR-spectra of aporphines have appeared, and this physical tool can be of paramount importance in structural elucidation work. Finally, the role of phenolic oxidative coupling in the biosynthesis of aporphines is now well recognized, and a number of experiments have been run to try to duplicate the synthetic processes of nature. All of the above topics will be discussed in the present review. The numbering system that will be used throughout is that recommended by The Ring Index, as shown in structure I . The term noraporphine is used solely in connection with structures which contain a secondary nitrogen, rather than the more common >N--CH3 group. 4

7

9

I

11. New Aporphine Alkaloids A. NEOLITSINE Neolitsine is the first aporphine found to possess two methylenedioxy groups. It is present in Neolitsea pulchella Alerrill, from which it was isolated as crystals melting a t 149"-150" ( [ a ] , , +56.5" in CHC13), and analyzing for ClsH17N04. The alkaloid gave a positive Labat test, and formed a picrate (mp 186" decornp.), a methiodide which crystallized

1.

THE A P O R P H I N E A L K A L O I D S

3

with 1 mole of methanol (mp 221'-22-i"), and a hydrochloride which charred a t 219" (2). The UV-spectrum of the alkaloid in ethanol showed maxima a t 310 and 284 mp (log E 4.11 and 3.9) characteristic of a 1,2,9,10-tetrasubstituted aporphine. The NMR-spectrum exhibited one AT-methylgroup a t 7.53 r . A methylenedioxy group appeared as two doublets centered a t 4.04 T and 4.17 T characteristic of C - l , 2 disubstitution, while another methylenedioxy group was represented by a singlet at 4.05 T and was therefore assigned the C-9,10 position. Neolitsine must thus be represented by 11.

I1

I11

B. LAUNOBINE From the bark and wood of Lccurzcs nobilis L. the new noraporphine launobine was obtained, C18H1704N (mp 214"-215" decomp. ; [a]'; + 192.7' in CHC13). The alkaloid has one methylenedioxy, one methoxyl, and one hydroxyl, and Clarke-Eschweiler N-methylation was found to give ( + )-bulbocapnine. Launobine is therefore norbulbocapnine (111)(3).

C. SPARSIFLORINE Sparsiflorine was originally isolated as a white amorphous powder, C17H1703N (mp 230"-232" decomp.), from the leaves of the shrub Croton sparsi$orus Alorung (Euphorbiaceae) ( 4 ); hydrochloride (mp 2 83"-2 84' decornp. ), hydrobromide (mp 2 7 6 - 2 7 8' decomp. ) , oxalate (mp 265"-267" decomp.), and picrate (mp 225"). The alkaloid was found to contain one methoxyl, three active hydrogens, and no methylenedioxy or N-methyl group. After repeated attempts, sparsiflorine was crystallized as silky fine needles (from alcohol) (mp 228" decomp.). The free base suffers ready oxidation and decomposes on standing or upon heating in solution. The 310, 275, 266, and hydrochloride ([OL]'? +43" in HzO), exhibits A:::

4

MAURICE SH;ZMMA

226 mp (log E 3.95, 4.23, 4.09, and 4.54) characteristic of a l,Z,lO-trisubstituted aporphine, and the phenolic character of the alkaloid was shown by a strong bathochromic shift in alkaline medium. The presence of a secondary amine and two phenolic hydroxyls in sparsiflorine resulted in the ready formation of an 0,N-diacetyl derivative (mp 245"), as well as an N,O,O-triacetyl derivative (mp 196"-197") under slightly more stringent conditions. Sparsiflorine also slowly formed an AT-methylmethiodide, C19H2203NI (mp 236"-238" decomp.), which when treated with diazomethane gave N,O,O-trimethylsparsiflorine methiodide (IV), (mp 21 8" decomp.), identical by IR-comparison with N,O-dimethyltuduranine methiodide. Sparsiflorine must therefore be a 1,2,10-trisubstituted noraporphine-the three substituents consisting of two phenolic hydroxyls and one methoxyl.

H

HO

u"-. k O

W

VI

The two phenolic hydroxyls are not vicinal since sparsiflorine did not give the characteristic catechol color test with ferric chloride and did not condense with methylene iodide to yield a product containing a methylenedioxy function. One of the hydroxyls must therefore be located at c-lo. The site of the methoxyl group was settled to be at C-2, thereby placing the second hydroxyl a t C-1, from a comparative study of the NMR-spectra of sparsiflorine, tuduranine (V), and l,lO-dihydroxy-2methoxyaporphine. In particular, the methoxyl group of sparsiflorine hydrochloride in trifluoroacetic acid appears a t 6.00 7.The C - 2 and C-1

1.

THE APORPHINE ALKALOIDS

5

methoxyl groups of tuduranine (V) hydrochloride appear a t 5.99 and 6.17 7 , respectively, so that the methoxyl in sparsiflorine must be situated a t C-2. Sparsiflorine is, therefore, 1,10-dihydroxy-2-methoxynoraporphine ( V I ) ( 5 ) .

D. MECAMBROLINE ( ISOFCGAPAVINE, ISOFUNGIPAVINE) Mecambroline was isolated from Meconopsis cainbrica Vig. (Papaveraceae), and the elemental data indicated the value CI8Hl7O3N. The alkaloid melts at 145", and exhibits [mlU + 7 6 " (in CHC13). A hydrochloride salt was obtained (mp 264"-266") as well as a picrate (mp 179"-180"). Color tests showed the presence of a methylenedioxy and a phenolic group. The UV-spectrum had A,,,,, 308 and 275 mp (log E 4.0 and 4.2), with a shoulder at 269 m p (log E 4.1), typical of a l,Z,lO-trisubstituted aporphine. 0-Methylation with diazomethane gave a base (rnp 111"-112") (6).

IS

Mecambroline was also obtained in 71% yield by refluxing the proaporphine alkaloid mecambrine (VII) in dilute hydrochloric acid (6, 7 ) . I n a footnote to the mecambroline paper, it was suggested ( 6 , 7 ) that mecambroline may be identical with Yunusov's isofugapavine (VIII) ( 8 ) . This is a logical suggestion. since. as previously mentioned, the UVspectrum of mecambroline is that of a 1,2,10-trisubstituted aporphine.

6

MAURICE S H A M X A

Mecambroline corresponds, therefore, to the free base of the quaternary alkaloid michepressine (IX).

E.

1,10-DIHYDROXY-2-METHOXYAPORPHINE

Two alkaloids have been obtained from the leaves of Ocotea glaziovii Mez (Lauraceae), both of which analyzed for C I ~ H ~ ~ One N Owas ~ . named glaziovine and shown to possess the proaporphine structure X. The other alkaloid was identified as 1,10-dihydroxy-2-methoxyaporphine (XI), and the description of its characterization follows (9). 1,10-Dihydroxy-2-methoxyaporphine (XI) was isolated as the hydrochloride (decomp. > 300"),from which the base was obtained as c~lorless crystals of monohydrate (mp 149"-152" decomp. ; [ a ] g - 35" in CHC13). The UV-spectrum was typical of an aporphine oxygenated at 1, 2, and 10,with HA,:? 307,275, 266,and 218 mp (log E 3.96,4.12,4.01,and 4.58). The alkaloid monohydrate gave a crystalline methiodide (mp 251 O253")which darkened rapidly in air. From the methiodide it was possible to prepare a metHochIoride hydrate (mp 226"-229").

'""rncH30m JY * h i 3

HO

HO

NhH3

HO

x

XI

The alkaloid free base did not show any fluorescence in UV-light when t.reat.ed wit.h 10% aqueous ethylenediamine, demonstrating the absence of a catechol group. The NMR-spectrum exhibited one methoxyl peak

1.

THE APORPHINE ALKALOIDS

7

a t 6.08 7 (in D20-NaOD a t 60 Mc, using benzene as an external standard, value corrected to TMS), rather close to the chemical shift of the corresponding methoxyl group in tuduranine (V) which comes a t 6.25 7 under identical experimental conditions. The N-methyl group was clearly evident a t 7.43 7. Methylation of the free base with dimethyl sulfate gave 1,2,10trimethoxyaporphine methosulfate, identical by IR-comparison with 0,N-dimethyltuduranine methosulfate prepared from tuduranine. 1,10-Dihydroxy-2-methoxyaporphine(XI) had previously been obtained in low yield from the reduction of domesticine with sodium in liquid ammonia, and had been characterized as a hydrochloride salt (mp 277" decomp.) (10).

F. CAAVERINE Caaverine, C I ~ H ~ ~ has O ~been N , obtained from the bark of Symplocos celastrinea Mart. (Symplocaceae). It is strongly sensitive to light, and [.I5 when crystallized from benzene melts a t 208"-210" (decomp.) ( -89" in methanol). The alkaloid has one methoxyl, one phenolic hydroxyl, and one secondary amino function. The UV-spectrum exhibited k~~~~ 310 and 2 7 2 mp (log E 3.7 and 4.25) characteristic of 1,2-disubstituted aporphines (11). An 0 ,N-diacetyl derivative could be obtained under mild conditions (mp 236"-238"), as well as a methylurethane (mp 245"-246"). 0-Methylation of the urethane with excess diazomethane yielded the corresponding 0-methyl methylurethane which was found to be identical with the methylurethane of the alkaloid nornuciferine (XII). The exact position of the 0-methyl group was fixed a t C-2, so that caaverine corresponds to expression XIII, since the NMR-spectrum of the alkaloid in trifluoroacetic acid exhibited a methoxyl singlet a t 6.07 7, and a C-1 methoxyl would have appeared further upfield. The structural elucidation of caaverine (XIII) was followed by a Pschorr-type synthesis of the racemic alkaloid, in the course of which the C-1 phenolic hydroxyl was protected as a benzyl ether.

G. ASIMILOBINE An investigation of the basic components of Asimina triloba Dunal (Anonaceae) yielded seven crystalline alkaloids, among them asimilo-213" in CHC13), which was bine, C17H1702N (mp 177"-179"; found in the wood and the root of t,he tree. Asimilobine is a noraporphine, since upon treatment with acetic

[.IF

8

MAURICE SHAMMA

anhydride in pyridine an 0,N-diacetyl derivative (mp 146") is formed. N-Methylation of the alkaloid by means of formaldehyde followed by reduction with sodium borohydride yielded the known alkaloid 1methoxy-2-hydroxyaporphine(mp 191"-193"; [a]: - 220" in CHC13), so that asimilobine must be 1-methoxy-2-hydroxynoraporphine(XIV)

I

OCH3

XIV

xv

OH

OH

XVI

K. CASSVFILINE (CASSYTHINE) Cassyfiline was isolated as light orange-brown microgranules (mp 21 7" decomp. ; [ a ] $ - 89.6" in CHCI3), from the stem of Formosan C'assytha Jiliformis L. (Lauraceae). The alkaloid analyzes for C1gH1905N, and its solution in organic solvents exhibits a strong green fluorescence (13). The NhIR-spectrum of the free base in deuteriochloroform indicated the presence of a C - l , 2 methylenedioxy group represented by two doublets centered at 3.94 and 4.09 T , two methoxyl groups shown by singlets a t 5.99 and 6.09 T , and two aromatic hydrogens as singlets at 2.40 and 3.23 T . Position C-11 must be unsubstituted to account for the

1.

THE APORPHINE ALKALOIDS

9

relatively downfield 2.40 absorption. I n addition, the alkaloid showed a positive FeC13 test. Treatment of cassyfiline with formaldehyde followed by reduction with sodium borohydride gave N-methylcassyfiline, C2oHzlOsN (mp 210"-211"; [a]? $24.6" in CHCI3). The NMR-spectrum was similar to that of cassyfiline, but with the addition of a singlet a t 7.47 r for the N-methyl group. 0-Methylcassyfiline, C20H2105N (mp 150"-151"; [ a ] g + 16.4" in CHCls), could be obtained from cassyfiline by reaction with diazomethane. Treatment of this derivative first with formaldehyde and then with sodium borohydride gave 0,N-dimethylcassyfiline (XV), C21H2305N (mp 139"-140", sintering at 133"; [a]: +42.6" in CHC13)' identical in terms of its mixture melting point and I R - and NMR-spectra with the alkaloid ocoteine. Cassyfiline is therefore a 1,2,3,9,10-pentasubstituted noraporphine, with a methylenedioxy at C-1,2. The determination of the position of the phenolic hydroxyl in Nmethylcassyfiline, and hence in cassyfiline itself, follows from the application of Barton's deuteration method as applied to apocrotonosine. N-Methyldeuterocassyfiline (XVI) was prepared from N-methylcassyfiline (XVIIa) by treatment with NaOD in DzO, and the NMRspectra of the two bases compared. From the disappearance of the singlet at 3.20 r it was clear that it was the C-8 position that had been deuterated, so that the phenolic group was placed a t C-9. If the phenolic group had been present at C-3, no aromatic deuteration would have occurred; while if it had been situated a t C-10, it is the downfield aromatic absorption that would have disappeared upon deuteration. Cassyfiline is thus correctly represented by expression XVIIb. An independent structural proof for cassyfiline has been psesented in a separate paper. It was noted that the alkaloid free base has ["Iu + 24" in CHC13, and this positive specific rotation is in accord with the chemical transformation of cassyfiline into ( + )-ocoteine (XV) (13a). I . GUATTERINE

Chattel-iapsilopus Nart. (Xnnonaceae) is rich in a iiumber of alkaloids, N O free ~ . base contains a methylone of which is guatterine, C I ~ H ~ ~ The enedioxy grouping, an 0-methyl and an N-methyl group, and an additional secondary alcoholic oxygen atom which in the aporphine series usually occurs a t C-7. Guatterine melts a t 146"-148" and exhibits [a]? -57.1" (CHC13) ( 1 4 ) . The NMR-spectrum of guatterine revealed the N-methyl and 0methyl groupings as singlets at 7.51 and 6.08 T , respectively; and the

10

MAURICE SHAMMA

methylenedioxy as two close doublets centered a t 4.1 and 4.25 T characteristic of a 1,2-disubstitution pattern on an aporphine nucleus. The C-6a proton appeared as a doublet centered a t 6.6 T and the C-7 hydrogen was also present as a doublet a t 5.5 r. The J value between the C-6a and C-7 hydrogens was 12 cps, clearly indicating a trans relationship. Four aromatic protons were present in a complex pattern that was ascribed to the four adjacent protons of an ortho-disubstituted benzene ring ; this tentative assignment was later substantiated by direct chemical evidence. The four aromatic adjacent protons must be those of ring D, so that the methoxyl must be placed a t C-3 to yield expression XVIII for guatterine.

XIX

XVIII

xx

XXII

XXI

XXIII

1.

11

THE APORPHINE ALKALOIDS

The action of acetic anhydride-sodium acetate on guatterine usually led to formation of a diacetyl derivative (mp 190"-192") which was formulated as X I X from spectral and chemical evidence. In one experiment, however, a different N-acetyl derivative was isolated (mp 222"223") which lacked an alcoholic or acetoxy grouping and was represented as XX. The final structural proof for guatterine (XVIII) rests upon its conversion by chromium trioxide in pyridine into the alkaloid atherospermidine (XXI) which was also found in G. psilopus and whose structure was established by its oxidative degradation to 1-azaanthraquinone-4-carboxylic acid (XXII). It is interesting t o note that the relative stereochemistry of the C-7 hydroxyl group in guatterine is opposite to that of the hydroxyl in ushinsunine (XXIII) where the J6a,7value is only 2.5 cps. The absolute configuration of guatterine has not yet been established. 111. Newly Clarified Structures A. GLAUCENTRINE

CH30p

Glaucentrine was originally isolated in the 1930's from three Dicentra species, and subsequently assigned structure XXIV. No degradation

HO

CH3O

\CH3

'

\CH~

CH31I:X$

CHBO

'

OCH3

OCH3

XXIV

xxv

OCH3

SXVI

XSVII

12

MAURICE SHAMMA

reactions were run on glaucentrine, and no UV-spectrum was recorded. Rather, the (-))-tartrate of the synthetic base XXV was found not to depress the melting point of the ( - )-tartrate of glaucentrine 0-ethyl ether. Similarly, the methiodide of 0-ethylglaucentrine did not depress the melting point of the resolved methiodide of base XXV (15). I n 1965, the actual synthesis of ( & )-l-hydroxy-2,9,10-trimethoxyaporphine (XXIV) (mp 190"-192") by an unambiguous route was reported, and the Synthetic material was found to be different from natural glaucentrine (16).It was then found that natural glaucentrine and natural corydine (XXVI)are identical, so that the name glaucentrine should be eliminated from the record (16).

B. THE QUATERNARY ALKALOIDF R O M Fagara tinguassoiba

A quaternary aporphine possessing one phenolic hydroxyl and three methoxyls had been isolated from the bark of Fagara tinguassoiba Hoehne and assigned structure XXVII (in the N-methyl quaternary form), partly on the basis of a comparison with a derivative of glaucentrine (17). Upon finding that the original structure assigned to glaucentrine was in error, the assignment for the Fagara alkaloid had to be reconsidered. The synthetic ( & )-l-hydroxy-2,9,10-trimethoxyaporphine(XXIV) which had been prepared by an unequivocal route was, therefore, quaternized with methyl iodide, and the iodide ion then exchanged for picrate. The resulting quaternary salt was identical in its UV- and I R spectra and its TLC Rfvalues with the quaternary alkaloid o f F . tinguassoiba also in the picrate form. It follows that the old structure XXVII (in the N-methyl quaternary form) for the F . tinguassoiba alkaloid should be replaced by XXIV (in the AT-methylquaternary form) (16). This structural reassignment has been subsequently further confirmed by an NMR-study of the natural Fagara alkaloid in CDC13 solution, and the corresponding alkaloid anion in alkaline dimethylsulfoxide solution. The C-11 aromatic hydrogen which falls at 1.96 T in CDC13 solution undergoes a downfield shift to 0.92 T in basic medium. Low field shifts of this magnitude have been observed for C-1 or C-11 hydrogens when adjacent to a hydroxyl group a t C-11 or C-1 respectively. It follows that the hydroxyl group of the Fagara alkaloid must be placed at C-1, as in XXII' (in the A-methyl quaternary form). Furthermore, the C-3 hydrogen of the alkaloid undergoes an upfield meta shift from 3.12 T (in CDC13) to 3.69 T in basic solution, and such a change is within the expected limits (18).

1.

THE A P O R P H I N E ALKALOIDS

13

C. ISOBOLDINE The alkaloid isoboldine was first isolated from Nandina domestica Thunb. and correctly assigned structure XXVIII ( 1 9 ) .This structural designation has been further confirmed by a synthesis of the alkaloid through phenolic oxidative coupling (20).

CH3O

OH

6H

XXVIII

XXIX

OH

SXX

I n 1964, isoboldine, as alkaloid A, methanolate (mp 121°-126"), solvent-free base (mp 180"; [a](::+ 41.2" in ethanol), was also reported in Symplocos celastrinea Mart., where it was found in large enough quantities that a variety of chemical transformations could be attempted (11). Treatment of either isoboldine (XXVIII) or the well-known boldine ( X X X ) with dihydropyran, then with diazomethane, and finally acid hydrolysis of the protective dihydropyranyl grouping, resulted in the formation of N-methyllaurotetanine (XXIX), whose structure had previously been clearly established. The hydroxyl group is therefore more reactive when a t C-9 than when situated either at C-1 or C-2 ( 2 1 ) . I n another set of reactions isoboldine (XXVIII) and boldine (XXX) were treated separately with diazomethane to give 0-methylisoboldine (mp 188"-189" decomp.; [a]',' 94" in CHClS), methiodide (mp 228"-229' decomp.). and 0-methylboldine, HBr salt (mp 198"-205" decomp. ; [m]: + 26" in ethanol), respectively (11,21). Comparison of O-methylisoboldine with N-methyllaurotetanine showed the two compounds to

14

M A U K I C E SHAMMA

be different. so that 0-methylisoboldine had to correspond to XXIV. Since 0-methylisoboldine (XXIV) and 0-methylboldine are also different, monomethylation of boldine (XXX) must have taken place preferentially a t C-9 to give 2-hydroxy-l,9,10-trimethoxyaporphine (XXVII), as could have been predicted on the basis of the previously mentioned dihydropyran-diazomethane experiment (11). 0-Methylisoboldine (XXIV) corresponds to the structure originally assigned t o glaucentrine. The fact that these two compounds proved to be different, however, gave one of the first indications that the structural assignment for glaucentrine, and hence that for the Fagara tinguassoiba alkaloid, had to be reconsidered.

D. LAURELLIPTINE The noraporphine laurelliptine was obtained from Beitschmiedia elliptica C. T. White, and was initially assigned the structure X X X I on the basis of the following evidence (22).

OCH3

OCH3

XXXI

XXXII

The alkaloid possesses two methoxyls and two hydroxyls, and yields O,O,N-triacetyllaurelliptine upon treatment with acetic anhydride. Methylation with diazomethane gives O,O-dimethyllaurelliptine. When

1.

THE APORPHINE ALKALOIDS

15

hydrogenated with Raney nickel in the presence of formaldehyde, ATmethyllaurelliptine (mp 121"-123"; [a]? + 41" inethanol), was obtained, so that laurelliptine must be a dimethoxydiphenolic noraporp hine. Treatment of N-methyllaurelliptine with diazomethane resulted in the formation of two products, namely 0,0,h7-trimethyllaurelliptine which was shown to be identical with glaucine (XXXII), and 0,Kdimethyllaurelliptine (mp 189"-191"; [ m ] Z + 43" in ethanol). The methiodide of the latter compound was found to correspond to the quaternary aporphine from Fagara tinguassoiba which at the time was believed to correspond to expression XXVII (in the N-methyl quaternary form), so that one of the two hydroxyl groups of laurelliptine was placed at (3-2. Laurelliptine gave a negative Quastel test for a 1,2-dihydroxyl group, and had the same R, value on plain and boric acid-sodium acetate-treated paper ; the alkaloid therefore does not possess an ortho dihydroxyl grouping. Finally, since N-methyllaurelliptine did not correspond to boldine (XXX), laurelliptine was assigned the structure X X X I (22). One year later, however, in 1964, a comparison of isoboldine (XXVIII) with N-methyllaurelliptine showed the two compounds to be identical, so that laurelliptine must be correctly represented by expression X X X I I I (11). 0,N-Dimethyllaurelliptine must then correspond to expression XXIV, and the C-9 hydroxyl of laurelliptine (XXXIII) is more reactive than that at C-1. The chemistry of laurelliptine has been summarized in a very recent paper (22a).

E. ROGERSINE The crystalline alkaloid rogersine, C ~ O H ~ ~iCH30H N O ~ . (mp 100"105', sintering at 85"; [a],, 3-111" in ethanol; methiodide, mp 199"200°), was obtained as one of the minor alkaloids of Phylica rogersii Pillans (Rhamnaceae).Spectral and analytical data indicated a 1,2,9,10tetrasubstituted aporphine with three methoxyls and one hydroxyl, and by a process of comparison and elimination expression XXXIV was suggested for the alkaloid ( 2 3 ) . A total synthesis of racemic XXXIV (mp 140"-145"), however, proved the structure of rogersine to be different from that postulated ( 2 4 ) .A comparative NMR-study then showed that rogersine corresponds to crystalline hr-methyllaurotetanine (XXIX), an alkaloid which had never previously been obtained in a crystalline form. The name rogersine should therefore be removed from the literature ( 2 5 ) .

16

MAURICE SHAMMA

F. LAURELINE Although the structure of laureline (XXXV) was not in doubt, an interesting new synthesis of this alkaloid that proceeds via a benzyne intermediate further reinforced the structural assignment (26). 3-Bromo4-methoxyphenylacetic acid was converted by reaction of the acid chloride with homopiperonylamine into the amide XXXVI. Treatment of XXXVI with phosphorus oxychloride followed by methyl iodide and sodium borohydride gave the brominated benzylamine XXXVII. Potassium amide in liquid ammonia then afforded the benzyne intermediate XXXVIII which without isolation underwent preferential addition of amide ion to give the amine XXXIX. Diazotization and Pschorr ring closure then gave ( & )-laweline (XXXV).

XXXV

XXXVI

XSSIX

G. OCOTEINE

The structure XV suggested ( 2 7 )for ocoteiiie has been vindicated by an unambiguous total synthesis (28).The racemic synthetic material, hydro-

1.

T H E A P O R P H I N E ALKALOIDS

17

iodide (mp 225" decornp.) was found to be identical with natural ocoteine by means of S M R - and IR-spectral comparisons. TABLE I

OCCURRENCE O F KSOWNAPORPHINESI N PLANTS

Aporphine

Quaternary aporphine from Fagara tinyucissoiba N-Methyllaurotetanine

Laurotetanine Laurifoline Laurolitsine Domesticine Actinodaphnine Corydine Isocorydine

h.'-Methylisocorydinium cation Corytuberine Magnoflorine

Anonaine Anolobine Roemerine

Nuciferine Sornuciferine Sorushinsunine Ocoteine

Source and reference

Fngara rhoifolia Engl. (28a) Phylica royersii (crystalline alkaloid) ( 2 3 ) Eschscholtzia californica Cham. The alkaloid forms a characteristic I-tartrate (mp 238"-239") (29) Neolitsea acuminatissima Kanchira & Sasaki (30) Litsea cubeba (30a) Fagara pterota Blanco, F . hyemalis Engl., F . chiloperone Engl. ( 3 1 ) Cinnamon camphora T. Nees & Eberm. ( 3 2 ) Glaucium oxylobum Boiss. & Bwhse. ( 3 3 ) Lnurus nobilis (K,O-dimethylactinodaphnineshown t o be identical with (+)-dicentrine)( 3 ) Glaucium oxylobum ( 3 3 ) A s i m i n a triloba ( 1 2 ) Phylicn rogersii ( 2 3 ) Litsea eubeba Pers. ( 3 0 a ) Papaver commutatum Fisch. Mey. 8: Trautr. (33a) Hernandia ovigera (33b) Fayara pterota, F . rhoifolia (31) Opium ( 3 4 ) This is definitely the most widely distributed aporphine. It has recently been found in opium ( 3 4 ) ,in Croton cumingii ( 3 5 ) ,and in most if not all Pagara ( 3 1 ) , Aconitum, Adonis, Aquilegia, Coptis, Delphinium, Nigelln, Thalictrum, and Trollius species ( 3 6 ) S e l u m b o nucijera Gaertn. (Selumbium speciosum Willd.) (37) Asimina triloba ( 1 2 ) Nelumbo nucifera ( 3 8 ) (+)-roemerineoccurs in Papauer d u b i u m L. (39), P. f u g a x Poir. ( 4 0 ) , and P . caucasicum Bieb. ( 4 1 ) S e l u m b o nueifera ( 3 8 ) ,S. Eutea. Willd. ( 4 2 ) ,andPapaver caucasicum ( 4 1 ) S e l u m b o lutea ( 4 2 ) dsinai~ trilobn ~ (12) Phoebe porphiria Meg (Nectandra porphiria Grieseb.) ( 3 1 ) and Tholictrunz.f e n d l e r i C. L. Anders ( 4 3 )

18

MAURICE SHAMMA

IV. Occurrence of Known Aporphines in Plants I n the search for new alkaloids, several known aporphines have been reisolated from the plant kingdom. The above listing of aporphines and the plants from which they have recently been reisolated (Table I, p. 17) represents an attempt to keep up with developments.

V. Two Aporphines of Unknown Structures from Corydalis gortschakovii What is apparently a new aporphine (mp 183"-184", [a]? + 181" in chloroform),containing three methoxyls and a hydroxyl group, has been isolated from Corydalis gortschakovii Schrenk ( 4 4 ) .Acetylation gave the 0,N-diacetyl derivative (mp 163.5"-164.5") which was optically inactive. The 0-methyl derivative yielded a methiodide which was identical with 304, the methiodide of 0-methyl corydine. The alkaloid exhibited A,, 268, and 220 (log E 3.6, 3.98, and 4.4). Another presumed aporphine (mp 232"-234") containing two methoxyls and a hydroxyl is also present in C. gortschakovii.

VI. Syntheses through Phenolic Oxidative Coupling The first synthesis of an aporphine using phenolic oxidative coupling was reported in 1962 when oxidation of N-methyllaudanosoline methXQ

XQ PFT.

H

o

OH

OH

XL

XLI XO

OH

XLII

XQ

OH

XLIII

cw.

~

1.

THE APORPHINE ALKALOIDS

19

iodide (XL) in aqueous ferric chloride solution was shown to give a 62% yield of XLI ( 4 5 ) . Under identical experimental conditions the quaternary benzylisoquinoline alkaloid ( + )-tembetarine (XLII) was then found to give ( +)-laurifoline (XLIII) in low yield ( 4 6 ) . Similarly the quaternary salt XLIV could be cyclized to the aporphine XLV ; interestingly enough the pentahydroxylated isoquinoline XLVI also afforded the aporphine XLI rather than a cularine derivative (47).

OH XLVI

Barton and Cohen (48)were the first to suggest the seminal idea that dienones could be intermediates in the biosynthesis of aporphine alkaloids from benzylisoquinolines, since such dienones could rearrange to the aporphine nucleus either through a dienone-phenol or a dienolbenzene rearrangement as shown in the scheme on the following page. The dienol-benzene rearrangement has been used to advantage to explain the structures of several " abnormal " aporphine alkaloids (49) from a biogenetic point of view, and has also allowed the first synthesis of the aporphine alkaloid isothebaine (L) (50).( & )-Orientaline (XLVII) was oxidized by alkaline ferricyanide to give a mixture of two dienones (XLVIII) in 4% yield. One of the dienones was reduced with sodium borohydride to a mixture of two dienols XLIX which, without

20

MIAURICE SHAJIJI.4

Dienone-phenol

Dienol -benzene rearrangement

rearrangement

OH

separation, was rearranged by treatment with acid. Racemic isothebaine (L)was isolated from the products in over-all 36% yield from the dienone.

ci

XLVII

XLVIII

CH30

OH

XLIX

L

The above sequence of reactions represents an accurate emulation of at least part of the natural process since it has recently been shown that

1.

21

THE APORPHINE ALKALOIDS

( )-orientaline (XLVII) labeled as indicated (*) when incorporated by pupaver orientale L. is transformed into labeled isothebaine (L).Furthermore ( + )-orientalhe (XLVII, with a-C-1 hydrogen) is incorporated twenty-eight times more efficiently than its enantiomer. The expected relationship thus obtains between precursor and product since naturally occurring (+)-isothebaine (L) also has an a-hydrogen at C-6a (51, 51a). Two studies have appeared dealing with the phenolic oxidative coupling of the dihydric benzylisoquinoline LI. I n the first study, oxidation of LI with potassium ferricyanide yielded two dienones (LII), one of which was obtained crystalline. The crystalline material was reduced with sodium borohydride to two noncrystalline dienols (LIII) which underwent dienol-benzene rearrangement in anhydrous methanolic hydrogen chloride to ( )-corydine (XXVI). Rearrangement of the

LI

LII

CH30 HO HO

CHs

CH3

OCH3

OCH3

LIII

HO LIV

22

MAURICE SHAMMA

dienols in aqueous methanolic hydrogen chloride gave ( )-isocorytuberine (LIV) ( 5 2 ) ,as well as the dienone LV, orientalinone (20). This dienone is presumably an intermediate in the transformation of LIII to LIV. In the second study, the isoquinolirie L I was oxidized to the dienone LII. Treatment of L I I with diazomethane afforded the amorphous tetramethoxy base LVI which was reduced with sodium borohydride to a mixture of diastereoisomeric dienols (LVII). Rearrangement of the dienols LVII using anhydrous methanolic hydrogen chloride gave ( _+ )-glaucine (XXXII) and a little 0-methylcorydine (LVIII). On the other hand, rearrangement of the dienols LVII in aqueous methanolic hydrogen chloride resulted in the formation of ( f )-pseudocorydine (LIX) and the dienone LX which could itself undergo acid catalyzed rearrangement to ( f )-pseudocorydine (LIX) ( 5 3 ) .

OCH

LVI

LVII

1. T H E

23

APORPHINE ALKALOIDS

The first synthesis ever reported of the alkaloid isoboldine (XXVIII) has also been achieved. Reticuline (LXI) was oxidized a t -10" with ferricyanide anion to give a 0.5% yield of the alkaloid. Even the bromoreticuline LXII upon phenolic oxidative coupling afforded isoboldine in an improved yield of 2.5% rather than the expected bromocorytuberine LXIII (20).

HO

.o'

'CH3

HO

CH30

CH30

-61' i)H

OH

1x11

LXI

'CH

HO

3

cH30QN HO

CH30

CH30

CH3

g

'CH3

OH 1x111

XXVIII

To date, therefore, no aporphine alkaloids with the 1,2,10,1l-oxygenation pattern have been synthesized in the laboratory by direct coupling of the type observed in the laurifoline and isoboldine syntheses. This may suggest that 1,2,10,1l-tetraoxygenatedaporphine alkaloids are derived in nature by a dienone-phenol type rearrangement.

VII. Reductions with Sodium in Liquid Ammonia I n the first sodium in liquid ammonia reduction of an aporphine, bulbocapnine (LXIV) was converted into 2,ll-dihydroxy-10-methoxyaporphine (LXV) ( 5 4 ) . Since that time several other reductions of aporphines have been carried ; they are outlined below. The aporphines that have been reduced with sodium in liquid ammonia include bulbocapnine (LXIV), nantenine (LXVI), domesticine (LXVII), 0 , O dimethylcorytuberine (LVIII),glaucine (XXXII),nuciferine (LXVIII), 1-methoxy-2-hydroxyaporphine(LXIX), and AT-acetylnornuciferine (LXX).

24

MAURICE SHAMMA

CH30 LSIV

1x1'

(55)

--f

HO

cH30w LXVI

HO

"CH3

@

0

CH3

CH30

CH3O

1.

25

THE APORPHINE ALKALOIDS

CH3

+ same products as above

(56)

OCH3

XXXII

H0

/

-..1;-I

'C'H3

+

LXIS /

(57)

HO CH3

CH3

+

\

\

/

/

26

MAURICE SHAMMA

Some tentative generalizations can be drawn from these studies. A C-1 methoxyl is hydrogenolyzed and the methoxyl group lost. A C-11 methoxyl is also hydrogenolyzed, although there is presently only one example (namely, the reduction of LVTII) to support this contention. A methylenedioxy group is transformed into a simple monohydroxyl function. The alicyclic ketones that are sometimes obtained are products resulting from further progress of the reduction.

VIII. The N-Demethylation of Quaternary Aporphines 0,O-Dimethyllaurifoline iodide (glaucine methiodide) (LXXI) can be smoothly demethylated to glaucine (XXXII)by refluxing in tetrahydrofuran-dioxane and lithium aluminum hydride. This method of dequaternization fails, however, whenever one or more phenolic groups are present in the aporphine salt, so that corytuberine methiodide (magnoflorine iodide) (LXXII) and isocorydine methiodide (menisperine iodide) (LXXIII) are recovered unchanged under these conditions (56, 58).

Refluxing ethanolamine has aIso been used to demetliylate quaternary aporphines, e.g., 0,O-dimethylmagnoflorine iodide (LXXIV) gives O,O-dimethylcorytuberine (LVIII) (56).However, ethanolamine treatment can lead to undesired 0-demethylation as well as t o Hofmann

1.

27

THE A P O R P H I N E ALKALOIDS

elimination since both salts LXXII and LXXIII give the diphenolic phenanthrene derivative LXXV (59).

':"'"D

CH30

LXXIV

LXXV

""0

HO

CH3O

1,XXVII

LXXVI

The ideal method of N-demethylation may turn out t o involve the use of thiophenoxide anion in refluxing Z-butanone. Under these conditions bulbocapnine methothiophenoxide (LXXVI) is converted into the corresponding tertiary free base bulbocapnine (LXXVII), in 7 2 % yield. The reaction mechanism is of the simple S,2 type, and consists of attack by the thiophenoxide anion on one of the N-methyl groups (60).

IX. Properties A. UV-SPECTRA The study of UV-spectra is a powerful tool for the structural elucidation of new aporphines ( 1 , 6 1 ) , and the spectral data in Table I1 are given as an addendum to the listings already recorded in the literature.

B. NMR-SPECTRA The KMR-spectra of nuciferine, glaucine, N-methyllaurotetani~~e, dicentrine, ocoteine, corydine, isocorydine, bulbocapnine, and a variety of noii-natural aporphines have been discussed in some detail (62). Trifluoroacetic acid or D20-NaOD may be used as solvent for those

TABLE I1 UV-SPECTRA

Position of substituents .~

Reference

Aporphine

.-

1,2,9,10

1,2,10,11

1,2,10

Neolitsine (11) 1,2,9-Trimethoxy-10-hydroxyaporphine.HI Thaliporphine (XXIV) 1,9,1O-Trimethoxy-2-hydroxyaporphine~ HC1 Launobine (111) Nandigerine (LXXXIII) Ovigerine. HC1 (LXXXVI salt) Hernovine (LXXXVIII) N-Methylcorydinium iodide (LXXXI) Sparsiflorine (VI) Mecambroline (VIII)

1,10-Dihydroxy-2-methoxyaporphine (XI)

1,2,3,9,10

Ocoteine (XV) Cassyfiline (XVIIb ) Preocoteine (XCIII) Cassythidino (XCVII) Caavorine ( X I I I ) Asimilobine (XIV) 2-Mcthoxy -N-acetylnoraporphinc Guatterine (XVIII)

310 (4.11) 284 (3.9) 303 (4.13) 280 (4.14) 222 (4.56) 305 (4.12) 280 (4.12) 220 (4.52) 304 (4.38) 280 (4.36) 309 (3.72) 270 (4.06) 223 (4.37) 314 (3.74) 271 (4.13) 225 (4.40) 317 (3.77) 270 (4.10) 234 (4.29) 221 (4.41) 306 (3.64) 272 (4.01) 306 (3.79) 273 (4.09) 222 (4.71) 266.5(4.09) 310 (4.0) 275 (4.23) 220 (4.56) 266 (4.09) 308 (4.0) 275 (4.2) 269 sh (4.1) 307 (3.96) 275 (4.12) 218 (4.58) 266 (4.01) 314 (4.1) 283 (4.2) 302 (4.2) 305 (4.26) 284.5(4.28) 220 (4.54) 312 (4.22) 278 (4.16) 302 (4.22) 309 (4.17) 286 (4.10) 217 (4.59) 310 (3.7) 272 (4.25) 308 (3.51) 274 (4.21) 310 (3.61) 270 (4.08) 211 (4.54) 281 (4.26) 242 (4.27)

2 24 43 61n

3 33b 33b 33b 61b

5

6 9 66

13 66 13n 11 12 24 14

1.

29

THE A P O R P H I N E A L K A L O I D S

alkaloids which are not soluble in deuteriochloroform ( 5 , 9). The general trends for the chemical shifts of the different protons of aporphine molecules have already been summarized (1). The influence of alkali on the NMR-spectra of phenolic aporphine alkaloids has been investigated, and this method has become a useful adjunct to NMR-studies in deuteriochloroform. The NMR-spectrum for each alkaloid dissolved in dimethylsulfoxide was first recorded, and the anion shifts were then studied by successive addition of small amounts of a concentrated alkali solution. Plotting the values for the chemical shifts versus the relative amount of alkali added greatly facilitated the interpretation of the data obtained. The aromatic protons of phenols experience a characteristic high field shift when dissociation to the phenoxide ion occurs. The usual upfield shifts ‘appear to be as follows, ortho: 0.47-0.54 ppm, meta: 0.25-0.42 ppm, and para: 0.86 ppm, although meta shifts as high as 0.57 ppm have been noted (18).Protons attached to an aromatic ring not bearing a hydroxyl undergo a high field shift of between 0.11 and 0.26 ppm (25). The only downfield shift observed when an aporphine is converted into its anion occurs when a phenolic function is present a t either C-1 or C-11. It is the adjacent proton at C-11 or C-1, respectively, that undergoes a low field shift of about one T unit. This very special phenomenon, due either to hydrogen bonding or to the anisotropy of the phenoxide anion, allows for the ready characterization of natural aporphines possessing a hydroxyl at C-1 and no substituent at C-11. Such an aporphine is the quaternary Fagara tinguassoiba alkaloid whose newly suggested structure (XXIV, in the N-methyl quaternary form) (16, 21) was further confirmed by the above spectral method, the downfield shift of the C-11 hydrogen in basic medium being 1.04 T units (18). The method of deuterium exchange as followed by NMR-analysis has also greatly facilitated the structural assignments for aporphines. A phenol when placed in hot alkaline deuterium oxide exchanges only its E.xan~ji,;;t~ion of the NMRLruni of ii ciact ins :‘I?>1 that one ,

5

LSXVIII

LSXIX

’~

LXSS

30

.

MAURICE SHAMMA

or more hydrogens have disappeared, and these can be assigned ortho or para to the phenolic function in the aporphine ( 6 3 ) .In this fashion the exact positions of the phenolic groups in apocrotonosine (LXXVIII) and in cassyfiline (XVIIb) were determined (13, 63).

C. ABSOLUTE CONFIGURATION AXD OPTICAL ROTATORY DISPERSION The aporphine alkaloids contain a twisted biphenyl system, and can exist either in the absolute configuration (LXXIX ; S series) or its mirror image (LXXX; R series) (61). Instruments have recently become available which permit the measurement of rotatory dispersion well below 300 mp which was the safe limit attainable with the older spectropolarimeters used. Aporphines exhibit a Cotton effect of high amplitude centered a t 235 to 245 mp, which is independent of substitution in the 1 , 2, 3, 9, 10, and 1 1 positions, and which is therefore diagnostic of the absolute configuration of the molecule. Thus bulbocapnine, glaucine hydrochloride, dicent,rine, nantenine, and boldine all exhibit a positive Cotton effect between 235 and 245 mp, and belong to the S series. Anolobine, nuciferine, and apomorphine hydrochloride show a negative Cotton effect and belong to the R series ( 6 4 ) .It is recommended that optical rotatory dispersion measurements down to 220 mp be carried out on all new aporphines before assignments of absolute configuration are made. In a separate study, it has been shown that the quaternary aporphines ( & )-magnoflorine iodide and ( f )-laurifoline chloride can be resolved into their respective enantiomers by means of paper chromatography (65).

X. Addendum: Additional New Aporphines The following aporphine alkaloids have been isolated and characterized after the main part of this review was written.

A. NANDIGERINE AND N-METHYLNANDIGERINE The noraporphine nandigerine, C ~ S H ~ ~ Owas ~ N isolated , from Hernandia owigera L. (Hernandiaceae). The base crystallized from methanol either as solvent free needles (mp 176"-177"; [a],, +248" in ethanol), or as plates of the methanol solvate, C I ~ H ~ ~ O ~ N . C H ~ O H (mp 99°-1000). The alkaloid hydrochloride salt melted a t 245"-247" (decomp.) (33b). The UV-spectrum of nandigerine, 314, 271, 225 mp (log E

1.

THE A P O R P H I N E ALKALOIDS

31

3.i4 4.13, 4.40),is consistent with its formulation as an 11-substituted aporphine. The NillR-spectrum in deuteriochloroform revealed the presence of three aromatic protons (3.16-3.39 T), one methylenedioxy group (close doublet a t 3.99 and 4.18 T),one methoxyl (6.40 T), and the absence of an N-methyl function. Catalytic reduction of nandigerine in the presence of formaldehyde afforded the amorphous 1C'-methylnandigerine, characterized as its crystalline hydrobromide, CIgH1904N HBr (mp 243"-245" decomp. ; ,1I.[ + 170" in HzO). The NNR-spectrum of N-methylnandigerine was essentially identical with that of nandigerine, except for a new peak a t 7.47 T attributable t o the N-methyl group. N-Methylnandigerine also was isolated as a naturally occurring alkaloid from H . ovigera. Treatment of nandigerine with diazomethane afforded the amorphous O-methylnandigerine.

-

LXXXII

1,XXXIII : R = H

LXXXIV; R=CH3

CH301Y CH30

LXXXY

HO

CH30

CH30fY

CH30

32

J I A U R I C E SHAN;1IA

Diazometliane 0-methylation of S-methylnandigerine, ur alternatively Clarke-Eschweiler Xmethylation of the amorphous 0-methylnandigerine, gave 0,N-dimethylnandigerine, C20H2104N (mp 129"130"), identical with bulbocapnine methyl ether (LXXXII). However, since N-methylnandigerine is different from bulbocapnine (LXXT'II), nandigerine must be assigned structure LXXXIII and N-methylnandigerine LXXXIV. 0-Methylnandigerine must then be represented by LXXXV.

B. OV~GERINE AND N-METHYLOVIGERINE Ovigerine, obtained from Hernundia ovigera, crystallized only as the hydrochloride, C18H1504N-HCl(mp 300" decomp. ; [.IU + 177" in HzO). The UV-spectrum of this salt, A::? 317, 270, 234 mp (log E 3.77, 4.10, and 4.29), was suggestive of a 1,ll-substituted aporphine. The NMRspectrum of the free base showed no signals characteristic of either N-methyl or methoxyl, but complex signals characteristic of two superimposed methylenedioxy groups appeared centered at 4.12 and 3.99 7. N-Methylation of ovigerine (CHz0-HCOOH) afforded amorphous N-methylovigerine, characterized both as the hydrobromide, C19H1704N.HBr (mp 243"-245' decomp.), and as the methiodide, C19H1704N-CH3I (mp 252"-253" decomp.). N-Methylovigerine also was isolated as a naturally occurring alkaloid from H . ovigera. The orientation of the methyleiiedioxy groups in ovigerine was proved in the following manner. N-Methylovigerine was heated for 15 hours with phloroglucinol and aqueous sulfuric acid in order to effect hydrolysis of the methylenedioxy groups. Treatment of the resulting crude phenolic base with diazomethane, followed by methyl iodide, afforded crystalline 0,O-dimethylmagnoflorine iodide (LXXIV). Ovigerine must therefore be assigned structure LXXXVI, so that N methylovigerine corresponds t o LXXXVII (33b).

C. HERNOVINE Besides producing the aporphines nandigerine, N-methylnandigerine, ovigerine, and N-methylovigerine, H . ovigera also contains the alkaloid hernovine, C18H1904N, which crystallizes from methanol as very sparingly soluble plates (mp 234"-236" decomp.), and was assigned structure LXXXVIII. I n analogy with the accompanying nandigerine (LXXXIII)and ovigerine (LXXXVI),hernovine (LXXXVIII)exhibits h 7 ~ ~ ~ 3272, 0 6 ,221 mp (log E 3.64, 4.01, 4.41) typical of a 1,ll-substituted aporphine. N-Methylation of hernovine (CHzO-NaBH4) gave the

1.

THE A P O R P H I X E ALKALOIDS

33

amorphous Xmethylhernovine (LXXXIX), characterized as its crystalline hydrochloride. CI9H2104N.HC'l (mp 245"-247" decomp.). The n'bII<-spectrum of X-methylhernovine revealed, in addition to the iV-methyl group at 7.45 7, two methoxyls a t 6.57 and 6.50 T . 0-Methylation of hernovine with diazomethane yielded the crystalline 0 , O dimethylhernovine (XC) (mp 174"-175"), confirming the presence of two phenolic hydroxyl groups in LXXXVIII. A-Jlethylation of 0,Odimethylhernovine, followed by treatment of the resulting N,O,Otrimethylhernovine with methyl iodide. gave 0,O-dimethylmagnoflorine iodide (LXXIV). The two methoxyls in hernovine are assumed to be a t positions 1 and 11 of the aporphiiie system, since they appear in the NMR-spectrum of X-methylhernovine at relatively high fields (6.57 and 6.50 T ) (336).

D. N-METHYLCORYDINIUM CATION The N-methylcorydinium cation was obtained from an extract of the bark ofPagara nigrescens Fries, and was first crystallized as the styphnate salt, (mp 206°-2070; [a]: + 129" in acetone). Two other crystalline salts were prepared, the picrate (mp 186"-187"), and the iodide which decomposed gradually between 190" and 200" ([a]? +154' in 50% ethanol-water). Analyses of the styphnate and picrate indicated the formula C21H2,$04@ for the cation. The UV-spectrum of the iodide, ?: : !A 306, 273, 266.5, and 222 mp (log E 3.79, 4.09, 4.09, 4.71), suggested that this new alkaloid was l,Z,lO,ll-tetrasubstituted.A strong bathochromic shift of the maxima in alkaline solution showed the presence o f a phenolic hydroxyl group, while the elemental analyses also required the presence of three methoxyls.

The NMR-spectrum of the alkaloid in trifluoroacetic acid also confirmed the presence of three methoxyl groups which appeared a t 5.90, 5.95, and 6.16 7.The 6.16 T absorption, being relatively upfield, is clearly indicative of a methoxyl at either C-1 or C-11.

34

M A U R I C E SHAMMA

Final chara~terizationof the new alkaloid as the N-methylcorydinium cation (LXXXI) was obtained by direct comparison of its iodide salt with authentic ( + )-corydine methiodide. and the two salts were shown t o be identical (61b).

E. THALIPORPHINE Besides yielding a wealth of alkaloids belonging to the benzylisoquinoline, bisbeiizylisoquinoline, and protoberberine series, Thalictrum fe?idlrri C. L. Anders also produces the new alkaloid thaliporphine (XXIV), CzoHz304N (mp 170"- 172") (43). The UV-spectrum of thaliporphine exhibits h~~~~ 305, 280, and 220 mp (log E 4.12,4.12, and 4.52) characteristic of a 1,2,9,1O-tetrasubstituted aporphinc, and undergoes a bathochrgmic shift in base. The NMRspectrum revealed the presence of three methoxyl and one N-methyl groups. Spectral and thin-layer chromatographic comparisons then showed that thaliporphine is identical with l-hydroxy-2,9,1O-trimethoxyaporphine which had been previously synthesized (16, 43). It follows that the unnamed alkaloid from Fagara tinguassoiba (see Section II1,B) corresponds to the N-methylthaliporphinium cation. Very recently the isomeric structure ( 5 )-1,9,10-trirnethoxy-2hydroxyaporphine has been synthesized, and has proved to be different from thaliporphine in its NMR-spectrum (61a).

F. PREOCOTEINE A new aporphine found in Thalictrum fendleri is preocoteine (XCIII) (66).This alkaloid was obtained only in small amounts as an oil, but its 312, 302, and 278 mp (log E 4.22, 4.22, 4.16) UV-spectrum showing ATII,': is diagnostic of a 1,2,3,'3,10-pentasubstituted aporphine, and is close to that of the well-characterized aporphine base ocoteine (XV) which hasX:',:,H 314, 302, and 283 m p (log F 4.1, 4.2, and 4.2) and is also present in 77. fendleri. Additionally, the UV-spectrum of preocoteine shows a hathochromic shift upon the addition of base, so that the molecule must be phenolic. The mass spectrum of preocoteine had a molecular ion a t m/e 371, corresponding to the formula C ~ I H ~ ~ O These ~ N data . indicated that in analogy with ocoteine, preocoteine is pentaoxygenated, but contains four methoxyl and one hydroxyl groups. The use of NRIR-spectroscopy in the structural elucidation of aporphines revolves mainly around the fact that methoxyl groups at C-1 or at C-11 appear at higher fields (6.60-6.28 T ) than other methoxyl groups

1. TI1E

A P O R P H I N E ALKALOIDS

35

while a C-11 hydrogen is always located farther downfield than the remaining aromatic protons (3.62-3.00 T ) . The SJIR-spectrum of preocoteine a t 60 JIc shows two superimposed methoxyl absorptions a t B.08 T and also at 6.12 T , so t h a t no methoxyl group is present either a t C-1 or at C-11. However, since all naturally occurring aporphines are substituted a t C- I , the phenolic function must be placed at t h a t position. The C-11 hydrogen was situated characteristically downfield as a singlet a t 6.01 T , while t h e C-8 hydrogen appeared as a singlet a t 3.26 T. I n order to eliminate t h e possibility of preocoteine possessing t h e alternate structure XCIV, t h e alkaloid was 0-methylated with diazomethane t o 0-methylpreocoteine, molecular ion at m/e 385 (CzzH2705N), which turned out t o be different from a sample of authentic 1,2,8,9,10pentamethoxyaporphine (XCV). (6.28-6.10 (:'.18-1.00

T).

T)

G. CATALPIFOLINE Hernandia catalpifolia has Fielded t h e new base catalpifoli~ie(XC) whose structure was proven by its identity with t h e diazomethane alkplation product of hernovine ( L X X X V I I I ) . The molecular formula of catalpifoline is CzoHZ3N04.The melting point is 174" - 175", with [ E ] , ) +220" in ethanol (33b). The interesting alkaloid hernandaline (XCVI), which is intermediate between aporphiiies a n d benzylisoquinoline-aporphine dimers has been found in t h e related H . ovigera L. (33b).

H. CASSYTHIDINE The nonphenolic base cassythidine (XCVII), C19H17N05, is a noraporphine found together with eassyfiline (XVIIb) (13a) in Gassytha

Jiliforrnis L. (Lauraceae). The free base has mp 206" - 207"; [ccIn + 15" in CHC13, and A~~~~~ 30'3, 286, and 271mp (log E 4.17, 4.10, and 4.59). The NTJIR-spectrum showed the presence of only one methoxyl group, and as the signal occurs a t low field (6.03 T ) i t is probably due to a methoxyl a t C-3. Two aromatic protons, as singlets, appear a t 2.15 T and 3.31 T , and these can be assigned to (2-11and C-8. Two methylenedioxy groups are also indicated by the NXR-spectrum. One of these groups must be a t C-l,2 and shows up as a pair of AB doublets a t 4.00 T and 4.13 T ( J = l . 5 cps) The other methylenedioxy group is as a singlet at 4.10 T ,and in analogy with neolitsine (11)was placed a t c-9,lO.

Cussythufilifomzis also showed traces of the presence of O-methylcassyfiline (XCVIII) on the basis of comparisons of the NMR-spectra of chromatographic fractions in which it predominated with the spectrum of authentic 0-methylcassyfiline prepared from cassyfiline, (XVIIb), and by comparative thin-layer chromatography. However, the naturally occurring 0-methylcassyfiline was not isolated in pure form. This base would correspond to norocoteine (13a). OCH3 I

OCH3 SC'VI

OH S C I S a : R = C'H3 S C T S b : I? = H

1.

THE A P O R P H I K E A L K A L O I D S

37

I. I1'-XETHYLACTINODAPHKIXE The tree bark of Seolitseu sericea (Blume) Koidz. (Lauraceae) has yielded a wide variety of aporphine alkaloids, one of which is S-methylactinodaphnine (XCIXa), C I ~ H ~ ~(mp O ~206", N [a]? + 59" in ethanol) identical with the X-methylation product from authentic actinodaphnine (XCIXb) ( 6 7 ) . REABKENCES 1. 31. Shamma and TV. A. Slusarchyk, Chem. Rev. 64, 59 (1964). 2 . W. H. Hui, S. S . Loo, and H . R. Arthur, J . Chern. Soc. p . 2285 (1965). 3. 31.Tomita, M. Kozuka. E. Sakagawa, and Y. Mitsunori, J . Phnrm. Soc. J a p a n 83, 763 (1963). 4. 8. K. Saha, Sci. Cult. (Crtlcuttn) 24, 572 (1959); c'hem. Abstr. 54, 1580 (1960). 5. A. Chatterjee, P. L. Majumdar, R'. Mukherjee, S. K. Saha, and S. K. Talapatra, Tetruhedron Letters p. 1539 (1965). 6 . J. Slavik and L. Slavikova, Collection Czech. Chem. Cornmun. 28, 1720 (1963); Chem. Abstr. 59, 11886 (1963). 7. J. Slavik, Collection Czech. Chem. Cornmun. 30, 914 (1965). 8. V. A. Mnatsakanyan and S. Yu. Yunusov, Dokl. A4krid.Nauk 1'2. SSR So. 12, p. 36 (1961); Chem. Abstr. 58, 1503 (1963). 9. R. Gilbert, M. E. A. Gilbert, M. M. DeOliveira, 0. R'ibeiro, E. Wenkert, B. Wickberg, U. Hollstein, and H. Rapoport, J . Am. Chem. SOC.86, 694 (1964). 10. T. Kitamura,J. P h a r m . Soc. J a p a n 80, 1104 (1960). 11. R. Tschesche, P. Welzel, R. Moll, and G. Legler, Tetrahedron 20, 1435 (1964); Chern. Abstr. 61, 5704 (1964). 12. M. Tomita and M. Kozuka, J . P h a r m . SOC.J a p a n 85, 77 (1965); Chem. Abstr. 62, 11863 (1965). 13. M. Tomita, S.-T. Lu, and S.-J. Wang, J . Phnrm. SOC. Jnpan 85, 827 (1965); Chem. Abstr. 63, 18187 (1965). 13a. 8. R. Johns and J. A. Lamberton, A u s t . J . ( " h e m . 19, 297 (1966). 14. W. M. Harris and T. A. Geissman, J . Ory. Chem. 30, 432 (1965). 15. R. H. E'. illanske gives a discussion of glaucentrine in .4lkaZoids 4, 119 (1954). 16. M. Shamrna and I?. A. Slusarchyk, Tetrahedron Letters p. I509 (1965). 17. S . V. Riggs, I,. Antonaccio, a.nd L. Marion, Ccc>z.J. Chem. 39, 1330 (1961). 18. W. H. Baarschers and K. G . R. Pachler, Tetrahedroii. Letters p. 345 (1965). 19. &I.Tornita and ill. Fujie, J . Phnrm. Soc. J a p n 82, 1457 (1962). 20. A. H. Jackson and J. A. Martin, C h e m Contnbuic. No. 18, p. 420 (1965). 21. R. Tschesche, P. Welzel, and CT. Legler, Tetmhedro,c Letters p . 445 (1966); Chem. rlbstr. 62, 14737 (1965). 2 2 . P. S. Clezy, A . W.Sichol, and E. Gellert, Ezperieriticc 19, 1 (1963). 2". P. S. Clezy, E. Gcllert, D. Y. K . Lau, and A. W.Sichol, Austrnliun J . Chem. 19, 135 (1966). 23. R. R. Arndt and W.H. Baarschers, J . Chem. SOC.p. 2244 (1964). 24. W.H. Baarschers and R . K . Arndt, Tetrrchedroiz 21, 2155 (1965). 2 5 . K. G. R . Pachler, R'. R. Arndt, and 1%'. H. Baarschers, Tetruhedrorb 21, 2159 (1965). 26. JI. 8. Gibson and J . 31.W-althew, ('hem. d. I x d . ( L o r ~ d op. ~ )185 (1965). 27. 31. J. Verncngo, Ezperientirc 19, 294 (1963).

38

MAURICE SHAJIM.4

28. T. K. Govindachsri, B. R . Pai, arid G. Shanmugasundaram, Tetrahedron 20, 2895 (1964). 28a. J. Sf.Calderwood and F. Fish, Chent. & I n d . ( Lo n d o n )p. 237 (1966). 29. R . H. F. RIanske and K. H. Shin, C a n . J . Chem. 43, 2180 (1965). 30. 111. Tomita, S. T. Lu, S . C. Fu, and Y. 31. Lin, J . Phvrni. Soc. J a p a n 85, 662 (1965). 30a. R1. Tomita, S. T. Lu, P. K. Lan, and F.11.Lin, J . Phurm. Soc. Jrcpan 85, 593 (1965). 31. Work done in Argcntina by V. Deulofeu, A. RI. Kuck, J. Coinin, E. Sanchez, and others, private communications (1966). 32. M. Tomit,a and &I. Kozuka, J . Pliarm. Soc. J u p a n 84, 365 (1964). 33. J. Slavik and L. Slavikova, Collection Czech. Ch.ern. Commun. 28, 2530 (1963). 33a. J. Slavik, J. Appelt, arid L. Slavikova, C'ollectioti Czech. Cheni. d'ommun. 30, 3961 (1961). 33b. &I. P. Cava, K. Bessho, B. Douglas, S. Markey, H.F. Raffauf, and J. A. Weisbach, Tetruhedron Letters p. 4279 (1966). 34. 11.M. Kijland, Phorwi. Weekblud 100, 88 (1965). 35. 11.Tomita, K. H. Lee, arid T. Xakano, J . Phurin. Soc. J a p a n 85, 2 i 6 (1965). 36. 51. M. Nijland and 0. F. Uffelie, Pharm. TVeek6Zad 100, 49 (1965). 37. K . Bernauer, H e l v . Chim.Acta 47, 2119 (1964). 38. J. Kunitomo, C. Yamamoto, and T. Otsuki, J . Phurm. Soc. J a p o n 84, 1141 (1964). 39. J. Slavik, Collection Czech. Chem. Cowmun. 28, 1738 (1963). 40. S. Y . Yunusov, V. A. Mnatsakanyan, and S. T. Akramov, Dokl. A k a d . ~VaukU Z .SSR p. 43 (1961); Chem. Abstr. 57, 9900 (1962). 41. S. Pfeifer and L. Kuhn, Phar.mazie 20, 394 (1965). 42. S. M. Kupchan, B. Dasgupta, E. Fujita, and M. L. King, Tetrahedron 19, 2 2 i (1863). 43. M. Shamma and B. S. Dudock, unpublished results (1966). 44. M. S. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Dolil. A k a d . Kuuk SSSR 162, 607 (1965); Chem. Abstr. 63, 123 (1965). 45. B. Franck, G. Blaschke, and G. Schlingloff, Tetrahedron Letters p. 439 (1962); B. Franck and G. Schlingloff, A n n . Chern. 659, 123 (1962). 46. S. &I. Albonico, A. M. Kuck, and V. Deulofeu, Chcni. & I n d . (London)p. 1580 (1964); Ann. Chern. 685, 200 (1965). 47. B. Franck, G. Hlaschke, and G. Schlingloff, Angew. Chwn. Intern. E d . Engl. 3, 192 (1964). 48. D. H. H. Barton and T. Cohen, Festschr. Arthur Sto2l p. 117 (1955). 49. A. It. Battershy, Proc. Chew&.Soc. p. 189 (1963). 50. A. R. Bat.tersby and T. H. Brown, I'rcc. G'hem. Soc. p. 85 (1964); A. R.. Bat.t.ersby, T. H. Brown, and J. H. Clements, J . Chem. Soc. p. 4550 (1965). 51. A . R . Battcrsby, R . T. Brown, J. H. Clements, and G. G. Iverach, ChewL. Commun. Xo. 11,p. 230 (1965). 51a. A. R. Battersby and T. H. Brown, Chern. Commun. p. I 7 0 (1966). 52. A. H. Jackson ancl J. A. Martin, Chem. Conamun. S o . 8, p. 142 (1965). 53. BI. Shamma and W. A. Slusarchyk, Che?n. C o m m u n . KO. 21, p. 528 (1965). 54. W. A. Ayer and W. I. Taylor, J . Chem. Soc. p. 452 (1956). 56. T. Kitamura, J . l'harm. Soc. J a p a n S O , 219 (1960); C'henl. Abstr. 54, 13162 (1960). 56. BI. Tomita and K . Fukagama, J . Pharm. Soc. Jupnn 83, 293 (1963); C'he?n. Abslr. 59, 5211 (1963). 57. J . Kunitomo arid M. Kaniiinura, J . Ph(171w.Soc. J a p o ) ~82, 1652 (1962). 68. AT. Tomita and T. Ibuka, J . Phorm. Soc. Jccpnt2 80, 1646 (1960); Cheni. Abstr. 59, 2854 (1963).

1. THE APORPHINE ALKALOIDS

39

59. M. Tomita and Y . Takano, .J. f’ktlrm. Soc. J a p a n 80, 1645 (1960); Chem. ilbstr. 5 5 , 7462 (1961). 60. M.Shamma,,K. C. Deno, and J. F. Remar, Tetrahedron Letters p. 1375 (1966). 61. ,M. Shamma, Ezperientia 16, 484 (1960). 6la. B. R. Pai, private communications (1966). Glb. A. &I. Kuck, Cyhem. h f n d . (Londoti) p. 11s (1966). 132. W. H . Baarschers, R. R. Amdt, K. Pachler, J. A . Weisbach, and B. Douglas, J . Chrm. Soc. p. 4778 (1964). 63. L. J. Hayes, K. L. Stuart, D. H. K. Barton, and G. W. Kirby, Proc. Chem. Soc. p. 261 (1964). 64. J. Cymerman Craig and S. K. Roy, Tetmhedro?A 21, 396 (1965); and J. Cymerrnan Craig, It. P. K. Chan, and M. Shamma, unpublished results (1966). 65. I. Kikkawa, J. Pharm. Soc. J a p a n 81, 732 (1961). 66. M. Shamma, R. J. Shine, and B. S. Dudock, Tetrahedron, in press. 67. T. Nakasato, S. Asada, and Y . Koezuka, J . Pharm. SOC.J a p a n 86, 129 (1966).

This Page Intentionaiiy Laft Blank

-CHAPTER

2-

THE PROTOBERBERINE ALKALOIDS P. W. JEFFS Duke University, Durham, North Carolina

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

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Occurrence . . .

111. Berberine and Related Alkaloids . . . . . . . . A. Berberine.. . . . . . . . . . B. Alkaloids of Berberis Zambertii Parker. C. Tetrahydroberberine (Canadine) . . . . .

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

D. Berberastine and the Alkaloids of ThaE E. Alkaloids of XyZopin deecreta (L. fil.). . F. Coramine.. . . . . . . .. .. .. .. . . .. . . .. . G. Corydalmine and Dehydrocorydalmine . . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Absolute Configuration of Alkaloids of the Tetrahydro Series . . . . . . . .

.. .. .. .. Ir. Alkaloids Relat.ed t.o Corydaline A. B a s e I I . . . . . . . . . . . . . . . . .. . . .. . . . . .. .. . .

I

.

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

1'1. Quaternary Alkal A. Introduction.

43 43 43 57 57 65 69 71 71 72 74

74 C,.

Ia

B. Corysamine and the Alkaloids of (?orydriZis i 7 C. Stereochemistry of Corydaline and Related Alkaloids

V. Ophiocarpine . . . . .

41

.. . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . .. .. . . .. . . .. . . .. . . . . .. ing an I2-methyl group . . . . . . .

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

VII. Synthesis . . . . . . .

78 82

85 85 85 87

91

A. Rerberine and Related Alkaloids

tives

. . . . . . . . . . . . . . . . . . . . . . . . . . 91 . . . . . . . . . . . 100

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

References

. .. . . .. . . ..

102

110

X. Addendum

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

. . . . . . . . . . . 110

I. Introduction Since the protoberberine alkaloids were last reviewed in Volume I V of this series, many important developments have taken place in the chemistry of this group of alkaloids. Isolation studies have resulted in the addition of thirteen new alkaloids whose structures, with one or two 41

42

P . W. JEFFS

exceptions, are known with confidence. Two of these new alkaloids, cyclanoline and steponine, were discussed briefly in Volume V I I and consequently they will only be ment’ioned incidentally in this chapter. Umbellatine and neprotine, reported as alkaloids of unknown structure in Volume I V , have been found ( I ) to be identical with berberine and jatrorrhizine, respectively. The alkaloid rotundine, whose previously proposed structure has been the center of controversy for a number of years, has been identified ( 2 ) as ( - )-tetrahydropalmatine. Many successful syntheses of this group of alkaloids have been recorded, including a large number which have emphasized the use of new approaches. The absolute configuration of alkaloids belonging to the tetrahydroprotoberberine* series has been established and progress has also been made in clarifying the relative and absolute stereochemistry of the C-13-substituted bases of this series. NMR-spectroscopy and mass spectrometry have proved useful tools in the structure analysis of certain protoberberine alkaloids, although, as yet, neither has been utilized extensively. The biosynthesis of berberine has been investigated thoroughly and a fairly complete picture of the way in which nature constructs this molecule is now known. The system of nomenclature for alkaloids of the tetrahydro series is somewhat confusing. Naturally occurring members of this series often occur in one of their optically active forms ; understandably, at the time of isolation, they were given trivial names of their own. The trivial names have survived despite the fact that the relationship of these alkaloids as tetrahydro derivatives of known quaternary alkaloids of the dibenzo [agIquinolizine series (cf. berberine), which themselves have trivial names, has in most cases been clearly established. Although i t would seem desirable to retain the names of the quaternary alkaloids of the series as parent names and to designate alkaloids of the tetrahydro series accordingly, this has its disadvantages in that the related quaternary bases of some alkaloids of the tetrahydro series are not known to occur in nature. A further complication exists in the case of certain alkaloids where the parent name is given to the tetrahydro base and the related quaternary alkaloid, although often naturally occurring, is named by using the prefix “dehydro-.” The current practice in naming alkaloids of the tetrahydro series seems

* This rorripound is frequent,ly referred to as tetrahydroanliydroberberine ; however, the simpler name tet rahydroberberine is equally correct and will he used throughout this chapter. Similarly, related alkaloids of this series will be referred to as tet’rahydro bases rather than t.etrahydroanhydro bases.

2.

THE PROTOBERBERINE ALKALOIDS

43

to be in favor of retaining the trivial name if the base is optically active but to use the prefix " tetrahydro- '' if the racemic form is being described. In this chapter all compounds of the tetrahydro series are referred to by naming them as the tetrahydro derivative of the related quaternary alkaloid where the quaternary base is known and has its own established trivial name. The trivial name of the tetrahydro base also is given, usually at the first time of reference.

11. Occurrence* The protoberberine alkaloids are widely distributed, occurring in at least eight botanical families. They occur most frequently in the various genera of the Papaveraceae but are also well represented in the Berberaceae, Menispermaceae, Ranunculaceae, Rutaceae, and Annonaceae families. Table I shows the additional plant sources of the protoberberines that have been reported since the appearance of the last review in Volume IV.

111.

Berberine and Related Alkaloids

A. BERBERINEt

I . Structure and Reactivity Berberine as a member of the class of compounds classified by Hantzsch ( 7 3 )as pseudo bases has commanded its share of discussion on this still controversial topic. The generally accepted view of Gadamer ( 7 4 ) that berberine exists in solution as an equilibrium mixture of three " tautomeric " forms (Ia-c) has been reexamined ( 7 5 ) . The evidence for the existence and structures of the ammonium form (Ia)and the pseudo-base form (Ib) is well established m d was discussed in more detail in the previous review of these alkaloids (Volume IV, Chapter 5 ) .More recent effortshave been concerned with seeking evidence for the presence of the aldehyde form (Ic) a.nd t.he possibi1it.y of it.s participation in certain reactions of berberine. The chemical approach to the study of this problem is beset with the usual difficulties encountered in a system containing several rapidly equilibrating forms in which each is capable of undergoing reaction with a given reagent. Certainly alkylation, which occurs a t C-8 with nucleo-

* This material is supplementary

t This material is supplementary

t o V o l u ~ n e1 V , pages 7 8 - 8 7 , to T:oliime 1x7, pages 87-91.

TABLE I BOTANICAL D I S T R I R C T l O X

1. Papaveraceae

Plant (Rc,fercmce) ~

Alkaloid ~~

Argenzoiie ueiir(i G. B. O.ilmh. (5)

9.platycerzcs Link e t Otto. (6 7 )

. ....

Berberine .4llocryptopine Protopine Argemonine Risnora,rgemonine Berheririe Coptisinen (trace) Allocryptopine Snnguinurine Chelerythrine Protopine Alkaloid A Berberine Copt isinea (t>race) A llocrypt opine Sa,nguinarinea Chelerythrinea Protopine Dihydrosanguinarine Dihydrochelerythrine Berberine Coptisine Allocryptopine Argemonine Norargemonine

Plant (Reference)

Alkaloid

. ..

Corydrclis c ~ i n h i ~ ~Cham. wr et Schlect. var. amurtnsis Maxim. ( 1 0 , 11)

Platycerine Sanguinarinc" (trace) ( f )-Tetrnhydrocopt isiiie ( + ) -Tetrahydrocoptisille [ ( + )-st,ylopine] Coptisino Chelidonirie Cheleryt hriiie Chelirubine l'robopine Allocrypt.opiiie Sanguinarine ( + )-Base I1 Dehydrobase-I1 ( + )-Corybulhine Dehydrocorybulbine ( + )-Corydaline I>ehvdrocoryd~litie ( f )-Tetrahydropaltriitt i tic Palmatine Base V (inp 194"-l $35') Base V I ( m p 1T1°-172L) (sinactine?) Tetrahydrobcrheririe'l 1'rot.opine

Cham. et Schlect. (12) C. uuqu8tijolui DC. ( 1 3 ) C.

07116ip4u

C. cam Srhweigg. et Korte (syn. C. tuberonn DC). (14)

C . decipieiin (syn. C'. purniki Koch.) ( 1 3 )

C. incicrcr (Thunb.) Pers. (15, 16, 1 7 )

C . peudoaduiiccc ( 1 8 )

C.

80kh

(L.) Swartz ( 1 9 )

Corydalie X (rnp 2 0 " ) Corydalis Y (rnp 229") ( f ) -Tetrahydropalmetine Protopine Corydeline Sonphenolic base (rnp 224"226') ( + )-Coryddine Prot opine Two unidentified bases Bane I (rnp 2 16"-217") Base I1 (rnp 235"-237") Base 111 (rnp 240") Base V (rnp 209"-210") Base V I I (amorphous) Coptisine Corysarnine Protopine Sanguinarine Biruculline Corypalrnine F 62 Corernine ( + )-Bicucculline ( f )-Biccucculline Protopine Corydeline ( )-Tetrahydrocoptisine ( f )-Tetrahydropalmatine ( )-Tetrahydropalrnatinea

+ +

+ )-Tetrahydroberberinen Protopine Allorryptopine Bulhocapnine Coptinine ( + )-Corydelrnine ( )-Corydaline Dehydrocorydalmine Deliydrocorydelinc ( f )-Tetrahydroroptixinr ( - )-Tetrehydrorolurnheiniric. ( f )-Tetrehgdropnlriiat inr Protopine Coptisinen Protopine Senguinarine Cheliruhinea Cheleryt hrinea Chelilut inen Uerbrine Coptisine Iwrorydine Protopine Sanguinerine Allocryptopine Cheleryt hrine Chelirubine Berberinea Coptisine Base ( m p li7°-178") Protopine Sanguinarine

(

Corytlnlirr spp. (described engosan) (PO)

M

Diceiitrn apec~rbctlia( P I )

jrcritrhe(Prain) Fedde

Dicrcriioetigiiicr ficrtiuiit

(42)

D . ltrctucoidee Hook f. et Thorns. (43)

+

P

3 l

TABLE I--continued

b P

45 __.______ ~~__.

Plant (Reference)

Alkaloid

Plant (Reference) ~

(

(

F u m a r i a offkinalis ( 2 4 )

Glaucium corniculatum Curt. (25)

+ )-Isocorydine

+ )-Corytuberine

Allocryptopine Chelerythrine Chelirubine Oxysanguinarine Corydalinea Protopinea Bulbocapninea Dicentrinea Berberinea Coptisine" Protopine Allocryptopine ( - )-Chelidonine ( )-Corydine ( )-Isocorydine Chelerythrine Sanguinarine Berberine Coptisine ( - )-Scoulerine aurotensine ( )-Scoulerine Domesticine Cory d in e Protopine Allocryptopine Sanguinarine

+ +

G. oxylobum Boiss. et Buhse ( 2 6 )

+

Macleaya microcarpa (Maxim.) Fedde (27)

Meconopsis paniculata (D. Don) Prain ( 2 8 )

Papaver d u b i u m L. ( 2 9 )

P. d u b i u m var Lecoquii ( 3 0 ) P . rhoeaa L. ( 3 1 )

1

Platystemon californicus ( 3 2 )

Alkaloid ___

Chelilutine Chelerythrine Coptisine Berberinea Allocryptopine Protopine Chelerythrine Chelirubine Chelilutine Macarpine Sanguinarine Coptisine Protopine Sanguinarine Coptisine Aporheine [( + )-romerine] Dubirheine Mecambrine Berberine Coptisine Protopine Rhoeadine Alkaloid I Alkaloid I1 Alkaloid I11 Alkaloid I V Coptisine Chelerythrine

Stylophorum diphyllum (33)

Chelirubine Protopine Sanguinarine Coptisine ( - )-Tetrahydrocoptisine Chelirubine Macarpine Diphylline [( & )-chelidonine] Sanguinarine

.

2. Berberidaceae

Berberis amurensis var. japonica (Regel) Rehd (34)

B. asiatica Roxburgh (35)

B. hauniensis Zab. ( 3 6 )

B. illiensis (37)

Berberine Palmatine Oxyberberine (berlambine) Jatrorrhizine Berbamine Magnoflorine Base (mp 190-"191") Berberine Palmatine Jatrorrhizine Berbamine Berberine Berberubine Jatrorrhizine? Palmatine Berbamine Columbamine Oxyacanthine Berberine

B. kawakamii ( 3 8 )

B. lamberti Parker ( 3 9 )

B. mingetsensis ( 4 0 )

B. serrata Koehne ( 4 1 ) B. silvataroucana ( 4 2 ) B. thunbergii DC. ( 4 3 )

Jatrorrhizine Berbamine Oxyacanthine Alkaloid A (mp 290") Berberin" Jatrorrhizine Palmatineb Berbamine Isotetrandrine Magnoflorine Berberine Columbamine Dihydroberberine (lambertine) Jatrorrhizine Oxyberberine (berlambine) Berbamine Berberine Oxyberberine (berlambine) Palmatineb Berbamine Isotetrandrine Base (mp 240'-242") Berberine Berberine Palmatine Jatrorrhizine Oxyberberine (berlambine) Berbamine Isotetrandrine Magnoflorine Oxyacanthine Base (picrate, mp 217"-223")

TABLE I-continued Plant (Reference) B. tschonoskyana Regel ( 4 4 )

B. vulgaris ( 4 5 )

Mahonia fortunei Fedde ( 4 6 )

M . japonica DC. ( 4 6 )

Alkaloid Berberineb Jatrorrhizine Oxyberberine (berlambine) Palmatineb Magnoflorine Obamegine Oxyacanthine Base (mp 89'-92") Berberine Columbamine Palmatine Berbamine Isotetandrine Oxyacanthine Bervulcine Vulracine Berberine Jatrorrhizine Palmatine Berbamine Magnoflorine Oxyacanthine Berberine Jatrorrhizine Palmatine Berbamine Magnoflorine Isotetrandrine

Plant (Reference)

Alkaloid

Mahonia limariifolia Takeda ( 4 7 )

M . morrisonensis Takeda (47)

-

Nandina domestica var. leucocarpa Makino ( 4 6 )

N . domestica f. shinananten Mort. ( 4 6 )

Berberine Jatrorrhizine Oxyberberine (berlambine) Palmatine Berbamine Isotetrandrine Magnoflorine Berber in e Jatrorrhizine Oxyberberine (berlambine) Palmatine Berberine Domesticine 0-Methyldomesticine Protopinem Berberine Jatrorrhizine Domesticine 0-Methyldomesticine Protopine Base (mp 128')

3. Annonaceae ~~

Enantia chlorantha (48a) E. polycarpa ( 4 8 b ) Xylopia descreta (L. fil.) ( 4 9 )

Palmatine Palmatine Descretamine Descretinine

S. japonzca Miers (55)

Descret ine ( - )-Norcoralydine (xylopinine) Xylopine

-~

-~

~

4. Magnoliaceae

~

Michelia compressa Mitxim. (50)

-

~~~~~~

..

~~~~

~~~

~

.

..

.~

Berberine Jatrorrhizine Palmatine Magnoflorine Oxyacanthine

~

~

5. Menispermaceae

_ _ ~

.

~~

6. Ranunculaceae

~

~

Cyclanoline Steponine

~~~~

-~

Burasia madagascarieiwis

~

~

-

Coptis japonica Makino ( 5 6 ) Hydrastis canadensis L. (57-59)

Thulictrum dasycarpurn var. hypoglaucurn ( 6 0 ) T. fendleri (61-63)

Palmatine

(51)

Cyclea insularis (Makino) Diels ( 5 2 )

Fibraurea tinctoria ( 5 3 )

Parabaena hirsuta (Becc.) Diels ( 5 3 a ) Stephania glabra ( 5 4 )

Cyclanoline Cycleanine Insularine Isochonodendrine Magnoflorine Palmatine Fibramine Fibraminine (mp 192"-193") .Palmatine ( - )-Tetrahydropalmatine Cycleanine Gindarycine Stephanine Base IV (mp 205")

T . thunbergii DC. ( 6 4 )

Xanthorhiza simplicissma (65)

Jatrorrhizine Bsrberastine Berberine ( - )-Tetrahydroberberine Tetrahydroberberastine Hydrastine Berberine Magnoflorine Berberine Jatrorrhizine Thalidastine Thalifendine Hernandezine Magnoflorine Thalifendlerine Berberine Magnoflorine Takatonine Berberine Jatrorrhizine Magnoflorine

7. Ruteceae -

Phellodendron amurense Rupr. (66)

Berberine Jatrorrhizine

01 0

TABLE I-continued __

~..

~~

-

P. umurense Rupr.

var.

sncchdiense Fr. Srhm.

(68)

~.

Plant (Reference)

Alkaloid

Plant (Reference)

P. amurense var. japonicum Ohwi ( 6 7 )

~.

~

~~~

-

~

Alkaloid -~

~~~

Phellodendrine Candicine Menisperine Berberine Jatrorrhizine Palmatine Phellodendrine Candicine Magnoflorine Berberine Jatrorrhizine Palmatine Phellodendrine

Magiioflorine Berberine Berberine

P.lavallei (69) P. udsonzz (70) _ _ _

~

_

~

-

8. Aristolochiaceae _ ~ _ _-~ -

Arastolochia debalzs Sieb et Zucc. ( 7 1 ) _

Cyclarioline Magnoflorine -

-

_

-

~

9. Convolvulaceae ~ _ - _

Calystegaa hydracene (72)

Palmatine (calystegine)

I

a b

Presence is based upon chromatographic and/or color reactions only. Presence is ascribed on the basis of the reported presence of shobakunine, which is a mixture of palmatine and herberine.

2.

51

THE PROTOBERBERINE ALKALOIDS

I8

Ib

Ic

philic reagents such as acetone in affording 8-acetonyldihydroberberine (II)?is of no help in deciding which form of berberine is reacting, since despite the cyclic nature of the product, reasonable pathways to I1 may be written from all three forms of berberine. Acylation, on the other hand, is less ambiguous in that only the aldehyde and carbinolamine forms are capable of undergoing reaction (possibly to the same product). Apparently berberine fails to undergo acetylation and this has been cited as evidence for definitely excluding the presence of the open-chain aldehyde form ( 7 5 ) . Since. there is little doubt that under certain conditions the OII

52

P.

W. JEFFS

pseudo-base form (Ib) exists in appreciable concentration it would seem that with judicious choice of reagent and reaction conditions acylation of berberine should indeed be possible. However, even if such a reaction were successful, it is doubtful if it would contribute to demonstrating the existence of the aldehyde form. Nonpolar solvents and high pH would obviously tend to favor the pseudo base and aldehyde forms over the ammonium species, and it is the disproportionation of berberine in strong base to oxyberberine (8ketodihydroberberine) (111)and dihydroberberine (IV) which has been construed as providing the strongest support for the participation of the aldehyde form. The reaction has been interpreted as involving an oxidation-reduction of the aldehyde group in Ic in analogy with the Cannizzaro reaction. Unfortunately, even this reaction does not constitute completely unambiguous evidence for the involvement of the aldehyde form of berberine since the products may be accounted for with equal plausibility by the scheme shown below.

IV Ib

I11

The application of physical methods has so far proved to be equally unsatisfactory in providing an answer to the problem. A reinvestigation (76) of the UV-spectrum of berberine (as the hydrochloride) has shown that the absorption curve of an aqueous solution is unaffected by the addition of alkali. I n contrast, in alcoholic solution low concentrations of base change the form of the spectrum appreciably until a curve corresponding to the carbinolamine form is obtained. Apparently a further increase in the concentration of base causes no further change in the spectrum. Consequently, if the aldehyde form is present it must be below the limit of detection by this method. Thus the existence of the aldehyde form of berberine and its involvement in a reaction still remain to be established.

2.

53

THE PROTOBERBERINE ALKALOIDS

2. Alkylation and Oxidation at the C-13 Position Introduction of an alkyl group a t the C-13 position of the protoberberine ring system is readily accomplished by direct alkylation of either the 8-acetonyl base ( 7 7 ) or the dihydro derivative (78) of the appropriate alkaloid. Reduction of the resulting salt, usually without isolation, affords the corresponding epimeric 13-methyltetrahydro bases. The conversion (79)of palmatine (V) to corydaline (VI) and mesocorydaline (VII) via the salt V I I I exemplifies the use of this reaction which constitutes an early example of the now well-known C-alkylation of an enamine.

i/

VIII

VI

VII

JX

54

P. W. JEFFS

The relative proportions of V I and V I I obtained from the intermediate salt VIII (R = H) apparently vary with the nature of the reducing agent ; zinc-acid systems afford corydaline predominantly (79) while borohydride reduction (80) is claimed to give corydaline exclusively. Products of types VI and VII may not originate exclusively from reduction of the imonium salt since a recent investigation (81)of the reaction of methyl iodide with dihydroberine has indicated the imonium salt corresponding to VIII (R = H) readily disproportionates to berberine and tetrahydroberberine (IX). Oxidation of 8-acetonyldihydroberberine (11)with permanganate was reported many years ago by Pyman (82) to give a product designated as neooxyberberineacetone. Structure Xa was preferred to the alternative Xb on the basis of its insolubility in sodium hydroxide solution. Treatment of neooxyberberineacetone with acid, after basification, gave neooxyberberine which was recognized as the phenolbetaine X I from its behavior toward methyl iodide in affording 13-methoxyberberinium iodide (XII). A more recent investigation of the oxidation of acetonylberberine with permanganate has been made by Kondo (83)and Kondo and Takemoto ( 8 4 ) .These authors have made the surprising claim that the initial product from the reaction, neooxyberberineacetone, is represented by structure XIII. The UV-spectrum, A,, 286 mp (log E 3.78), and the fact that the I R spectrum of its acetylation product showed carbonyl absorption a t 1745 and 1712 cm-1 were taken as evidence for preferring it to the structures Xa and Xb considered by Pyman. The formation of XI11 from I1 is a reaction which, as far as the author is aware, has no precedent in the chemistry of enamines, and as such this structure must be regarded as being highly unlikely. Further evidence against structure XI11 is that, in agreement with the early work of Pyman, neooxyberberineacetone on acid hydrolysis (retro-Mannich) and subsequent basification affords the phenolbetaine XI. Although the structure of neooxyberberineacetone must remain in doubt, with the possible exception of its reported UVspectrum, all the remaining spectroscopic and chemical data are accommodated by structure Xb (see Section X). The reduction of the phenolbetaine VIII with sodium borohydride or lithium aluminum hydride affords the alkaloid ( & )-ophiocarpine (XIV; R =OH). I n contrast, reduction of X I with zinc-acetic acid gives a mixture of two isomers having the empirical formula, CZOH2104N, isomer-a* (mp 169"-171"; picrate, mp 181"-187"), and isomer-b (mp

* The designations isomer-a and isomer-b are those of the reviewer, and are used for convenience of exposition.

2.

XI

THE PROTOBERBERINE ALKALOIDS

55

XI1

180"-181" ; picrate, mp 163"-164"). The UV-spectra of these compounds were identical 285 mp, log E 3.71) and typical of a tetrahydroprotoberberine base. Isomer-a was eventually recognized as tetrahydroberberine when it was found that it underwent dehydrogenation readily with mercuric acetate to give berberine. A similar reaction attempted with isomer-b failed to give any isolable product. Comparison of the IR-spectra of the two isomers was made and, whereas tetrahydroberberine exhibited the expected Bohlmann bands, the Japanese workers claimed that similar absorptions in isomer-b were obscured. This evidence, in conjunction with the results from the dehydrogenation studies, was interpreted as indicating that the isomers differed only in the nature of the B :C ring fusion (85).The known conformational mobility, involving inversion of the nitrogen atom in quinolizidine systems, makes such a suggestion quite untenable.

56

P. W . JEFFS

T

The problem has been resolved by the recent work of Schopf and Schweickert (86) who have shown that isomer-b is represented by structure XV (see Chart I). The mass spectrum confirmed its formulation

r-

Zn, H @

1

Zn, H @

CHARTI. Suggested mechanistic course for the rearrangement of neooxyberberine (XI) on reduction with zinc and acetic acid.

%. THE PROTOBERBERINE ALKALOIDS

57

as an isomer of tetrahydroberberine, but otherwise the spectra of these two compounds differed considerably. In particular, the characteristic fragment arising from the retro-Diels-Alder cleavage of ring C in tetrahydroberberine and related alkaloids (see Section 111, C, 3) was absent in the mass spectrum of the isomer, which instead had a peak a t m/e 174 attributed to the ion x. From this observation it was inferred that ring C is 5-membered, which limits the only reasonable formulation of isomer-b to structure XV. The NMR-spectra of XV and of tetrahydroberberine are very similar, as might be expected. However, significant differences are observed in the nine-proton pattern (four CH2 and one CH) occurring in both spectra between 2.5 and 4.5 6 . Also, in contrast to the earlier report, the IR-spectrum of isomer-b clearly shows the presence of Bohlmann bands a t ca. 2800 cm-1. Without being completely decisive, this evidence is entirely consistent with structure XV for isomer-b. Its formation has been rationalized as illustrated in Chart I. The rearrangement step has ample precedent from the studies made by Prelog and Leonard and their respective co-workers on the Clemmensen reduction of a-aminoketones.

B. ALKALOIDS OF Berberis lambertii PARKER The alkaloids berlambine (mp 199"-200") and lambertine (mp 163"), isolated from B. lambertii (39),have been shown (87)to be oxyberberine (111)and dihydroberberine (IV), respectively (Section 111,A, 1). The presence of oxyberberine has since been noted to occur in other Berberis species (see Table I),whereas dihydroberberine is so far unique to B. lambertii. C. TETRAHYDROBERBERINE (CANADINE)* 1 . Von Braun Degradation

The reaction of tetrahydroberberine with cyanogen bromide is somewhat unusual and has been the subject of a recent study of Sallay and Ayers (88). Treatment of tetrahydroberberine with cyanogen bromide gave two products, an unsaturated cyanamide XVI and the bromocyanamide XVII ( R = Br) in the ratio of 1 :2. Both products exhibited strong absorption a t 4.55 p, typical of the presence of a nitrile group. The formation of XVI from the von Braun degradation requires the intermediacy of the bromocyanamide XVIII, which was presumed to undergo *This material is supplementary to Volume IV, pages 91-92.

58

P . W. JEFFS

f

2.

59

THE PROTOBERBERINE ALKALOIDS

elimination under the conditions of the reaction, or during chromatographic separation. The formulation of the unsaturated cyanamide as XVI rather than the possible alternative XIX, which could arise by dehydrobromination of the accompanying bromocyanamide, resulted from the failure to effect a direct dehydrobromination of XVII. This was proven by effecting the desired dehydrobromination via the reaction sequence 0

XVII (R = Br) + XVII (R = NEt2)

--f

0

XVII (R = NEt3I) + X I X ,

and establishing the nonidentity of the product with the unsaturated cyanamide isolated from the von Braun reaction. Structure XVI for the unsaturated cyanamide from the von Braun reaction was supported by its UV-spectrum which was typical of a stilbene. Similarly, the styrenetype UV-spectrum of the dehydrobromination product X I X was cited as further evidence for its structure. The preferred cleavage of the C-14-N bond of tetrahydroberberine in the von Braun reaction rather than the expected C-8-N bond cleavage, is, as indicated by Sallay and Ayers, merely a further example of the well-known ease with which transannular reactions between the nitrogen 0

Ur

SSI

ss

SSII

SSITa

and C-14 take place in this ring system. The occurrence of XVII as the primary product, rather than the alternative structure X X which is predicted on the basis of the rules formulated by von Braun, requires a n

60

P. W. JEFFS

explanation. A possible answer to the anomalous course of this reaction may be seen by considering the two transition states XXI and XXII which would ensue from attack at the C-6 and C-8 positions, respectively. Inspection of models reveals that in the transition state leading to attack at C-8 the incoming bromide ion is prevented from approaching along a colinear N-C-8 reaction coordinate by the C-9 methoxyl (see XXIIa), whereas approach of the bromide ion to C-6 may proceed unhindered in achieving colinearity of the centers involved.

2. Rearrangement of Alkaloid N-Oxides in the Tetrahydro Series The chromate-induced transformation of strychnine N-oxide (XXIII) to pseudostrychnine (XXIV) prompted Bentley and Murray (89) to investigate the use of this reaction in the tetrahydroprotoberberine series. The N-oxides of epiberberine (XXVa), tetrahydroberberine (XXVb) and tetrahydropalmatine (XXVc), underwent the chromate-induced N-oxide to carbinolamine conversion to afford the corresponding 14hydroxy systems, XXVI, XXVIIa, and XXVIIb, respectively.

xxv a; R 1= RB= OCH3, R3 = Rg = OCHzO b; Ri=Rz=OCH20, R3 = R4 = OCH3 C ; R1= Rz=R3=Rg=OCHs

XXVI

XXVII a; HI=Rz=OCH~O, R3 = H4 = OCHa b; R1=Rz=R3=Rg=OCHs

It was anticipated that these carbinolamines would be in equilibrium with the corresponding 10-memberedring aminoketones. However, UVand IR-spectral data on 14-hydroxyepiberberine (the only one of the

2.

T H E P R O T O B E R B E R I N E ALKALOIDS

61

three which could be isolated) showed it to exist exclusively as the carbinolamine tautomer. Confirmation of the structure of this compound, as well as supporting evidence for the greater stability of the carbinolamine form in this compound, was provided by its preparation from cryptopine (XXVIII) according to the sequence XXVIII + X X I X +

xxx + XXVI

The abnormal course of the von Braun reaction in this sequence is explicable on the same grounds used for rationalizing the products obtained from the von Braun reaction of tetrahydroberberine, namely, the proper access of the bromide ion to the C-S benzylic carbon atom in the intermediate N-cyano compounds is prevented by the presence of the C-9 oxygen atom of the methylenedioxy group. Although 14-hydroxyepiberberine appears to exist exclusively in the carbinolamine form, its transformation to cryptopine was readily affected by methyl iodide. I n contrast, prolonged treatment of the carbinolamine methyl ethers XXVI (OCH3 instead of OH), XXVIIa (OCH3instead of OH), and XXVIIb (OCH3 instead of OH) with methyl iodide was required to convert them to the corresponding aminoketones, cryptopine (XXVIII), allocryptopine (XXXIa), and cryptopalmatine (XXXIb).

ssr111

ss1s

T

I

('HJI

R = H and R=CH3

sss The overall conversion of these tetrahydroberberine alkaloids to the 10-membered ring aminoketones has provided a good laboratory analogy for what is thought to be the biosynthetic route to the protopine alkaloids. SXVI

62

P. W. JEFFS

XXVIII

3. Mass Spectra I n recent years mass spectrometry has established itself as a powerful tool for the investigation of the structures of complex molecules. Many examples already exist where the establishment of the structure of an alkaloid, particularly in the case of certain indole alkaloids, has been determined almost exclusively by mass spectrometry. Experience has shown that the most useful structural information is obtained from the mass spectrum when the system under study has an aromatic nucleus attached to an alicyclic framework that is capable of undergoing fragmentation readily. I n such cases a simple and interpretable fragmentation pattern usually obtains. I n the protoberberine series the tetrahydro bases possess this desirable structural feature and therefore were chosen for study (90). The fragmentation behavior of this class of alkaloid on electron impact is exemplified by the mass spectrum of norcoralydine (xylopinine) (see Section 111,E, I), as illustrated in Fig. 1.

L

!-,[I

100 120

140 160

FIG. 1. Mass spectrum of (-)-norcoralydine Budzikiewicz eb al. (go)].

(( - )-xylopinine) [adapted from

I n the upper mass range the molecular ion and M-1 peaks are abundant and the occurrence of the M-15 peak is also observed. Representation

Q'

2. THE PROTOBERBERINE ALKALOIDS

b.

I

X

__f

8 \ /

3

Q 3 ,

3

I

Q1

m

2 . E

..

m

0

0

. E

(D 3

*

Ql

. E

p

63

64

P. W. JEFFS

of the M-1 fragment as a would seem to be reasonable by analogy with that proposed for the M-1 fragment in the aporphine series (90). Similarly, the M-15 fragment has been represented by the resonance stabilized ion b, resulting from the expulsion of a methyl radical from the 3-methoxyl group. The most pronounced peak in the spectrum occurs a t m/e 164 and, as suggested, it indicates that scission of the molecule must be predominant. I t s genesis has been explained by what corresponds to a retro-Diels-Alder process (illustrated by arrows) which leads to the observed ion, as fragment c (m/e 163), and the neutral molecule d . The only other significant peaks in the spectrum are at m/e 149, which corresponds to the loss of a methyl radical from c, and a t m/e 190. Retention of the charge by the nitrogen-containing fragment d and subsequent loss of a hydrogen to form the isoquinolinium ion e (m/e 190) has been proposed to explain the origin of the latter. The mass spectrum of tetrahydroberberine shows the same type of characteristic fragmentation pattern with fragments at m/e 164 and m/e 149 corresponding to c and c-Me in the norcoralydine spectrum and the fragment ascribed to the isoquinolinium species e is now found a t the expected m/e 174.

I

f m/e 178 Thalictricavine

-e __f

Mee m/e 174

Tetrahydroberberine

e

-...-

OCH3 m/e 164

-CHI. Ij

m/e 149

2.

THE PROTOBERBERINE ALKALOIDS

65

Thalictricavine (see Section IV, C, 1) shows the expected behavior. The most intense peak in the mass spectrum occurs a t m/e 178 and is attributed t o the fragment f (90).The other principal ions are the parent peak and that which corresponds to fragment e. Since the primary modes of fragmentation are not altered by changes in substitution the mass spectrometric shift method is applicable and provides a means of determining the distribution of substituents between the aromatic rings as well as localizing substituents on rings B or C. The results have indicated the potential utility of mass spectrometry in affordingdiagnostically useful information in this series of protoberberine alkaloids. Some examples of its subsequent use in contributing to structural information on new alkaloids are found in the discussion of thalifendine and thalidastine (Section 111,D, 2).

D. BERBERASTINE AND

THE

ALKALOIDS OF Thalictrumfendleri

1 . Berberastine

This alkaloid has been isolated recently in very small yield from the much investigated plant, Hydrastis canadensis L. (57). Analysis of the iodide indicated the molecular formula C2oH1805N@10. It contains two methoxyls and a methylenedioxy group, one hydroxyl function, and is + 107"). The UV-spectrum of berberastine is optically active typical of a protoberberine alkaloid and its near relationship to berberine was suggested from its IR-spectrum which, apart from the presence of hydroxyl absorption, closely resembled that of berberine iodide. The conversion of berberastine in hydrochloric acid to dehydroberberine (XXXII)established its relationship to berberine and left only the possibility of its formulation as 5- or 6-hydroxyberberine. The placement of the hydroxyl a t either of these positions is in accord with the optical activity of the alkaloid, and of the two positions, Nijland (91) favored its location a t C-5 in proposing the structure of bttrberastine as XXXIII. Further support for structure X X X I I I for berberastine was derived from its reduction to tetrahydroberberastine (XXXIV)by zinc and acid. Spenser and MonkoviE (58)have pointed out that since the hydroxyl is retained in this reaction its location a t C-5 is established. The alternative structure containing the C-6 hydroxyl is a carbinolamine, and as such it would not be expected to survive the reduction. More compelling reasons for placing the hydroxyl a t C-5 are available

66

(1%

P. \IJEFFS .

SSSII OC'Hs

' SXSIII

OCH3

1(%

OCHJ OC'HJ

SSSIV

from the biosynthetic studies (Section VIII, B) that have shown that noradreiialine is an efficient precursor o f berberastine. Berberastiiie is the first member isolated of what appears t o be an expanding group of protoberberine alkaloids having a C-5 oxygen substituent (see Section 111,D, 2 and VIII, B).

2. T h a l i f e n d i n e a n d Thalidastine I n a recent study (61, 62) the plant Thalictruin f e n d l e r i has been shown to contain berberine, jatrorrhizine, magnoflorine, two new protoberberine bases, thalifendine and thalidastine, and a new benzylisoquinoline alkaloid, thalifeiidlerine. Thalifendine, C19H1604N@(chloride, mp siiiters > 230") is an optically inactive yellow quaternary base possessing a UV-spectrum, AmnX 231 mp (log E , 4.17), 269 mp (log E, 4.15), and 348 mp (log E , 4.10), typical o f a protoberberine alkaloid. The NMR-spectrum, recorded in trifluoroacetic acid, indicated the presence of one aromatic methoxyl group, 4.24 6, a methylenedioxy group, 6.15 6, and signals at 6.95, 7.52, 7.95 (two), 8.52, and 9.55 6 corresponding to six aromatic hydrogens. The fact that the alkaloid turned orange on addition of weak base suggested the remaining oxygen functioil was present as a phenolic hydroxyl group. Hydrogenation of thalifendine gave a tetrahydrobase XXXV (R = H) (mp 209"21 1 ") which on methylatioil with diazomethane afforded tetrahydroberberine. This conversion, and the non identity of thalifendine with the known base berberubine (XXXVIa),left only the possibility of structure XXXVIb for the new alkaloid (61).

2.

67

THE P K O T O B E K B E K I N E ALKALOIDS

The mass spectrum of tetrahydrothalifendine showed, besides the molecular ion a t m/e 325, peaks a t m/e 176 and 150 of ions resulting from the familiar retro-Diels-Alder fragmentation of ring C (Section 111,C, 3). The accompanying base thalidastine. Cl9H1,O5W.is one of the major alkaloidal constituents of the plant. The chloride (mp 2330" decomp.), obtained as yellow-brown crystals, is optically active ([.In + 138"), and exhibits a UV-spectrum which strongly resembles that of thalifendine and berberine. Addition of base to thalidastine produced a deep red color indicating the phenolic nature of the alkaloid.

m/e 1 7 6

SXXV

m/e 150

The alkaloid is somewhat unstable losing a molecule of water on standing for several weeks at room temperature, or more rapidly by heating to 80" in vucuo, or in hot dilute hydrochloric acid to afford deoxythalidastine chloride (XXXVII), C,9Hl,04?LT@C1". In addition to absorptions corresponding to a methoxy group (4.32 a), and a methylenedioxy group (6.34 6), in the NMR-spectrum of deoxythalidastine, signals attributable to eight aromatic hydrogens were present as six one-proton singlets (7.43, 8.03, 8.04, 8.22, 9.37, and 9.88 6) and a pair of doublets (7.92 and 8.69 6 , J = 7 . 2 cps). The UV-spectrum of XXXVII is characteristic of a dehydroberberinium salt having a 2.3,9,1@oxygenation pattern. Shamma and Dudock (63) were able to arrive a t this coiiclusion after

68

P. W. JEFFS

inspection of the UV-spectral data for the many synthetic dehydroberberine salts, in which representatives of both 2,3,9,10- and 2,3,10,11oxygenation patterns were available from the work of Bradsher and systems have co-workers (92, 93). They noted the 2,3,9,1O-~ubstituted long wavelength absorption maxima a t 348-358 and 460-490 mp, whereas the 2,3,10,11-substituted bases absorb a t 322-332 and 413-422 "P

The location of the phenolic hydroxyl at C-10 and the placement of the methylenedioxy group in ring A became possible when it was found that hydrogenation of deoxythalidastine afforded tetrahydrothalifendine (XXXV; R = H).

SSSVII

SSSVIII

I n view of the facile dehydration of thalidastine the remaining oxygen function was accounted for by assigning a hydroxyl group at C-5 in proposing structure XXXVIII for the alkaloid ( 6 2 ) . Corroborative evidence for this structural proposal was obtained from the mass spectrum of tetrahydrothalidastine (XXXV; R =OH) (mp

BH

r

In.

OH

A

I,

inje 150

m/e 192

-HzO

m/e 324

\ L mje 341

OH

2. THE

P R O T O B E R B E R I N E ALKALOIDS

69

201"-202") which contained peaks corresponding to the molecular ion m/e 341, and ions originating from the retro-Diels-Alder process and their further fragmentation products as shown below. A recent synthesis of deoxythalidastine by Bradsher and Andrew (93a) has confirmed its proposed structure as XXXVII. Thus, thalidastine joins berberastine as the second fully characterized protoberberine alkaloid having a C-5 hydroxyl function. The evidence cited does not rigorously exclude the possibility of locating the hydroxyl a t the C-6 position.

E. ALKALOIDSOF Xylopia descreta (L. fil.) Investigation of Xylopia descreta, a member of the Annonaceae family, has resulted in the isolation of four new protoberberine alkaloidsxylopinine, descretine, descretinine, and descretamine, in addition to the aporphine base, xylopine (49).

1. Xylopinine Xylopinine, C21H~.=,N04 (mp 182"-183"; [a],, -297" in CHCls), was 287 mp, isolated in 0.026% yield. The UV-spectrum of the alkaloid (&, log E 3.91) was typical of a tetrahydroprotoberberine base. Its structure followed when it was found to be identical with the synthetic base ( - )-norcoralydine (XXXIX ; R = CH3), which had been prepared earlier by Corrodi and Hardegger (94) from the cyclization of ( - )-N-norlaudanosine with formaldehyde (Section 111, H).

2. Descretine Descretine, C ~ ~ H Z ~ (mp N 180"-181" O ~ dec.; [.ID - 300" in CHC13), contains three methoxyl groups and one phenolic hydroxyl group.

SSSIX

Methylation with diazomethane afforded ( - )-norcoralydine. The location of the hydroxyl a t C-3 was ascertained from the isolation of 6ethoxy-7-methoxy-l -keto-1,2,3,4-tetrahydroisoquinoline (XL) from the

70

P.

W. JEFFS

oxidation of 0-ethyldescretine (XXXIX; R = CzH5) with alkaline permanganate (95)and serves to characterize descretine as 3-0-demethyl( - ) -norcoralydine (XXXIX ; R = H).

3. Descretinine and Descretamine These alkaloids were isolated in yields of 0.025 and 0.007%, respectively. Descretinine, C Z ~ H ~ ~(mp N O 212"-214" ~ dec.), - 371' in pyridine), contains three methoxyl groups and one phenolic hydroxyl. Its methylation with diazomethane to ( - ) -tetrahydropalmatine (XLI) serves to identify descretinine as a tetrahydroprotoberberine with a 2,3,9,10-oxygenation pattern. The nonidentity of descretinine with ( - )-tetrahydrojatrorrhizine [( - )-corypalmine] (XLII) and ( - )-tetrahydrocolumbamine [( - )-isocorypalmine] (XLIII) means that it is either 9- or 10-0-demethyltetrahydropalmatine. Since the latter structure has been proposed for the dextrorotatory alkaloid, corydalmine (Section 111, G) the possibility exists that this alkaloid is enantiomorphic with descretinine. There is, however, a considerable difference in the reported melting points for these compounds; if it were not for the uncertainty that exists regarding the reported values for corydalmine, this would suggest that descretinine has the alternative structure XLIV. I n view of the lack of more decisive evidence, however, the location of the phenolic hydroxyl group must still remain in doubt. The racemic forms of both XLIV and XLV have been

SLI

SI.11

SLIII

SLIY

2.

T H E P R O T O B E R B E R I N E ALKALOIDS

71

synthesized (93, 96), but unfortunately no direct comparison of samples has been made with descretinine or corydalmine. - 368" in pyridine), Descretamine, C19H2104N (mp 221"-224"; [.ID contains two methoxyl groups and two phenolic hydroxyl functions. Methylation with diazomethane gave ( - )-tetrahydropalmatine, which implies that descretamine is a bisdemethyl ( - )-tetrahydropalmatine (see Section X ) isomeric with (-)-scoulerine (XLVI). At the time of writing the location of the hydroxyl groups has not been determined.

F. CORAMINE An investigation of Corydalis pseudoadunca has resulted in the isolation of a new diphenolic protoberberine alkaloid, coramine, C19H~104N (mp 247'-252'; - 391"; 0,O-diethylether, mp 164"-166") (18). Methylation of coramine gave an 0,O-dimethyl derivative which was identified as ( - )-norcoralydine [( - )-xylopinine]. This served to characterize coramine as a tetrahydroprotoberberine alkaloid having a 2,3,10,11-oxygenation pattern. No evidence has been presented for the position of the phenolic hydroxyl groups in coramine and only positions C-2 and C-11 are excluded by virtue of its nonideiitity with the known alkaloid coreximine (see Volume IV, p. 112; also Section V I I of this chapter).

G. CORYDALMINE AND DEHYDROCORYDALMINE Among the nine alkaloids isolated by Imaseki and Taguchi (20)from a Corydalis species occurring in China, and described as engosan (Table I), are two new protoberberine bases : corydalmine, CzoHz304N (mp 238"239"vac. ; [u]D + 337.4"inCHC13),anddehydrocorydalmine, CzoHzo04N@ (iodide, CzoH2004NI 2Hz0, mp 238"-240' dec.). The presence of three methoxyl groups and a phenolic hydroxyl group in corydalmine indicated the extended molecular formula Cl7HI4N(OMe)30H,and its formulation as a tetrahydroprotoberberine base was suggested from the UV-spectrum (A,,,,, 284 mp, log E 3.56). The

-

72

P. W. JEFFS

accompanying quarternary base, dehydrocorydalmine, contained three methoxyls and a phenolic hydroxyl group. Its methylation with diazomethane to palmatine served to characterize it as a protoberberine base having 2,3,9,10-oxygenation pattern. Reduction of dehydrocorydalmine gave an optically inactive compound (mp 2 12"-2 14")which was identified as ( k )-corydalmine on the basis of a comparison of its IR-spectrum with that of ( - )-corydalmine. The structure of corydalmine as lO-hydroxy-2,3,9-trimethoxydibenzo[ug]quinolizidine (XLV) was proposed by Imaseki and Taguchi after comparisons of ( k )-corydalmine (mp 213"-215") with the known protoberberine isomers, ( k )-tetrahydrojatrorrhizine [( k )-corypalmine] (XLII), ( k )-tetrahydrocolumbamine [( & )-isocorypalmine] (XLIII), and ( & )-tetrahydropalmatrubine (XLIV) had revealed its nonidentity with these bases. A recent synthesis of ( f )-1O-hydroxy-2,3,9-trimethoxydibenzo[ug]quinolizidine (mp 187.5"-188.5") by Telang and Bradsher (96) (Section VII) has revealed a large difference in the melting point of this compound and that reported for ( k )-corydalmine. I n the absence of a direct comparison of samples the reason for this large discrepancy remains unresolved.

H. ABSOLUTECONFIGURATION OF ALKALOIDS OF THE TETRAHYDRO SERIES Absolute stereochemistry a t the C-14 position in those alkaloids which are unsubstituted at the adjacent C-13 center has been determined by Corrodi and Hardegger ( 9 4 ) .The approach taken was to determine the absolute configuration of the isoquinoline base ( - )-N-norlaudanosine acid (XLVII) by degrading it as shown to N-p-carboxyethyl-L-aspartic (XLVIII) of known absolute configuration. Cyclization of ( - )-N-norlaudanosine with formaldehyde and acid gave the protoberberine alkaloid ( - )-norcoralydine [( - )-xylopinine] whose absolute configuration is therefore defined according to the Cahn-Ingold-Prelog sequence rule as 14 R. The assignment of the absolute configuration of ( - )-norcoralydine, and the knowledge that changes in aromatic substitution patterns have no great effect on the specific rotation in this series, permitted an assignment of absolute configuration to be made to other tetrahydroprotoberberine alkaloids. Thus, all alkaloids of this series having only a single center of asymmetry a t the C-14 position, and which are levorotatory, are assigned to the 14 R series, and those which are dextrorotatory have the enantiomeric 14 S configuration.

2.

THE PROTOBERBERINE ALKALOIDS

73

OCH3

SLVII

SLI'III

S S S I S : R = CH3

Optical rotatory dispersion (ORD) spectra have also been used to assign absolute configuration to these alkaloids. ( - )-Tetrahydropalmatine (XLI)exhibits a negative Cotton effect in the region of 300 mp and this has been correlated with the representation of its absolute configuration as 14 R on the basis of a comparison with the positive plain dispersion curve shown in this region by ( + )-1,2-diphenylethylamine

(XLIX) (97). I n the reviewer's opinion, the simple diphenylethylamine, with its greater degree of flexibility, does not really constitute a suitable model for such a correlation to be made with any degree of confidence. Much more convincing evidence from the ORD-spectra of this group of alkaloids has been made possible by recent developments in instrumentation which have permitted measurements to be made down to 186 mp. Craig and Roy (98) have described the relation between the direction of the optical dispersion curve in the region 220-225 mp and the absolute configuration of various classes of aIkaIoids possessing a n asymmetric center cc to the nitrogen atom. The correlations were derived initially from ORD measurements made on amino acids of known absolute configuration in which the L series was found to exhibit a negative slope toward shorter wavelengths in the region 220-225 mp. From measurements made on other nitrogen-containing compounds of known absolute configuration it would seem that the method is of general applicability for the determination of the absolute configuration of amines. This generality is accounted for in the tentative suggestion

74

P. W. JEFFS

that the Cotton effect in this region is due to an excitation of the nitrogen lone-pair electrons. The disappearance of this absorption band in acid solution is consistent with this explanation. Application of this method t o the tetrahydroprotoberberine series is illustrated in the ORD-curves of the tetrahydropalmatine enantiomers shown in Fig. 2.

FIG.2. Optical rotatory dispersion curves of tetrahydropalmatine enantiomers [reproduced from Craig and Roy (98)].

IV. Alkaloids Related to Corydaline* A. BASEI1 The alkaloid, C ~ I H ~ ~(mp O 144"-146"; ~ N [.In + 306") (in CHC13),was isolated by Taguchi and Ima,seki (10)from Corydalis ambigua Cham. et Schlect. var. ainurensis Maxim. I t s UV-spectrum, which exhibited a single maximum at 286 mp (log E 3.82), suggested its representation as a

* This material is supplementary t o Volume IV, pages

103-107.

2.

THE PROTOBERBERINE A L K A L O I D S

75

protoberberine alkaloid (99). Analytical data, and the NMR-spectrum of base 11,indicated the presence of two methoxyls and a methylenedioxy group. Cleavage of the methylenedioxy group with phloroglucinol and sulfuric acid, followed by methylation of the product, afforded ( + )corydaline (VI) and indicated its formulation as a stereoisomer of thalictricavine or thalictrifoline. Its relationship with the latter was readily established by the oxidation of base I1 to the dehydrobase L, which proved to be identical with delzydrothalictrifolinium iodide. Reduction of L with zinc and sulfuric acid gave a mixture of thalictrifoline and ( I)-base I1 (mp 190"-191") which provides additional support for the representation of these alkaloids as stereoisomers. A transquinolizidine conformation of the B:C ring juncture in base I1 was inferred from its IR-spectrum and from the facile dehydrogenation of the alkaloid by mercuric acetate. The relative stereochemistry a t the 13,14-positions, surprisingly left unassigned by the Japanese workers, is defined as portrayed in structure LI by virtue of the above-mentioned conversion to corydaline. The positive value for the optical rotation of base I1 requires that this structure represents its absolute configuration (see Section IV, C, 2 for a discussion of the assignment of absolute configuration in this series).

LI

L

B. CORYSAMINE AND

THE ALKALOIDSOF Corydalis incisa (THUNB) PERS.

In study of Corydalis incisa cultivated in North America, Manske reported the presence of five alkaloids, protopine, bicuculline, corypalmine, and an alkaloid of unknown structure designated as alkaloid FG2 ( 1 7 ) . A more recent investigation (15,16)of the same species, but of Japanese origin, has afforded five new tertiary bases (see Table 11),a new quarternary alkaloid, corysamine, and the known alkaloids protopine, sanguinarine, and coptisine. With the exception of corynoline (base I),which has

76

P. W. JEFFS

been characterized as a new alkaloid belonging to the m-naphthaphenanthridine series (99a),no further investigations have been reported on the remaining four tertiary bases. TABLE I1 SEW TERTIARY ALKALOIDS OF Corydalis incisa (THUMB.) PEKS. Compound

Properties -~

Base I (corynoline) Base I1 Base I11 Base V Base V I I

~~~~~~~~

mp 216-217", C21H~105N,I R , 3.10 p ( O H ) ; UV, A,,, (log E 3.94), 290 p (log E 3.86) mp 235-237"' C21H2105N mp 240°, CzzH2306N mp 209-210", C21H1905N C21H2104N2 (methiodide, mp 163")

242 p

Corysamine, C2oHls04N@,isolated as its iodide (mp 300'; chloride * 3 8 2 0 , mp 230"), is reduced by sodium borohydride to a tertiary base, tetrahydrocorysamine, C20H1904N (mp 202"-203" ; methiodide, mp 266" dec.; picrate, mp 189"). The close correspondence of the UV-spectra of corysamine and its borohydride reduction product with the spectra of coptisine and tetrahydrocoptisine, respectively, implied that corysamine is a protoberberine alkaloid. The four oxygens were assumed to be present in two methylenedioxy groups on the basis of the demonstrated absence of methoxyl groups in the alkaloid. Since corysamine differs by CH2 from the molecular formula of its congener coptisine (LII),the Japanese workers suggested its formulation as a methyl coptisine. They were subsequently able t o substantiate this suggestion and also establish the location of the methyl group a t the C-13 position by the conversion of coptisine to tetrahydrocorysamine (100).The method used as described below had been devised earlier by von Bruchhausen (101). Alkylation of acetonylcoptisine (partial structure LIII) with methyl iodide afforded the C-13 methyl compound (partial structure LIV), which on removal of the acetonyl group (retro-Mannich) gave a mixture of quaternary bases. Reduction of this mixture with zinc and acetic acid gave tetrahydrocorysamine as the major product together with a smaller quantity of unreacted tetrahydrocoptisine. It follows from these reactions that tetrahydrocorysamine and corysamine are represented by the structures LV and LVI, repectively. Further support for the structure of corysamine was obtained (102) from the conversion of tetrahydrocorysamine, by demethylenation and

2.

77

T H E PROTOBERBERINE ALKALOIDS

4

subsequent methylation of the product with diazomethane, to corydaline

(VI). I n view of the 13,14-cis configuration in corydaline the above conversion indicated that tetrahydrocorysamine must have the same relative stereochemistry a t these positions. The structure of corysamine is the same as that given by Kitasato (103)for worenine, an alkaloid whose structure is based on somewhat scant evidence. The nonidentity of these alkaloids is suggested by the considerable discrepancies in the reported melting points of the corresponding salts (worenine, chloride mp 295" ; corysamine, chloride mp 230"), and in their corresponding tetrahydro compounds (tetrahydroworenine, mp. 213°-2140; tetrahydrocorysamine, mp 203"-204"). Although such comparisons of literature values are never completely satisfactory, the nonidentity of these alkaloids has been proposed (100). The fragmentary nature of the evidence available for worenine makes any structural proposal for the alkaloid entirely speculative. However its representation as 13-methylcoreximine (LVII) is a possibility.

78

C.

P. W. J E F F S

STEREOCHEATISTRY O F CORYDALIXE A S D

RELATED ALKALOIDS

1. Relatice ConJiguration Advances in the chemistry of the corydaline type alkaloids since the last reporting have involved proposals for the relative and absolute configuration of ( + )-corydaline and related alkaloids. The relative stereochemistry a t the asymmetric centers at C-13 and C-14 in corydaliiie (VI) and mesocorydaline (VII) have been assigned ( 1 0 4 , 1 0 5 )the cis and trans configurations, respectively. Assignments were based on considerations of IR-spectral data and upon the previous findings ( 106) that corydaline and mesocorydaline, like the related isomeric 13-methylet8etrahydroberberines, undergo Hofmanii degradation to give characteristically different products. Corydaline, in contrast with mesocorydaline, shows Bohlmann bands in the region of 2800 cm-1 in its IR-spectrum. This was interpreted t o indicate a trans-quinolizidine structure for corydaline and a B : C cis configuration for mesocorydaline. Hofmanii degradation of corydaline results in cleavage of the C-14-nitrogen bond to afford the 10-membered ring structure LVIII (R1=R, = OCH3). I n contrast with this behavior, mesocorydaline under Hofmann conditions undergoes fission in the B-ring a t the site of the C-6nitrogen bond resulting in formation of the base LIX (R, = Rz = OCH3). The epimeric C-13 methyltetrahydroberberines, which had been reported earlier by Freund and Fleischer ( 7 7 ) ,showed similarly differing

LT-III

2.

79

THE PROTOBERBERIXE ALKALOIDS

behavior on Hofmann degradation. The isomer, V I (OCH20 at 1 and 2 positions instead of OCH3) (mp 21 2') which exhibited Bohlmann bands in its IR-spectrum (101),afforded the 10-membered ring product LVIII (R1=Re = OCHeO), whereas the isomer VII (OCH20 at 1 and 2 positions instead of OCH3) (mp 112') gave the base LIX (K1= PL2 = OCH20). I n order to rationalize the IR-spectral differences and the differing course of the Hofmanii degradations, the possible conformations of the two configurational isomers of C- 13 methyl substituted tetrahydroprotoberberines were considered first by Bersch (104),and later by Jeffs (205),and the conclusions are based upon the following arguments. The isomer V I with a cis relationship of the hydrogens a t C-13 and C-I 4 may be represented by the three conformations VIa-c. Conformation VIa, possessing the trans-quinolizidine structure, is anticipated to be tha most stable for this isomer, and therefore, from its predominance a t equilibrium, it would be expected to exhibit the Bohlmann bands in its IR-spectrum. The diastereomer VII, in which the C-13 and C-14 hydrogens are trans, can similarly exist in three possible conformations VIIa-c. However, in this case the trans-quinolizidine conformation is destabilized by an energetically unfavorable nonbonded interaction of the C-13 methyl hydrogens with the aromatic C-1 hydrogen. Consequently, the most stable conformation is likely to be one of the two cis-quinolizidine structures VlIb or VIIc in which this steric compression is relieved. Thus, isomer VII would not be expected to show absorptions in the region of 2800 cm-1 in its IR-spectrum.

VIIt,

VIIC

80

P. 1 % ' . JEFFS

The presence of Bohlmann bands in the IR-spectrum of corydaline and the higher melting 13-methyltetrahydroberberineisomer was therefore suggestive of the presence of cis hydrogens a t C-13 and C-14. This assignment is fully consistent with the results of the Hofmann degradation of these bases which afford the 10-membered ring systems. The stereochemical requirement of trans coplanarity of the centers involved in a concerted elimination leading to the 10-membered ring products can be met only by the c i s isomer. Examination of a Drieding model reveals that, irrespective of conformation, the trans isomer cannot attain the geometry necessary for a favorable concerted elimination which would lead to the 10-membered ring product. Further evidence for the conformational preference of a trans B :C ring fusion in corydaline is available from the report by Kondo (80)that this alkaloid undergoes ready dehydrogenation with mercuric acetate to afford dehydrocorydaline (LX), whereas mesocorydaline apparently remains unaffected under the same conditions. The reduction of dehydrocorydaline to corydaline by borohydride, reported in the same study, was interpreted by Kondo as evidence for corydaline having a 13,14-trans configuration. However, the arguments used in making this assignment are without adequate foundation and they do not present any serious challenge to those cited in support of structure VI for corydaline. A knowledge of the stereochemistry of corydaline and mesocorydaline has permitted stereochemical assignments to be made to the other known 13-methyl-substituted tetrahydroprotoberberine alkaloids (105). Corybulbine (LXI)and isocorybulbine (LXII)have a c i s configuration a t C- 13 and C- 14 since both afford corydaline on methylation with diazomethane (80).The previously reported conversion (102)of thalictricavine (LXIII) to corydaline, by acid-catalyzed cleavage of the methylenedioxy group followed by subsequent methylation, also serves t o identify it stereochemically with the corydaline series. As anticipated, corybulbine, isocorybulbine, and thalictricavine show (80)absorptions in the region of 2800 cm-1 consistent with the presence of a 13cr-methyl group in this series, and hence with the predominance of the B :C trans conformation. Furthermore, the formation of the 10-membered ring compound (LXIV) from the Hofmann degradation of thalictricavine provides additional support for identifying it stereochemically with the corydaline series. The oxidation of base I1 to dehydrothalictrifoline (Section IV, A) implies that thalictrifoline and base I1 are epimeric a t the C-13 position. Since the trans configuration a t the 13,14-position in base I1 (LI) is established, thalictrifoline is represented by structure LXV (absolute

2.

THE I'HOTOBERBERINE ALKALOIDS

81

LS

LSIV

LSV

stereochemistry is not implied). Independent corroboration of the structure of thalictrifoline comes from the observation that ( + )mesocorydaline is obtained from LXV by methylation of the product obtained from acid cleavage of the methylenedioxy group (107).At the time it was only presumed that this product was mesocorydaline since it depressed the melting point of ( & )-mesocorydaline. However, the nonidentity of this product with optically active and racemic corydaline, and its subsequent conversion to racemic mesocorydaline by oxidation to the dehydrobase, followed by reduction with zinc-iiydrochloric acid combination, leaves no doubt it was indeed ( + )-mesocorydaline. Thalictrifoline is so far unique in that it is the only naturally occurring member of the 13-methyltetrahydroprotoberberineaIkaloids which has the 13,14-trans configuration. The stereochemical assignment for this alkaloid is consistent with the absence of the Bohlmann bands in its IR-spectrum.

2. Absolute Conjguration Optical rotational data accumulated from the tetrahydroprotoberberine bases which do not possess a C-13 substituent (Section 111, H )

82

P. W.JEFFS

has been used to assign the absolute configuration a t the C-14 position in corydaline and related alkaloids (105).This has been made possible by the knowledge that introduction of the additional center of asymmetry at the C-13 position does not significantly affect either the sign or the magnitude of rotation, which is apparently wholly determined by the configuration a t the adjacent C- 14 position. The corydaline alkaloids which have been isolated to date in optically active form have all shown positive rotations and positive Cotton effects. Consequently, the absolute stereochemistry a t the C-14 position of these alkaloids has been designated by a 14 /3-hydrogen configuration. The structures given above for corydaline (VI), corybulbine (LXI), isocorybulbine (LXII), thalictricavine (LXIII), and base I1 (LI) represent the absolute configuration of the naturally occurring ( + )-series. The extension of the above premise has not been taken to include thalictrifoline since this alkaloid, like mesocorydaline, belongs to a conformationally distinct series and hence, determination of the absolute configuration of the naturally occurring form of this ( + )-base must await further study.

V. Ophiocarpine* Progress in the chemistry of this alkaloid since the last reporting has resulted in the establishment of its stereochemistry and absolute configuration. The absolute configuration of ( - )-ophiocarpine (XIV; R = O H ) at C-14 was established (108)by its correlation with ( - )-tetrahydroberberine (IX). This was achieved by hydrogenolysis of ( - )-ophiocarpine acetate (XIV; R = OAc) which afforded a separable mixture containing 13% of ( - )-tetrahydroberberine and 42% of racemic tetrahydroberberine. Isolation of ( - )-tetrahydroberberine from this reaction is in contrast to the hydrogenolysis of ophiocarpine which apparently gives exclusively racemic tetrahydroberberine (109). The relative configuration of the two asymmetric centers at C-13 and C-14 in ophiocarpine has been ascertained by a number of independent methods. Comparison of the IR-spectra of ophiocarpine and 1S-epiophiocarpine (LXVI, R = H) showed both to possess absorptions in the region of 2800 cm-1 characteristic of a trans-quinolizidine conformation for these isomers. Important differences however were apparent in the hydroxyl region of the spectra. Ophiocarpine has a broad absorption near 3520 cm-1 indicating the presence of strong hydrogen bonding,

* This material is supplementary to Volume IV, pages 99-100, and Volume VI, page 425.

2.

T H E P R O T O R E R B E R I N E ALKALOIDS

83

whereas 13-epiophiocarpine shows only free hydroxyl stretching at 3600 cm-l. Measurement of the basicities of XIV ( R = OH) and LXVI (R =€I) indicated ophiocarpine was a stronger base. Intramolecular hydrogen bonding of the 13-hydroxyl group to the nitrogen, which would result in base strengthening, can only occur in the B : C trans system when the hydroxyl group is axial (partial structure LXVII). Ophiocarpine was accordingly assigned the stereochemistry indicated in structure XIV (R = OH).

LXVI

H\

‘0

LXVII

A study of the NMR-spectra of both isomers supported the stereochemical assignments. The doublet of the 13-hydrogen signal in 13epiophiocarpine appears a t higher field than the corresponding signal in ophiocarpine. Deshielding of this hydrogen in ophiocarpine has been reasonably attributed to the magnetic anisotropy of the aromatic rings, with which it has near coplanarity in this isomer. Differences in chemical shift of the aromatic C-1 hydrogens are also apparent; the signal in 13-epiophiocarpine occurs a t lower field (7.35 6) than the corresponding signal in ophiocarpine (6.70 6). The deshielding of the aromatic hydrogen in LXVI (R = H) has been ascribed to a steric effect. However, it seems more likely that it is primarily due to a field effect since if there is a nonbonded interaction between the 13 /3-hydroxyl and the C-1 hydrogen it must be small, otherwise the molecule would tend to alleviate the situation by adopting a cis B : C ring juncture, as indeed it does (108)in 1-methoxy-13-epiophiocarpine (LXVI; R = OCH3).

84

P. W. JEFFS

Although the simple expedient of using the J13,14 values for assigning relative stereochemistry a t the 13,14 positions in ophiocarpine and its 13-epimer has not been used, the use of this approach is exemplified by the stereochemical assignments made by Battersby and Spencer (110) for the related 1-methoxyophiocarpines ; a small splitting (513,14E 1.5 cps) being characteristic of the cis isomer and a relatively large cbupling (J13,14 = 9 cps) characterizing the trans isomer. Battersby and Spencer have preferred to assign a B :C trans stereochemistry to the latter compound. However, the results of conformational analysis (Section IV, C) predict a c i s B :C stereochemistry and this has received experimental support from the work of Ohta et al. (108).

IS

2.

THE PROTOBERBERINE ALKALOIDS

85

VI. Quarternary Alkaloids Containing an N-Methyl Group* A. INTRODUCTION This group is a t present represented by four members; ( - ) - N methyltetrahydroberberine chloride (a-1-canadine methochloride) (LXVIII), cyclanoline (LXIX) (55), steponine (LXX) (55), and phellodendrine. The alkaloid LXVIII, first reported by Jowett and Pyman in 1913 ( I l l ) ,has been isolated more recently from Zanthoxylum venejicum F. M. Bailey by Cannon et al. (112).Its stereochemistry is probably correctly represented as shown since on thermal equilibration it affords the diastereomer which is identical with the second salt (LXXI) obtained from the methylation of ( - )-tetrahydroberberine (IX).

B. PHELLODENDRINE Phellodendrine is a quaternary base isolated from Phellodendron amurense Rupr. (66),and other Phellodendron species (see Table I) as its iodide, CzoH2404NI (mp 258"-258.5" dec. ; [a]=- 132").ItsUV-spectrum showed a single maximum a t 288 mp (loge 3.85). The oxygen functions were accounted for in two methoxyls and two phenolic hydroxyl groups. Methylation of phellodendrine iodide with methyl iodide in methanolic potassium hydroxide afforded 0,O-dimethylphellodendrine iodide, which on Hofmann degradation gave an optically inactive crystalline methine (mp 93.5"-95" ; hydrobromide, mp 209"-21 lo). On the basis of comparison of the physical constants of 0,O-dimethylphellodendrine methine with those of laudanosine methylmethine (LXXII)(mp 94"-95"; hydrobromide, mp 209.5'-211"), these bases were supposed by Tomita and Kunitomo (68) to be identical. Thus phellodendrine was represented by the isoquinoline structure LXXIII.

* This material is supplementary

t o Volume VII, page 424.

86

P. W. JEFFS

I n a subsequent study by the same authors (113), the previously suggested structure for 0,O-dimethylphellodendrine methine was found 264 mp, log E 4.15, ,A, 290 mp) to be inconsistent in its UV-spectrum,,A,( which is in better accord with the spectrum of a styrene rather than a stilbene. Support for this contention was obtained from the IR-spectrum which showed absorptions at 10.20 and 10.97 p, characteristic of a vinyl group. These data indicated that the structure of 0,O-dimethylphellodendrine methine was most satisfactorily accommodated in a structure derived from the Hofmann degradation of a tetramethoxytetrahydroprotoberberine alkaloid. Comparisons with norcoralydine methine (LXXIV) and tetrahydropalmatine methine led to its identification with the former.

OCH3

LSSIV

I

OH

LXXVII

Further evidence for the structure of phellodendrine was obtained from the N-demethylation of 0,O-dimethylphellodendrine to a product identified as ( - )-norcoralydine (113). These reactions served to characterize phellodendrine as a ( - ) - N methyltetrahydroprotoberberine base with a 2,3,1O,lLoxygenation pattern. The position of the two phenolic hydroxyl groups was established by the oxidation of 0,O-diethylphellodendrinet o 5-ethoxy-4-methoxy-1ketotetrahydroisoquinoline (LXXV) and 5-ethoxy-4-methoxyphthalic

2.

87

THE PROTOBERBERINE ALKALOIDS

acid (LXXVI). These results permit the formulation of phellodendrine as structure LXXVII (214). The structure of phellodendrine has been confirmed by a recent synthesis of the racemic alkaloid (115) (Section VII).

VII. Synthesis Several new approaches to the synthesis of the tetracyclic ring system of the protoberberine alkaloids have been developed in the last 10 years. Bradsher and co-workers have developed a general method for synthesizing the protoberberine ring system. It involves the condensation of a properly constituted 1-isoquinoline carboxaldehyde with the appropriately substituted benzyl bromide. Acid-catalyzed cyclization of the resulting quaternary salts affords the fully aromatic tetracyclic ring system which on catalytic reduction leads directly to the tetrahydroprotoberberine skeleton. Recent modifications (93) of this synthetic method involving the use of the oxime, or better, the ethylene acetal of the 1-isoquinoline carboxaldehyde, have permitted the use of less vigorous conditions for the production of the tetracyclic intermediate

-8

CH30

i'H

/ \

'i;

0

CH 2

SLY

CHART 11. Synthesis of ( f )-10-hydroxy-2,3,9-trimethoxydibenzo[a,g]-quinolizid~e (XLV).

88

P. W. JEFFS

and also have given improved yields. ( & )-Tetrahydropalmatine (XLI) (Section 111, E), ( )-tetrahydrocoptisine[( & )-stylopine] (LXXVIII), ( f )-tetrahydropalmatrubine (XLIV), and ( & )-1O-hydroxy-Z,3,9-trimethoxydibenzo[ag]quinolizidine (XLV) have all been synthesized by this method. The synthesis of the latter compound, illustrated in Chart 11, was undertaken to provide corroborative evidence for the structure proposed by Imaseki and Taguchi for the alkaloid corydalmine. The discrepancy in the melting points of the synthetic product and ( t )-corydalmine has been referred to earlier (Section 111,H) and points to the need for a reexamination of the structure of corydalmine. A second general method for the synthesis of the protoberberine alkaloids has been described by Battersby et al. (116).The method, which utilizes a 1,Z-dihydroquinoline as a key intermediate, has been used to synthesize ( _+ )-norcoralydine ( X X X I S ; R = CH3) and ( & )-coreximine (LXXIX), as illustrated for the latter in Chart 111.

I

OH LSSIX

CHART111. Synthesis of (

)-coreximine (LXXIX).

The success of the approach depends on the ability of lithium aluminum hydride to reduce the isoquinolinium salt LXXX smoothly to the corresponding 1,2-dihydroisoquinoline. The 1,2-dihydroisoquino-

2.

THE PROTOBERBERINE ALKALOIDS

89

line is an eneamineand as such its cyclization by formic acid to the tetracyclic system undoubtedly proceeds via the imonium salt as represented below.

Huffman and Miller (117) have reported the synthesis of 2,3-dimethoxyberbine (LXXXI) (see Chart I V ) by essentially the same procedure. A simple route to the berberine ring system has been described recently by Dyke and Brown (118, 119). Treatment of the isoquinolinium salt LXXXII ( R = H ) with aqueous base, and without isolation of the intermediates LXXXIII ( R = H ) and LXXXIV ( R = H ) , gave on treatment with hydrochloric acid 2,3-dimethoxyberbine (LXXXI) and the lactam LXXXV (R = H). Evidence for the structure of the lactam was obtained from its reduction by lithium aluminum hydride to LXXXI and by its dehydrogenation to the isocarbostyril LXXXVI, which had been prepared by an independent route from LXXXI via LXXXVII, according to the scheme shown in Chart IV. The isolation of the lactam LXXXV from the reaction is interesting a.nd illustrates an unusual acidcatalyzed cyclization of the intermediate isocarbostyril LXXXIII (R = H). By employing the simple modification of reducing this intermediate to LXXXIV ( R = H ) before cyclization, a 50% yield of 2,3dimethoxyberbine was realized. When using the appropriate tetramethoxyisoquinolinium salt LXXXII (R = OCHS), the protoberberine base norcoralydine (119)was obtained in 39% yield by this method. In contrast to the results obtained in the synthesis of 2,3-dimethoxyberbine, the intermediate isocarbostyril LXXXIII (R=OCH3) was quite stable to acid and could be readily isolated. Attempts to induce the cyclization of this compound with acid were unsuccessful. The above method constitutes the most efficient synthetic route to the protoberberine alkaloids so far devised. In addition to the new synthetic approaches described, some successful syntheses have been accomplished by using previously described routes. Among these are the syntheses of (k)-coreximine (LXXIX) (mp 237"-238") and its N-methyl derivative, ( 5 )-phellodendrine (LXXVII) (mp > 300°), completed by Tomita and Kunitomo (115). The route

90

+

O @ .

r "-

B

i"

P. W. JEFFS

+I

v

h

c

CHARTIV. Transformations of the isoquinolinium salts LXXXII ( R = H or OCH3) and the synthesis of ( & ).norcoralydine.

2.

91

THE P R O T O B E R B E R I N E ALKALOIDS

used employed the Bischler-Naperalski reaction for the synthesis of the properly constituted benzylisoquinoline, which was used in a Mannich condensation with formaldehyde to construct the protoberberine skeleton. Using the same approach these authors (120) have synthesized the coreximine isomers, LXXXVIII (mp 232"-233'), LXXXIX (mp 21 lo213'), and XC (mp 263" dec.)* together with their respective N-methyl derivatives XCI (iodide, mp 264'-271'), XCII (iodide, mp 282' dec.), and XCIII (iodide, mp 264'-270').

xc

XCIII

VIII. Biosynthesis A. BERBERINE AND RELATED ALKALOIDS Speculations on the biosynthesis of berberine date back to the beginning of the century (121).Most of the early proposals recognized the structural relationship of the protoberberine alkaloids with the simpler benzylisoquinoline bases, from which it was supposed that they are derived. The additional carbon atom necessary for the formal conversion

* One of these isomers must be (

)-coramine.

92

P. W. JEFFS

of the benzylisoquinoline system to that of the protoberberine alkaloids was assumed by Sir Robert Robinson (122) to originate from formaldehyde or its biological equivalent. These hypotheses, although not always correct, have been of inestimable value in guiding tracer experiments on living plants. Experiments on the biosynthesis of berberine and related alkaloids have had, in addition to these guidelines, the benefit of the knowledge gained from previous tracer studies on the biosynthesis of the isoquinoline alkaloids of the papaverine and the morphine series, where it was known that two molecules of the aromatic amino acid, tyrosine, are built into these alkaloids via a pathway involving the intermediacy of norlaudanosoline (XCIV).

XCIV

Spenser and co-workers (123) have investigated the biosynthesis of berberine and related alkaloids elaborated by Hydrastis canadensis L. I n separate feeding experiments, ~-glucose-'4C (uniformly labeled), ~~-phenylalanine-2-1%,~~-tyrosine-2-14C,~~-tyrosine-3-14C,and 3,4-dihydroxy-2-phenylethylamine1-14C (dopamine) were administered to the growing plants. Of tJhe compounds tested tyrosine was the most efficient precursor of the major alkaloids, berberine and hydrastine, and dopamine was almost as good. Glucose was a much less efficient precursor, and the incorporation of phenylalanine into these alkaloids was almost negligible. Controlled degradation of the labeled berberine obtained from the feeding experiment with tyrosine-2-14C is illustrated in Chart V. The results of the degradation established that the label was restricted to the carbon atoms of positions C-1 and C-3. This indicates that two molecules of tyrosine participate in the biosynthesis of berberine and that each unit of this amino acid is incorporated in a specific manner. Since it is reasonable that the two molecules derived from tyrosine which are involved in the formation of the benzylisoquinoline system should be different, an inequality of labeling a t C-1 and C-3 in the derived alkaloids was anticipated. Whereas this was true for hydrastine, the ratio of activity at the two positions in berberine was approximately unity.

2.

THE PROTOBERBERINE ALKALOIDS

93

d CHO

CHARTV. Degradation scheme used for berberine obtained from administering tyrosine2-14Cand dopamine-1-I4C, separately, to H . candensis. A Indicates labeling pattern from tyrosine-f-14Cexperiment. 0Indicates labeling p&tern from dopamine-1-14Cexperiment.

Despite this result, proof that tyrosine gave rise to two dissimilar intermediates in the biosynthesis of both berberine and hydrastine was provided by the finding that only one molecule of dopamine is incorporated into these alkaloids (58).Degradation of the labeled berberine, obtained after administering 3,4-dihydro~y-2-phenylethylarnine-l-~~C,

94

P . W. JEFFS

showed that the label was restricted exclusively to the C-3carbon atom (Chart V). The foregoing results are in consonance with the ideas proposed many years ago by Robinson and others, and are best interpreted as tyrosine giving rise to 3,4-dihydroxy-2-phenylethylamine and 3,4-dihydroxyphenylacetaldehyde which condense to form the 1-benzylisoquinoline intermediate, norlaudanosoline. Insertion of the C-1 unit of the berberine bridge would then complete the skeleton of the protoberberine alkaloids. The low incorporation of phenylalanine precludes its involvement as an intermediate in the normal biosynthetic pathway to tyrosine and indicates that tyrosine and phenylalanine have different metabolic pathways in H . canadensis. Further experimental evidence on the nature of the benzylisoquinoline intermediates, as well as information cn the formation of the berberine bridge, has been provided by Barton and Battersby and their respective collaborators. The idea that the berberine bridge might be formed by the oxidative cyclization of an N-methyl group rather than from a Mannich condensation of formaldehyde was conceived independently by both groups (124) and proved to be correct by separate experiments. ( k )-Laudanosoline (XCV),labeled with 14C a t both the C-3position (64% of the total activity) and in its N-methyl group, when administered to Berberis japonica gave rise to radioactive alkaloids (125).Conversion followed by oxidaof the berberine to phenyldihydroberberine (XCVI), tion, gave benzoic acid containing 34% of the total activity of the alkaloid. Similarly, ( & ) - r e t i d i n e (XCVII)labeled both in the 6-methoxyl group (5.9%) and in its N-methyl group (94%) when fed to H . canadensis gave radioactive berberine (126).Location of the labels a t the expected positions was established by acid hydrolysis to formaldehyde (5.6%) and by conversion to benzoic acid (9 1yo),as described above, and is illustrated in Chart VI. Taken together these experiments establish ( a )the formation of the berberine bridge by oxidative cyclization of the N-methyl group, ( b )the derivation of the methylenedioxy group by oxidative cyclization of the 0-methoxyphenol grouping," and ( c )the validity of laudanosoline and reticuline as intermediates in the biosynthetic pathway. Gupta and Spenser (127)have demonstrated that the carbon atoms of

* The biosynthesis of methylenedioxy groups from 0-methoxyphenols appears t o be quite general on the basis of the five cases investigated to date.

2.

THE PROTOBERBERINE ALKALOIDS

95

XCVII

SCI7

J

\A

CHzO

SCVI

CHARTVI. Biosynthetic origin of the berberine bridge. t Indicates position of label in berberine derived from XCV. A Indicates position of label in berberine derived from XCVII.

the berberine bridge and the methylenedioxy group in berberine originate from the X-methyl group of methionine. Evidence for stereospecificity, and hence enzymatic control, of the incorporation of reticuline was provided by a series of elegant experiments with the labeled enantiomers of the precursor (128). Feeding of ( + )-aryl-3H-reticuline (absolute configuration as in XCVII) and ( - )-aryl-W-reticuline to H . canadensis in separate experiments resulted in the former being incorporated into berberine fifteen times more efficiently than the ( - )-isomer. Corroboration that ( +)-reticuline is the true precursor was obtained from the results of administering a mixture of ( - )-aryl-3H-reticuline and ( )-reticuline-3-14Cto H . canadensis.

96

P. W. JEFFS

Comparison of the 3H:14C ratio in the derived berberine was in complete agreement with the use of the ( + )-isomer. The fact that some incorporation of ( - )-reticdine is observed is probably best explained by assuming some racemization of the test precursor since reticuline is known to be racemized through its equilibration with 1,2-dehydroreticuline in Papaver somniferum. It is noteworthy that protosinomenine (XCVIII), despite being so similar to reticuline, and possessing the necessary C-8 hydroxyl group (protoberberine numbering) to permit cyclization, is not incorporated into berberine in H . canadensis.

XCVIII

XCIX;

a ; R l = H , Rz=CH3 h ; H1=CH3, R z = H

C

Preliminary characterization of some of the other intermediates involved in the biosynthesis of berberine in H . canadensis has been reported. Both the isomeric ( ~f:)-norreticulines XCIXa and XCIXb are efficiently incorporated into berberine indicating that each is methylated to reticuline. Evidence for postreticuline intermediates is less equivocal. ( f )-Tetrahydroberberubine-12-3H(C) was only poorly incorporated (0.0064%) into berberine, and although ( & )-tetrahydroberberine was efficiently incorporated (8.9%), the ease with which it undergoes autoxidation to berberine makes interpretation of the result difficult. However, ( - )-tetrahydroberberine [( - )-canadinel, having the same absolute configuration as ( + ) - r e t i d i n e ,does occur in H . canadensis, and its isolation from a feeding experiment with labeled reticuline showed it to be radioactive (0.035% incorporation). Nevertheless, the demonstration

Y

2. THE P R O T O U E R U E R I N E ALKALOIDS

97

98

P. W. JEFFS

of the presence of ( -)-tetrahydroberberine in this plant does not necessarily mean it is an obligatory intermediate in the biosynthesis of berberine. Further work with labeled optically active tetrahydroberberines is needed to resolve this point. The foregoing experimental results are presented in summarized form in the integrated scheme shown in Chart VII. Tracer studies with Chelidonium majus have provided additional examples of the importance of ( +)-reticuline as a precursor of other protoberberine alkaloids (129). ( + )-Reticuline and ( - )-reticuline, containing tritium a t C-1 and multiple 14C labels a t the positions shown (see Chart VIII), when administered to C. mujzcs plants resulted in the significant incorporation of the (+)-isomer into protopine (CI), chelidonine (CII), and ( - ) tetrahydrocoptisine [( - ) -stylopine] (LXXVIII). Incorporation of ( - ) - r e t i d i n e did occur, but only to a very small extent. Degradation of the labeled ( - )-tetrahydrocoptisine, in a manner analogous to the route described earlier for berberine, located the labels in the predicted positions. Since the relative activities of the carbon atoms were comparable to those of analogous carbon atoms in the test precursor, ( + )-reticdineis obviously incorporated intact into ( - )-tetrahydrocoptisine.

C1

CII

LXXVIII

The tritium label (at the ‘2-14 position) was found t o be only about 50% retained, and in fact the actual amount varied from one feeding experiment to the next (130). An oxidation-reduction equilibrium

2. THE P R O T O B E R B E R I S E ALKALOIDS

o

n

c

99

I

h

v

I

c

+ )-Reticdineand ( - )-scoulerineas precursors of ( - )-tet'rahydrocoptisineand chelidoniiie. v

CHARTVIII. (

100

P.

W. JEFFS

involving 1,2-dehydroreticuline is thus occurring, but it is not as rapid as that found in P . somniferzim. Degradation of the active chelidonine established the position of the labels as shown in CII, in agreement with its derivation from the protoberberine ring system as suggested first by Sir Robert Robinson (131), and later by Turner and Woodu-ard in Volume 111,page 54. Furthermore, the absence of tritium is in keeping with the proposed intermediacy of the dihydroisoquinoline (CIII) (see Chart VIII). Conversion of the tetrahydroprotoberberine ring system into chelidonine was established from separate feeding experiments wit>htritiumlabeled ( - )-scoulerine (XLVI) and ( & )-tetrahydrocoptisine. The intact incorporation of these precursors was confirmed by degradation experiments which demonstrated the same labeling pattern in chelidonine as in the precursors. Isolation of radioactive tetrahydrocoptisine from the scoulerine-feeding experiment suggests that scoulerine is a postreticuline intermediate in the biosyiithesis of both ( - )tetrahydrocoptisine and chelidonine in C. majus.

B. BERBERASTINE Monkovib and Spenser ( 5 8 ) ,in seeking information on the origin of the benzylic hydroxyl group in hydrastine, administered DL-noradrenaline2-14C (CIV) to H . canadensis. Somewhat surprisingly, both berberine and hydrastine a t first appeared to be radioactive. However, the results obtained in degrading the berberine sample were inconsistent with that expected of a radiochemically pure material and indicated the presence of a hitherto unsuspected contaminant(s). Rigorous purification of hydrastine and berberine removed essentially all the radioactivity previously associated with these alkaloids. It was shown that the activity of the berberine sample wa,s accounted for by the presence of a trace quantity of a highcounting alkaloid, subsequently identified as the recently discovered base berberastine (see Section 111,D.l). Conversion of the noradrenaline-derived berberastine to berberine and degradation of the resuItant berberine, as depicted in Chart TT, demonstrated the occurrence of the label a t the C-5 position and indicated the specific iiicorporation of one noradrenaline unit into the berberastine molecule. I n addition, dopamine was found to be incorporated efficieiitly into berberastine ; in fact, the specific activity of the berberastine was

2.

THE PROTOBERBERINE ALKALOIDS

101

significantly higher than that of the berberine and ( - )-tetrahydroberberine samples derived from the same experiment. The low yield of the dopamine-derived berberastine precluded its degradation. The results of the noradrenaline and dopamine experiments have permitted certain conclusions to be drawn regarding the biosynthesis of berberastine. Since both the dopamine and noradrenaline experiments gave berberastine of a much higher specific activity than that found in berberine and tetrahydroberberine, the latter alkaloids cannot be precursors of berberastine. Further, since noradrenaline is efficiently incorporated into berberastine, whereas berberine and tetrahydroberberine from this experiment have negligible activity, the C-5 hydroxyl group must be introduced a t an early stage in the biosynthesis, certainly prior to the formation of the benzylisoquinoline intermediate. The involvement of noradrenaline as a precursor of berberastine implies the probable intermediacy of 4-hydroxynorlaudanosolinein the biosynthesis of this alkaloid.

OH

CIV

cv

Although it is doubtful whether the number of alkaloids derived from 4-hydroxynorlaudanosoline will approach those biosynthesized via norlaudanosoline, some indications are becoming available that the former group will expend in the near future. Of the three new minor alkaloids in H . canadensis, whose presence was first revealed by the selective incorporation of labeled noradrenaline, one has been identified as a 5-hydroxytetrahydroberberine(CV) by virtue of its identity with the reduction product of berberastine (59).

IX. Table of Physical Constants of Protoberberine Alkaloids and Their Derivatives (TABLE111) Compound ~~~~

~

.

~~

Formula ~

(f)-Alkaloid F 51 ( - )-Base I1 Picrate ( & )-Base I1 ( )-Berberastine (pseudo-base form)

+

Iodide Berberine (pseudo-base form) Picrat'e ( - )-Capaurimine ( - j-capaurine 0-Methyl 0 - Ethy1 ( & )-Capaurine (capauridine) 0-Methyl ( - )-Cheilanthifoline 0-Ethyl Columbamine Chlorido Iodide Nitrate Coptisine Chloride Pierate ( - )-Coreximino Hydrochloride 0,O-Dimethyl 0,O-Diethyl

~~~

~~~

Melting point ("C) -~ ~. .__

CzoHn04N 171 C21H2304x 144-146 C Z ~ H ~ ~ O ~ N . C ~ 168-169 H ~ O ~ N ~ CziHz304N 190-19 1 C20H1906N 132-137 CzoHls05NI > 310" CaOHl905N 144 CzoHls04N*C6Hz031\T3 274 C20H2305rV' Cz1HzjOgN CzzHz705N Cz3HzsOsN C21HZ505N CZZH2705N ClYHI904N

CzlHz304N -

CzoHzo04NC1-4.5HzO CzoHzo04h'I CzoHzo04N

212 164 152 134 208 142 184 144

[.Iu

(solveut') ~~

-

+ 306" (CHC13j -

+ 107" (CzHsOHj -

-285" (CHC13) -271' (CHCl3) - 264" ( C H 3 0 H )

-

__

-311" (CH30H)

-

-.

__

194 223-224 232

CigHi404N .HzO > 330 CigH1404N ' C s H ~ 0 7 N 3 250-255 C19HZ104N 262 B,HCl 236-237 CziHz504N 177 Cz3Hz904N 131

-

_-275'

(CHCl3)

-

r

0 E3

Reference ~

13% I 0 , 99 10, 99 99 91 91 133 I34

132 135

135 135 135 I ;Is 13 6 I36 -

I37 39, 138 137 139 140 141

I41 141

141

'd 4 r: cl M

r

2

( _+ )-Coreximine

+

-

-391" (CH30H)

-

f

303" (CHC13) -

-t- 298" (CzH50H) __ -

+ 300" (CHC13) -

-

+ 110' (CzH50H) + 137" (CzH50H) -

i-337" (CHC13) -

15, 16 15, 16

230 300 214-215 184 208 154

- 115'

(CH3OH)

-

- 296" (CzH50H)

55 55 55 55

T H E PROTOBERBERINE ALKALOIDS

+

170 247-252 164-166 191-193 244 (vac.) 245-250 129-1 30 160 220-222 207-208 136 206-207 220 64-70 (amorph.) 238-249 135-136 165 193-195 238-239 (vac.) 212-214

115, 116 115 142 142 143 143 18 18 144 145 145n 146 147 145 148 148 149 150 150 101 101 101 20 20

2.

Hydrochloride 0,O-Dimethyl 0,O-Dimethgl picrate 0,O-Diethyl ( - )-Coramine 0,O-Diethyl 0,O-Diacetyl ( )-Corybulbine Hydrochloride 0 -Ethyl 0-Acetate ( & )-Corybulbine Nitrate ( )-Corydaline Hydrochloride Hydriodide a-Methiodide 6-Methiodide ( )-Corydaline Chloroaurate Hydrochloride ( + )-Corydalmine ( & )-Corydalmine Corysamine Chloride Iodide Cyclanoline Chloride Iodide 0,O-Diethyliodide 0,O-Diethyl-N-demethyl

TABLE 111-continued

F

0

-~

Compound 0,O-Diethyl-N-demethyl hydrochloride 0,O-Dimethyliodide Dehydrobase I1 (dehydrothalictrofoline) Iodide Dehydrocorydalmine Iodide Dehydrocorydaline (pseudo-base form) Dehydrocorybulbine Chloroaurate Dehydroisocorybulbine Iodide Dehydro thalictricavine Iodide ( - )-Descretamine ( - )-Descretine 0-Ethyl ( - )-Descretinine Dihydroberberine (lambertine) 8-Acetonyl 8-Keto (oxyberberine) Dihydrocoptisine 8-Acetonyl 8-Keto Dihydrodehydrocorydaline 8-Keto Dihydroeipberberine 8-Acetonyl

Formula

Melting point ("C) 255-258 (vac.) 215 (208)

[aID(solvent)

- 251' (50% CzH50H) - 126" (CH3OH)

Reference 55 55

282 (dec.)

99

238-240 (dec.) 112-1 13

20 151

194-195

147

260

145

'd

r+ M

247 (dec.) 221-224 (dec.) 180-1 81 158-159 212-214 (dec.) 162-1 64 168 (dec.) 198-199 194-196 188 (dec.) 292 228-228.5 170-172 162

-

- 362" (pyridine) - 300" (CHCls) -

-271" (pyridine) -

-

99

49 49 95 49 87, 133 134, 152 153 139 100 139 154 155 155

r

2

8-Keto

143 183 165-1 67 253-2 5 5 268 173 266 (dec.) 281 (dec.) 206

156 157 158 I58 158 159 159 159

B.HBr B.HCI

206 210-2 12 225( dec. ) 152-153 158-159 182-183 (180-181) 222-225 (dec.) 216-219 (dec.)

159 -

- 282" (CHC13) - 357" (CHC13) -

-

+ 299" (CHC13) + 129" (CaH5OH) -

-

+ 82" (HzO) -

-297" (CHC13)

134 108

108 I08 160 100 145, 161 150 137 39, 138 137 162 163 49,94 94

94

ALKALOIDS

B.CH3I

+

Hydrobromide Hydrochloride

155

222 161-162 227-229 (dec.) 141-143 176 186 187-188 ( 1 79-180) 2 18-221

+

Methiodide Jatrorrhizine Chloride Iodide Nitrate ( )-Mesocorydaline ( f )-Mesocorydaline ( - )-Norcoralydine [( - )-xylopinine]

240-241

2 . THE J!HOTOBERBERlNE

Dihydropalmatine 8-Acetonyl 8-Keto Uihydropseudoberberine Hydrochloride 8-Keto Dihy dropseudoepiberberine Hydrochloride Hydroiodide 8-Keto Epiberberine Picrate ( - )-Epiophiocarpine Methiodide 0-Acetate ( f )-Epiophiocarpine 0-Acetate ( )-Isocorybulbine

TABLE 111-continued

Compound -

.

( f )-Norcoralydine

Hydrochloride 14-Methoxy N - 0xide ( - )-Ophiocarpine a-Methiodide j3-Methiodide 0-Acetate ( & )-Ophiocarpine 0-Acetate Picrate Palmatine Chloride Iodide Pseudoberberine Chloride Iodide Picrate Pseudoepiberberine Iodide Picrate ( - )-Scoulerine 0,0-Diethy1 ( )-Scoulerine Steponine Chloride Iodide 0 , O -Diethyliodide

+

Formula

Melting point ("C)

[alD(solvent)

Reference

-

141 141 89 89 164 108,144 108 108 84, 165 84,160

177 236-237 215 159-1 60 188 271 253-255 (dec.) 141-143 252 (274) 172-174 (176-177) 200-201

- 284" (CHC13) -

- 357' (CHC13) -

-

3 4

84

205 24 1

-

156 137

300 (dec.) 274 305 (dec.)

-

158 158 158

303 (dec.) 237-238 204 (194-195) 155 192-193

-

159 154 135, 165 166 167

235 (dec.) 177-178 225

'd

-

- 129" (H2O) - 115" (CzH50H)

-

55 55 55

M

r

2

0,O.Diethyl-N-demethylhydrochloride ( - )-Tetrahydroberberine [( - )-canadinel a-Methochloride p-Methochloride a-Methiodide p-RIethiodide ( f )-Tetrilhydroberberine a-Methochloride p-Methochloride a-Methiodide 8-Methiodide 14-Methoxy N-Oxide N-Oxide picrate ( + )-Tetrahydroberberubine(nandinine) ( + ) -Tetrahydroberberubine 0-Ethyl ( + )-Tetrahydrocoptisine ( - )-Tetrahydrocoptisine ( f )-Tetrahydrocoptisine ( - )-Tetrahydrocolumbamine (isocorypalmine)

0-Ethyl 0-Ethyl hydrochloride ( f )-Tetrahydrocolumbamine Hydrochloride ( f )-Tetrilhydrocorysamine Methiodide Picrate ( - )-Tetrahydroepiberberine[( - )-sinactinel Hydrochloride

247-268 135 262 262 220 264 171 150 288 (dec.) 251 248 178-179 158-1 59 196-197 195-196 187-188 (vac.) 129 202 202 222-223 (21 7-618 (dec.)) 240 82 230 223 215 202-203 266 (dec.) 189 174 272 (dec.)

- 255" (50%CzHsOH) - 308" (CH30H) - 136" (HzO) - 160" (HzO)

-

+ 303" (CHC13) (167) -

t 3 1 0 " (CHC13) - 315" (CHC13) -

-312" (CHC13)

55 164 111 111 111 111 164 168 168 168 168 89 89 89 169 169, 170 171 172, 1 7 3 172 173 174 166 166 167 131 16 16 16 175 175

E3

e 0 H 0

m

M

2

3 * E* r

I!

z

F

0

P

TABLE 111-continued ~~

0 cc3

-

Melting point Compound (

Formula

Hydrochloride 14-Hydroxy 14-Bfethoxy S-Oxide N-Oxide hydrochloride N-Oxide picrate ( )-Tetrahydrojatrorrhizine[( )-corypalmine] ( - )-Tetrahydrojatrorrhizine [( - )-corypalmine]

+

169-1 70 (170-171 ) B.HC1 286 (246) CzoHz105N 144 CziHz305N 233-235 C20H2105N 150-15'2 CzoHzi 05N.HCl 236-237 C P O H ~ ~ O ~ N . C ~ H190 ~O~N~ CZOH2304N 235-236 C20H2304N 246 (vac.) (236 (vac.)) CzzHz704N 120 CzoHz304N 218 CziHz504N 142 CziHz504N 142 B.HC1 232 C 2 1H2 5 0 4N 145 B.HC1 215-216 CzoHz304N 140 CzzHz704N 116 CzoHz104N 160-1 61 C Z O H ~ ~ O ~ N . C ~ H ~149-150 O ~ X C (dec.) T~ C1qHi90sN 201-202 CigHi904N 209-21 1 C20II1904N 21 3-214 C20H21041\T

)-Tetrahydroepiberberine

+

0 -Ethyl ( f )-Tetrahydrojatrorrhizine ( + )-Tetrahydropalmatine ( - )-Tetrahydropalmatine Hydrochloride ( f ) -Tetrahydropalmatine Hydrochloride ( f )-Tetrahydropalmatrubine 0 -Ethyl ( f )-Tetrahydropseudoepiberberine Picrate Tetrahydro thalidastine ( )-Tetrahydrothalifendine ( f ).Tetrahydroworenine Thalidastine Chloride

("C)

[.ID

(solvent)

Reference 139,155 92,139 89

89 89

80 89

I76 I07 166 I77 176 135 137 137 137 170 I70 159 I59 62 61 103

62

?

3 GI

h Y Y

@

Thalifendine Chloride ( + ) -Thalictricavine ( If- )-Thalictricavine ( + )-Thalictrifoline ( )-Thalict.rifoline Worenine Chloride

0 cj

0 W

110

P. W. JEFFS

X. Addendum Since the writing of the manuscript several important publications on the protoberberine alkaloids have appeared. Iwasa and Naruto (179) have shomi that the compound described by Pyman as neooxyberberine is represented by the structure shown in formula CVI.

A new phenolic base, stepharotine, C21H2505N (hydrobromide, mp 227"229@; [.ID - 203@in MeOH), has been isolated from Stephania rotunda Loureiro, and structure CVII has been proposed for the alkaloid (180). Slavikova and Slavik (181)have isolated a diphenolic protoberberine alkaloid, HFI, C19H2104N (mp 201"-203"; - 356" in CHCIB) from Hunnemannia fumariaefolia Sweet. It was characterized as a ( - )-0,Obisdemethyltetrahydropalmatine by methylation to ( - )-tetrahydropalmatine. The position of the phenolic hydroxyl groups had not been determined, but mass spectrometry indicates one is in ring A and the second in ring D. HF:FEREI;CES 1. T. R. Govindachari, B. R . Pa,i, S. Rajadurai, and U. Ramadas, Proc. I n d i a n Acad. 8 c i . A47, 41 (1958). 2. M. Kaivanishi and S. Sugasawa, Chena. & P h n n n . Bull ( T o k y o ) 13, 5 2 2 (19G5). 3. X. A. Dominguez and V. Barragan, J . Org. Chem. 30, 2049 (19%). 4. L. Slavikova, T. Shun, and J. Slavik, Collection Czech. Chem. Commzcn. 25, 7% (19GO). 5. L. Slavikova and J. Slavik, C'ollechm Czech. Chem Commun. 21, 211 (195fi). 6. J. Slavik and L. Slavikoviz, C'ollectioa Czech. C.'hem. Commun. 28, 172s (1963). 7. H. G. Boit and H. Fleiitje, Sntzcrzc,issenschcen 47, 323 (1960). 8. F. J. Bandelin and W. Malesh, J . .47n. Phnrpn. dssoc. 45, 502 (1956) 9. J. Slavik, Collection. Czech. C h e m C o n z m u ~20, . 198 (1955). 10. H. Tagurhi and I. Imaseki, J . Phrirm. Soc. Jnpnn 83, 578 (19F3). 11. H. Taguchi and I. Imaseki, J . P h a r m . Soc. Jnpn)? 84, 573 (1964). 12. JemHung Chu, Lin-Hsing Ho, and Yen Ch'en, Actn. Chim. Sinicn 28, 195 (1962); see Chem. Ahstr. 59, 14035 (19G3). 13. H. G. Boit and H. Elirnke. Sntur?r~issenschnften46, 427 (1959).

2.

THE PROTOBERBERINE ALKALOIDS

111

14. H. Trabert and U. Schneidewind, Phnrm. Zentralhnlle 98, 447 (1959); see Chem.

Abstr. 54, 819 (1960). C. Tani and S. Takao, J . Pharm. Soc. J a p a n 82, 594 (1962). C. Tani and N. Takuo, J . Pharm. Soc. Jnpitn 82, 598 (1962). R. H. F. JIanske,J. A m . Chem. Soc. 72, 3207 (1930). M. S. Yunusov, S. T. Akrarnov, and S. Yu. Yunusov, Dokl. A k a d . S a n k . SSSR 162, 607 (1965); see C'hcni. Abstr. 63, 6695 (1965). 19. R. H. F. hIanske, Can. J . C'hem. 34, 1 (1956); A. Gheorghiu, E. Ionescu-Rlatiu, and 31. Manuchian, Ann. Pharm. Franc. 20, 468 (1962); A. Gheorghiu and E. IonescuMatiu, ibid. 22, 589 (1964). 20. I. Imaseki and H. Taguchi, J . Phnrm. Soc. J a p a n 82, 1214 (1962). 21. J. Slavik, Collection Czech. Chem. Commun. 24, 2506 (1959). 22. L. Slavikova and J. Slavik, Chem. Listy 51, 1923 (1957). 23. J. Slavik and L. Slavikova, Collection Czech. Chem. Commun. 26, 1839 (1961). 24. J. Susplugas, El. Lalaurie, G. Privat, and R. Got, T m v . Soc. Pharm. Montpellier 21,28 (1962); see Chem. Abstr. 57, 2331 (1962). 25. J. Slavik and L. Slavikova, Collection Czech. Chem. Comnmn. 22, 279 (1957). 26. J. Slavik and L. Slavikova, Collection Czech. Chem. Commun. 28, 2530 (1963). 27. J. Slavik a.nd L. Slavikova, Collection Czech. Chem. Commun. 20, 356 (1955). 2% <J. Slavik, Collection Czech. Chem. Commun. 25, 1663 (1960). 29. J. Slavik, Collection Czech. Chem. Commun. 28, 1738 (1963). 30. W. Egels, Planta M e d . 7, 92 (1959); see Chem. Abstr. 53, 15476 (1959). 31. J. Slavik, Collection Czech. Chem. Commun. 24, 2506 (1959). 32. J. Slavik, Collection Czech. Chem. Commun. 28, 1917 (1963) 33. J. Slavik, Collection Czech. Chem. C o m m u n . 26, 2933 (1961). 34. N.Tomita and T. Kugo, J . Phnrm. Soc. J a p a n 75,753 (1955);Phnrm. Bull. (Tokyo) 4, 121 (1956). 35. R. Chatterjee, A. Banerjee, A. K. Barua, and A. K. Das Gupta,J. I n d i a n Chern. Soc. 31, 83 (1954). 36. P. Petcu, Arch. Pharm. 298, 73 (1965). 37. D. R. Dzhalilov, M. I. Goryaev, and G. K. Kruglykhina, Izw. A k a d . N a u k K a z . SSR, Ser. Tekhn. i Khim. N n u k 3, 15 (1963); see Chem. Abstr. 62, 15069 (1965). 38. Tsang-Hsiung Yang and Sheng-Teh Lu, J . Pharm. Soc. J a p a n 80, 847 (1960). 39. R. Chatterjee and A. Banerjee, J . I n d i a n Chem. Soc. 30, 705 (1953). 40. Tsang-Hsiung Yang and Sheng-Teh Lu, J . Pharm. Soc. J a p a n 80,849 (1960). 41. P. Petcu, Pharmazie 19, 53 (1964);see Chem. Abstr. 60, 11845 (1964). 42. P. Petcu, Farmacin (Bucharest) 11, 243 (1963); see CIiem. *4bstr. 59, 11887 (1963). 43. M. Tomita and T. Kikuchi, J . Phnrm. Soc. J a p a n 76, 597 (1956),;M. Tomita and Tsang-Hsiung Yang, ibid. 80, 845 (1960). 44. M. Tornita and T. Kugo, J . Pharm. Soc. Japan, 79, 317 (1959). 45. W. Dopke, Naturzcissenschnften 50, 595 (1963). 46. M. Tomita and M. Sugamoto, J . f'harm. Soc. J a p a n 81, 1090 (1961). 47. Y. Tsang-Hsiung, J . Pha,rm. Soc. J n p n n 80, 1304 (1960). 48. G. Seitz, ~ - a t u r z c i s s e ) i s c h a ~46, t e ~263 ~ (1954). 48a. A. Bums, M. Osowiecki, and G. Regnier, Compt. Rend. 248, 1397 (1959). 49. J. Schmutz. Helv. chin^. Acta 42, 335 (1959). 50. K. Ito, J . Pharm. Soc. J n p a n 80, 705 (1960). 51. A. Resplandy, M e m . Znst. Sci. Madagascar D10, 37 (1961); see Chem. Abstr. 58, 14018 (1963). 52. M. Tomita and T. Kikuchi, J . Pharm. Soc. J a p a n 77, 69 (1957). 15. 16. 17. 18.

112

P. W. JEFFS

53. Jen-Hung Chu, Jui-Ch'un Cli'eii, and Sheng-Ting Shen, Actti. C ' h i ~ ~ S'inico t. 28, 89 (19fi2); see C'henr. d h s t r . 60, 6887 (1964). 53a. 31. Tomita, T. Asada, and Y. IVatanabe, J . Pharw. S'oc. Japroi 72, 205 (1952). 54. I. I. Shchelchkova, T. IY.Il'inskaga, and A . D. liuzovkov, Khim. Prirodotr. Soedin. Akrcd. S ( t u k . L'z. S S R p. 271 (19ii5); see C'lrem. ilbstr. 64, 6709 (1966). 55. 11. Tomita, Y. \Ta.tanabe, arid 21. Fuse, J . Phtrrm. h'oc. J a p c r ~77, 274 (1957); Y. Watanabe, ibid. p. 278; 21. Tomita, T. Ibuka, and K. Tsuyama, ibitl. 84, i i 6 (1964). 56. C. Tani and N. Talrao, J . Phtrrm. SOC.Japctn 77, 803 (1957). 87. 31. 31. Sijland, Phurnz. Weekblctd 96, 640 (1961). 58. I. Nonkovid and I. D. Spenser,J. d m . C'heira. Soc. 87, 1137 (1965); Cau. J . C'heni. 43, 2017 (1965). 59. I. D. Spenser, privccte co,n,municcition (1965j. 60. R. Hogg, J. L. Beal, and hl. P. Cava, Lloydier 24, 45 (1961). 61. 11. Shamma, M. A. Greenberg, and B. S. Dudock, Tetrahedron Letters p. 3595 (1965). 62. &I.Shamma and B. S. Dudock, 2'etrahedro.a Letters p. 3825 (1965). 63. 31. Shamma, B. S. Dudock, BI. 1'. Cava, K. V. Rao, D. R. Dalton, D. C. DeJongh, and S. R. Shrader, Chenz. Covairiun. p. 7 (1966). 64. T. Tomimatsu, hl. hZat.sui,A. Uji, andY. Kano,J. Phnrm. Soc.Japnn 82,1560 (1962). 65. F. T. Hussein, J. L. Beal, and M. P. Cava, Lloydia 26, 254 (1963). 66. J. Kunitomo, J . Pharnz. SOC. Japan 82, 611 (1962). 67. J. Kunitomo, J . P h u r m Soc. Japan 81, 1370 (1961). 68. ill. Tomita and J. Kunitomo, J . Pharm. Soc. J a p a n 78, 1444 (1958). 69. V. I. Frolova, A. I. Ban'kovskii, and h.1. B. Volynskaya, M e d . Prom. SSSR 12, 16 (1958); see Chem. Abstr. 53, 11536 (1958). 70. Hung-Yuan Hsu, Taiwun. Phnrm. Assoc. 7, 2 (1955); see Chem. Abstr. 50, 15339 (1966). 71. 3.1. Tomit,a and K. Fukagawa, J . Pharwa. Soc. J a p a n 82, 1673 (1962). 72. Jen-Hung Chu and You-Ho Chian, A&. Chim. SiTiicn 21, 168 (1955); Chem. Zentr. 131, 1859 (1960); Wei-Yuan Hung and Yuh-Cheng Chen, Actu. Chim. Sinictc 23, 230 (1955); see Chenb. Abstr. 15827 (1958). 73. A. Hant'zsch, Chem. Ber. 32, 575 (1899); A. Hantzsch and 31.Kalb, ibid. p. 3109. T i . J. Gadamer, ATcA.Phurna. 243, 1 1 (1905). 75. D. Beke, -4cto China. Acnd. Sci. Hn7ig. 17, 463 (1958);PeriodicnPoZyfech.1, 51 (1955); see Chenz. rlbstr. 52, 9132 (1958). For a review of the subject, see D. Beke, Advan. Heterocyclic Chem. 1, 167 (1963). 76. B. Skinner, J . Chem. Soc. p. 823 (1950). 77. hl. Freund and K. Fleischer, Ann. Chenz. 409, 188 (1915). 78. J. Gadamer, Arch. Phnrna. 248, 681 (1910). 79. J . Gadamer and W. Klee, Arch. Phccrm. 254, 295 (1916). 80. Y. Kondo, .I.Phnrm. Soc. J n p n ~83, 1017 (1963). 81. T. Takemoto and Y. Kondo, J . Phnrm. Soc. Japnn 82, 1408 (1962). 82. F. L. Pyman, J . Chens. SOC.99, 1690 (1911). 83. Y . Kondo, J . Pharm. Soc. J a p a n 84, 146 (1964). 84. T. Takemoto and Y . Kondo, J . Pharm. Soc. Jnprtn 82, 1413 (1962). 85. T. Takemoto, Y. Kondo, and K. Kondo, J . Phnrm. Soc. J a p a n 83, 162 (1963). 86. C. Schopf and h1. Schweickert, C'hem. Ber. 93, 2566 (1963). 87. R. Cha.t.terjecand P. C. Nait,i, J . I n d i a n Chem. Soc. 32, 609 (1955). 88. I. Sallay and R. H. Ayers, Tetrohedron 19, 1395 (1963). 89. K. W. Bentley and A. W. Murray, J . Chem. SOC.p. 2497 (1963).

2 . THE

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113

90. XI. Ohashi, J. 51. LVilson, H. Budzikiewicz, 51. Shamma, W. A. Slusarchyk, and C. Djerassi, J . .4m.C‘hem. SOC. 85,2807 (1963). See also, H. Budzikiewicz, C. Djerassi, and D. H. EZ’illiams, itc “Struct.ure Elucidation of Satural Product,s,” Vol. 1, p. 181. Holden-Day, Sari Francisco, California, 1964. 91. 51. M. Sijland, Phnrtn. It’eekb-blad. 98, 301 (1963). 92. C. I<. Bradsher and J. H. Jones, J . Org. Cheni.. 23, 430 (1958); C. K. Bradsher and S. L. U u t t a , J . Am. Chem. Soc. 82, 1145 ( 1 9 6 0 ) ; J . Org. Chem. 26, 2231 (1961). 93. N. L. Dutta and C. K. Bradsher, J . Org. Chem. 27, 2213 (1962). 93a. C. K. Bradsher and H. Andrew, private communication (1966). 94. H. Corrodi and E. Hardegger, Helu. Chirn. Actn 39, 889 (1956). 95. F. Bernoulli, H. Linde, and K. Meyer, Helv. Chim. Acta 46, 323 (1963). 96. S. A. Telang and C. K. Bradsher, J . Org. Chem. 30, 752 (1965). 97. G. G. Lyle, J. Org. C h e m 25, 1779 (1960). 98. J . C. Craig and S. K. Roy, Tetrahedron 21, 401 (1965). 99. H. Taguchi and I. Imaselti, J. Pharm. Soc. J a p a n 84, 955 (1964). 99a. N. Takao, Chem. & Pharm. Bull. (Tokyo) 11, 1312 (1963). 100. C. Tani, N. Takao, and S. Takao, J . Pharm. Soe. J a p a n 82, 748 (1962). 101. F. van Bruchhausen, Arch. Pharm. 261, 28 (1923). 102. C. Tani, N. Takao, S. Takao, and K. Tagahara, J . Pharm. Soc. J a p a n 82, 751 (1962). 103. Z. Kitasato, ActaPhytochim. ( J a p a n )3, 175 (1927); see Chem. Abstr. 22, 1779 (1928); J. Plmrm. Soc. Japan 47,315 (1927). 104. H. W. Bersch, Arch. Pharm. 291, 595 (1958). 105. P. W. Jeffs, Experientia 21, 690 (1965). 106. H. W. Bersch, Arch. Pharm. 283, 36 (1950). 107. R. H. F. Manske, Can. .J. Res. B21, 111 (1943). 108. M. Ohta, H. Tani, and S. Morozumi, Chem. Ce- Phurm. Bull. (Tokyo) 12, 1072 (1964); 31. Ohta, H. Tani, S. Rlorozumi, and S. Kodaira, ibid. p. 1080. 109. T. R. Govindachari, S. Rajadurai, and N. Viswanathan, J . Sci. I n d . Res. ( I n d i a ) 18B, I76 (1959). 110. A. R. Battersby and H. Spencer, J. Chem. Soc. 1087 (1965). 111. H. A. D. Jowett and F.L. Pyman, J . Chenz. Soc. 103, 290 (1913). 11 2. J . H . Cannon, G. K. Hughes, E. Rit,chie, and W. C. Taylor, AustraZianJ. Chem. 6, 86 (1953). 113. M. Tomita and J. Kunitomo, J . Pharm. Soc. J a p a n 80, 880 (1960). 114. 53. Tomita and J . Kunitomo, J . Pharm. Soc. J a p a n 80, 886 (1960). 115. XI. Tomita. and J. Kunitomo, J . Pharm. Soc. J a . p m 80, 1238 (1960). 116. A. R. Bat.t.ersby, D. J. LeCount, S. Garratt., and R. I. Thrift, Tetmh.edron 14, 46 ( 1961). 117. J. W.Huffman and E. G. Miller, J . Org. Cheni. 25, 90 (1960). 118. D. If’. Brown and S. F. Dyke, Tetrah.edron Letters p. 3587 (1964). 119. S. F. Ilg-ke, p r i v a t e comuwn;c(ttiou (1966). 120. Al. Toniita and J. Kunitomo, J. Phczrm. SOC. J a p a n 80, 1245 (1960). 121. E. Winterstein and G. Trier, it? “Die Alkaloide,” p. 307. Borntrager, Berlin, 1910. 122. R. Robinson, in “The Structural Relations of Katural Products,” p. 86. Oxford Univ. Press, London and New York, 1955. 123. J. R. Gear and I. D. Spenser, Con. J. Chem. 41, 783 (1963); and references cited therein. 124. A. R. Battersby, Proc. Chem. Soc. p. 189 (1963); D. H. R. Barton, Proc. Chem. SOC. p. 293 (1963).

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125. A. R. Battersby, R. J. Francis, >I. Hirst, and J. Staunton, Proc. C h e m SOC. p. 268 (1963). 126. D. H. R. Barton, R. H. Hesse, and G. W. Kirby, Proc. Chem. SOC.p. 265 (1963). 127. R. N. Gupta and I. D. Spenser, Can. J . C’hem. 43, 133 (1965). 128. D. H. R. Barton, R. H. Hesse, and G. W. Kirby, J . C‘hem. Soc. p. 6379 (1965). 129. A. R. Battersby, R. J. Francis, E. A. Ruveda, and J . St.aunt.on, C‘hem. C‘onzmun. p. 89 (1965). 130. A. R. Bat.tersby, private comnzunication (1966). 131. R. Robinson, in “Structural Relations of Satural Products,” p. 89. Oxford Univ. Press, London and New York, 1955. 132. R. H. F. Rlanske, Can. J . Res. B18, 80 (1940). 133. J. Gadamer, Arch. Pharm. 243, 31 (1905). 134. R. Chatterjee, J. I n d i a n Chem. Soc. 28, 225 (1951). 138. R. H. F. Manske, Can. J . Res. 9, 436 (1933). 136. R. H. F. Rlanske, Can. J . Res. B18, 100 (1940). 137. K. Feist, Arch. Pharm. 245, 586 (1907). 138. H. Kondo and &I.Tomita, Arch. Pharm. 268,549 (1930). 139. R. D. Haworth and W. H. Perkin, Jr., J . Chem. SOC.p. 1769 (1926). 140. Huang-BIinlon, Chem. Ber. 69, 1737 (1936). 141. R. H. F. Manske, Can. J . Res. B16, 81 (1938). 142. R. H. F. Manske,J. Am. Chem. SOC. 72, 4796 (1950). 143. R. H. F. Manske and W. R. Ashford, J . Am. Chem. SOC.73, 5144 (1951). 144. R. H. F. Manske, Can. J . Res. B21, 13 (1943). 145. D. Bruns, Arch. Pharm. 241, 634 (1903). 145a. E. Spiith and A. Dobrowsky, Chem. Ber. 58, 1274 (1925). 146. J. J. Dobbie, A. Lauder, and P. G. Paliatseas, J . Chem. SOC. 79, 87 (1901). 147. J. Gadamer and D. Bruns, Arch. P h a n n . 239,39 (1901). 148. R. H. F. Manske, Can. J . Res. B20, 49 (1942). 149. &I. Freund and W. Josephi, Ann. Chem. 277, 1 (1893). 150. F. von Bruchhausen and H. Stippler, Arch. Pharm. 265, 152 (1927). 151. 0. Haars, Arch. Pharm. 243, 154 (1905). 152. H. Schreiber, Dissertation, Marburg (1888). 153. J. Gadamer, Chern. Ztg. 26, 291 (1902). 154. J. Gadamer and F. von Bruchhausen, Arch. Pharnz. 259,245 (1921). 155. W. H. Perkin, Jr.,J. Chem. Soc. 113, 492 (1918). 156. K. Feist and G. Sandstede, Arch. Pharm. 256, 1 (1918). 157. R. D. Haworth, J. B. Koepfli, and W. H. Perkin, Jr., J . Chem. SOC. p. 648 (1927). 158. R. D. Haworth, W. H. Perkin, Jr., and J. Rankin,J. Chem. SOC.125, 1686 (1924). 159. J. S. Buck and W. H. Perkin, Jr., J . Chem. SOC.,125, 1675 (1924). 160. T. R. Govindachari and S. Rajadurai, J . Chem. Soc. p. 557 (1957). 161. E. Spiith and H. Holter, Chem. Ber. 59, 2800 (1926). 162. J. Gadamer, Arch. Pharm. 240,50 (1902). 163. 0. Haars, Arch. Pharm. 243, 17i (1905). 164. R. H. F. Manske, Can. J . Res. B17, 51 (1939). 165. R. H. F. Manske and M. R. Miller, Can. J . Res. B16, 153 (1938). 166. R. H. F. Rlanske, Can. J . Res. B18, 414 (1940). 167. J. Gadamer, E. Spiith, and E. Rlosettig. Arch. Pharm. 265, 675 (192i). 168. F. L. Pyman,J. Chem. SOC. 103, 817 (1913). 169. E. Spath and W. Leithe, Chem. Ber. 63,3007 (1930). 170. E. Spiith and G. Burger, Chem. Ber. 59, 1486 (1926).

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THE PROTOBERBERINE ALKALOIDS

115

171. G.Frerichs and P. Stoepel, J r c h . Phnrni. 251, 311 (1913). li2. R.H.F.JIanske, Cnn. J . Res. B20, 52 (1942). 153. E.Spiith and P. Julian, Chetn. Ber. 64, 1131 (1931). 154. R.H.F. JIanske, Ctcn. J . Res. B17,95 (1939). 175. K. Goto and H. Sudzuki, Bull. Chem. SOC.J u p n ~4, 120 (1929). 156. E.Spiith, E.Jlosettig, and 0. Trothandl, C'henb. Ber. 56, 875 (1923). 177. E.Spiith and E. Mosettig, Chenb. Ber. 60, 383 (1925). 178. It. H.F.JIanske, J . 47n. Chent. h'oc. 75, 4928 (1953). 179. J. Iwasa and S. Saruto J . Pharm. SOC.Jnpon 86, 534 (1966). 180. 11. Tomita, 31. Kozuka, and S. Uyeo, J . Pharin. SOC.J a p a n 86, 460 (1966). 181. L. Slavikova and J . Slavik, Collection Czech. Chern. Commun. 31, 1355 (1966).

This Page Intentionaiiy Laft Blank

-CHAPTER

3-

PHTHALIDEISOQUINOLINE ALKALOIDS JAROSLAV STANEK Charles University,Prnha, Czechoslovakia

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

117

....

............. ......... . . . . 117 111. Constitution ........................................................ 118 .... . . . . . . . . . .... . . . . 120 IV. Syntheses 11. Shihunine

V. Discovery, Isolation, and Properties

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

....

VI. Physiology and Pharmacology. References

..........

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

120 122 123

I. Introduction

No new phthalideisoquinoline alkaloids have been discovered during the past 10 years, but several reviews of the chemistry of narcotine and simiIar alkaloids have been published (1-3). Shihunine is a new type of alkaloid remotely related t o this group. 11. Shihunine Shihunine, C12H1302N (mp 79"; picrate, mp 163"-164") (I) was obtained from Dendrobium lohohense Tang et Wang ( 4 ); its phthalidepyrrolidine structure was established by reduction and decarboxylation t o 1-methyl-2-phenylpyrrolidine, by oxidation to phthalic acid, and with the help of IR-spectral data.

A two-step synthesis of shihunine ( 5 )started with dimethyl phthalate ; its condensation with 1-methyl-2-pyrrolidone afforded 3-(l-methyl-20xopyrrolidinylidene)phthalide which, on ketonic fission, yielded shihunine. 117

118

JSR0SL;IV S T A N E K

111. Constitution Since the structures of the known phthalideisoquinoline alkaloids are known, recent papers deal with problems of their absolute configurations. Narcotine (11)contains two asymmetric centers at C-1 and at C-9; it is known (6-8) that natural ( - )-a-narcotine may be converted into ( - )-P-narcotine by the action of hot methanolic potassium hydroxide and that it is the carbon atom bearing the hydroxyl group which takes part in this epimerization. Similarly, natural p-hydrastine may be converted into unnatural a-hydrastine (6,9).The application of ORD-curves was not entirely successful (10)but a combination of this method with NMR-spectra and chemical proofs solved this problem (7,11-17). Both narcotines were converted into the corresponding 13-hydroxytetrahydroprotoberberines ( 7 , 11-14) whose stereochemistry was established. These findings combined with the NMR-spectra ( 7 , 14, 16) and optical-rotation data as well as IR-spectra (15) resulted in the presentation of absolute configurations of both narcotines as given below. Narcotoline, known to be close related to narcotine ( l a ) , agrees in its conformation with natural narcotine ( 7 , 14, 15). Natural hydrastine is known to belong to the ,&series, and its absolute configuration was established via chemical proofs in connection with the stereochemistry of ophiocarpine (9, 19) as well as via NMR-spectra (16)

I1

‘R4

0

R5

3.

119

PHTHALIDEISOQUINOLINE ALKALOIDS

and optical-rotation data ( 1 5 ) . Conformations of other less accessible alkaloids have been reported (15, 16). In summary, the absolute configurations of a-narcotine and pnarcotine are given by the structural formulas I11 and IV, respectively, together with absolute configurations of some other alkaloids.

Ri a-Narcotine a-Hydrastine Narcotoline

R2

R3 CH30HOH-

-0-CHz-0-0-CH2-0-0-CHz-0-

R4

CH30CH30-

CH30-

R5 CH30CH30CH&-

Cahn, Ingold, and Prelog configurations at C-1 C-9 R

R R

R R R

Cahn, Ingold, and Prelog configurations at

Ri P-Narcotine P-Hydrastine Capnoidine

Rz

R3

-0-CH2-0-0-CH2-0-

C&OH-

-0-CH2-0-

H-

R4 CH&CH30-0-CHz-0-

R5 C&CH30-

C-1

c-9

R R R

S S S

The absolute configurations of the hydrastines &s given here are according to the Japanese authors (9, 19) though exactly opposite configurations have been postulated by other authors (15, 16). The absolute configurations of minor phthalideisoquinoline alkaloids are still under discussion; corlumine and bicuculline are thought to have the same configurations as narcotine but adlumine should differ a t C-9 (16). According to another communication, adlumine, adlumidine, bicuculline, and corlumine differ in their configurations a t C-1 ( 1 5 ) ,these being designated as S according to the system of Cahn, Ingold, and Prelog. The reduction of the phthalideisoquinoline alkaloids to the corresponding diols has been exhaustively studied; namely, those from U - and

120

JAROSLAV STANEK

p-narcotine by the action of lithium aluminum hydride (7,13-15,20-22), and those similarly obtained from hydrastine (15, 19, 22), narcotoline (21), and bicuculline (15). The optical rotations of all of the diols a t different wavelengths were reported (15).

IV. Syntheses Narcotine was obtained by methylation of narcotoline ( 7 , 23). By a similar procedure, X-ethylnarcotoline was prepared and converted into the homolog of narceine, called narcetyline (mp 195") (24). The biosynthesis of narcotine was studied with labeled tyrosine (25, 26) and methionine (27) fed to poppy plants. Radioactivity of tyrosine was found in equal amounts in both the isoquinoline and benzyl residues (25). Biosynthesis of hydrastine was followed by administering labeled dopamine (28-30), tyrosine (29-31 ), phenylalanine (29, 31) and methionine (32) to Hydrastis canadensis L. Two moles of tyrosine (30) but only 1 mole of dopamine were utiIized (30).The lactone carbonyl group, the methylenedioxy group, and the N-methyl as well as the O-methyl groups are derived from labeled formate and methionine ( 3 2 ) .

V. Discovery, Isolation, and Properties Narcotine has been reported as present in Papaver rhoeus L. (33)and P. paeoniflorum Hort. (34). Some other sources are doubtful; its occurrence in RauwolJia heterophylla Roehm and Schult. (35) may be due to industrial impurities (36), and, for the same reason, the isolation of narcotine from Xtrychnos melinoniuna Baillon is questionable (37). The recovery of narcotine from aqueous solution a t varying pH values by ether extraction (38)and its solubility in a number of solvents (39) have been reported. The preparation of isotonic solutions has also been described (40). A number of salts of narcotine were prepared (41-50)-some for oral use, since they are less bitter (47-49). Regeneration from its picrate with an anion-exchange resin proceeds with an almost quantitative yield (41). Fluorescence of complexes of narcotine with manganese chloride and cadmium halides was studied (51, 52). Narcotine-N-oxide, a well-known compound (53),is of recent interest because of its possible use in medicine (22, 54-56). UV- and IR-spectra of narcotine have been reported (57-59) and used

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for its identification (60) and quantitative determination (61-66) ; the NMR-spectrum of narcotine was also reported (67). Further comparatively voluminous literature on the detection and identification of narcotine has appeared (68-91); paper chromatography and paper electrophoresis were repeatedly utilized for the detection of narcotine (92-117) as well as for its quantitative determination (65, 80, 84, 118-152) and separation (153-175). Paper chromatography, even in conjunction with electrophoresis, has been advocated for the quantitative separation and estimation of narcotine (116, 176-191). Thin-layer chromatography (154,155,167,192-196) and gas chromatography (197) are more recent techniques. Dry poppy heads with a content of 0.01% narcotine may be utilized for preparative purposes (198-201). Narcotine is polarographically inactive (202,203)but its polarographic estimation is possible, based upon the quantitative oxidation of narcotine to cotarnine (202-206). For the oscillopolarographic estimation of narcotine see Molnar et at. (207-209). The presence and the content of narcotoline in opium (0.03-0.06%) as well as in the poppy were studied once more (210-213) and the content of narcotoline in various portions of the plant from the early stages to the full development of the capsule was reexamined (92, 213-219). Very young plants (2-3 weeks) are rich in narcotoline (213); its content rapidly decreases (212, 220), but the products of this scission are not meconine and cotarnoline (195),which are formed rather easily by mild chemical means (149, 195). The content of narcotoline in poppy capsules (0.1-0.2%) is useful for preparative purposes (212, 221-224). I n connection with this problem, colorimetric determination (223),paper chromatography (92, 94, 103, 107, 108, 112, 189), potentiometric determination (225),and thin-layer chromatography (161) were utilized. Indirect determination of narcotoline is possible via cotarnoline ( l a g ) , especially polarographically (826, 227). The dissociation constant of narcotoline has been determined

(828). The isolation of hydrastirie from Hydrastis canadensis L. and its separation from other alkaloids were reexamined (229-232). Following several communications concerning the isolation of hydrastine from Berberis laurina Thunb. (233-235) it appears that this alkaloid is, after all, not present (836, 237). Hydrastine picrate has been described (238) and the degradation of its X-oxide has been studied (22). The identification of hydrastine (75, 78, 239),particularly by means of fluorescence (230, 233, 240), by UV-spectra (59, 60), and by IR-spectra ( 6 4 , has been reported. The quantitative determination of hydrastine can be achieved by titration with perchloric acid (120),by fluorescence

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after oxidation to hydrastinine (241),spectroscopically (118, 212), paper chromatographically (163, 178, 183, 186, 243-245), and by thiii-layer chromatography (167). It is inactive polarographically but can be determined after oxidation, again to hydrastinine (203-205), and the oscillopolarographic method has also been recommended (207,208,246). Corlumine and bicuculline were found in Corydalis govaniana Wall. and their UV- and IR-spectra were described (247).The identification of bicuculline (248) and the effect of pH on the electrophoretic separation of bicuculline, corlumine, and corlumidine (183,186)have been reported. Optical rotation data for bicuculline, adlumine, adlumidine, capnoidine, corlumine, and corlumidine at different wavelengths have been given ( 1 5 ) . The classic isolation of narceine from opium has been repeated (249), but its chromatographic separation was recommended (174, 175, 250). The accumulation and distribution of narceine in the poppy during the vegetative period was followed (151, 251, 252) and narceine (mp 170") was isolated in a yield of O.O2y0from dry poppy heads (253).Its salt with theophyllineacetic acid may find practical application (254) as a pharmaceutical. UV- ( 5 8 , 5 9 )and IR-spectra (64)of narceine were reported and methods for its identification (42, 69, 70, 109, 111, 112, 116, 238), estimation (61, 118, 120, 126, 128, 133, 146, 147, 255, 256), and separation, generally with the help of chromatographic methods (92,94,97,98,101,103,115, 116, 151, 162, 178, 182-184, 186, 188-191), were described. Direct polarographic estimation of narceine is possible (202) and this also applies to the oscillopolarographic determination (207, 246). It is doubtful whether or not the acutumine, C ~ ~ H Z ~ O from ~N, Menispermum dahuricum DC. (257, 258), belongs to the group under discussion, but information to permit a definite relegation is not yet available.

VI. Physiology and Pharmacology The biological properties of narcotine have been reviewed ( 1 ) . The antitussive activity of narcotine once more was a subject of many papers (259-271) and the question of this property, when compared with that of codeine, still remains unclear. Codeine is said to be superior in this respect to narcotine ( 2 7 2 ) ;but, according to other authors (273, 274), narcotine has some advantage over codeine. The antitussive activity of different stereoisomers of narcotine have also been studied ( 2 7 1 ) .Narcotine-Naxide showed an increased antitussive activity (271, 275, 276) and narcotine resinate was recommended as a long-acting aiititussive (277, 278), as were the esters of 5-hydroxymethylnarcotiiie (279).The phar-

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macology of narcotine (280-284) and of narceine (280,282,285)a n d their t'oxicities (282, 286, 287) have been reported. Protective action of narceine a n d liydrastine against lethal doses of ultraviolet light on Streptococcus fuecalis was found t o be far greater t h a n t h a t of narcotine (288). REFERENCES 1. P. Boulanger, Exposes A4nn.Biochim. M e d . 9, 281 (1948); Chem. Abstr. 46, 6173

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132. R . Budesinsky and J. Korbl, Collection Czech. Chem. Commun. 25, 76 (1960). 133. S. Kori, Y. Takami, and 31. Fujita, Y u k u g a k u Zasshi 80, 196 (1960); Chem. Abstr. 54, 12489 (1960). 134. 31. Cihakova and J. Zyka, Cesk. Farm.. 5, 572 (1956); Chem. Abstr. 54, 11382 (1960). 135. D. 31. W. Anderson and J. L. Duncan, Chem. & I d . (London)p. 457 (1959). 136. K. Reiss, Z. d n c t l . Chern. 167, 16 (1959). 137. F. Pellerin, J. A. Gautier, and D. Demay, Anu. Pharm. Franc. 20, S o . 2, 97 (1962); Chem. Abstr. 57, 15243 (1962). 138. H. Roemisch, Phnrmazie 16, 373 (1961); Chem. Abstr. 57, 12638 (1962). 139. V. hI. Merlis, &I. R. Bagrecva, and G. G. Kzelovskaya, X e d . Prom. SSSR 16, No. 2, 46 (1962); Chem. dbstr. 57, 3565 (1962). 140. S. Makisumi, H. Ota, and T. Usui, Kagaku Keisatsu Kenkyusho Hokoku 14, 337 (1961); Chem. Abstr. 56, 15615 (1962). 141. M. Palurnbo and S. Sacca, Farmaco ( P a v i a ) ,E d . Prat. 17, 65 (1962); Chem. Abstr. 56, 1439T (1962). 142. M. Rink, Pharmnzie 15, 519 (1960); Chem. Abstr. 56, 11705 (1962). 143. F. Egai, Yakuzaiqaku 20, 134 (1960); Chem. Abstr. 56, 7432 (1962). 144. S. Vedsoe, Aeta Pharmacol. Toxieol. 18, 157 (1961); Chem. Abstr. 56, 6589 (1962). 145. S. Vedsoe, Acta Pharmacol. Toxicol. 18, 119 (1961); Chem. Abstr. 56, 6291 (1962). 146. M. Langejan, Pharm. Weekblad 92, 693 (1957); Chem. Abstr. 52, 3265 (1958). 147. J. Zyka, Bull. Sarcoties, C . S . Dept.Social L4ffairs10, No. 1, 35 (1958); Chem. Abstr. 52, 17620 (1958). 148. B. Budesinsky, Cesli. Farm. 5, 579 (1956); Chem. Abstr. 51, 8370 (1957). 149. S. Pfeifer, Pharmutie 13, 100 (1958); Chem. Abstr. 53, 1635 (1959). 150. S. Makisumi and H. Ota, Yonago Acta Med. 4, 31 (1959); Chem. Abstr. 54, 13554 (1960). 151. G. Kleinschmidt, Planta M e d . 7, 471 (1959); Chem. Abstr. 54, 9203 (1960). 152. W. Poethke and D. Anand Rao, Sci. P h a r m . 31, 116 (1963); Chern. Abstr. 59, 11188 (1963). 153. Kum-Tatt Lee and C. G. Farmilo, J . Pharm. Pharmacol. 10,427 (1958); Chem. Abstr. 52, 20886 (1958). 154. S . Y . Mary and E. Brochmann-Hanssen, Lloydia 26, 223 (1963); Chem. Abstr. 60, 78Tl (1964). 155. W. Poethke and W. Kinze, Arch. Pharm. 297, 593 (1964). 156. S. L. Tompsett, Acta Pharmacol. Toxicol. 17, 295 (1960); Chem. Abstr. 55, 10558 (1961). 157. G. blachata, i2likrochim. Aeta No. 1, p. 79 (1960); Chem. Abstr. 58, 5972 (1963). 158. W. Doepke, Arch. Pharm. 295, 605 (1962). 159. J. Biichi and R. Huber, P h a r m . Acta Helv. 36, 571 (1961); Chem. Abstr. 56, 7425 (1962); 61, 290T (1964). 160. S. Kori, Y. Tanaki, and hZ. Fujita, Y a k u g a k u Zasshi 81, 980 (1961); Chem. Abstr. 56, 6091 (1962). 161. D. Seubauer and K. Mothes, Planta M e d . 9, 406 (1961); Chem. Abstr. 57, 2332 (1963). 162. P. Fischer and ,4.Burgin, Pharm. Acta Helv. 31, 515 (1956); Chem. Abstr. 51, 6945 (1957). 163. F. Micheel arid \V. Leifels, Mikrochim. Acta p. 444 (1961); Chem. Abstr. 55, 21489 (1961). 164. D. hl. Smirnov, illed. i Khim. Prom. Kazukhstana Nauchn.-Tekhn. Sb. No. 3, p. 53 (1961); Chem. Abstr. 57, 13892 (1962).

128

JAROSLAV STANEK

165. A. Waksmundzki, T. Wawrzynowicz, and T. Wolski, A n n . Cniu. X a r i a e CurieSklodowska, Lublin-Polonia, Sect. A A 17, 27 (1962); Chem. Abstr. 62, 5148 (1965). 166. N. A. Izmailov, S. Kh. Mushinskaya, and V. A. Danel'ants, Med. Prom. S S S 'R 18 47 (1964); Chem. Abstr. 61, 5450 (1964). 167. W. Kamp, W. J. M. Onderberg, and W. A. van Seters, Pharm. Weekblad 98, 993 (1963); Chem. Abstr. 61, 1707 (1964). 168. M. Ikram, G. A. Miana, and M. Islam,J. C h r o m t o g . 11, 260'(1963); Chem. Abstr. 59, 10451 (1963). 169. H. Sakurai and M. Umeda, Yakugaku Zasshi 81, 1027 (1961); Chem. Abstr. 55, 26367 (1961). 170. Japanese Patent 15,364 (1960); Chem. Abstr. 55, 3933 (1961). 171. Y. T. Sun, J . Taiwan Pharm. Assoc. 7, 14 (1955); Ch.em. Abstr. 50, 17339 (1956). 172. M. Schmall, E. G. Wollish, and E. G. E. Shafer, B n a l . Chem. 28, 1373 (1956); Chem. Abstr. 50, 17332 (1956). 173. F. Ugai, Takamine Kenkyusho Nempo 12, 62 (1960); Chem. Abstr. 55, 8765 (1961). 174. A. Bettschart and H. Fluck, Pharm. Acta Helv. 31, 260 (1956); Chem. Abstr. 50, I7317 (1956). 175. H. Brauninger and G. Borgwardt, Pharmazie 10, 591 (1955); Chem. Abstr. 50, 8134 (1956). 176. Z. Haussermann, Arch. Pharm. 289, 303 (1956); Chem. Abstr. 51, 1531 (1957). 177. J. Holubek, S. Kudrnac, and M. Novak, Pharmazie 13, 95 (1958); Chem. Abstr. 53, 1635 (1959). 178. K . Macek, J. Hacaperkova, and B. Kakac, Pharmazie 11, 533 (1956); Chem. Abstr. 51, 1538 (1957). 179. H. Thies and F. W. Reuther, Naturwissenschaften 42, 462 (1955); Chem. Abstr. 51, 4649 (1957). 180. S . Ghosh Majumdar and N. G. Ganguli, Chem. & I n d . (London)p. 1237 (1956). 181. A. A. A. Rahman, Arch. Pharm. 290, 326 (1957); Chem. Abstr. 51, 17099 (1957). 182. F. Micheel and W. Leifels, Chem. Ber. 91, 1212 (1958). 183. G. B. Marini-Bettolo and J. A. Coch Frugoni, Gazz. Chim. Ital. 86, 1324 (1956); Chem. Abstr. 52, 653 (1958). 184. M. Danilovic and N. Ristic, Arkiv Farm. Belgrade 12, No. 2, 112 (1962); Chem. Abstr. 58, 10038 (1964). 185. G. Nadeau, G. Sobolewski, L. Fiset, and C. G. Farmilo, J . Chromutog. 1, 327 (1958); Chem. Abstr. 53, 3600 (1959). 186. G. B. Marini-Bettolo and J . A. Coch Frugoni, Rend. Ist.Super. Sanita 21, 319 (1958); Chem. Abstr. 53, 1633 (1959). 187. J. Kolankiewicz and M. Nikoronow, Acta Polon. Pharm. 16, 115 (1959); Chem. Abstr. 53, 18319 (1959). 188. W. Debska, Poznan. Towarz. Przyjaciol N a u k , Wyclzial Lekar., Prace Komisji Farm. 2, 23 (1962); Chem. Abstr. 59, 6451 (1963). 189. N. A. Izmailov, A. K. Franke, and I. S . Simon, Med. Prom. SSSR 113, No. 11, 36 (1959); Chem. Abstr. 55, 15838 (1961). 190. K. V. Street, ActuPharnuzcoZ. Tozicol. 19, 312 (1962); Chem. Abstr. 59, 6199 (1963). 191. J. Zarnack and S. Pfeifer, Pharmuzie 18, 288 (1963); Chem. Abstr. 59, 6197 (1963). 192. W. Poethke and W. Kinze, Pharm. Zentralhalle 102, 692 (1963); Chem. Abstr. 60, 11846 (1964). 193. V. E. Chichiro, Aptechn. Delo 12, 36 (1963); Chem. Abstr. 61, 10534 (1964). 194. W. Poethke and W. Kinze, Pharm. Zentralhalle 103, 577 (1964); Chem. Abstr. 62 2669 (1965).

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195. L. Dryon,J. I'hnrm. Belg. [ S . S . ] 19, 19 (1964); Chem. Abstr. 61, 5460 (1964). 196. 1 ' . Schwarz and &I. Sarsunova, Pharmcizie 19, 267 (1964); Chem. Abstr. 61, 2906 (1964). 197. H. A. Lloyd, H. 31. Fales, P. F. Highet., J. A. Vanden Heuvel, and W. C . Wildman, J . Am. Chem. Soc. 82, 3791 (1960). 198. H. Ludwiecki and P. Gorecki, Actn Poloii. Phnrm. 13, 447 (1956); Chem. Abstr. 51, 9090 (1957). 199. W. Poethke and E. Peehmann, Plantrc M e d . 7, 456 (1959); Chem. Abstr. 54, 10239 (1960). 200. M. Lukasiewiez, J. Tomko, R. Spaldonova, and 0. Bauerova, Fnrmncirt 29, 357 (1960); Chem. Abstr. 61, 11212 (1964). 201. Yu. V. Shostenko and S. Kh. Illishinskaya, Teoriyn i Prukt. Iotanogo Obmeiia, Akad. ,Yauk K n z . SSR, Tr. Resp. Soveshch. p. I76 (1962); Chem. Abstr. 61, 13125 (1964). 202. M. Matsumoto, Y a k u g n k u Znsshi 73, 1006 (1955); Chem. Abstr. 50, 532 (1956). 203. J. Holubek and J. Volkc, Pharmazie 12, 261 (1957); Chem. Abstr. 52, 2337 (1958). 204. K. Kovacz and 1 ' . Cieleszky, Acta Chim. Acad. S c i . Hung. 26, 12 (1956); Ckem. Abstr. 52, 14083 (1958). 205. J. Holuhek and J. Volke, Pharmazie 11, 577 (1956); Chem. Abstr. 51, 6949 (1957). 206. J. Holubek, S. Kudrnac, and M. Sovak, Phnrmnzie 13, 95 (1958); Chem. Abstr. 53, 1635 (1959). 207. L. Molnar and K. Molnarova, Pharmazie 14, 575 (1959); Chem. Abstr. 54, 12488 (1960). 208. K. Moinarova and L. Molnar, A c t n Chim. Acad. Sci. H u n g . 18, 93 (1959); Chem. Abstr. 54, 6783 (1960). 209. P . Kalvoda, Collection Czech. Chem. Commun. 25, 3071 (1960); Chern. Abstr. 56, 7969 (1962). 210. S. Pfeifer, Arch. Pharm. 290, 209 (1957). 211. A. S. Labenskij, Zh. Prikl. Khim. 31, 323 (1938); Chem. Abstr. 52, 11350 (1958). 212. S. Pfeifer and K. Heydenreich, ~ a t u r w i s s e n s c h a f t e t48, , 431 (1961). 213. R. Miram and S. Pfeifer, Snturwissenschoften 45, 573 (1958). 214. R. Miram and S. Pfeifer, Sci. P h n r m . 27, 34 (1959); Chem. Abstr. 53, 17432 (1959). 215. K. Heydenreich, R. Miram, and S. Pfeifer, Sci. Pharm. 29, 221 (1961); Chem. Abstr. 56, 13257 (1962). 216. S . Pfeifcr and K. Heydenreich, Saturwissensclmften 48, 222 (1961). 217. S. Pfeifer and K. Heydenreich, Phnrmatie 17, 107 (1962); Chem. Abstr. 57, 3564 (1962). 218. K. Heydenreich and S. Pfeifer, Sci. P h a r m . 30, 164 (1962); Chern. Abstr. 58, 7135 ( 1963). 219. D. Keubauer, Plnntu M e d . 12, 43 (1964); Chem. Abstr. 61, 7362 (1964). 220. B. Goeber and 9. Pfeifer, Phnrmcizie 18, 146 (1963); Chem. Abstr. 59, 2128 (1959). 221. K. Heydenreich and S. Pfeifer, Sci. I'horm. 30, I7 (1962); Chem. Abstr. 57, 16745 (1962). 222. S. Pfeifer and F. Weiss, Phnrmnzie 10, 701 (1955); Chem. Abstr. 50, 10339 (1956). 223. S. Pfeifer and F. Weiss, Phormnzie 10, 658 (1955); Chem. Abstr. 50, 13371 (1956). 221. Hungarian Patent 151,555 (1964); Chem. Abstr. 61, 13133 (1964). 225. S . P. Dzyuba and 5:. P. Georgievs'kii, Farmatsevt. Z h . (Kiev)17, No. I, 11 (1962); Chem. Abstr. 57, 2854 (1962). 226. J. Holubek and J. Yolkc, Chem. Listy 52, 589 (1958); Cliem. Abstr. 53, 5918 (1959). 227. J. Holubek and J. Volke, Collectioii Czech. Chem. Commuri. 24, 1436 (1959); Chem. Abstr. 54, 108 (1960).

130 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 2.55. 256. 257. 258. 239. 260.

JAROSLAV STANEK

S. Pfeifcr, rlrch. Phnrm. 289, 288 (1956); P h r m . dbstr. 50, 17339 (1956). A . Roux, L4nu.Phrtrm. Frctnc. 15, 119 (1957); C'hem. dhstr. 51, 1.5066 (1957). J . BLichi antl H. Schumacher, I'horm. Acttt Helu. 32, 403 (1937). G. Biglino, Boll. C h i m . F a r m . 99, 195 (1960); Chem. dbstr. 54, 1438 (1960). U.S. Patent 2,880,179 (19.59); C'hem. dbstr. 53, 14611 (1939). C. H. Liberalli and C. Aisic, d m t i s Fac. F u r m . Odotitol I:niu. sYcto I'rrulo 12, 93 (1934); C'hem. B b s f r . 50, 9687 (1956). C. H. Liberalli and C. Aisic, Antiis Fac. Ftrrm. OdorrtoZ t ' t z i v . S u o Pmdo 14, 21 (1936); Chent. dbstr. 52, 14084 (1958). W. Kress, T'ribuna E'nrm. (Brctzil) 24, 30 (1956); Chrm. dbstr. 51, 6950 (1957). C. Stellfeld, Tribunn Fm-wa. ( B r a z i l ) 23, 169 (1955); Che?n. dbstr. 52, 2339 (1958). C. H. Libcralli a n d C. Aisic, Anais Fnc. F a r m . OdontoZ C'niu. Suo f'tiulo 15, 135 (1958); Ch.enL. dbstr. 53, 20697 (19;59). V. T. Pozdnyakova, T r . L'uov X e d . Iiist. 12, 6 (1957); Chern. Abstr. 54, 15837 (1960). M. S. ElRidi, K. Khalifa, and 31. Mamoon, Proc. Pharna. SOC.Egypt, Sci. E d . 37, No. 12, 133 (1953); Chem. Abstr. 51, 8368 (1957). A. Gheorgiu, A. Constantinescu, and E. Tonescu-Blatiu, Farmucia (Buchurest) 7 , 539 (1959); Chem. Abstr. 54, 14678 (1960). M. L. Bartos, Bol. I n s t . Quirn. d g r . (Rio de Jctneiro) 46, 9 (1956); C h e m . Abstr. 52, 654 (1958). M. S. ElRidi, K. Khalifa, and A . Mamoon, J . I'harm. Phnrmocol. 8, 602 (1956); Chem. Abstr. 50, 15324 (1956). E. de Camargo FonsecaMoreas and E. T. Martucci Palma, AnaisFac. Farm. Odontol U n i v . Sao Puulo 12, 149 (19.54); Chem. Abstr. 50, 15350 (1956). G. B. Narini-Bettolo a n d J. A. Coch Frugoni, Farrnaco ( f a v i a ) ,Ed. Prat. 12, 329 (1957); Chem. Abstr. 54, 12491 (1960). Ch. L. W'inek, J. L. Bed, andJI. P. Cava,J. Chromatoy. 10, 246 (1963); Chem. Abstr. 59, 15858 (1963). V. Parrak. Pharmazie 11, 205 (1956): Chem. Abstr. 51, 5361 (1957). 0. E. Edwards and K . L. Handa, Can. J . Chern. 39, 1801 (1961). E. G. C. Clarke, J . P h a r m . Pharmacol. 9, 187 (1937). H. Hausermann and H. J. $checker, Arch. Phurm. 290, 509 (1967). A. Mariani and 0. iJfarian-Narelli, Rend. 1st. Super. Snnita 22, 759 (1959); Chem. Abstr. 54, 11374 (1960). G . K. Silronov, B u l l . Xnrcotics, C.N. Dept. Social A B a i r s 10, S o . 1, 20 (1958); Chem. Abstr. 52, 17619 (1958). R. Aksanowski, M. Jurzysta, J. Kraczkowsak, antl Z. Wiierzowski, Dissertationes Phnrm. 14, 47 (1963); C'hem. dbstr. 57, 8904 (1962). Hungarian Patent 148,695 (1961); Chem. Abstr. 58, 10252 (1963). French Patent 1,369,374 (1964); Chem. Abstr. 62, 602 (1965). . A. H . Witte, P h u r m . H'eekbltrd 91, 588 (1956); Chem. Abstr. 5 0 , 16043 (1956). H. Ellert, T. Jasinski, and K . Bfarcinkowska, ilctcr Polon. P h a r m . 17, 29 (1960); Chrm. dbstr. 54, 11807 (1960). T. A . Tl'inskaya, T r . Vseso. Souchn.-IssZed, Inst. Lekarstv. i rlromnt. Rnst XO. 11, p. 51 (1959); Che.rn. Abstr. 55, 18893 (1961). T. A . Il'inskaya, Aptechn. Delo 7, S o . 6, 10 (1958); Clrenz. Zentr. 131, 9220 (1960). C. Reichle and H. Friebel, Arch. E r p t l . Puthol. Plinrmakol. 226, d58 (1935); Chem. Abstr. 50, 2865 (1956). A. F. Green and N. B. Ward, Brit. J . Pharmncol. 10, 418 (19.35); Chem. Abstr. 52, 7532 (1958).

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261. L. Kallquist and R. lIelander, .-1rr)rci,riir/el-For.sch. 7, 301 (1957); Chem. dbstr. 51, 13228 ( 1 9 5 i ) . 262. K . Takagi, H. Fukutla, and K. l-ano, I7crX.uyrtkuZtinshi 77, 1358 (1957);Chem. dbstr. 52, 4107 (l!j.%). 263. H. A. 13ickerinan, E. German. B. 11.Cohcn, arid S. E. Itkin, I n [ .J . Jfed. S c i . 234, 191 (1957): C h ~ m=Ib,str. . 52. 16464 (1958). 264. G. I?. Folej-, K . E. JIcC'arthy, V. 11.Hunns, E. F. Snell, U. 31. Guirard, G. W'. Kidder, T. C . Dewey, and P. S. Thayer, ~ 4 t i j a .- \ , l - .Acctrl. S r i . i 6 , 413 (1958); C'hcm. Abstr. 53, 9337 (1959). 265. H. Plisnier arid L. Hcrnalsteen, (.'ompit. H e i i d . Soc. Biol. 153, 363 (1959); Chem. Abstr. 53, 22339 (19.59). 266. B. Silvestrini arid G. Maffii, Ftrrmrtco (Pnuiti),Ed. Sci. 14, 440 (1959); Chem. Abstr. 54, 9106 (1960). 267. S. Hara and S. Yanaura, Jctpcrn. J . Phnrmrcol. 9. 46 (1959); Ch.em. Abstr. 54, 14465 (1960). 268. C. Penafiel Sagues, Annles Fnc. Quina. Fnrm., C T j t i z ; . Chile 11, 171 (1959); Chem. dbstr. 54, 25576 (1960). 269. H. Friebel, 6th Coptgr. I ~ t e r Thertrp., ~. Strrrssbourg, 195.9 p. 185. Inst. Pharmacol., Strassbourg, Franc?, 1959; Chena. d h s t r . 56, 6612 (1962). 270. H . Roner, Helz;. Physiol. I'lrtrrmncol. A c f i r 20, 316 (1962): ( ' h e m . Abstr. 58, 7270 (1963). 271. Y. Ota, S . Endo, and 31.Hira.sau-a, Chem. & Pharrri. Kuil. ( T o k y o ) 12, 569 (1964); Chrm. d b s t r . 61, 4834 (1964). 272. S. Yanaura, S i p p o ~ iYnkurigakuZrisshI54, 688 (1958): Chem. dbstr. 53, 18290 (1959). 273. J. La Barre arid H. Plisnier, Arch. Iritem. Phnrmcrcodyn. 119, 205 (1959); Chem. Abstr. 53, 14307 (1959). 274. J. La Barre and H. Plisnier, Bull. Xtrrcotics, 1J.N. Dept. Socinl Afluirs 11, No. 3, 7 (1959); Che,n. Abstr. 54, 10139 (1960). 275. K. Takagi, H . Fukuda, arid 11.Sato, Ycikugctku Ztxsshi 81, 266 (1961); Chem. Abstr. 55, 13771 (1961). 276. Japanese Patent 18,832 (1964); Chem. Abstr. 62, 5312 (1964). 277. Japanese Patent 19,296 (1961): Chem. Abstr. 57, 9965 (1962). 278. British Patent 905,930 (1962): Chem. Abstr. 58, 1319 (1963). 279. U S . Patent 3,056,791 (1962); Chem. Abstr. 58, 5549 (1963). 280. J. BIercier and E. Mercier, Compt. R e d . Soc. B i d . 149, 760 (1955); Chem. Abstr. 50, 2848 (1956). 281. L. C. Weaver, W.hi. Alexander, B. E. Abreu, A. B. Richards, W.R. Jones, and R. ITT. Begley, J . Phnrmncol. ExptI. Therctp. 123, 287 (1958); Chem. d b st r. 52, 17515 (1958). 2 8 2 . J. Szegi, J. Rausch, K. A'Iayda., and J. Sagy, Actcz I'hysiol. Acu.d. S c i . H u n g . 16, 325 (1959); C'hem. Abstr. 54, 15664 (1960). 283. Ch. Tanaka, S i p p o n Ynkurigciku Znsshi 57, 538 (1961); Chem. Abstr. 57, 17333 ( 1962). 284. Ch. Tanaka,Sippo,i YokurigcikuZnsshi 58,225 (1962): C'hem. d b s t r . 60,11241 (1964). 285. B. Kelentai, E. Stenszly, and F. Czollncr, =Irch. Exptl. Ptrthol. Phnrmakol. 233, 550 (1938). 286. hi. Aurousseau and J. Savarro, A i ? > i . Phtrrm. Frmic. 15, 640 (1957): ('hem. dbstr. 52, 10411 (1958). 287. C . A. Winter and L. Flataker, Tosicol. A p p l . I'hnmancol. 3, 96 (1961): Chcm. Abstr. 55, 10710 (1961). 288. J. P. Street and C. F. Poe, r 7 ) i i r .C'olo.StudiesrSer. Chem. Pharm. [ S . S . ] p. 68 (1962); Chem. Abstr. 58, 10328 (1963).

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BISBENZYLISOQUINOLINE AND RELATED ALKALOIDS &I. CGRCUMELLI-RODOSTAMO B N D JIARSHALL KULKA Cizi Royal ( 6 6 ) Limited, Research Ltrboratories Guelph, O)ztario, C'uriada

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

134

11. Alkaloids Containing One Dipheriyl Ether Linkage. . . . . . . . . . . . . . A. R.lagnoline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Berbamunine C. Dauricine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

138 138 139 141 141 142 143 144 146

D. Daurinoline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Magriolamine and Fetidine. . . ............... F. Thalisopine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Thalicarpine arid Thalmelatine. H. Liensinine, Isolicnsiiiine, and Kcfcrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111. Alkaloids Containing Two Dipheriyl Ether Linkages. . . . . . . . . . . . . . . . . . . . . . A. Oxyacanthine and 0-Methyloxyacanthine (Obaberine) . . . . . . . . . . . . . . . . . B. Daphnandrine, Daphnoline, Aromoline, and Homoaromoline. . . . . . . . . . . . C. Repandine, Epistephanine, and Hypoepistephanine . D. Cepharanthine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Sepeerine, Ocotinc, and Rodiasine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Thahnine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Berbamine an H. Tetrandrine

............. L. Atherospermoline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31. Tenuipine and Sortenuipine . . . . . . .... S . ThalicberiiiearidO-Methylthalicbcrir~c.. . . . . . . 0. Isochoiir~roderidririe,Cgclcaniiie, arid Sorcj-cleaniiie . P. Iiisulariiic and Irisulariolirie, . , . . . , . . . . . . . . . , . , . . . . . . . . . . , . . , . . . . . . . Q. Hebeerine, Curine, d-Chondrocurine, arid Tuboruraririe. . . . . . . . . . ... . . . . . R. Tiliacorine a n d Tiliuriric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1';.

A%kaloitlsCoiitltiihg Three D i p h % j1 EtElcr Lirlkagca . . . . . . . . . . . . . . . . . . . . .

148 148 148 150 150 151 152 152 153 153 154 1% 156 157 158 159 159 161 161

C. Meiiisarine . . . , . ,

163 163 163 165

A. Pilocereirie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Piloceredine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

167 167 168

IT. Melaiithioidine ( A Hisphcncthylisoquinolirie Alkaloid) References

.......

....................... 133

169 170

134

31. CURCUXELLI-RODOSTANO A N D NARSIIALL KULKA

I. Introduction Reviews on the bisbenzylisoquinoline alkaloids were published by one of us (31. K.) in 1954 ( 1 ) and 1960 ( 2 ) .Our present purpose is to describe further advances in the field and to supplement the recent excellent genera1 survey of the bisbenzylisoquinoline alkaloids by Grundon ( 3 ) . Investigations over the past eight years have resulted in the isolation and identification of over thirty new bisbenzylisoquinoline alkaloids. This achievement, in such a short time, can be attributed not only t o increased activity in this field but also t o the application of modern physical methods. NMR-spectroscopy, which has played the greatest role, was first applied in this field by Bick and his collaborators ( 4 ) .Useful correlations between the chemical shifts of methoxyl and methylimino protons and their structural environment were found mainly in the oxyacanthineand berbamine-type alkaloids. The methoxyl-group chemical shifts were found to vary considerably with the position of the substituent. This was explained by the spatial variation of the magnetic field caused by the n-electron currents in the benzene rings. Thus a methoxyl group lying above a neighboring benzene ring is highly shielded; but when situated beside a benzene ring and roughly in its plane deshielding occurs. AccordingIy, methoxyI groups a t position 12' (see formula) are responsible for peaks in the region 6.056.13 T , whereas methoxyl groups a t 7 , lying in most conformations over ring B', have the highest chemical shifts, at 6.80-6.98 T . The chemical

shifts corresponding to positions 6 and 6' lie within these extremes. The resonance of the 6-methoxyl group occurs near 6.25 T , but that of the 6'-methoxyl group depends on the stereochemistry of the alkaloid ; it is near 6.4 T if the configurations of the two asymmetric centers differ; otherwise it has a value of about 6.65 T. Evidently then, a study of the NMR-spectrum may not only locate the methoxyl groups but can also narrow the stereochemical possibilities.

4. BISBENZYLISOQUINOLINE AND R E L A T E D ALKALOIDS

135

The oxyacanthine-type alkaloids can be distinguished from those of the berbamine type through examination of the methylimino-group resonances. For alkaloids of the oxyacanthine type both these resonances occur near 7.45 r, whereas for the berbamine series they give wellseparated peaks near 7.4 and 7 . 7 7. The remaining two modern methods, mass spectrometry and the study of ORD-curves, have not yet been used extensively in the bisbenzylisoquinoline field; but the basic work has already been done ( 5 , 6) and undoubtedly they will be increasingly useful in the future. The metal-ammonia reductive cleavage of the bisbenzylisoquinoline alkaloids has continued over the past eight years to be instrumental in unraveling their stereochemistry. It has provided the means of establishing not only the relative stereochemistry of these alkaloids but also their absolute configuration. The latter was made possible after the determination of the absolute configuration of the usual cleavage products I-IV. It was found ( 7 , 8) that the dextrorotatory coclaurine-type bases I-IV have the S-con-

I; Rl=R2=RS=Me 11; Ri=Mo, Rz=R3=H 111;Kl=Rz=Me, R3=H I V ; Rl=Ra=hIe, Rz=H V ; R1 =Me, Rz = R3 = Et VI; R1=Me, Rz=Et, R3=H

VII; R1=R2=Me, R3=Et VIII; R1=Et, Rz=Me, R I = H I X ; Rl=Me, & = H , Ra=CHtPh X; R1=R3=Me, R ? = E t X I ; R I = R ~ = H R2=Me , XII; R l = H , Rz=Ra=Me XI11 ; R1= Ph, Kz = R3 =hle

figuration. The correlation ( + ) = S, ( - ) = R, which was extended to several of the less common cleavage products, has been used by Tomita and Kunitomo in conjunction with available data on the reductive cleavage of bisbenzylisoquinoline alkaloids to assign absolute configurations to over thirty members of this group ( 9 ) . The Faltis theory, which postulates that bisbenzylisoquinoline alkaloids originate in the plant through enzymatic dehydrogenation of the benzylisoquinoline units 1-(4'-hydroxybenzyl)-6-methoxy-7hydroxy-1,2,3,4-tetrahydroisoquinoline(coclaurine) or 1-(4'-hydroxy, benzy1)-6,7 -dihydroxy- 1,2,3,4-tetrahydroisoquinoline (norcoclaurine), has been accepted and refined. This theory has played a role in influencing

136

& CURCUMELLI-RODOSTAMO I. A N D MARSHALL KULKA

researchers in their structural assignments to new alkaloids, and the assignments based on biogenetic considerations have generally proved to be correct. Barton and Cohen (10) and Erdtman and Wachtmeister (11) have related the concept of free radical coupling of plienols to the biogenesis of natural products, and suggested that bisbenzylisoquinoline alkaloids are formed by this reaction from benzylisoquinoline units. The mechanism of the reaction consists of generation of the resonance-stabilized phenoxy free radical by one-electron oxidation of the phenoxy anion, followed by coupling and tautomerization to form hydroxylated diphenyls or diphenyl ethers. Intermolecular coupling may involve any

two radical sites, and thus both carbon to carbon and carbon to oxygen coupling occurs, as exemplified above. Bisphenols can undergo intramolecular coupling either carbon to carbon or carbon to oxygen, if the stereochemistry allows, to form cyclized products. Initial attempts to apply the pairing of radicals to the synthesis of bisbenzylisoquinoline and aporphine alkaloids did not meet with success because of the interference of the basic nitrogen. I n 1963 Franck and Blaschke (12, 13) circumvented this interference by quaternizing the nitrogen and thus were able to carry out biogenetic-type syntheses. When magnocurarine (XIV)was treated with potassium ferricyanide a t 20°, carbon to oxygen coupling occurred to form the bisbenzylisoquinoline XV in 18% yield. Theoretically magnocurarine (XIV) can produce many dimerization products by intermolecular oxidative coupling, because with its two phenolic hydroxyl groups it has eight potential radical sites (indicated by arrows). However, the radicals of the benzyl moiety were not generated or were inert, as evidenced by the fact that the methiodide of 1-(4'-hydroxybenzyl)-2-rnethyl-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline (111) did not react under the oxidative

4.

B I S B E N Z Y L I S O Q U I N O L I N E A N D RELATED A L K A L O I D S

137

coupling conditions. Of the possible types of free radical pairing which can occur in the isoquinoline moiety, the carbon to oxygen type to form XV was chosen on the evidence of the NMR-spectrum of the dimer. The oxidative coupling of phenols has been applied successfully to the synthesis of some alkaloids. One example is the conversion of the isobutylisoquinoline cactus alkaloid, lophocerine, to pilocereine, another cactus alkaloid. However, no bisbenzylisoquinoline alkaloids have as yet been synthesized from benzylisoquinoline units by the oxidative coupling method. This is probably due to the fact that hydroxyl groups in the benzyl moiety fail to generate radicals, as indicated by the experiment with compound 111. The synthesis of the bisbenzylisoquinoline alkaloids with one diphenyl ether linkage, such as dauricine, magnoline, and berbamunine, from hydroxybenzylisoquinolines must await conditions of oxidative coupling which will exclusively generate

f XIV

SY

radicals in the benzyl moiety. However, the present oxidative pairing method should be readily applicable to the conversion of alkaloids with one diphenyl ether linkage to alkaloids with two diphenyl ether linkages as, for example, berbamunine to oxyacanthine and berbamine. The only bisbenzylisoquinoline alkaloids whose structures preclude the simple oxidative pairing mode of synthesis are those containing three diphenyl ether linkages (trilobine, isotrilobine, menisl-trine, normenisarine, and micranthine). However, Barton and Cohen (10)have proposed a mechanism for the formation of the dibenzo-p-dioxin system of these alkaloids which comprises phenoxy free-radical coupling with a subsequent migration reaction. Biogenetic significance is attached to the fact that benzylisoquinoline alkaloids occur in the plant with bisbenzylisoquinoline alkaloids. Examples of such occurrence are thalifendlerine with hernandezine in Thalictrum fendleri (Auth.?) and magnoflorine with thalicarpine in Thalictrum dasycarpum Fisch. and Lall. In each case the simpler alkaloid may well be the precursor of the bisbenzylisoquinoline alkaloid.

138

M, CURCUMELLI-RODOSTAMO AND MARSHALL KULKA

Several of the new bisbenzylisoquinoline alkaloids possess unique structural features not previously represented. Hernandezine and thalsimine are the first alkaloids having an oxygen function a t C-5. Thalicarpine and thalmelatine are the first bisbenzylisoquinoline alkaloids containing an aporphine moiety. I n thalicberine and 0methylthalicberine one of the two ether linkages is attached to C-6’ instead of the usual C-7‘. Tiliacorine and tiliarine are unique examples of bisbenzylisoquinoline alkaloids having a diphenyl system in place of the diphenyl ether system common to most alkaloids. It can be theorized that such a system is formed by carbon to carbon pairing of phenoxy free radicals. Liensinine, isoliensinine, and neferine represent a new group of bisbenzylisoquinoline alkaloids with one ether bridge, in which the latter connects the benzyl with the isoquinoline moiety. They supply the missing intermediates for the alkaloids of the bebeerine-curine type. The isolation of melanthioidiiie has introduced for the first time an alkaloid of the bisphenethylisoquinoline type. 11. Alkaloids Containing One Diphenyl Ether Linkage

A. MAGNOLINE(203, -)* The constitution of magnoline (XVI)was elucidated by degradation in 1940; but the stereochemistry of it remained unknown for many years

thereafter and only recently was established. Magnoline was assigned the SR-configuration (9), as shown in formula XVI, for it was found to be the antipode of the new alkaloid berbamunine whose absolute configuration was established as RS ( 9 , 1 4 ) .

A synthesis of magnoline has not yet been achieved but an attempt toward this end led to the related compound XXV (15).Reaction of the acid chloride of 2-methoxy-4’,5-bis(carboxymethyl)diphenyl ether (XVII) with 3-metlioxy-4-benzyloxyphenethylamine afforded the * Surnbers in parentheses refer t o pages in Chapter 33, Volume I\‘, a n d i n Chapter 21, Volurne \TI, respectively; a dash indicates no reference.

4. BISBENZYLISOQUINOLINE AND

RELATED ALKALOIDS

139

diamide X X I . The latter, when treated with phosphorous oxychloride, was converted to the bisdihydroisoquinoline derivative XXIII. Catalytic hydrogenation of this compound followed by methylatioii yielded

compound X XV.

B. BERBAMUNINE Berbamunine (XXVI) (mp 190"-19 1"), a new bisbenzylisoquinoline alkaloid having a single diphenyl ether linkage, was isolated by Tomita and Kugo (16)from Berberis amurensis Rupr.

S S I ; R1=CH2Ph, Rz=hfe SSII; R 1 =Me, Rz = CHzPh

Examination of its fuiictional groups indicated the formula (NCH3)2 . Permanganate oxidation of C32H25(OCH3)2(OH)3(-0-) O,O,O-trimethylberbamunine afforded 2-methoxy-5,4'-dicarboxydiphenyl ether (XVIII). Hofmann degradation of O,O,O-trimethylberbamunine methiodide yielded a methine base which was found to be identical with the methine base X X X obtained by Hofmann degradation of 0-methyldauricine methiodide. The recorded experiments thus revealed that O,O,O-trimethylberbamunine, 0-methyldauricine, and O,O,O-trimethylmagnoline have the same constitutional formula XXVII.

140

31. CURCUMELLI-RODOSTA1O AXD MARSHALL KULKA

XSS

SSXVIII;R=H X X S I S ; R = El.

MeN

SXXI ; R1= OMe, R2 = Br, R3 = Ac X X X I I , R l = O M r , R e = O H , R3=Me SXXIII; Ri=Kz=H, Rz=Me XXXIV; R l = OMe, R Z= Hi-,R3 = CHzPh XXXV; R1=OMe, R z = M r , R 3 = H XXXVI; R l = O M e , R P = C H ~ K M CR3=H ~, XXXVII; R1= O E t , Rr = Me,R3 = H

S L :R = H r SLI: R = H SLTI: It=OH

The position of tlie t h e e plienolia h j droxyl groups in berbamunine was showii t o be as in XXVI by subjecting the ethylated alkaloid (XXVIII) to cleavage with sodium in liquid ammonia aiid identifj7ing t h e products as ( - )-AT-methyl-0,O-diethylcoclaurine (V) aiid ( + )- 1-( 4’-hydroxybenzyl)- 2 -methyl-6-methoxy - 7 -etlioxy - 1,2,3.4-tetrahydroisoquiiioline (171) ( 1 4 ) . The sodium-ammonia cleavage also permitted Tomita and Kunitomo t o assign the RS-configuration t o the alkaloid (9) (Section I).

4.

BISBENZYLISOQUIXOLINE AND R E L A T E D ALKALOIDS

141

C. DAURICINE (207,445) The only feature of the structure of dauricine (XXIX) not previously known was the absolute configuration. This now follows from the estabIished correlation between the sign of rotation of the coclaurine derivatives ILIV and their stereochemistry (Section I).The products (I and 111) obtained on treatment of 0-methyldauricine (XXVII) with sodium in liquid ammonia had been found to be levorotatory. Thus the RR-configuration can be assigned to the alkaloid (9). A synthesis of 0-methyldauricine (XXVII) has been described in Volume VII, p. 446 ( 2 ) .A similar approach, applied recently, resulted in the formation of a mixture of the racemates XXIX ( 1 7 ) .The Ullmann condensation of ( L- )-3'-bromo-4'-O-acetylarmepavine(XXXI) and ( k )-armepavine (111)yielded a noncrystalline phenolic product which was found to have several physical properties identical with those of dauricine. A difference in the pattern of the NMR-spectra indicated that the synthetic product was a mixture of diastereoisomers. The first total synthesis of ( k )-dauricine was reported by Kametani and Fukumoto in 1964 (18,19).Arndt-Eistert reaction of homoveratrylamine with the acid chloride X I X afforded the amide XXII. BischlerNapieralski cyclization of the above amide gave the dihydroisoquinoline derivative XXIV, the methiodide of which when reduced with zinc dust and ethanol-hydrochloric acid afforded ( )-dauricine. The identity of the synthetic product with ( i )-dauricine was concIuded through a comparison of its physical properties (spectra and chromatographic behavior) with those of an authentic sample of the alkaloid. Meltingpoint determination of a mixture of derivatives of the two specimens is not recorded. Dauricine, which had been known in an amorphous state, was recently isolated as a crystalline chloroform adduct, C ~ ~ H ~ ~ OCHC13, G N Z(mp . 100"-103") (20). The crude amorphous dauricine was found to contain a small amount of unidentified bases (21).

D. DAURINOLINE Daurinoline (XXXVIII) was isolated in small amount, as an amorphous yellow powder, from Menispermum dauricum DC. ( 2 2 ) . Elemental analysis of the base and was found to fit the formula C37H420tjN2 .HaO. Methylation of daurinoline yielded 0-methyldauricine (XXVII). Ethylation gave 0,O-diethyldaurinoline (XXXIX), which on cleavage with sodium in liquid ammonia afforded ( - )-0-ethylarmepavine( V I I )

142

31. CURCUJIELLI-RODOSTAMO A N D M-4RSHALL KULKA

and ( - )- 1-( 4’-hydroxybenzyl)-2-methyl-6-ethoxy-7-methoxy1,%.3,1tetrahydroisoquinoline (VIII). These results permitted the assignment of structure XXXVIII to the alkaloid.

E.

n~AGIVOLAMISE(209,

447)

AND

FETIDINE

The structural elucidation of magnolamine (XLIII) has been completed by determination of its stereochemistry through synthesis and degradation. The Ullmann reaction of ( - )-6’-bromolaudanosine (XL) and ( - )armepavine (111)resulted in the formation of the antipode of tetramethyl-

XLI’I; R1=CHzCOCl. R z = M e XLVII; R 1 = C O C l , R z = C H z P h

L: RI=CHzPh, R 2 = M e I,I; R1= Rz = CHzPh

magnolamine (23). Thus it follows that tetramethylmagnolamine (XLIV) and magnolamine have the SS-configuration (9) (Section I). The confirmatory degradative experiment consisted of the sodiumammonia fission of tetramethylmagnolamine and the characterization of the products formed. As expected cleavage afforded ( + )-laudanosine (XLI)and (+)-armepavine (111)( 2 4 ) . Early attempts to synthesize magnolamine resulted in the preparation of compound XLVIII ( 2 5 ) .This was obtained by condensation of the acid chloride XLVI with 3-methoxy-4-benzyloxyphenethylamine followed by cyclization of the resulting diamide L. The synthesis was not pursued further.

4. BISBENZYLISOQUIXOLI?rTE AND

R E L A T E D ALKALOIDS

143

A total synthesis of a mixture of diastereoisomers having the coiistitution of magnolamine was reported recently by Kametani and Yagi ( 2 6 ) .Arndt-Eistert reaction of 3-methoxy-4-benzyloxyphenethylamine with the diazoketone prepared from the acid chloride XLVII furnished the diamide LI. Bischler-Kapieralski cyclization of the latter afforded the dihydroisoquinoline derivative XLIX, whose methiodide was reduced with sodium borohydride to the stereoisomers of constitution XLV. Debenzylation of the latter mixture gave a noncrystalline product which behaved similarly on paper chromatography to magnolamine and had I R - and UV-spectra which were superimposable on those of the alkaloid. Fetidine (LII), C41H5008Nz.HzO (mp 132'-135"), was isolated from the above-ground parts of Thalictrurn foetidurn L. ( 2 7 ) . The alkaloid was found to contain two methylimino groups, seven methoxyl groups, and one diphenyl ether linkage. Oxidation of fetidine with permanganate gave l-oxo-2-methyl-6,7-dimethoxy-l,2,3,4-tetraIiydroisoquinoline. Reduction with sodium in liquid ammonia furnished ( + )-laudanosine (XLI) and ( + )-laudanidine (XXXII). Thus it was concluded that the alkaloid is represented by formula LII, or a variation of this formula having the ether linkage attached to C-10 or C-13.

F. THALISOPINE Formula L I I I was proposed for thalisopine (mp 151"-153"), an alkaloid from Thcclictrzoti isopyroides C.A. May (28) o n the basis of the

144

>I.

CURCUMELLI-RODOSTAMO A N D

MARSHALL KULKA

products obtained by its reductive cleavage (29). Treatment of thalisopine with sodium in liquid ammonia afforded armepavine (111) and ( + ) - 1- (4'-methoxybenzyl)- 2 -methyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (XXXIII). Attention should be drawn to the fact that the formation of these two products is consistent not only with the proposed constitution LIII but also with formula LIV.

G. THALICARPINE AND THALNELATINE Thalicarpine (LX), C41H4gOgN2 (mp 160"-161") was first isolated from Thalictruin dasycarpum Fisclz. and Lall. (30).Later it was obtained from Thalictrurn minus L. var. elatum Jacq. (31) and from Hernandia ovigera (Auth.?)( 3 2 ) . Analysis showed the presence in the molecule of seven methoxyl groups

LIX

L X ; R=,Me LSI: R = H LSII: K = E t

and two methylimino groups. The "MR-spectrum of the alkaloid indicated the presence of six S-methyl protons, twenty-one 0-methyl protons, fourteen aliphatic protons, and seven aromatic protons (33, 34). Characterization of the products obtained by reductive cleavage of

4. B I S B E X Z Y L I S O Q U I N O L I S E A N D

RELATED ALKALOIDS

145

thalicarpine limited the plausible structures for the base to six. Sodium in liquid ammonia reduction of the alkaloid afforded ( - )-6’-hydroxylaudanosine (XLII) and ( + )-3,&dimethoxyaporphine (LV). The Sconfiguration of the aporphine product was well established but whether ( - )-6‘-hydroxylaudanosine (XLII)has the R- or S-configuration was not known a t the time. The above results, coupled with the established fact that the aporphines are stripped of methoxyl substituents situated a t C-2 and C-5 when submitted to the sodium-ammonia reaction, indicated that thalicarpine is expressed by one of the formulas LVIII, LIX, LX of SS- or RS-configuration. Compound RX-LVIII was synthesized by the Ullmann condensation of ( - )-6’-bromolaudanosine (XL) with isocorydine (LVI) and was reported to be identical with thalicarpine. However, scrutiny of the spectral properties of thalicarpine showed that they are incompatible with structure RX-LVIII (32).For example, there is no AB quartet in the aromatic proton region of the NMR-spectrum of the alkaloid as would be expected of the neighboring aromatic protons in structure RX-LVIII. Accordingly the condensation of compounds XL and LVI was reexamined and, as expected, the earlier result was not reproduced. The structure of thalicarpine SS-LX was finally established by synthesis. The alkaloid was obtained by the Ullmann reaction of S-(+ )6’-bromolaudanosine (XL) and X-N-methylaurotetanine (LVII). An interesting corollary of the foregoing discussion is that ( - )-6’hydroxylaudanosine (XLII), unlike the common levorotatory cleavage products I-IV, has the S-configuration. Thalicarpine was found to have hypotensive activity of a transient nature accompanied by respiratory toxicity and weak adrenolinic activity (30). Thelmelatine (LXI), C40H4608N2 (mp 131°-1350) was isolated from Thulictrzcm wiinzcs L. var. elatum Jacq. (31). The alkaloid was found to contain six methoxyl groups and one hydroxyl group. When treated with diazomethane it was converted to thalicarpine (LX). Thus it was proved that thalmelatine is formally derived from thalicarpiiie by replacement of a methoxyl group by a hydroxyl group. The position of the hydroxyl group in thalmelatine was determined through the following experiments (31, 35). The alkaloid was converted to 0-ethylthalmclatine (LXII) arid this was submitted to sodiumammonia cleavage. One of the two products obtained was (+)-3,6dimethoxyaporphine (LV). The other was found to differ from the bknzylisoquinoliiie derivative XLII obtained by reductive cleavage of thalicarpine. Thus it was concluded that the hydroxyl group is located

146

hI. CURCUMELLI-RODOSTAMO A N D MARSHALL KULKA

in the benzylisoquinoline moiety of the thalmelatine molecule. The exact position of the hydroxyl group was established through the permaiiganate oxidation of 0-ethylthalmelatine (LXII) and the identification of the oxidation product as l-oxo-2-methyl-6-methoxy-7-ethoxy1,2,3,4-tetrahydroisoquinoline. Upon completion of this work formula RS-LVIII was believed to represent the structure of thalicarpine, and an erroneous structure was accordingly assigned to thalmelatine (31). This was later revised to structure SS-LXI (32).

H. LIENSININE,ISOLIENSININE, AND NEFERINE Liensinine (LXIII), a phenolic alkaloid of molecular formula

C ~ ~ H ~ Z (mp O ~ 95’-99’), NZ was isolated from the drug “Lien Tze Hsin” [embryo of Nelumbiuin speciosum Willd. (Nelumbo nucifera Gaertn.)] of continental China (36) and from the embryo of Japanese lotus (37).

OMe

LSX : 1< = M e 1,SSI: R=Et

Liensinine was found to contain two methylimino groups, three methoxyl groups, and two hydroxyl groups (36).The st,ructure assigned t o the alkaloid was established by degradation and confirmed by synthesis. The methobromide of 0,O-dimethylliensinine (LXIV) was converted by two successive Hofmann degradations to a nitrogen-free compound (LXIX)which was subjected to permanganate oxidation and ozonolysis.

4.

I3ISUEIYZYLISOQCINOLINE A N D RELATED d L K . I L O I D S

147

The products obtained were p-methoxybenzoic acid and p-methoxybenzaldehyde, respectively. An analogous reaction sequence starting from 0,O-diethylliensinine (LXV) led to p-ethoxybenzoic acid and p-ethoxybeiizaldehyde (38). X second degradative approach was more informative, for the products obtained accounted for all thirty-seven carbon atoms of the alkaloid. Permanganate oxidation of 0,O-dimethylliensinine (LXIV) afforded p-methoxybenzoic acid, 1-oxo-2-methyl-6,7-dimethoxy-1,:‘,3,4-tetraliydroisoquinoline, and a compound (0-methylliensinic acid) which was found to have structure LXX, mainly by degradation to 4,5,5‘-tricarboxy-2,:”-dimethoxydiphenyl ether. Similarly the permanganate oxidation of 0,O-diethylliensinine (LXV) yielded p-ethoxybenzoic acid and the acid L X X I (0-ethylliensinic acid). The above data revealed the constitution of the alkaloid to be as indicated in formula LXIII. The stereochemical problem was solved by application of the reductive cleavage reaction. Treatment of 0,O-dimethylliensinine (LXIV) with sodium in liquid ammonia afforded ( - )-0-methylarmepavine (I) and the ( - )-N,O-dimethylcocIaurine IV. Accordingly (Section I), liensinine was assigned the RR-configuration as shown in the formula (39). The alkaloid was synthesized by the Ullmann condensation of L ( 3 ’ bromo - 4‘- benzyloxybenzyl) - 2 -methyl - 6,7- dimethoxy - 1,2,3,4-tetrahydroisoquinoline (XXXIV) and 1-(4’-benzyloxybenzyl)-2-methyl-6methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline( I X ) followed by removal of the benzyl groups ( 4 0 ) . Isoliensinine (LXVI), a colorless oily base, was first isolated from Formosan “Lien Tze Hsin ” [embryo of h’elumbiurn speciosum Willd. (A7eZurnbonucifera Gaertn.)] ( 4 1 , 4 2 ) Later . it was found in the same drug of the Hong Kong market ( 4 3 ) . Formula C ~ ~ H ~ ~was O ~assigned I S Z to the alkaloid through elemental analysis of the crystalline hydrochloride and perchlorate. The NMRspectrum of isoliensinine showed the presence of two methylimino groups, three methoxyl groups, and two hydroxyl groups (41, 4 2 ) . The alkaloid was converted to 0,O-dimethylisoliensinine and 0,0diethylisoliensinine on treatment with diazomethane and diazoethane, respectively. The former compound was found to be identical with 0 , O dimethylliensinine (LXIV).I n order to establish the position of the two hydroxyl groups in isoliensinine the diethyl derivative (LXVII) was bisected by means of the sodium-ammonia reaction. The products obtained were ( - ) - 1-(4‘- methoxybenzyl) - 2 -methyl - 6 - methoxy - 7 hydroxy- 1,2,3,4-tetrahydroisoquinoline (IP) and ( - )-O,O-diethylS~methylcoclaurine(r). The structure of isoliensinine is therefore represented by formula LXVI.

148

31. CURCUMELLI-RODOST 4310 AND ItIARSHALL KULK-4

Recently a new alkaloid, neferine (LXT’IIT), was isolated from Lien Tze Hsin”, of the Hoiig Kong market (43 ) and from the embryo of Japanese lotus (37). n’eferine, C38H4406K2. was converted to O-methylneferine which was found to be identical with 0,O-diniethylliensinine (LX1LT).When Oethylneferine was subjected to the cleavage reaction by sodium in liquid ammonia, ( - )- 1-(4’-methoxybenzyl)-d-methyl-fi-methoxy-7-hydrox~1,2,3,4-tetrahydroisoquinoline( I V ) , and ( - )-O-ethylarmepavine (PII) were obtained. By reason of these findings structure 1,XYIII was assigned to the alkaloid (43). “

111. Alkaloids Containing Two Diphenyl Ether Linkages

A.

OXYACANTRINE

( 2 13, 447) A N D O - & f E T H Y L O X Y A C A N T H I N E ( OBABERINE)

Two additional sources for oxyacanthine (LXXII) have been found : the alkaloid was isolated from Berberis tschonoskyana Regel (44) and from Magnolia compressa Maxim. (MichPlia comnpressa Maxim.) (45). Oxyacanthine (LXXII) was assigned the SR-configuration by means of available data on the reductive cleavage of O-methyloxyacanthine (LXXIII) (Section I) (9). Obaberine (SR-LXXIII) (mp 139°-1400) was isolated together with obamegine and oxyacanthine from Berberis tschonoskyana (44). Various reactions of obaberine, such as the Hofmann degradation and reductive cleavage, suggested that it is identical with O-methyloxyacanthine (LXXIII) ( 4 6 ) . The identity was confirmed when, in the course of this work, O-methyloxyacanthine was obtained for the first time in crystalline form and the melting point of a mixture of the two specimens was determined.

B. DAPHNANDRINE (218, -), (221, -),

DAPHNOLINE ( 2 2 0 , 452), ,lRORIOLINE HOMOAROMOLINE

AND

The experiments leading t o constitutions LXXIV, LXXV, and LXXVI for daphnandrine, daphnoline, and aromoline, respectively, have been reviewed previously ( I , 2 ) . Correlation experiments had established conclusively that the isoquinoline-moiety hydroxyl group occupies the same position in all three alkaloids. The fact that daphnaiidrine gave a positive test with Jfillon’s reagent was takcn as evidence for placing the hydroxyl in question a t position 7 . However, this evidence is equivocal, and Bick et al. (47)sought to resolve the existilip i J n r p r + q ; n t r

4. BISBENZYLISOQUINOLINE A N D R E L A T E D ALKALOIDS

149

LXXXIII

LXSXI; R=Me LSXXII; R = H

LXXXIV; R = H LXXXV; R = M e

by a more reliable experiment. Accordingly they subjected O-ethyldaphnandrine to cleavage with potassium in liquid ammonia and isolated a phenolic product which was identified as the dextrorotatory isomer of compound VI. Thus the formulas previously advanced for the alkaloids were rigorously established. The conversion of the three alkaloids to 0-methyloxyacanthine (LXXIII) ( 1 )showed that they have the SR-configuration ( 9 ) . A new alkaloid, homoaromoline (LXXVII), was isolated with aromoline (LXXVI) from Thalictrum thunbergii (Auth. 2 ) (T.thunbergii DC.) (48). The aromoline obtained from this source was a t first not recognized as such but was thought to be a new alkaloid (thalicrine). Treatment of aromoline (LXXVI) for two days with diazomethane gave homoaromoline. Of the three possible methylaromolines two, oxyacanthine (LXXII) and obaberine (LXXIII), are known. Homoaromoline, then, must be assigned the remaining structure LXXVII (48-51).

150

M.

CURCUMELLI-RODOSTAMO A N D

MARSHALL KULKA

C. REPANDINE (217, 451), EPISTEPHANINE ( 2 2 2 , 453), HYPOEPISTEPHANINE ( 2 2 3 , 453)

AND

The structures of repandine, epistephanine, and hypoepistephanine are SS-LXXII, LXXXI, and LXXXII, respectively. The constitutions and relative stereochemistry of the three alkaloids were elucidated by investigations reviewed previously ( 1 , 2 ) . Their absolute configuration was elucidated in 1962 (9) (Section I). Epistephanine and hypoepistephanine belong to the few bisbenzylisoquinoline alkaloids containing a carbon-nitrogen double bond. The reduction of this bond in epistephanine with zinc-sulfuric acid and in epistephanine dimethiodide with zinc-sulfuric acid and with sodium borohydride has been discussed previously ( 2 ) . In this section the reduction of hypoepistephanine (LXXXII) with both reagents and of epistephanine (LXXXI) with sodium borohydride will be briefly considered. Reduction of hypoepistephanine (LXXXII) with zinc-sulfuric acid was found t o be stereoselective ( 5 2 ) . The SR-LXXVIII stereoisomer, which was found to have the designated structure by methylation to oxyacanthine (LXXII), was obtained in higher yield. Reduction with sodium borohydride, on the other hand, involved stereospecific addition of hydrogen. The dihydrohypoepistephanine (LXXVIII)formed had the RR-configuration, as shown by its methylation to the antipode of repandine (LXXII). Reduction of epistephanine with sodium borohydride was also found to be stereospecific. The dihydroepistephanine (LXXIX) formed was converted by methylation to the antipode of O-methylrepandine and was thereby shown t,o have the RR-configuration.

D. CEPHARANTHINE( 2 2 3 , 456) The constitution of cepharanthine (LXXXIII) was established in 1956 through work reviewed previously ( 1 , Z ) . In this section an account is given of the experiments which led to the stereochemistry of the alkaloid. One of the earlier experiments showed that the sodium-ammonia cleavage of cepharanthine (LXXXIII) gave ( + )-1-(4’-hydroxybenzyl)2-methyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (LXXXIV) and ( - ) - 1 - (4’-methoxybenzyl)- 2 -methyl - 6 -methoxy - 7 - hydroxy- 1,2,3,4tetrahydroisoquinoline (IV). Since the absolute configuration of the latter compound was shown to be R, Tomita and Kunitomo were able to

4. BISBENZYLISOQUINOLINE

A N D R E L A T E D ALKALOIDS

151

assign the same configuration to the asymmetric center C-1' in cepharanthine (9). The absolute configuration of the other cleavage product was established by Kunitomo (53). This investigator converted S-( + )-methylarmepavine (I) through three steps without inversion (I + XI1 + XI11 -> LXXXV) to compound LXXXV, which was also obtained by methylation of the cleavage product LXXXIV. This experiment clearly showed that the dextrorotatory cleavage product LXXXIV has the Sconfiguration and therefore cepharanthine is represented by LXXXIII.

E. SEPEERINE, OCOTINE,AND RODIASINE Sepeerine ( L x x x ) (C36H38N206 * 3H20) (mp 197"-199") was obtained with ocotine and rodiasine from Nectandra rodioei Hook. (54, 55). The structure of the alkaloid (LXXX)was elucidated by Grundon and McGarvey and shown to be related to oxyacanthine (55,56).Methylation and acetylation of sepeerine showed that it contains three methoxyl groups, one methylimino group, one phenolic hydroxyl group, and one secondary amino group. The alkaloid was converted to N,O-dimethylsepeerine dimethiodide, which was found to be identical with the dimethiodide of N,O-dimethyldaphnandrine (LXXIII) (O-methyloxyacanthine dimethiodide). The hydroxyl group was located by conversion of O-ethyl-N-methylsepeerine dimethiodide through the Hofmann reaction to a methine base and oxidation of the latter with permanganate to 2-ethoxy-5,4'-dicarboxydiphenylether (XX). At this stage the experimental facts had revealed that sepeerine is de-N-methyloxyacanthine. Determination of the position of the secondary amino group in the molecule was accomplished by means of the reductive cleavage of Nacetyl-0-methylsepeerine. The reaction afforded two phenolic products ; one of these was basic and identified as ( +)-armepavine (111).Sepeerine is accordingly regarded as SR-LXXX. The structures of ocotine and rodiasine are not yet known. Octine (mp 162"-164"), to which formula C35H3806N2 was tentativeIy assigned, was found t o contain four methoxyl groups and one methylimino group (55). Rodiasine (mp 195")was first isolated as the dimethiodide from Ocotea rodiei ( 5 7 ) . The elemental analysis of this alkaloid did not distinguish between C38H44N206 and C36H40N206. The alkaloid was found to contain two methylimino groups, four methoxyl groups, and a phenolic hydroxyl group (55).

152

M. CURCUMELLI-RODOSTAMO A N D MARSHALL K U L K A

F. THALMINE

Thalmine (LXXXVI) (mp 253”) was isolated from Thalictrum minus L. in 1950 (58). The results of a structural investigation of the alkaloid were announced recently (59). The sodium-ammonia reduction of thalmine yielded 1 - (4’- methoxybenzyl) - 2 - methyl - 6 - methoxy - 1,2,3,4 - tetrahydroiso quinoline(XXXIII).Reductivecleavageof 0-ethylthalmine (LXXXVII) afforded 1 - (4’-hydroxybenzyl)-2-methyl-6-ethoxy - 7 - methoxy - 1,2,3,4tetrahydroisoquinoline (VIII) and 1-(4’-methoxybenzy1)-2-methyl-Bmethoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline (IV). On the basis of these results formula LXXXVI was proposed for the alkaloid.

G.

(215,448) A N D 0-METHYLBERBAMINE (ISOTETRANDRINE) (2 15, 449)

BERBAMINE

Berbamine (LXXXVIII) and 0-methylberbamine (isotetrandrine) (LXXXIX)have been isolated from the following new sources : Mahonia lomariifolia Takeda, M . morrisonensis Takeda (60),M . philippinensis ( ‘2 ) (61), Berberis morrisonensis Hayata ( 6 2 ) , B. kawakamii Hayata (63), B. mingetsensis Hayata ( 6 4 ) ,Atherosperma moschatum Labill. (65),and Pycnarrhena manillensis Vidal (66). After Tomita and his collaborators announced their work on the reductive cleavage of 0-methylberbamine (LXXXIX)in 1951,formula LXXXVIII was considered representative of the berbamine molecule. However, it was not till 1956 that the position of the hydroxyl group was rigorously established (65).0-Ethylberbamine (XC) was submitted to

LXXXVI ; H.= H LXXXVII; R = Et

4.

BISBENZYLISOQUINOLINE A N D RELATED ALKALOIDS

153

the sodium-ammonia fission reaction and afforded ( - )-O-ethylarmepavine (VII) and ( + )-N-methylcoclaurine (11). Thus the earlier structural assignment was confirmed. Characterization of the two cleavage products of O-methylberbamine led to structures RX-LXXXIX and RS-LXXXVIII for this compound and berbamine, respectively (9) (Section I).

H. TETRANDRINE (216, 449)

A new source for this alkaloid is the species Cyclea peltata Miers (C. bu.rmanni) (6'7, 68). Tetrandrine had been shown to be a diastereoisomer of O-methylberbamine (LXXXIX)through the sodium-ammonia cleavage reaction. Later, by means of the same reaction, the absolute configuration of the molecule was determined and structure SS-LXXXIX assigned to the alkaloid (9) (Section I). A synthesis of tetrandrine, announced by Tomita and his co-workers (69),started from the coclaurine derivative 8-11(a product obtained by cleavage of O-methylberbamine). Ullmann condensation of the phenol 8-11with the bromo compound XCV, obtained from the former compound through the steps of bromination and methylation, furnished tetrandrine.

I. FANGCHINOLINE (219, -) About twenty-five years ago an investigation of the Chinese drug Han-Fang-Chi " led to the discovery of the alkaloid fangchinoline (XCI). Degradation experiments had then shown that fangchinoline is formally derived from tetrandrine by substitution of an isoquinolinemoiety methoxyl group by a hydroxyl group. The elucidation of the structure of the alkaloid was completed in 1958. Hsing and Chang (70) observed that fangchinoline gives a negative Millon's reaction, and this fact suggested that the hydroxyl group occupies position 6 or 6'. Yet when they submitted O-ethylfangchinoline (XCII) to sodium-ammonia cleavage, ( + ) - N - methylcoclaurine (11) and compound X were obtained. This experiment showed conclusively that the hydroxyl group is attached to C-7 as in formula XCI. It follows from the structural relation of fangchinoline to tetrandrine that the former also has the SS-configuration ( 9 ) . "

'

154

M. CURCUMELLI-RODOSTAMO AND MARSHALL KULKA

XCV

SCVIII;K=H XCIX; H = OMe

X C V I ; R1= OMe, Rz = H

C

XCVII; R1=H, Rz=OMe

J. OBAMEGINE (STEPHOLINE) Obamegine (XCIII), C36&@&2* 1iCGH6 (mp 171"-173"), is a new berbamine-type alkaloid isolated from Berberis tschonoskyana Regel ( 4 4 ) and later from Stephania japonica Miers ( 7 1 ) . The information obtained about the functional groups of obamegine is Methylindicated in the formula C32H24(OCH3)2(OH)z(-O-)2(NCH3)2. ation of the alkaloid gave 0,O-dimethylobamegine which was found to be identical with 0-methylberbamine (isotetrandrine) (LXXXIX). The problem of establishing the position of the two hydroxyl groups in the alkaloid was solved through the reductive cleavage of 0,O-diethylobamegine (XCIV). The reaction gave ( - )-N-methyl-0,O-diethylcoclaurine (V) and ( +)-N-methylcoclaurine (11)and it was thus concluded that obamegine has structure RS-XCIII ( 7 2 ) . The base isolated from Stephaniajaponica Miers was named stepholine as it was first thought to differ from obamegine. An erroneous identification of the products obtained by reductive cleavage of 0,O-diethylstepholine led to the proposal of a wrong structure for the alkaloid ( 7 1 ) . Recently, however, the cleavage products were reexamined and were shown t o be identical with those obtained from 0,O-diethylobamegine ; furthermore, a comparison of the properties of stepholine and obamegine clearly showed their identity (73).

4. BISBENZYLISOQUINOLLNE

A N D R E L A T E D ALKALOIDS

155

K. HERNANDEZINE AND THALSIMINE Hernandezine (XCVI) (mp 19Z0-193", when recrystallized from hexane) occurs in Thalictrum hernandezii Tausch ( 7 4 ) , Th. fendleri (Auth.?),and Th. rochebrunianum Franch. and Sav. (75). A preliminary structural investigation of hernandezine was reported by Padilla and Herran ( 7 4 ) . The alkaloid was assigned formula C39H4407N~and was found to contain five methoxyl groups and two methylimino groups. Oxidation of hernandezine with permanganate furnished 2-methoxy-4',5-dicarboxydiphenylether (XVIII). Information regarding the substituents of the two tetrahydroisoquinoline groupings was obtained by NMR-spectroscopy. The methoxyl-group region of the NMR-spectrum of hernandezine shows peaks at 6.09, 6.17, 6.21, 6.66, and 6.76 7.I n keeping with the work of Bick et al. ( 4 )(Section I),the first peak was correlated with the C-12 methoxyl group, one of the next two peaks and those a t 6.66 and 6.76 were attributed to methoxyl groups situqted a t C-6, C-6', and C-7, respectively. The remaining peak (at 6.21 or 6.17 r )was considered to arise from a methoxyl group attached to C-S', as in formula XCVII. The sodium-ammonia cleavage of hernandezine wasnot turned to account in this investigation; it was reported to furnish a phenolic product (mp 138"-139") which was subjected to elemental analysis but not characterized further. Shamma and his collaborators pointed out (75)that on the basis of the recorded melting-point and analytical figures this cfeavage product may well be AT-methylcoclaurine(11);if so, formula XCVII should be replaced by XCVI. A study of the mass spectrum of hernandezine provided fresh evidence in favor of formula XCVI, for the presence of a peak a t m/e 461, suggesting the loss of a neutral grouping of mass 191 from the molecular ion, is readily explicable only in terms of this formula. The constitution of hernandezirie was conclusively established as XCVI by reexamination of the sodium in liquid ammonia cleavage of the alkaloid, and isolation of a nonphenolic product which was shown to be the trimethoxybenzylisoquinoline XCVIII. Evidently the methoxyl group at C-6 was eliminated during the reaction. I n line with this result, sodium in liquid ammonia cleavage of 0-methylthalifendlerine (XCIX) was found to yield the same trimethoxy base XCVTII. Thalsimine (mp 14Oo-l42'), an alkaloid of Thalictrum simplex L. (76), was shown to have constitution C by the following experiments. Sodium borohydride reduction of the alkaloid (C)t o dihydrothalsimine, followed successively by methylation and two Hofmann degradations, gave a nitrogen-free substance which was found to be identical with the

156

RI. CURCUMELLI-RODOSTAMO A N D MARSHALL KULKA

corresponding compound derived from hernandezine. The position of the carbon-nitrogen double bond in the molecule was established through the sodium-ammonia reduction of thalsimine or dihydrothalsimine. CIeavage of both compounds furnished coclaurine. Gpon completion of this work an erroneous formula was assigned to thalsimine (77, 7 8 ) ,but this was later revised to formula C ( 7 5 ) .

L. ATHEROSPERMOLINE This alkaloid, C35H3606N2.CHC13 (mp 183"-1XX0), was recently isolated from the leaves of the Tasmanian sassafras Atherosperma moschatum Labill. (79). The elucidation of the structure of atherospermolirie (CI) was based mainly on evidence obtained from its &AIR-spectrum and ORD-curve.

H

H

N

\

:/

F

g

e

M

e

/N

W

\

OH

OR

(/ M

\

(211.; R = H C V ; R = Me CVI; R=Et

CI

CII; R=Me CIII: R = H

C'VIII; R1= CHtCHZXMez, Rz = C H O C I S ; Rl=CH:CHz, R z = C H O C X ; R1=Et, Rz=CHO C X I ; R r = E t , K*=;Mc

CVII

e

Elemental and functional group analysis showed the presence in the molecule of one metliylimiiio group. one secondary amino group, two methoxyl groups. and tn-o liydroxyl groups. The methylimino-group resonance a t 7 . 3 8 T is consistent only with a structure of the berbamine or oxyacanthine type (1).Tlie structural possibilities were further limited through an examination of the ORD-curve of atherospermoline. The shape of tlie curve indicated t h a t tlie alkaloid has either a berbamine-type structure 1% itli the XS-configuration or an oxyacanthine-type structure of SR-configuration. The use of NMK-spectroscopy made possible a choice between the two alternatives, and furthermore located the two hydroxyl groups in tlie molecule. Tlie peaks a t 6.24 and 6.70 in the NJIR-spectrum of atherospermoline were assigned t o the 6 and 6’-methoxyl groups, respectively. Positions 7 and 12 were thus inferred t o be occupied by hydroxyl groups. The high chemical shift (6.70 T ) of t h e (i’-methoxyl group showed t h a t the two asymmetric centers in atherospermoline have the same configuration. a condition met only by the berbamine-type structure. The remaining problem of locating the secondary amino group was considered next. Tlie chemical shift of the 2 - and 2’-methyl-group protons in alkaloids of the berbamine type is in the vicinity of 7.7 and 7.4 T , respectively. Thus the presence of the single methylimiiio-group absorption at 7.38 T provided evidence for structure CI.

31. TEXUIPINE(-,

460) AND NORTEXUIPIXE (-,

460)

Early work led t o the conclusion t h a t tenuipine (CII) contains three methoxyl groups, two methylimino groups. aiid one methylenedioxy group ; nortenuipine was erroneously believed to be de-K-methyltenuipine. Subsequent study of tlie NXR-spectra of tenuipine and riortenuipine (1)resulted in the proposal of formulas C I I and CIII for the two alkaloids, respectiwly. This study was supplemented later by degradation (80). The ”JR-spectrum of tenuipine (CII) was found to have methoxylgroup peaks at 6.25, 6.65. and 6.82 T , a pair of methylimino-group peaks a t 7.40 and i . 6 5 T . and a peak a t 4.02 T which was attributed t o the methylenc~dioxy group. The three methoxy-group resonances were assigned t o positions 6.6’, and 7 , respectively. The position of the two metliylimiiio peaks indicated t h a t tlie alkaloid is of tlie berbamine type, and the high chemical shift of tlie 6’-methoxyl group suggested t h a t the two asymmetric centers have the same configuration. The position of the methylcnedioxy group was rigorously established by the degradation of tenuipine t o ~,.3-metliyleiiediox~~-.l-’,S-diform~ldipheri~l ether (repaiidulinal). Tenuipine n as thus assigned formula CII.

A study of the K’RIR-spectrum of nortenuipine (CIII)resulted in the rejection of the earlier views on its structure. The peaks at 7.37 and 7.68 T clearly showed the presence of two methylimino groups in the molecule. The peaks at 6.22 and 6.67 T were assigned to the 6 and 6’-methoxylgroups and thus position 7 was shown to carry a hydroxyl group. N. THALICBERINE AND O-METHYLTHALICBERIXE

Thalicberine CIV (mp 161’) and its methylation product O-methylthalicberine CV (mp 186”-187’) were isolated from the leaves of Thnlictrum thunbergii (Auth.?)( T .thunbergii DC.) (81).The latter alkaloid was also obtained from the commercial drug “Takatogusa” (81) and from Thalictrum minus L. (58, 59). The functional groups of thalicberine and O-methylthalicberine are indicated by their respective formulas C3zH2402(0CH3)3(0H)(NCH3)2and C ~ Z H ~ ~ O Z ( ~ C H ~ ) ~ ( N C H ~ ) ~ . The structure of the diphenyl ether moiety of O-methylthalicberine was determined by degradation. O-Nethylthalicberine dimethochloride was converted through the Hofmann elimination reaction to a methine base (CVII) which was oxidized with permanganate to an acid identified as 2-methoxy-5,4’-dicarboxydiphenyl ether (XVIII) (81). The assignment of a tentative structure to the two alkaloids was made possible through the application of the reductive cleavage reaction. Sodium-ammonia cleavage of O-methylthalicberine (CV) afforded ( + )methylarmepavine (I)and ( + )-N-methylisococlaurine (XI).Cleavage of O-ethylthalicberine (CVI) gave ( + )-ethylarmepavine (VIT) and ( + )-Amethylisococlaurine (XI). These results led to the proposal of structures XX-CIV and SX-CV for thalicberine and O-methylthalicberine. respectively (82). The assumption that the oxygen bridge between the isoquinoline groupings is attached to C-8 was based on biogenetic considerations. Obviously at this stage the structural investigation was incomplete. The selective cleavage of the oxygen bridge between the two isoquinoline units in thalicberine was studied next (83, 84), but this reaction proved of little value to the structural problem. The work which conclusively established the structure of thalicberine (SX-CIT’) and O-methylthalicberine (SS-CV) was reported in 1963 by Tomimatsu and Kano (85). Ozonolysis of the Hofmann elimination product CVII furnished, among other products, the diaminodialdehyde CVIII. Hofmann degradation of the dimethiodide of compound CVIII yielded the divinyl compound CIX, which was converted by catalytic hydrogenation to compound CX. Clemmensen reduction of the latter furnished compound CXI whose structure was established by synthesis.

4.

B I S ~ E S Z Y L I S O Q U I _ U O L I S EANI) RELATED ALKALOIDS

159

0. ISOCIIOSDRODESDRISE (224, 461), CYCLEASISE ( 2 2 7 , -k61), A N D XORCYCLEASISE Since the appearance of the previous review ( Z ) , the structural elucidation of isochondrodendrine (CXII) and cycleaiiiiie (CXIII) has been completed ; both alkaloids were found to have the RR-configuration (9) (Section I). Norcycleanine (CXIV). C37H4006N2.0.5H,O (mp 249"-251"), a new alkaloid of this group, was isolated in 1958 from Cyclea insularis Makino (867, and later from Chondrodendron tomentosum Ruiz and Pav. (87). Functional-group analysis revealed the presence in the molecule of three methoxyl groups, two methylimino groups, and one hydroxyl group. Norcycleanine was converted by methylation to cycleanine (CXIII) and was thereby shown to be formally derived from the latter alkaloid by replacement of a methoxyl group by a hydroxyl group. The position of the hydroxyl group was assumed to be 7 , for the alkaloid gave a negative test with Gibbs's reagent. This was confirmed (88)by means of the reductive cleavage of O-ethylnorcycleanine (CXV) to ( - )-armepavine (111)and ( - ) - 1-(4'- hydroxybenzyl) - 2 - methyl-6 - methoxy - 7 ethoxy-l,2,3,4-tetrahydroisoquinoline (VJ). Norcycleanine was thus assigned structure CXIV.

1'. INSULARINE ( 2 3 5 , 465) AND INSULANOLINE Insularine, an allialoid of Gyclea insularis (89),has been the subject of extensive investigations. Formula CXVI, involving a depsidan ring, was previously proposed for the alkaloid, but the stereochemical problem remained unsolved. Recent cleavage studies have shown that both asymmetric centers of insularine have the R-configuration. The alkaloid was cleaved by sodium in liquid ammonia to two crystalline phenolic bases and an amorphous phenolic base (90). One of the crystalline bases was identified as ( - )-X-methylcoclaurine (11).The other, a new levorotatory compound named liomoarmepavine, was found to have constitution XXXV by degradation (90) and by synthesis ( 9 1 ) . The amorphous product, which was presumed t o be CXIX formed through incomplete cleavage, was metliylated and the resulting dimethyl ether (CXX) subjected to a second cleavage with sodium and liquid ammonia. There was obtained ( - )-hornoarmepavine (XXXV) and ( - )-methylarmepavine (I). These results confirmed the proposed formula for insularine and were furthermore of potential value in the solution of the stereochemical problem. Elucidation of the latter (9, 92) had to await the determination of the

160

31. CURCUILIELLI-RODOSTAMO AND MARSHALL KULKA

qb /

/

0

CXII; R l = R z = H

CXIX; R = H

CXXI; R1=R2=H, R3=Me

CXIII; R l = R z = M r

CXX; R = I f ( .

C X X I I ; R1= Rs = H, Rz = Me CXXIII; R1 =Rz = R3 =Me

CXIV; R I = H , Rz=Mr CXV; R1=Et, R z = M e

MeN

CXVI; R = M e CXVII; R = H C'XVIII; R = E t

CXSIV; R = H CXXV: R = M p

absolute configuration of ( - )-N-methylcoclaurine (11)(Section I) and of the novel cleavage product ( - )-hornoarmepavine (XXXV). The configuration of ( - )-XXXV was determined as R by comparison with synthesized S-hornoarmepavine (XXXV).Thus S-( + )-armepavine (111) was submitted to the Alannich reaction with dimethylamine and formaldehyde and the resulting aminophenol (XXXVI) hydrogenated t o X-( + )-hornoarmepavine (XXXV). These results clearly show that insularine has the RR-configuration. Insulanoline (CXVII), C37H380&2. H20 (mp 195"), containing a

4. B I S B F , S ~ Y L I S O Q L ~ ~ T O L I ?Ai X ED

RELATED I L K A L O I D S

161

phenolic hydroxyl group, occurs in the rhizome of Cyclea in.su1ari.s with insularine (86). The identity of 0-methylinsulanoline with insularine (CXYI) ( 8 6 ) , coupled with the identification of two cleavage products obtained from 0-ethylinsulanoline (CXVIII) as ( - )-S-methylcoclaurine (11) and (-)-XXXYII (93) showed that the alkaloid has structure RR-CXVII.

Q. BEBEERINE ( 2 2 7 , -), CURINE (230, 462), d-CHOXDROCLJRINE( 2 3 3 , 462). A S D TCBOCURARINE (231, 162) The investigations resulting in the elucidation of the constitution of these alkaloids were reviewed previously ( I , 2). The absolute configuration of the alkaloids was determined in 1962 by comparison of their cleavage products with specimens of known absolute configuration (9) (Section I).Bebeerine and curine were found to have structures XS-CXXI and RR-CXXI, respectively. I n d-chondrocurine (CXXII) and tubocurarine (CXXIV) the configuration a t C-1 is S and R a t C-1'. A synthetic route to ( & )-0,O-dimethyltubocurarine iodide (CXXV), via the racemate of 0,O-dimethylbebeerine (CXXIII), was announced in 1959 by Tolkachev and his collaborators (94). It started by the condensation of 3-methoxy-4-hydroxyphenethylaminewith 4-benzyloxyplienylacetic acid to give the amide CXXVI. Reaction of the potassium salt of the latter with the methyl ester of 3-bromo-4-methoxyphenylacetic acid in the presence of copper powder gave compound CXXVII. This on condensation with 3-methoxy-4-hydroxy-5-bromophenethylamine afforded compound CXXVIII, which was methylated to CXXIX. The latter compound was cyclized with phosphorous oxychloride to the diliydroisoquinoline derivative CXXX. Dehenzylation of CXXX followed by intramolecular Ullmaiiii condensation yielded compound CXXXI. The latter was converted to racemic dimethylbebeerine (CXXIII) by reduction with zinc dust in acetic acid followed by methylation. Finally, treatment of ( & )-CXXIII with methyl iodide furnished the dimetliyl ether of ( )-tubocurarine iodide, identified by comparison of its UV-spectrum with that of the dimetliyl ether of natural tubocurariiie iodide and by melting-point determination of a mixture of the two specimens.

R. TILIACORISEAND TILIARINE '

Tiliacoririe (CXXXII) and tiliarine (CXXXTII)were isolated from the roots of Tiliacora racernova Colebr. (95, 96).

\/

CXXVIII: H = H CXSIX: R =Me

CXXXI

These are the only known bisbenzylisoquinoline alkaloids containing a dipheiiyl grouping. Tiliacorine is represented by formula CXXXII and tiliarine (CXXXIII) is a de-A’-methyl derivative of a stereoisomer of tiliacorine (97-100). There is no indication yet as to which of the two alternative positions is occupied by the secondary amino group. The structure of the diphenyl moiety was established hy degradation. Oxidation of the O-methyl derivatives of both alkaloids (CXXXIV and CXXXV) with perinanganate furnished 2,%’-dimethoxy-5,5’-dicarboxydiphenyl. Oxidation of the alkaloids with permanganate furnished 4-methoxyisophthalic acid. This acid must have originated from the diphenyl system through the oxidation of the pheiiyl group bearing the hydroxyl group. The position of the latter was confirmed by the permanganate oxidation of O-ethyltiliacorine (CXXXVI) and O-ethyl-X-

methyltiliarine diphenyl.

(CXXXVI) to 2-methoxy-t2'-ethoxy-5,ci'-dicarboxy-

MeSf, 1-q

M

M ' e0 \ ~

e

X

M

I-e

CXXXVII

CXXXII; R 1 = R P = M e , R 3 = H

RSH

CXXXIII; R1=H, H z = M e or vice v e r s a , R ~ = H C X X X I V ; R1= Kz= R3=Me ('XXSV;R l = H , R2=R3=Me C S X X V I ; I t l = K P = M e , X3=Et

Me0 CXXXVIII; R = H CXXXIX; R = CHO

The isoquinoline moiety of the molecules was formulated as shown for the followiiig reasons. Tiliacoriiie was found t o contain three methoxyl groups, two methylimiiio groups, and one hydroxyl group ; in tiliarine one of the methylimino groups is replaced by a secondary amino group. Both alkaloids gave a prominent blue color with a mixture of nitric and sulfuric acids, indicative of the presence of a dibenzo-p-dioxin system. Finally, the UV-spectra of the two alkaloids were found to be related to those of trilobiiie and menisarine. Evidence in support of formula CXXXII came recently from the characterization by synthesis (101) of the dimethiodide CXXXVII obtained through the oxidation of tiliacorine with manganese dioxidesulfuric acid. The synthesis of CXXXVII involved treatment of 2,7bis(l-aminoethyl)--l-,n-dimetl~oxydibenzo-p-dioxin(CXXXVIII) with formic acid to give the diformyl derivative CXXXIX and cyclization of the latter with phosphorous oxycliloride followed by quatcrnization.

IV. Alkaloids Containing Three Diphenyl Ether Linkages

A. ISOTRILOBINE ( 2 3 8 , 466) 'Isotrilobine, an alkaloid of menispxmzcczus p!zzts, had been assigned constitution CXL. Recent degradative studies have completed

the structural elucidation by slioning that hoth asymmetric centers have the S-configuration (103.103). Earlier work had shon-ii that the sodium in liquid aimnoilia cleavage of compounds containing the dibenzo-pdioxin system was unsatisfactory because it gave o-hydrosy~iplieiiyl derivatiws as ivcll as the cspected o-li~-drox~tliplieii~l ethers. Later it was found (102)that addition of sodium hytlride to the solution of sodiuni

CXLI; R1=Kz=-?Ie, R 3 = R 4 = H CXLII; R1=H, R z = M e or vice versa, R 3 = R 4 = M e C S L I I I ; R1= Et, R:! = R3= Rq= Me CXLIV: R , = E t , RZ=Me, R 3 = R 4 = H OBle

)yRR

Nhlr

CLI; Rl=Me, R z = H CLII; R i = E t . R z = M r

in liquid ammonia minimized the formation of the undesired diphenyl derivatives. Application of the sodium-sodium hydride in liquid ammonia cleavage procedure to isotrilobine (CXL) yielded (besides a small quantity of diphenyl derivative) the pheiiolic base CXLV. The latter was methylated with diazoniet haiie aiid the methyl ether CXLI'I subjected t o a second-stage fission with sodium in liquid ammonia. A11 three products that can formally arise by cleavage of the dipheiiyl ether linkage in CXLVI were actually obtained. The two phenolic cleavage

4. BISBENZYLISOQUINOLINE AND RELATED A L K A L O I D S

165

products were identified as ( + )-CXLIX and ( + )-IV.The nonphenolic product was ( + )-1-(4‘-methoxybenzyl)-2-methpl-6-methoxy-1,2,3,4tetrahydroisoquirioline (XXXIII), which was shown to have the S-configuration (104).Since this compound originates from both benzyltetrahydroisoquiiioline moieties of isotrilobine the latter must have the SS- configuration. The conversion of epistephanine (LXXXI) to the antipode of isotrilobine (105)and of 0-methylrepandine (LXXIII) to isotrilobine (106) were recently reported. 0-Methylrepandine (LXXIII)was demetliylated with liydrobromic acid to the tetrahydroxy compound CLI which, because of the proximity of the two phenolic groups, dehydrated readily to form compound CXLI. Nethylation of the latter yielded isotrilobine (CXI,). Epistephanine (LXXXI) was converted similarly to the antipode of isotrilobine.

B. TRILOBINE(238, 466) Trilobine, another alkaloid occurring in menispermaceous plants, was previously given the ambiguous formula CXLII. It can now be assigned the SS-configuration by virtue of its methylation to isotrilobine (CXL). I n order t o locate the secondary amino group, the alkaloid uas fiacetylated, and the N-acetyltrilobine was subjected to cleavage with sodium-sodium hydride and liquid ammonia (102, 107). The phenolic base CXLVII, obtained by partial cleavage, was methylated and the resulting compound (CXLVIII)was submitted to a second-stage cleavage with sodium in liquid ammonia. There was obtained 1-(4’-methoxybenzyl)-2-methyl-6-methoxy - 1,2,3,4-tetrahydroisoquinoline(XXXIII) and 1-( 4’-rnethoxybenzyl)-2-acetyl-6-methoxy-8-hydroxy1,2,3,4-tetrahydroisoquinoline (CL).These results show that trilobine is represented by CXLII (R1=H). Confirmation of this structure came when N-ethyldihydroepistephanine (CLII) was converted t o the antipode of N-ethyltrilobine (CXLIII) (108).This synthesis was achieved by hydrobromic acid demethylation of N-et,hyldihydroepistephanine (CLII), cyclization of the resulting tetrahydroxy compound to the dibenzo-p-dioxin derivative CXLIV, and methylation of the latter. C. MENISARINE(’342, -) The structure of menisarine, an alkaloid occurring in the Formosan Cocculus sarmentosus Diels, has not been completely established, but the originally proposed constitutions CLIII or CLIV have been corroborated

166

hi. CURCCMELLI-RODOSTAMO A N D MARSHALL KULKA

by synthesis of a menisarine derivative (109).The condensation of 2,7bis(2-aminoethyl)-4,9-dimethoxydibenzo-p-dioxin (CXXXVIII) with the acid chloride of 2-metl~oxy-4',5-biscarboxymethyldiphenyl ether (XVII) under high dilution yielded the diamide CLV. Cyclization of the diamide by the Bischler-Napieralski reaction, reduction of the resulting product with sodium borohydride, and finally methylation with formic acid and formaldehyde yielded the bisbenzylisoquinoline derivative CLVI. Comparison of the IR-spectrum of the latter compound with that of N-methyldihydromenisarine showed that they are identical. Furthermore, the IR- and UV-spectra of the methine base obtained from the methosulfate of CLVI by Hofmann degradation were found to be

\

/ CLIV

CLVI

identical with those of the methine base obtained from N-methyldihydromenisarine by a similar degradation. Thus it was confirmed t h a t the constitution of menisarine is either CLIII or CLIV. An alkaloid, C ~ S H ~ ~ O(mp ~ N 205°-2060), Z believed to be of the menisarine type, has been isolated along with isotrilobine from an Indian drug found in the Bombay market and said to have originated from Xtephania ~ e r n ~ n d ~?4'alp. f o ~ i(110). ~ It was found to contain one

4.

BISBENZYLISOQUINOLINE AND RELATED ALKALOIDS

167

methoxyl and two methylimino groups. A positive color reaction with sulfuric-nitric acid indicated the presence of a dibenzo-p-dioxin system. The UV-spectrum of the alkaloid is similar to that of trilobine and the hydronienisarine-type bases.

V. Trisisobutylisoquinoline Alkaloids A. PILOCEREINE (-, 469) Pilocereine, an alkaloid occurring in several giant cacti, was assigned formula CLVII in 1957. This assignment was founded on elemental analyses, molecular weight determination (Rast), and the identification of the products obtained by reductive fission of the alkaloid, O-methylpilocereine, and 0-ethylpilocereine (111). Redetermination, however, of the molecular weight of pilocereine by mass spectrometry showed formulation CLVII to be in error and indicated instead a “trimeric ” expression such as CLVIII (112).Further

-

-

MeN

I

\ OMe /

? F < ! 7 O H

-

1 OXe

0

CLIX; Rl=Rz=H C L X ; Ri=OEt, R z = H C L X I ; R1 s OEt, Rz = O H C L X I I ; R1 =O H , Rz = H CLXIII; Ri=H, R z = O H C L X I V ; R l = O M e , R2=H C L X V ; R1= OMe, Rz = OH

0

168

M. CURCUMELLI-RODOSTAMO AND MARSHALL KULKA

support for a “trimeric” formula came from a study of the NMRspectrum of pilocereine acetate. The spectrum showed the presence of one acetyl group, four aromatic hydrogens, three methoxyl, three methylimino, and three isobutyl groups. The data could be explained by several “ trimeric ” alternatives and a choice between them was made as follows: Constitution CLVIII was selected on the basis of the results obtained by repetition of the potassium in liquid ammonia cleavage of O-ethylpilocereine. A careful search for products revealed that the reaction yielded, besides compounds CLIX, CLX, CLXI, and CLXII identified previously, the cryptophenolic base CLXIII. Formation of this is compatible only with formula CLVIII. The base “isopilocereine,” obtained in small yield by the potassiumammonia cleavage of pilocereine (I11) and O-methylpilocereine (113), was shown by degradation and synthesis to have the “dimeric” formula CLVII (If4-1 19) assigned previously to pilocereine. The one-electron oxidative coupling of phenols, which had been applied to quaternary salts of coclaurine-type bases (12, 13), offered a synthetic route to pilocereine. Thus the bromobenzylate of lophocerine (CLXII) was oxidized in aqueous solution a t 20” with three equivalents of ferric chloride to the quaternary salts of CLVIII and CLVII. These were obtained in approximately equal yields totaling 79 yo.Debenzylation with hydrogen and palladium catalyst yielded pilocereine (CLVIII) and “ isopilocereine ” (CLVII) (120). Oxidation of lophocerine methiodide with three equivalents of potassium ferricyanide furnished pilocereine trimethiodide while the use of two equivalents of oxidant resulted in the formation of “isopilocereine ” dimethiodide (12, 120-122). B. PILOCEREDINE The alkaloid piloceredine (CLVIII) (mp 165”-166”) was isolated as a racemate from the cactus Lophocereus schottii Britton and Rose; it was shown to be diastereoisomeric with its companion alkaloid, pilocereine (CLVIII),by the experimental results given below (112,123).Potassiumammonia cleavage of O-methylpiloceredine yielded compounds CLIX, CLXIV, and CLXV, which were also obtained by reductive cleavage of O-methylpilocereine. The identification of 1-isobutyl-2-methyl-6-methoxy-7-ethoxy-l,2,3,4-tetrahydroisoquinoline (CLX) as one of the products obtained by reductive fission of O-ethylpiloceredine located the hydroxyl group. The IR-spectra of piloceredine and pilocereine were found to be identical when measured in chloroform but differed considerably when determined in liquid petrolatum mull. The X-ray

4.

BISBEN~YLISOQUINOLINE

AND RELATED ALKALOIDS

169

diffraction patterns were also different. The fact that the two alkaloids exhibit a marked depression in melting point when mixed and that the melting points of their acetates differ showed that they are not just polymorphic.

VI. Melanthioidine (A Bisphenethylisoquinoline Alkaloid) Melanthioidine (CLXVI) was isolated from Androcymbium melanthioides WilId. (124) with androcymbine, an alkaloid containing the 1-phenethylisoquinoline system. High-resolution mass spectrometry established the molecular formula of melanthioidine as C ~ ~ H ~ Z (125). N Z OThe ~ presence of two phenolic hydroxyl groups was shown by IR- and UV-spectroscopy and by conversion of the alkaloid to an 0,O-diacetateand an 0,O-dimethyl derivative. The NMR-spectrum of melanthioidine revealed the presence of two methylimino groups (singlet at 7.56 T), two methoxyl groups (singlet at 6.21 T), ten aromatic protons (peaks in the region 3.1-3.5 T), and eighteen non-aromatic protons (unresolved peaks in the region 6-9 T).

A

C’LSVI ; K = H CLSVII; R = M e

CLS\’lII

The KMR-spectrum was found to be similar to that of l-phenethylisoquinolines. This fact, together with its simplicity and the foregoing information about the functional groups, suggested that the alkaloid has a symmetrical bisphenethylisoquinoline structure. The sodium-ammonia cleavage of 0,O-dimethylmelanthioidine (CLXVII) afforded almost exclusively one phenolic compound shown by mass spectromet’ry and synthesis to have Lhe constitution CLXVIII ; the configuration was inferred from the ORD-curve of the base.

170

M . CURCUMELLI-RODOSTAMO A N D MARSHALL KULKA

The aforementioned results led to the proposal of structure CLXVII for 0,O-dimethylmelanthioidine. The ether linkages were attached to rings C and C' as shown on biogenetic grounds. The problem of locating the hydroxyl groups in melanthioidine (CLXVI) was solved by a study of the mass spectrum of the alkaloid. Of significance to this problem is the presence of a peak at m/e 485. This was attributed to loss of CsH902 from the molecular ion through cleavage at a and b (or a' and b') with hydrogen transfer. The composition of the fragment showed that it carried two hydroxyl groups, one necessarily being the hydroxyl present in the alkaloid. Thus the structure of melanthioidine is represented by CLXVI.

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(1962). 113. K. Urssho. (“/tcrr!.~ ~ P h c t r 7 ~ i , B(tTt lo/k. y o )11, 1504 (1963); C‘hr/n.=Ihsfr. 60, 9323 (1964) 114. 31. Tornita, T. liiliuc.hi, I<. BPssho, and T.Inuhushi, Cheni. 6.Phurm. Bull. ( T o k y o ) 11, 1 4 i i (lO(i3); C h w z . d b s t r . 60, 9330 (196.2).

174

31. CURCUJIELLI-RO UOSTA 310 AN I1 JI.1RSHALL K CLKA

115. XI. Tornita, T. Kikuchi, K. Brssho, T. Hori, and 1 '. Inubushi, C'hem. & l'hmm. Bull. ( T o k y o ) 11, 1481 (1963); (.'hem. J b s t r . 60, 9321 (1964). 116. K . Llessho, C ' J ~ P I ~&. Phrtrm. Bull. ( T o k y o ) 11, 1491 (1963); C'hon. dhstr. 60, 9322 (1964). 117. K. Llrssho, C ' h e m d: Phnr7n. Bull. ( T o k y o ) 11, 1495 (1963); L'hem. dbstr. 60, 9322 (1964). 118. K. Bessho, C'hem. d: Phctrm. Bull. ( T o k y o ) 11, 1500 (1963); C'lteni. Abstr. 60, 9323 (1964). 119. K. Ressho, C h o n . CC. Phorm. BuZl. ( T o k y o ) 11, 1507 (1963); C h e m . Ahstr. 60, 9323 (1964). 120. B. Franck, G. Ulaschke, and K. Lemejohann, Ann. Chem.685, 207 (196.5). 121. 13. Francli and G. Blaschke, Tetrahedron Letters p. 569 (1963). 122. J. &I. Bobbitt, K . Ebermann, a n d 31. Schubcrt, Tetrcthedroii Letters p. 575 (1963). 123. C. Djersssi, T. Sakano, and J. 31. Bobbitt, Tetmhedro?t2, 58 (1938). 124. J. Hrbeli and F. Santavf, Collection Czech. Chern. C ' o m m u ~27, . 255 (1962). 125. A. R.. Battrrsby, R. B. Herbert, a n d F. santavy, Ghem. Commun. p. 415 (1965).

-CHAPTER

5-

LUPINE ALKALOIDS* FERDINAND BOHLMANN A N D DIETERSCHCMANN Organisch-C'hemisches Institut der Technischeri Cnicersitut, B e r h , C e r m o i y

I. Occurrence .. .. .. .. . . .. . . .. .. .. .. .. .. ..

1i G

. . . .. . . .. .. . . . . .. .. . . . . .. . . . . . . . . . . .. . . 11. General Properties. . . . . . . A. Spectroscopic Properties. . . . . . . . . . . . . . B. Absolute Configuration of the Quinolizidine Bases. . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . .. .. . . .. . . .. . . . . .. C. Biogenesis . . . .

176 176 178 181

111. Bicyclic Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

184 184 187 ...

B.. --. Lusit'anine . . . . . . . ........... .. . . ............. . .. ... ......... .. .. .. .. ......... . . . . . . . .

I

I V. Tricyclic Alkaloids .................................................. A . Angustifoline .................................................... B . Dehydroalbine ......................................... C .. N-Blethylalbine . . . . . . . . . . .................................... D. Tetrahydrorhombifoline . . . ...........................

188 188 188 188 190 190 190 190 190 190

.. .. V.. Tetracyclic Tetracyclic Alkaloids Alkaloids:: Sparteine Group Group.................................. V A.. Sparteine Sparteine........................................................ .. .. .. .. .. .. .. .. .. .. .. .. .. A .. . . . . .. .. .. .. .. . . . . . . . . . . B. Diplospartyrine . . . . . . . . . . . . . . . . . . . . . . . . ......................... C. 17-Oxosparteine . . . . . . . . . . . D. 17-Oxolupanine . . . . . . . . . . . . . . . . . .................... E.. Lupanine Lupanine ....................... ......................................... E ............................ F. Alkaloids with Pyridone Nuc , Thermopsine, Baptifoline, . . .. . . .. . . . . and 13-Epibaptifoline . . . . . . ................................. G . Aphylline; Aphyllidine ....................... . . .. . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . H. Monspessulanine ................................................. ............... I. Oxoaphyllidine .............................. J. Argyrolobine . . K. Retamine. .. .. .. .. .. . . . . .. .. .. .. .. . . .. .. L. Hydroxylupanine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M. Ot.her 13-Subst.ituted Lupanine and Aphylline Derivatives. . . . N. hlultiflorine; 13-Hydroxymultiflorine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

201 201 204 206 208

VI. Tetracyclic Alkaloids: Xatrine Group. . . . . . . . A. &latrine . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . B. Sophoramine ; Sophocarpine ; Isosophoramine

208 208 212

VII. Ormosin Alkaloids.

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

References. . . . . . . . .

* Translated from the German by R. H. Manske. Supplementary to Volume 111, page 119; Volume VII, page 253. 175

191 191 191 191 194 194 195 195 196 196 196 196 197 197 199 199 200 200

200 200

213 218

176

F E R D I N A N D ROHLMANN AND D I E T E R SCHUMAKN

I. Occurrence The quiriolizidine alkaloids (lupine alkaloids) occur in the Leguminosae family. subfamily Faboideae, where they are restricted to the Sophoreae, Podalyrieae, and Genisteae tribes ( I ) . They have been previously reviewed by Leonard (2) in these volumes. The present review is complete to the end of 1965.

11. General Properties

A. SPECTROSCOPIC PROPERTIES Of particular value in structural determination of the quinolizidine alkaloids is a pair of “trans bands” in the IR-spectrum at 2700-2800

H

H

H

7.21

7.21

I*

H7.i2

6.83

1v

v

5.

LUPINE ALKALOIDS

177

cm-1. These are attributed to the CH-deformation in the trans fused quinolizidine system. Of special interest is the trans-diaxial conformation of the free electron pair on the nitrogen and the adjacent hydrogens. Here tertiary hydrogens make a greater contribution to the trans bands than do secondary hydrogens ( 3 ) . The NMR-spectra are difficult to interpret because the proton signals in general come close together. The cr-protons adjacent to the tertiary nitrogen in fixed cyclic systems have been more exhaustively studied (4-6). The positions of the signals were fixed through deuterium labeling. a-Protons oriented c i s to the electron pair in nitrogen undergo a “deshielding ” effect, whereas trans-oriented protons are “shielded, ” e.g., lupinine (I), sparteine (11), 8-isosparteine (111). Protons alpha to a lactam nitrogen have also been identified. Here the anisotropy of the lactam group has a pronounced effect ( 5 ) , e.g., 4-quinolizidone (IV), 1 3e-methoxylupanine (V). The mass spectra of a number of lupine alkaloids have been determined and their interpretation has been confirmed by deuteration (7).

VI

I H

178

F E R D I N A N D BOHLMANN AND D I E T E R SCHUJIAKN

Several characteristic examples follow ( V I is lupine; V I I is tetrahydro desoxycytisine).

m-" +

1

VII

Ring A is largely retained presumably because of the stability induced in the carbons adjacent to the more basic N-1. In cytisine ( V I I I ) the pyridone system remains largely unchanged, fragmentation being centered about N-2.

CH2

0

VIII

0 146

N

I1

0 160

97

137

Sparteine (11)shows intense peaks a t m/e 193, 137, 136, 98, 97. These ions arise from a break of two bonds in rings B or C ; m/e 98 and 136 involve a hydrogen migration as well. Ring A is largely retained in this system as well, 5t fact emphasized in that 85-90% of the fragments of 13-hydroxysparteine retain it.

B. ABSOLUTE CONFIGURATIONOF

THE

QUINOLIZIDINEBASES

Until fairly recently only the absolute configuration of ( - )-lupinhe (VI) was known and its correlation with the quinolizidine bases had not been achieved. Two recent publications (8, 9) have reported such correlations for a number of alkaloids. The oxidation of ( - )-anagyrine (IX) with permanganate gave the 17-oxolactam (X); upon ozonization it was converted to the dilactam (XI) which on hydrolysis to the intermediate XI1 followed by decarboxylation and lithium aluminum hydride

5.

179

LUPINE ALKALOIDS

reduction generated ( + )-aminolupinane ([a]? + 56.4') (XIII). This is identical with the base ([a];! +56.7") prepared from the tosylate of ( + )-epilupinine (XIV) by ammonolysis. The C-15 alkaloids in Table I therefore have the configuration shown. TABLE I COKFIGUR.4TION Alkaloid ~

( - )-Anagyrine ( )-Sparteine ( - )-Lupanine ( - )-Thermopsine ( - )-a-Isolupanine ( )-a-Isosparteine ( - )-P-Isosparteine

+ +

XIV (

OF

Cis ALKALOIDS Configuration ~

7 R:9 R : l l R 6 S:7 R:9 R:ll R 6 S:7 R:9 R : l l R 7 R:9 R:ll S 6 S:7 R:9 R:ll S 6 S:7 R:9 R : l l S 6 R:7 R : 9 R : l l R

XI11

+ )-Epilupinine

t 0

@

&2NH2

COOH

\

N

XI1

0

x

1 I

H (-))-Anagyrine ( I X ) XI

180

FERDINAND BOHLMANN AND DIETER SCHUMANN

VIII

XVI

( - )-Cytisine

1

H XV

T

2. TsCl 1. AlH4-

H

H

Q 0

+

0

-& N

H

\

IX ( - )-Anagyrine

The correlation of cytisine with - )-anagyrine ( I X ) was achieved by permanganate oxidation of the latter followed by lithium aluminum hydride reduction, tosylation to X V of the reduction product, dehydrogenation with mercuric acetate, and final hydrogenation to the epimeric tosylate ([I.: + l o o ) (XVI). The same compound ([m]g +9.8") was obtained by tosylating the reduction product, ( + )-desoxotetrahydrocytisine (VII), of cytisine (VIII). Table I1 shows the absolute configuration of several alkaloids. TABLE I1 ABSOLUTE CONFIGURATIONOF SEVERAL ALKALOIDS

Alkaloid

Configuration

( - )-Cytisine ( - )-Methylcytisine ( - )-Rhombifoline

7 R:9 S 7 R:9 S 7R:9S

5.

181

L U P I N E ALKALOIDS

C. BIOGENESIS Exhaustive studies with labeled compounds have, in recent years, elucidated most problems in the biogenesis of these alkaloids (10-26). C. Schopf in 1931 suggested that lupinine arose from two molecules of lysine or their biochemical equivalent. The possibility of its synthesis from piperidine and a Cs-compound such as glutardialdehyde was also noted. Sparteine could arise from three molecules of lysine or two of lysine and one of ketodiaminopimelic acid. Such reactions were realized in vitro under so-called physiological conditions in the syntheses of lupinine and bases with the sparteine skeleton. The oxidized bases resulting from such processes are viewed as being intermediates in the synthesis of the natural products. Numerous experiments with plants largely confirmed these speculations. Cadaverine (1:5-14C) and lysine COOH I

2

10

VI CHzOH

I

I

1

CHzOH

>

-

+

* CHzO

CHzOH

J

(2-14C) were incorporated overwhelmingly in lupinine, sparteine, lupanine, hydroxylupanine, matrine, and N-methylcytisine. In accord with theory it was found that C-atoms 2, 6, 10, and 11 of lupinine (VI) each contained one quarter of the radioactivity administered as cadaverine (1 : 5-14C) to Lupinus Zuteus L. as a result of degradation studies. Oxydation and decarboxylation yield carbon dioxide with one quarter of the radioactivity. Methylation followed by Hofmann degradation and ozonization also generated one quarter of the radioactivity as formaldehyde. Whether or not lysine is incorporated directly (unsymmetrically) or via cadaverine (symmetrically) was determined by feeding lysine-2-14C. '

182

FERDINAND BOHLMANN AND DIETER SCHUMANN

If the former, only two carbons would be radioactive. Degradation, however, showed that radioactivity was equaIly distributed between all four C-atoms-2, 6, 10, and 11. Consequently, in this case a t least, cadaverine is a metabolic intermediate. Radioactive sparteine (11)was incorporated in good yield when lysine (2-14C) and cadaverine (1 : 5-14C) were administered to L. Zuteus and Sarothamnus scoparius L. When the alkaloid was degraded by chromic oxide oxidation it gave succinic acid and a mixture of amino acids. The Schmidt degradation of the former generated carbon dioxide and ethylenediamine. The amino acid mixture contained ,3-alanine and y-aminobutyric acid, which was further degraded to carbon dioxide and trimethylenediamine.

The distribution of the radioactivity was as anticipated : C-atoms 2, 15, and 17 were active whereas C-atoms 3, 4, 5, 12, 13, and 14 were not.

Lysine-2-14C was incorporated via a symmetric intermediate. The incorporation of doubly tagged oc-15N-lysine-2-14Cinto sparteine showed that the radioactivity of the 15N was increased almost exactly by a factor of three over that of the ingested amino acid. A primary decarboxylation is therefore probable and 3 moles of lysine enter the molecule, the nitrogen being incorporated. This is strictly analogous to the incorporation of the amino acids into nicotinic acid. The carbonyl carbons of lupanine, hydroxylupanine (L. angustifolius L.), and of matrine (XVII) (Sophora tetraptera F. Mill.), which were obtained from cadaverine (1: 5-14C) administration, were isolated as benzoic acid. This was accomplished by reacting the alkaloids with phenyl lithium and oxidizing the product. In all cases the benzoic acid had one sixth of the activity of the degradation product. It is therefore probable that the biogenesis of the three named alkaloids follows a similar course.

5.

183

LUPINE ALKALOIDS

When tritium-labeled sparteine is administered to the plant it gives rise to radioactive lupanine and hydroxysparteine. Lupinine-14C is changed to sparteine in recognizable amounts. The equation below is a representation of the above facts. CHzOH

VI

0 XVII

Sparteine oxidation derivatives

Labeled cadaverine and lysine when administered to Cytisus laburnum L. gave rise, in good yield, t o cytisine and its N-methyl derivative. The formation of N-methylcytisine from cytisine is a secondary process and may be a detoxication mode. The elimination of C - 2 as benzoic acid provided one fifth of the total activity. The formation of cytisine (VIII) from sparteine by degradation is a possibility. Nowacki and Byerrum (27-30) were unable to observe activity a t C-2 of cytisine and arrived a t other conclusions. I n view of the ready conversion of angustifoline into epihydroxylupanine (31-33) the former was postulated as the precursor of the tetracyclic lupine bases ( 3 4 ) .

0

VIII

184

F E R D I N A N D B O H L M A N N A N D DIETER S C H U M A N N

This would seem to be questionable in view of the ready converse conversion of hydroxylupanine into angustifoline (and tetrahydrorhombifoline) ( 3 5 ) . Sodium formate (14C) and formaldehyde (14C) are only incorporated in trace amounts a t C-1 in lupanine and hydroxylupanine. The biogenetic pathway to lupine alkaloids from piperidylquinolizidine could not be demonstrated in spite of the ready chemical conversion of such bases to close relatives of the tetracyclic lupine alkaloids (36). Specific experiments to demonstrate the biogenesis of the Ormosia alkaloids have not been reported although the involvement of 4 moles of lysine (below) would seem probable (37).Of interest is the copresence of

4 moles lysine resp. cadaverine

+ / % H NH

U

epihydroxylupanine, angustifoline, ormosanine, and jamine in Ormosia jamaicensis Urb.-the first as possible CHzO donor and the last as acceptor (38-40).

111. Bicyclic Alkaloids

A. LUPININE ; EPILUPININE The tosylate of epilupinine (XIV) is thermally stable, whereas that of Iupinine (XVIII)is quarternized, the structure of the resulting salt (XIX)

XVIII

XX

-0Ts

XXI

186

6. LUPINE ALKALOIDS

having been elucidated (41). Reduction with lithium aluminum hydride generates lupinane ( X X ) , whereas the action of alkali regenerates lupinine and the action of chloride ions gives rise to chlorlupinine (XXI). The molecular weight determination of the tosylate proves i t to be monomeric; on heating it undergoes a rearrangement to a product of unknown structure. A synthesis of epilupinine under physiological conditions was accomplished as follows ( 4 2 ) .Ethyl N-benzyliminodiva.lerate ( X X I I ) yields an acyloin ( X X I I I ) which was reduced with lithium aluminum hydride to the diol XXIV, the benzyl group of which was removed by hydrogenoljisis. Subsequent oxidation with periodic acid at 25", pH 5, gave a n intermediate dialdehyde which cyclized to lupinaldehyde (XXV). This unstable aldehyde on reduction with lithium alumilium hydride gives only the more stable epilupinine (XIV).

XIV

J

A mixture of lupinine and epilupinine is obtainable by the following series of reactions. The betaine XXVI on cyclic hydrogenation and subsequent decarboxylation with 20 yohydrochloric acid gives a mixture of epimeric lupininic acids (XXIX). The dicarboxylic ester XXVIII is also obtained by the mercuric acetate dehydrogenation of the piperidine derivative X X X and by the alkylation of monomeric piperideine with a y-bromopropylmalonic ester. The last route is presumably a first Mannich condensation followed by a n alkylation. Hydrolysis of the malonic esters, decarboxylation (XXIV), esterification, and reduction with lithium aluminum hydride complete the synthesis of a mixture which consists of 80% dl-epilupinine and 20% dl-lupinine. Thermal

186

F E R D I N A N D BOHLMANN AND D I E T E R S C H U X A N N

ROOC

COOR

XXVIIX

i

XXIX

I

.1 VI, XIV

xxx decarboxylation of the malonic acid derivative yields equal amounts of the epimers. A simple synthesis of the lupininic acids has been reported as follows ( 4 3 ): ethyl a-pyridylacetate and an acrylic ester or acrylic nitrile undergo a simple Michael addition and hydrogenation of the product generates an epimeric mixture ( 7 : 3 or 1:4, respectively) of epilupininic and lupininic acids. COOR

The reduction of ~l4t5-imonium salts (XXXII) of substituted quinolizidines with sodium borohydride is influenced by substituents a t position 3 (44). The stereochemical course of the reaction is dependent upon the more stable conformation of the imonium salt. Quasiaxial hydrogen in position 3 hinders the approach of the reducing agent on that side and there result the energetically less stable quinolizidines XXXIII.

.?. L U P I N E ALKALOIDS

187

R

R XXXII

XXXII-Salz

1

1 i H ~

XXXIII

The reduction of d59lo-imonium salts of 1-alkoxycarbonylquinolizidines (XXXIV) with sodium borohydride proceeds stereospecifically to give trans-quinolizidines with axial alkoxycarbonyl groups in the stable conformation XXXV. d 1910-Dehydroquinolizidines react like active enamines with a variety of mesomeric electrophiles (45, 46). COOR

XXXIV

COOR

,

XXXV

B. LUSITANINE Aside from ( + )-ammodendrine the main constituent of the aerial portion of Genista lusitanica L. [Echinospartumlusitanicum (L.)Rothm.] is lusitanine, ClzHzoOhiz (mp 186"; [a]%+ S o ) ( 4 7 ) .Catalytic reduction generates the epimeric acetylaminolupinanes. Hydrolysis followed by reduction with sodium borohydride gives epilupinine along with some lupinine. These reactions point to structure XXXVI for lusitanine and spectral data are consonant therewith (48). A synthesis was achieved by first oxidizing lupiniiie to the corresponding aldehyde and condensing the latter with acetamide (49).

188

FERDINAND BOHLMANN AND DIETER SCHUMANN

XXXVl

IV. Tricyclic Alkaloids

A. ANGUSTIFOLINE Angustifoline, C14HzzONz (mp 81'; [a12 - 8.0°), has been isolated from Lupinus angustifolius L., L. polyphyllus L., and L. albus L. Its structure was elucidated almost simultaneously by three different groups (31-33). It forms an N-acetyl derivative, has a terminal double bond as indicated by IR-spectra and proved by oxidation to formaldehyde, and reduction of the lactam grouping with lithium aluminum hydride generates a trans-quinolizidine system (trans bands in the IR-spectrum), and these facts lead to structure XXXVII for angustifoIine.

0

0 XXXVII

XXXVIII

Its conversion to 13-epihydroxylupanine (XXXVIII) by reaction with formaldehyde (31, 33, 50) via the intermediate XXXIV ( R = H , a

5.

189

L U P I N E ALKALOIDS

reaction which proceeds stereospecifically) confirms both its structure and configuration. The cyclization with formaldehyde proceeds under physiological conditions (pH 5, 25”) and is consequently of interest biogenetically. It is also possible to reverse this condensation by a suitable choice of the C- 13-substituent (35). Dehydrogenation of angustifoline with N-bromosuccinimide gives a homogeneous compound (XL) whose structure was largely determined by NMR-spectra (32). This oxidation product is identical with alkaloid “W-102” (32, 51) isolated from L. albus. Angustifoline is identical with jamaicensine

which, along with jamaidine ( 13-epihydroxylupanine) was isolated from Ormosia jamaicensis Urb. and from 0. panamensis Benth. (33, 38). Cytisine (VIII) was the starting point in a synthesis of angustifoline. Tetrahydrocytisine (XLI) was converted to the N-chloro derivative (XLII) with hypochlorite. The elimination of hydrogen chloride from the latter leads specifically to the Schiff base (XLIII) which is stereospecifically alkylated with ally1 magnesium chloride. The approach of the reagent from the under side of the molecule is sterically very improbable (52).

SIII

+

pH+ 0

0

XLII

/ 0

0 XLIII

SXXVII

190

F E R D I N A N D BOHLMANN AND D I E T E R SCHUMANN

B.

DEHYDROlLBINE

Dehydroalbine (XLIV), C ~ ~ H I ~ O(mp N Z 50"; [m]? - 103"; perchlorate, mp 252"), was isolated from the seeds of L. albus ( 5 3 ) . Its imonium salt has structure XLV. Vigorous hydrogenation converts it into XLVI which is epimeric at C-11 with dihydrodesoxyangustifoline.

XLVI

C. N-METHYLALBINE This alkaloid (XLVII), C15HzzONz (mp 67.5'; [ m ] g - 559), is related to multiflorine and was isolated from L. albus ( 5 4 , 5 5 ) .Spectral comparison with multiflorine and N-methylangustifoline permitted structure XLVII t o be assigned to it.

XLVII

D. TETRAHYDRORHOMBIFOLINE This liquid base (XLVIII), Cl5Hz4ONz ([el& + 81"; hydrochloride, mp 189"), was isolated from L. angustifolius (56).It was synthesized by reacting tetrahydrocytisine with 1-bromobutene ( 3 ) . It is formed in the fragmentation of the tosyl derivative of the epimeric 13-hydroxylupanine (35) (L, LI) via the intermediate imonium structure (XLIV).

5.

191

L U P I N E ALKALOIDS

0

0 XLVIII

XLI

T

V. Tetracyclic Alkaloids: Sparteine Group A. SPARTEINE The synthesis of sparteine, following the hypothesis of Schopf, can be accomplished from acetone, formaldehyde, and piperidine (57). The resulting Mannich base is dehydrogenated with mercuric acetate and the resultant intermediate spontaneously cyclizes to 8-ketosparteine (LII), from which Wolff-Kishner reduction generates dl-sparteine (11).

LII

192

F E R D I N A N D BOHLMANN A N D D I E T E R SCHUMANN

Another synthesis under physiological conditions has been reported (36).The piperidinoquinolizidine (LIII),obtainable from epilupinine via bromolupinine, cyclizes when dehydrogenated with mercuric acetate to a mixture of LIV and LV which on reduction with sodium borohydride gives a separable mixture of sparteine and allomatrine. The epimeric piperidinoquinolizidine obtainable from lupinine gives a mixture of a-isosparteine (LVIII) and allomatridine (LVI). The dehydrogenation

LIII

!

L1v

\

LVI

LV

proceeds largely with the formation of the d5~10-irnoniumsalt, the further condensation of which leads to the matrine type. Part of the dehydrogenation nevertheless gives the d495-irnonium salts and these give rise ultimately to sparteine and a-isosparteine. Dehydrosparteine diperchlorate reacts with butyl hydroperoxide in pyridine to give a 17-hydroxydehydrosparteinesalt (LIX) (58) which rearranges to a mixture of dehydro bases; these in turn can be reduced to a mixture of N-formylpiperidylquinolizidine (LX) and piperidylquinolizidine (LXI). This is a method for opening the sparteine nucleus.

5.

193

LUPINE ALKALOIDS

?H

LIX

CHO

CHO

LX

LXI

The monoperchlorate of sparteine under the above conditions gives only the formyl derivative. In acid solution, however, only the piperidylquinolizidine is obtained. Drastic dehydrogenation of sparteine with mercuric acetate gives in addition to the normal bisdehydro salt another salt (LXII) whose structure has been confirmed (59). The salt exists in the open form

LXII

LXIII

194

FERDINAND B O H L N A N N AND DIETER SCHUMZANN

(LXIII). Oxidation and decarboxylation followed by reduction give piperidinoquinolizidine (LXI). The conformation of sparteine in solution has been determined bv means of NMR-spectra. Ring C is present in the boat form and hence rings C and D are joined trans ( 6 ) .

N

I1

B. DIPLOSPARTYRINE " Spartyrine " is obtained by oxidizing sparteine with chromicsulfuric acid. It is identical with 6-diplospartyrine (LXV) which is obtained by condensation of 17-hydroxysparteine with Al4-dehydrosparteine a t pH 7 (60). The analogous condensation of 17-hydroxysparteine with All-dehydrosparteine gives rise t o 6-diplospartyrine (LXV).Colored by-products are also formed and possible structures are given.

LXV

The chemical behavior of sparteine-N-oxide has been studied (61,62). It is readily obtained by reacting sparteine with hydrogen peroxide and is mostly the N-16-oxide though some of the N-1 oxide is also formed.

5.

195

LUPINE ALKALOIDS

Both were obtained in a pure state. Sparteine can be converted into a-isosparteine by the method of von Braun in 46% yield. The required platinum oxide is generated in situ ( 6 3 ) .

c. 17-OXOSPARTEINE 17-Oxosparteine, in contrast with aphylline and lupanine, suffers hydrolysis only under energetic conditions. Its hydrolysis with concentrated hydrochloric acid was reexamined and the resulting amino acids were characterized as their esters (LXVII, LXVIII, LXIV) and the corresponding alcohols. One more ester (LXX) was obtained by first dehydrogenating with mercuric acetate and then reducing with sodium borohydride ( 6 4 ) .

0

LXVII and

LXVIII and

COOR

LXX

COOR

LXIX

The alcohols obtainable from the esters possess the same stable conformations as their progenitors with one exception : the alcohol LXXI (from the ester LXVII) is fixed in an unfavorable conformation

LXXI

LXXII

196

F E R D I N A N D ROHL31.4NX A N D D I E T E R SCHUMANN

because of hydrogen bonding. X correction of the structure earlier suggested for oxosparteine alcohol was therefore necessary ( 65).

D. 1i - O X O L U P A S I N E This base (LXXII), C15H2202PVT2 (mp 154";

[ct]13 + 139") occurs in

L. polyphyllus and L. angust(folius (31, 51). Reduction with lithium aluminum liydridc generates sparteine and the oxidation of lupanine with ferricpaiiide gives 17-oxolupanine.

E. LUPANINE The stability to hydrolysis of lupanine (LXXIII) has been thoroughly studied (66, 6 7 ) . I t s equilibrium with lupaninic acid (LXXIV) in 0.2 N hydrochloric acid is 11.8 "/o in 10 N hydrochloric acid 0 % , and in 1 N potassium hydroxide 90% in favor of the acid. The equilibrium is achieved eight times more rapidly in acid than in alkaline solution.

0 LXXIII

LXXIV

The structure of Beckels " ethoxylupanine " (LXXV), which is prepared by the reaction of bromine on lupanine in ethanol, has been elucidated (68). 17-Hydroxylupanine is readily obtainable from it.

Lupanine is comparatively easily dehydrogenated with mercuric acetate (68, 69), a property not usual for cis-quinolizidine structures. The conformation, with ring C in boat form, appears to be the favored conformation equilibrium (5, 35, 7 0 ) .

197

5 . L U P I N E ALKALOIDS

F. ALKALOIDS WITH PYRIDOXE XUCLEVS : ATAGYRINE, THERXOPSINE, BAPTIFOLINE, ASD 13-EPIBAPTIFOLISE Anagyrine ( I X )was synthesized as follows : The condensation product of a-picoline, formaldehyde, and acetic anhydride, n-acetoxymethylvinylpyridine (LXXVI), a product which had already served as an intermediate in a cytisine synthesis, was reacted with malonic acid yielding the vinylpyridine LXXVII, during the formation of which the acetyl was eliminated. The compound reacted with piperidein (Mannich) with concomitant ring closure and decarboxylation to LXXI’III (R = H). Esterification gave a mixture which under equilibrating conditions gave the single stable isomer LXXVTIIa (€3=AT). This on successive reduction, bromination, ring closure, and finally exhaustive ferricyanide oxidation gave anagyrine as the single product ( 7 1 ) . ,OAc

LXXVI

LXXCII

LXXVIII

LXSVIIIa

0-w I

\ x+

N

11

0 IX

Thermopsine (LXXIX)is a C-1 I -epimer of anagyrine and is obtainable from the latter by first deliydrogenat>ingwith mercuric acetate followed by reduction, a method also available for the conversion of lupanine into a-isolupanine (LXXX).

DIETER SCHCM.INN

0

0

IX

0

0

LXXX

LXXIX

Thermopsine can also be prepared from 1Sa-hydroxylupanine (LXXXI). Dehydrogenat,ion gives an enamine (LXXXII) whose lactam group may be reduced with lithium aluminum hydride. Elimination of water with phosphorus pentoxide gives a diene (LXXXIII) which on oxidation with ferricyamide gives a good yield of thermopsine ( 5 2 ) .

WOH WOH +

0

0

LXXXII

LXXXI

LXXXIII

Baptifoline (LXXXIV) whose structure has heen elucidated (72, 7 3 ) can be synthesized from cytisine (52) by a route analogous to the synthesis of angustifoline. Hydrogen chloride was eliminated from S-chlorocytisine ( L X X S I X ) . The resultant base (XC) adds ally1 magnesium chloride stereospecifically and this reaction is followed by cyclization with formaIdehyde to generate epibaptifoline (XCI) which is reduced to 13a-hydroxylupanine (XXXVIII). Solvolysis of the 13aisomer converts it into the 13e-isomer. Recently ( - )-epibaptifoline

5.

199

L U P I N E ALKALOIDS

m*

(LXXXIV), C15HzoOzNz (mp 21 5 " ) , has been obtained from Retuina sphaerocurpa Boiss. ( 7 4 ) .

s

lj/ c1

s

'OH

0

__f

0 VIII

LXXXIV

LXXXIX

XCI

XC

G. APHYLLINE; APHYLLIDINE The dehydrogenation of aphylline (XCII) with mercuric acetate gives first XCIII and then XCIV. Such dehydrogenations of lactams had not been previously known. Vigorous reduction of the bisdehydro base gives a-isosparteine ( 7 5 ) .

@ L @ H

0 SCII

0 XCIII

1 0

XVIII

XCIV

200

F E R D I N A N D BOHLMANN A N D DIETER SCHUMANN

The hydrolysis of aphylline and of aphyllidine (XCV) gives aphyIIinic acid (mp 214") and aphyllidinic acid (mp 221"), respectively. Aphyllinic acid can be converted into sparteine by the following sequence of reactions : esterification, Bouveault-Blanc reduction, chlorination, and cyclization with alkali ( 7 6 ) .Aphylline and aphyllidine react with sodium amide in benzene solution to give the corresponding amides, XCVI and XCVII ( 7 7 ) .

CONHz XCVI

CONHz XCVII

Aphyllinic acid can be decarboxylated at 320". A number of its esters have been described as well as its N-methylation by the Leuckhart, reaction (78).

H. MONSPESSULANINE The structure of the long-known monspessulanine (C), C15HzzONz (mp 102"; [a]? + 168O) was arrived at from spectral data and its conversion into 11-epiaphylline (79). Its synthesis from retamine (XCVIII) via 17-oxoretamine (XCIV) confirms its structure (80). 0

/

XCVIII

XCIX

0

C

I. OXOAPHYLLIDINE Oxoaphyllidine (CI), C ~ ~ H Z O O(mp Z N ~184"; [u],, - 21°), whose structure is given in CI, was isolated from Anabasis aphylla L. (81).

5. L U P I N E ALKALOIDS

20 1

0 /I

I1 0

CI

J. ARGYROLOBINE This alkaloid (CII), ClsHzzOzNz (mp 169"; [a]= + 13.3') was obtained from Argyrolobium megarhizum Bolus along with ( - )-aphyllidine, cytisine, and N-methyl cytisine. On reduction it gives ( - )-sparteine and therefore it is CII (82).

CII

K. RETAMINE This alkaloid YCVIII), which is present in virtually all species of Genista ( 1 ) has 1,sen the subject of many investigations. It had been long known that its nuclear structure was that of a hydroxy sparteine but location of the hydroxyl offered much difficulty. The hydroxyl is secondary (83).The following and other reactions are fully explicable on the structure (XCVIII) which is 12a-hydroxysparteine (84-86). I

202

FERDINAND ROHLMANN AND DIETER SCHUMAKN

*4solution of the alkaloid has the given conformation exclusively. I t s IR-spectrum indicates a $ring bonded hydrogen (3520 cm-1). Reaction with thionyl chloride to ‘‘ chlorretamine ” (CIII) proceeds with inversion but the solvolysis of the latter t o epiretamine acetate (CIV) proceeds without inversion and hydrolysis of the acetate gives epiretamine (CV)a series of reactions attributed to the influence of the electron pair on N-16. The action of thionyl chloride on epiretamine gives “chlorisoretamine ” by inversion and t,his on reaction with electrophilic reagents only undergoes an elimination. The halogen in compound GI11 is activated by the proximity of the N-16 to such an extent that sodium borohydride reduces the compound to sparteine (11).

CIII

CIV ;R = Ac CV; R = H

CVI

CVII

%*y

Dependent upon the conditions (1 2 0 O - 1 SOo), the elimination of water from retamine as well as from 13a-hydroxysparteine gives a variable mixture of dehydrosparteines which have been characterized by their chemical reactions and above all by their NMR-spectra.

CYIII

CIS

C‘s

A synthesis of retamiiie has been achieved as follows (86): 3-pyridinol ((3x1) was converted t o the diol (CXII) via its K-oxide; the diol was acetylated, and converted into the nitrile CXIII by a solvolytic reaction. The ester (CXIV) obtained from the iiitrile was condensed with ethyl

5.

CXI

CXII

COOR

COOR c-

t-

\

203

LUPINE ALKALOIDS

N

0

cxv

CXIV

CXIII

4

--

H OH

0

SC\'III

hydroxymethylenepyridyl-2-acetate to the quinolizone CXV which, following hydrogenation and reduction with lithium aluminum hydride, gave a mixture of isomers from which retamine was chromatsographically isolated. This synthesis, however, is not unambiguous because the hydroxyI could also be at C-5. The formation of the dehydro base (CXVI), however, becomes difficultly explicable on such a basis.

204

FERDINAND BOHLMANN AND DIETER SCHUMANN

A very simple synthesis of retamine was achieved by first hydroborating the dehydrosparteine (CVIII) and then oxidizing the product. The resulting mixture consisted of epiretamine and retamine in the ratio 9 : 1 ( 8 5 ) .The addition of the diborane is stereospecific to 90% and takes place from the less hindered side. The hydroboration of dllrlz-dehydrosparteine (CVI) (87) in the presence of triethylamine followed by oxidation gives a mixture in which retamine was shown to be present. This series of reactions required the trans addition of the diborane-a reaction which had not previously been encountered. The hydroboration of Alz,13-dehydrolupanine (CXVII) ( 8 8 ) ,obtained from hydroxy lupanine, and subsequent oxidation lead to a mixture from which (-)-retamhe could be isolated. This is the enantiomer of the naturally occuring retamine.

---f

+

CXVIII

+

t

p 0 CXVII

CVI

Pharmacologically, retamine belongs to the alkaloids which have an effect on the nongravid uterus (89). I n small doses (50 pg/kg) it lowers blood pressure in dogs. With larger doses (5-10 mg/kg) the blood pressure sinks virtually to zero with intermittent cessation of breathing followed by intense tachypnea. The action is confined to the heart and the circulation following bilateral vagotony a t the throat. I n mice, by subcutaneous injection, it enhances diuresis (90). Of biogenetic interest is the content of retamine in Genista species a t different stages of growth. In spring the green plants contain mostly ( - )-sparteine but in the fall, and particularly in older plants, retamine is the main constituent (91). The preparation of the isomeric and epimeric 7 - , 8-, 9-, and 14hydroxysparteines has been described. The epimeric 14-hydroxysparteines are chemically and spectrally very similar to the retamineepiretamine pair (84, 86).

L. HYDROXYLUPANINE (LXXXI) The configuration a t C- 13 was determined by measuring the hydrolysis rate of the azobenzenecarboxylic ester of the alkaloid. This widely occurring alkaloid is 13a-hydroxylupanine; that is, the hydroxyl is

5.

205

LUPINE ALKALOIDS

axial ( 7 3 ) ;this conclusion is confirmed by the observation that the cyclization of angustifoline with formaldehyde generates the more stable epimer with the equatorial hydroxyl, XXXVIII (73).

For the synthesis of 13-hydroxysparteine the starting material was a-picoline N-oxide (CXVIII)which was nitrated and the nitro group then replaced by benzyloxy. The action of acetic anhydride induced the Boekelheide rearrangement to the acetoxymethyl derivative CXIX. The latter, via the alcohol, the chloride, the cyanide, and the ester, was condensed with ethyl hydroxymethylenepyridylacetate to the quinolizone CXX, hydrogenation and reduction of which with lithium aluminum hydride gave a separable mixture of hydroxysparteines. The

6 -h + k OAc

.1

‘K

0 CXVIII

.1 0

‘N

CXIX

i

How ROOC

0

cxx

CXXI

CXXII

206

F E R D I N A N D BOHLBIANN AND DIETER SCHUMANN

13e-derivative (CXXI) was identical with the product obtainable from 1%-hydroxysparteine (CXXII)by epimerization via the 0-tosylate and the 0-acetate. The reverse epimerization was not possible (72). The conversion of hydroxylupanine to hydroxy-m-isolupanine can be brought about by first dehydrogenating with mercuric acetate and then reducing (98).Epihydroxylupanine ( 13e-hydroxylupanine) (XXXT'III ), first named jamaidine, has only been found in 0. jamaicensis (33, 38). It is consequently much less common than its 13a-isomer (LXXXI) in the Leguminosae-Faboideae ; this may be due to the comparative ease with which it is transformed into other products. For example, both of the epimeric tosylates (L and L I ) generate angustifoline and tetrahydrorhombifoliiie when treated with triethylamine in acetonitrile. They differ only in their rates of reaction, the equatorial one reacting faster. Under other chosen conditions either product may become the major one. In the presence of sodium borohydride the only product is tetrahydrorhombifoline (XLVIII) and in the presence of silver oxide angustifoline (XXXVII)is the only product ( 3 5 ) .

XXXVII

0

L, LI

iid XLVIII

The solvolysis of either tosylate with methanol gives 13-epimethoxylupanine, identical with the natural alkaloid (CXXVI).The reactions of the 13-tosylates are influenced by the specific stereochemistry of rings C and D. The corresponding tosylate of hydroxy-m-isolupinane does not react in the same way.

&I. OTHER 13-SUBSTITUTED LUPANINEAND DERIVATIVES

hPHYLLINE

Virgiline, C15H2402N2 (mp 250" ; [m]F - 29") is 13a-hydroxyaphylline. It occurs in Virgilia capensis Lam. [ V . oroboides (Berg.) Salter] along with oroboidine (93,94, 96) which proved to be identical with ( + )-calpurnine

5.

207

LUPINE ALKALOIDS

(CXXIV), CzoH2703N3 (mp 154"; [a]: + 59"), isolated from Calpurnia Zasiogyne E. Mey. [C. subdecandra (L'Herit.) Schweickerdt]. The latter on reduction with lithium aluminum hydride gives ( - )-hydroxysparteine and alkaline hydrolysis gives ( + )-hydroxylupanine and pyrrol-2-carbonylic acid. The same plant also contains another alkaloid which has been shown to be 0-(2-pyrrolylcarbonyI)-virgiline(CXXV), Cz0Hz703N3 (mp 271"; [a],, - 2 3 " ) (95).

Lupinus angustifolius contains 13-epimethoxylupanine (CXXVI), Cl6Hz6OzNz (mp 97" ; [a]? + 64.5"), from which epihydroxylupanine may be obtained by ether scission (50, 51, 56). Its synthesis has been described above (35,50).This plant as well as L. polyphyllus also contains the lfollowing esters of 13a-hydroxylupanine: the tiglic ester (CXXVII), C20H3003N2 (perchlorate, mp 240" (260°), [a]$ +28.1") (56, 97); the trans-cinnamate (CXXVIII), C24H3003nTz (mp 166"; [m]',"+ 42") (98); the cis-cinnamate (CXXIX)(hydrochloride, mp 145"; [a]: + 26.1") (97); and the benzoate (CXXX), CzzNz803Nz (mp 205"; [a]? + 3 5 " ) (97).

0

CXXIX;

R=Ph

coCXSS;

R=Ph-cO-

208

F E R D I N A N D BOHLM.4"

N.

A N D DIETER SCHUNANN

~~~ULTIFLORIW ; E13-HYDROXYMULTIFLORINE

Multiflorine (CXXXI), C15H220N2 (mp 109"; [a]'," - 299"), was isolated as alkaloid LVI from L, varius L. (99),L. muEti$orzcs Lam. ( l o o ) , and L. albus (101).During hydrogenation it takes up 3 moles of hydrogen and is converted to ( - )-sparteine. Its UV-spectrum is consonant with its structure as A2-dehydro-4-ketosparteine (101).L. albus in addition has yielded two further alkaloids, namely, 13-hydroxymultiflorine (CXXXII), C15HzzOzNz, and A5-dehydro-13-hydroxymultiflorine (CXXXIII),C15H~oOzNz(102).

CXXXI

CXXXII

CXXXIII

VI. Tetracyclic Alkaloids: Matrine Group

A. MATRINE I n addition to matrine and its N-oxide,SophoraJEavescensAit. contains methylcytisine, anagyrine, baptifoline, and a newly described base, sophoranol (CXXXV), C15H240N2 (mp 171"; [a]'," +6S0), which is a hydroxymatrine (103, 104). The configuration of matrine has been

CXXXIV

cxxxv

5.

209

LUPINE dLKA%LOIDS

determined on the basis of its IR-spectrum and dehydrogenation rates (105) and the correlation of matrine with sophoranol has fixed the structure of the latter. Sophoranol may be obtained by the hydroxylation, which proceeds with unusual ease, of the product from the dehydrogenation of matrine with mercuric acetate. The dehydrogenation gives two dehydromatrines (CXXXVII and CXXXVIII), the former of which on reduction regenerates matrine; the latter gives a mixture of matrine and mostly allomatrine (CXXXVI) (106). The latter is the more stable isomer and is the enantiomer of leontine (107).

CXXXVI

CXXXVIII

CXXXVII

The configurations and conformation of matrine and allomatrine have been confirmed by NMR-spectra ( 5 ) .The axial protons on C-11 and (2-17 in matrine, in contrast with those on allomatrine, are shifted to lower fields because of the effect of the tertiary nitrogen, a fact entirely explicable by structure CXXXIV. The separation of sophocarpine and matrine can be achieved by one of two methods (108).The action of alkali hydrolysis matrine whereas sophocarpine remains unaffected; or the N-oxides may be prepared by reaction with hydrogen peroxide and then separated by crystallization. Octadehydromatrine (CXL) and allomatridine are available synthetically from an azajulolidine (109).Alkaline hydrolysis of the pyridone and decarboxylation yields an octadehydromatrine (CXL) which under forcing conditions of hydrogenation gives allomatridine.

210

&+&

F E R D I N A N D BOHLMANN AND D I E T E R SCHUMANN

ROOC

x /

s /

0

0

CXXXIX

CXL

J

The total synthesis of matridine (110)and of matrine (107, 110, 111) have been detailed. 3-Ketoquinolizidine (CXLI), which was obtained by reacting ethyl pyridylacetate with ethyl /3-halogenpropionic ester, was

CXLI

CXLII

ROOC

?cooR

-

ROOC

J?

-

COOR

CXLIII

8 - :$j N

CXXXIV

0

CXLV

RCO

0

ROOC

ROOC

CXLIV

t-

ROOC$OOR 0

5.

211

LUPINE ALKALOIDS

subjected to a double enamine synthesis with acrylonitrile. Complete hydrogenation gives dl-matridine in good yield in spite of the fact that alIomatridine is the more stable isomer. For the synthesis of matrine the penultimate intermediate was 2,B-dioxoquinolizidine (CXLV). The Schiff's base CXLII was reduced and converted to the lactam CXLIV. Dieckmann ring closure, hydrolysis, and decarboxylation gave CXLV which, following a double enamine synthesis with acrylonitrile, and final hydrogenation gave dl-matrine. Hence the synthesis of dl-leontine (CXXXVI) (allomatrine) is available. A synthesis of matrine under milder conditions although in poorer yield has also been reported (106).The ester half-aldehyde of glutaric acid was condensed to the Schiff base CXLVI with aminolupinane. Dehydrogenation conditions caused cyclization with the formation of a mixture which upon reduction yielded matrine, allomatrine, and lupanine.

Go%R dS" -&-& f'l

OHC

COOR

( ; " O R

LXXIII CXXXIV CXXXVI

CXLVI

The reaction product (CXLVII) of matrine and cyanogen bromide primarily undergoes the von Braun degradation. The halogen can be

CXLII

- &-& CS

CN

CXLVII

CXLVIII

Br-

212

F E R D I N A N D BOHLJZANN AND D I E T E R S C H U M A N S

eliminated catalytically and the cyano group can be removed by hydrolysis. Dehydrogenation with mercuric acetate gives the enamine CXLVIII (112).

B.

S O P H O R A M I N E ; SOPHOCA4RPINE; ISOSOPHORAXINE

The structures of sophocarpine (CXLIX) and sophoramine (CL) follow from t,heir syntheses from matrine (113), which was first converted to a dichIoro derivative by the action of thionyl chloride and sulfur dichloride. One of the halogens was removed by catalytic reduction. The second halogen was then eliminated as hydrogen chloride to

CLI

CL

CSLIX

give a base identical with ( - )-sophocarpine, C15HzzONz.H20 (mp 54"; [ a ] g - 32"). Dehydrogenation of ( - )-sophocarpine to ( - )-sophoramine, C15H200N2 (mp 164"; [a]:" -9S0), can be brought about by heating in solution with palladium-charcoal in the presence of maleic acid as hydrogen acceptor. The alkaloid (hydrodide, m p 292") (114) obtained from Genista rhodorhizoides Webb and Berth. is presumably identical with sophoramine.

213

5 . LUPINE ALKALOIDS

Isosophoramine (CLI), C15HzoONz (mp 140"; [ a ] D + 53.3"), was isolated from Sophora pachycarpa Schrenk. (115). Its synthesis from matrine was accomplished via the dichloro derivative (CLII) already described. When heated in pyridine to 250", ( + )-isosophoramine is formed in good yield (116).The isomerization at C-6 is viewed as taking place via the retro-Mannich product (CLIII). Energetic reduction of it gives ( + )-allomatrine. The preparation of 13-alkyl derivatives (CLIX) of sophoramine has been described. The vinylogous-activated methylene is quite reactive and the condensation is followed by dehydration and aromatization. The products proved to be pharmacologically inactive. A latter publication also deals with the structure and derivatives of this alkaloid (117).

CLIV

CLI

VII. Ormosia Alkaloids These alkaloids have been exhaustively examined only recently although their existence has been known for some 50 years (118).They occur along with other lupine alkaloids in Ormosia species. Their structures are known for the greater part although none has been synthesized. Three well-defined alkaloids have been isolated from 0. panamensis Benth. : ormosinine, C20H33N3 (mp 220" ; + 9.0') ; panamine, C20H33N3 (mp 36"-40"; - 1 1 " ) ; and ormosanine, C20H35N3 (mp

214

F E R D I N A N D BOHLMANN A N D DIETER SCHUMANN

+

168"; [a]$& 3.3') (39). Ormosanine and ormojamine, C20H31N3 mp) 125"; [cY]!$' - 144') were isolated from 0. jnrnaicensis (119-121). Ormo-

sanine was isolated from Piptanthus nanus M. Pop. as piptamine (122) and from 0.jamaicensis as alkaloid A (119, 120). The original investigation of 0. dasycarpa Jacks. (118) reported the presence of " ormosine " and '' ormosinine " but a later investigation (123) failed to confirm these findings. I n addition to ( - )-sparteine two new alkaloids were reported : dasycarpine, C20H3sN3 (tripicrate, mp 152"; perchlorate, mp 240") and alkaloid-I, C20H3703N3 (mp 207" ; [a]',"

+ 25.3').

CLVI

A more recent examination of P. nanus revealed the presence of a new base, piptanthine, C20H35N3 (mp 143") (124). Piptanthine (CLVIII) reacts with formaldehyde to form homopiptanthine (CLXI) (mp 189") which suffers hydrolysis to its progenition on acid treatment. With phosgene, or less satisfactorily with ethyl chloroformate, in the presence of triethylamine there is formed homoxypiptanthine (CLX) (mp 155'). Lithium aluminum hydride reduction of the latter gives homopiptanthine. Ormosanine (CLV) and formaldehyde condense to jamine (CLVI), C21H3sN3 (mp 154"), (125) the structure of which was determined by

215

5. LUPINE ALKALOIDS

X-ray methods. Jamine also occurs naturally in 0. jaicensis and 0. panurnensis (40).These alkaloids are racemic and resolution has been only partially successful (40). The structure of ormosanine follows inevitably from that of jamine. The correlation of ormosanine with ormosinine was accomplished by mild catalytic dehydrogenation of both alkaloids to the same product, CLVII (40, 126). The correct configuration a t C-6 was determined recently (127).

1-1-11 \ CLVII

Panamine can also be dehydrogenated but the reaction does not proceed so smoothly. Reduction of the product proceeds with the absorption of 3 moles of hydrogen in which only the unhindered pyridine ring is reduced. Perhydrogenation does not generate ormosinine and H

Hzil’t

CLV

OH, \

CLVIII

COC12

H

CLIX

CLX

CLXI

216

F E R D I N A N D BOHLMANN A N D D I E T E R SCHUMANN

condensation with formaldehyde does not give jamine. Ormosinine is changed to panamine through acid catalysis and panamine is quantitatively reduced to ormosanine with sodium borohydride (37, 40). The important observation was made that ormosanine is isomerized to piptanthine (CLVIII)by catalytically activated hydrogen in acetic acid (127).The configuration a t C-6 is changed so that the cis-quinolizidine structure is altered to the trans-quinolizidine. A similar irreversible epimerization is undergone by homoxyormosanine (CLIX)into homoxypiptanthine (CLX). Ormosanine generates dextrorotatory piptanthine whereas piptanthine from 0. nanus is levorotatory. The IR-spectra confirm the configuration of ormosanine and piptanthine a t C-6. The former displays a trans band (boat configuration of ring B) only in potassium bromide pellets whereas the latter shows the tram band in solution as well as in potassium bromide.

CLVIII in KBr + CC14

CLV in KBr

Earlier structures for panamine, ormosinine, and ormojanine have been reviewed (37,128)and panamine is CLXII. It has been shown that

CLXII

the above-mentioned reduction of panamine to ormosanine is rationally feasible. It proceeds stereospecifically since the otherwise possible imonium structure is unlikely because of the strain involved. Ormosinine gives products of unknown structure on hydrogenation. Isomerization ensues in the presence of weak acids (strong acids prevent it) and must take place a t C-11 in which the /%proton a t this position in

5.

217

LUPINE ALKALOIDS

>LCHR -OR HX<

>X-CHR-X<

4

H 1 7

R-@J

I

11H1-

>K-CH~R

ormosinine (CLXIII) takes the m-position in panamine. A probable mechanism is shown.

CLXIII

Ormojanine (CLXIV) behaves analogously to panamine toward sodium borohydride. The NMR-spectrum of it evidences an olefinic proton and the Hofmann degradation product (CLXV) generates a diene which indicates 2 olefinic protons. The position of the double bond in CLXV violates the Bredt rule but the presumpticn is that the rule does not necessarily apply to rings of such size.

CLXIV

CLSV

218

F E R D I N A N D BOHLMANN AND D I E T E R SCHUMANN

REFERENCES 1. 2. 3. 4. 5.

6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16. 17.

18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

R . Bernasconi, S. Gill, and E. Steinegger, Pharm. Acta Helv. 40, 246 and 275 (1965). N. J. Leonard, Alkaloids 7, 253 (1960). F. Bohlmann, Chem. Ber. 91, 2157 (1958). F. Bohlmann, D. Schumann, and H. Schulz, Tetrahedron Letters p. 173 (1965). F. Bohlmann and D. Schumann, Tetrahedron' Letter8 p. 2435 (1965). F. Bohlmann, D. Schumann, and C. Arndt, Tetrahedron Letters p. 2705 (1965). N. Xeuner-Jehle, H. Nesvadba, and G. Spiteller, Monatsh. Chem. 95, 687 (1964). S. Okuda, K. Tsuda, and H. Kataoka, Chem. & f.nd. (London) pp. 1115 and 1751 (1961). 8 . Okuda, H. Kataoka, and K. Tsuda, Chem. & Phnrm. Bull. ( T o k y o )13,487 and 491 (1965). H. R . Schutte and E. Nowacki, Naturwissenschaften 46, 493 (1959). H. R . Schutte, Arch. Pharm. 293, 1006 (1960). H . R . Schiitte, F. Bohlmann, and W. Reusche, Arch. Pharm. 294, 610 (1961). H. R . Schutte, E. Nowacki, and C. Schafer, Arch. Pharm. 295, 20 (1962). H. R. Schutte, H. Aslanov, and C. Schiifer, Arch. Pharm. 295, 34 (1962). H. R . Schutte and C. SchBfer, Naturwissenschaften 48, 669 (1961). M. Soucek and H. R. Schiitte, Angew. Chem. 74, 901 (1962). K. Mothes and H. R. Schutte, Angew. Chem. 75, 279 (1963). H . R. Schutte, G. Sandke, and J. Lehfeldt, Arch. Pharm. 297, 118 (1964). H. R. Schiitte and J. Lehfeldt, 1.Prakt. Chern. [a] 24, 143 (1964). H. R. Schutte, H. Hindorf, K . Mothes, and G . Hubner, Ann. Chem. 680, 93 (1964). H. R. Schutte and H. Hindorf, Naturwissenschaften 51, 463 (1964). H. R. Schiitte and H. Hindorf, 2. Naturforsch. 19b, 855 (1964). H. R. Schutte and J. Lehfeldt, 2. Naturforsch. 19b, 1085 (1964). H. R. Schiitte and H. Hindorf, Ann. Chem. 685, 187 (1965). H. R. Schutte and H. Hindorf, Ann. Chem. 685, 194 (1965). H . R . Schutte and J. Lehfeldt, Arch. Pharm. 298, 461 (1965). E. Nowacki and R . U. Byerrum, Biochem. Biophys. Res. Commun. 7, 58 (1962). E. Nowacki and R. U. Byerrum, Bull. Acad. Polon. Sci., Ser. Sci. Biol. 12,483 (1964). E. Nowacki and R. U. Byerrum, Bull. Aead. Polon. Sci., Ser. S c i . Biol. 12,489 (1964). E. Nowacki, Genet. Polon. 5, 189 (1964). F.-Bohlmann and E. Winterfeldt, Chem. Ber. 93, 1956 (1960). L. Marion, M. Wiewiorowski, and M. D. Bratek, Tetrahedron Letters p. 1 (1960). H. A. Lloyd, J . OTg. Chem. 26, 2143 (1961). M. Wiewiorowski and I. Reifer, Bull. Acad. Polon. Sci., Ser.Sci. Uiol. 9, 441 (1961). F. Bohlmann and D. Schumann, Chem. Ber. 98, 3133 (1965). F. Bohlmann, E. Wintcrfeldt, and U. Friese, Chem. Ber. 96, 2251 (1963). E. M. Wilson, Tetrahedron 21, 25561 (196). H . A. Lloyd and E. C. Horning, J. Org. Chem. 25, 1959 (1960). H. A. Lloyd and E. C. Horning, J . Am. Chem. SOC. 80, 1506 (1958). P. Naegeli, W. C. Wildman, and H. A. Lloyd, Tetrahedron Letters p. 2069 (1963). H. Schulz, Diplomarbeit, Techn. Universitiit, Berlin (1961). E. E. van Tmnelen and R. L. Foltz, J . Am. Chem. Soc. 82, 502 (1960). K. Winterfeld and K. Kniers, Arch. Pharm. 293, 478 (1960). F. Bohlmann, E. Winterfeldt, R . Mayer-Mader, and B. Gatscheff, Chem. Ber. 96, 1792 (1963). F. Bohlmann and 0 . Schmidt, Chem. Ber. 97, 1354 (1964).

5. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80.

LUPINE ALKALOIDS

219

F. Bohlmann, D. Schumann and 0. Schmidt, Chem. Ber. 99, 1652 (1966). E. Steinegger and K. Wicky, Pharm. Acta Helv. 40, 610 (1965). K. Wicky and E. Steinegger, Phurm. Acta Helv. 40, 658 (1965). K. Wicky, private communication (1965). 31. D. Bratek and M. Wiewiorowski, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 9, 705 (1961). M. D. Bratek and M. Wiewiorowski, Roczniki Chem. 33, 1187 (1959). F. Bohlmann, E. Winterfeldt, H. Overwien and H. Pagel, Chem. Ber. 95, 944 (1962). M. Wiewiorowski and J. Wolinska-Mocydlarz, Bull. Acad. Polon. Sci., Ser. Sci.Chim. 12, 217 (1964). M. Wiewiorowski and J. Wolinska-Mocydlarz, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 9, 709 (1961). M. Wiewiorowski and J. Wolinska-Mocydlarz, Bull. Acad. Polon. Sci.,Ser. Sci.Chirn. 12, 213 (1964). F. Bohlmann, E. Winterfeldt, B. Janiak, D. Schumann and H. Laurent, Chem. Ber. 96, 2254 (1963). E. E. v. Tamelen and R. L. Foltz, J. Am. Chem. Soc. 82, 2400 (1960). F. Bohlmann, E. Winterfeldt, and G. Boroschewski, Chem. Ber. 93, 1953 (1960). F. Bohlmann, E. Winterfeldt, and G. Boroschewski, Chem. Ber. 94, 3174 (1961). C. Schopf and K . Keller, A7aturwissenschaften 45, 39 (1958). M. Wiewiorowski and P. Baranowski, Bull. Acad. Polon. Sci.,Ser. S c i . Chirn. 10, 537, 543, and 549 (1962). P. Baranowski and M. Wiewiorowski, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 12, 761 (1964). M. Wiewiorowski, L. Lompa-Krzymien, and K. Golankiewicz, Bull. Acad. Polon. Sci.,Ser. Sci. Chim. 13, 757 (1965). F. Bohlmann, E. Winterfeldt, and D. Schumann, Chem. Ber. 93, 1948 (1960). F. Galinovsky, J. Derkosch, H. Nesvadba, P. Meindl, and K. H. Orgler, Monatsh. Chem. 88, 967 (1957). J. Suszko, M. Wiewiorowski, and W. Meissner, Bull. Acad. Polon. Sci., Ser. Sci.Chim. 7, 87 (1959). W. Meissner and M. Wiewiorowski, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 10, 591 (1962). M.Wiewiorowski, W. Meissner, a n d J . Bartz, Bull. Acad. Polon. Sci.,Ser. S c i . Chim. 9, 721 (1961). M. Wiewiorowski and A. B. Legocki, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 11, 5 (1963). F. Bohlmann and P. Strchlke, Tetrahedron Letters p. 167 (1965,). E. E. van Tamelen and J. S. Baran, J. Am. Chem. Soc. 80, 4659 (1958). F. Bohlmann, E. Winterfeldt, and H. Brackel, Chem. Ber. 91, 2194 (1958). F. Bohlmann, E. Winterfeldt, 0. Schmidt, and W. Reusche, Chem. Ber. 94, 1767 (1961) (see footnote 3). I . Ribas, private communication (1965). A. I. Ishbaev, A. S. Sadykov, and K. A. Aslanov, Z h . Obshch. K h i m . 35, 194 (1965). A. I. Ishbaev, A. S. Sadykov, and K . A. Aslanov, Z h . Obshch. K h i m . 33,687 and 689 (1963). A. S. Sadykov and R. N. Nuriddinov, Z h . Obshch. Khirn. 30, 1744 (1960). A. S. Sadykov and A. I. Ishbaev, Zh. Obshch. K h i m . 30, 1733 (1960). E. P. White, J. Chem. Soc. p. 4613 (1964). F. Bohlmann and D. Schumann, Tetrahedron Letters p. 2433 (1965).

220

F E R D I N A N D BOHLMANN A N D DIETER S C H U M A N N

A. S. Sadykov and R.S . Suridrlinov, Zh. Ohshch. h'him. 30, 1736 arid 1 i 3 9 (1960). Y. Tsuda ant1 L. Marion, Cau. J . Chem. 42, 764 (1964). F. Fraga, I. Galivan, A. Duran, E. Sloane, and I. Ribas, Tetrctherlrojr 11, Si (1960). F. Bohlmann, E. IVinterfeldt, D. Schumann, C . Zamack, and D. tt'andrey, Chem. Ber. 95,2365 (1962). 85. F. Bohlmann, H. Orerwien, and D. Schumann, Chem. Rev. 98,659 (1965). 86. F. Rohlmann, E. U'interfeldt, D. Schumann, and B. Gatscheff, Chem. Ber. 98, 653 (196.5). 87. I. Ribas, J. L. Castcdo, and A. Garcia, Tetrahedroiz Letters p. 3181 (1965). 88. Kju Hi Shin, L. Fonzes, and L. Marion, Cnn. J. Chem. 43,2012 (1965). 89. F. Sandbcrg, P h n r m . Weekblad 93,8 (1958). 90. E. Steinegger, R . Rernasconi, and G. Ottaviano, Phrirm. Acta Helv. 38, 371 (1963). 91. E. Steincggcr and R. Bernasconi, Piiarm. Actu Helc. 39,480 (1964). 92. J. Suszko, J. Bartz, arid &I. Wiewiorowski, Bull. Acmrl. polo)^. Sci., Ser. Sci. Chim. 8,41 (1960). 93. G. C. Gerrans and J. Harley-Mason, Chem. & I d . ( L m d o n ) p. 1433 (1963). 94. G. C. Gerrans and J. Harley-Mason, J . Chem. Soc. p. 2202 (1964). 95. E. P. White, J . Chem. S o c . p. 5243 (1964). 96. A. Goosen, J. Chem. Soc. p. 3067 (1963). 97. &I. D. nratek-Wiewiorowski, M. Wiewiorowski, and I. Reifer, Bull. Acad. Polon. Sci., Ser. Sci. Chim. 11, 629 (1963). 98. Sf. Wiewiorowski and M. D. Bratek, Bull. Acad. Polon. S c i . , Ser. Sci. Biol. 10, 349 (1962). 99. W. D. Crow, Austrnliaii J . Chcm. 12, 474 (1959). 100. J. Comin and V. Deulofeu, Australiun J . Chem. 12,468 (1959). 101. M. Wiewiorowski and J. Wolinska-Blocydlarz, Bull. Acnd. Polon. Sci., Ser. Sci. C h i m . 9, 709 (1961). 102. M.Wiewiorowski, J. Bartz, and W. Wysocka, Bull. A c a d . Polon. Sci., Ser. Sci. C h i m . 9, 715 (1961). 103. F. Bohlmann, D. Ra.htz, and C. Arndt, Chem. Ber. 91,2189 (1958). 104. S. Okuda, I. Murakoshi, H. Kamata, Y. Kashida, J. Haginiwa, and K. Tsuda, Chem. & Phnrm. Bull. ( T o k y o ) 13,482 (1965). 105. F. Bohlmann, W. Weise, D. Rahtz, and C. Arndt., C'hem. Ber. 91, 2176 (1958). 106. U. Friese, Dissertation, Techn. Universitbt, Berlin (1965); F. Bohlmann, D. Schumann, U. Friese, and E. Poetsch, Chena. Ber. 99, 3358 (1966). 107. L. Mandell, K. P. Singh, J. T. Gresham, and W. J. Freeman, J . - 4 r ~Chem. ~. SOC. 87,5234 (1965). 108. A. S. Sadykov and Y . A. Pakanaev, Zh. Obshch. Khim.29, 2439 (1959). 109. K. Tsuda and H. Mishima, J . Org. Chem. 23, 1179 (1958). 110. L. Rlandoll and K. P . Singh, J . Am. Chem. Soc. 83, l i 6 6 (1961). 111. L. Mandell, K. P. Singh, J. T. Gresham, and W. Freeman, J . Am. Chem. Soc. 85, 2682 (1963). 112. H . Minato and K. Takeda, Chem. & Pharm. Bull. ( T o k y o ) 9, 92 (1961). 113. S. Okuda, H . Kamata, K. Tsuda, and I. Murakoshi, Clwm. & I n d . ( L o ~ Z o np.) 1326 (1962). 114. A. G. Gonzalez, A. H. Toste, and B. K . Hernandez, A?rnk?sReal. Soc. Espan. Fis. Quim. (Madrid) B55, 607 (1959). 115. A. S. Sadykov, Yu. K. Kushmuradov, and K. A. Aslanov, Dokl. Aknd. SaukSSSR 145,829 (1962). 116. S. Okuda, H . Kamata, and K. Tsuda, C'hem. & Phnrm. Bull ( T o k y o ) 11, 1349 (1963). 81. 82. 83. 84.

5 . L U P I X E ALKALOIDS

221

117. Y. K . Kushmuradov, A. S. Satlykov, and K. A. Aslano\,, Z h . Obshch. K h i m . 33, 1683 (1963). 118. K . Hess and F. Merck, Chrm. Ber. 5 2 , 1 9 i 6 (1919). 119. C. H. Hassall and E. 31. Wilson, C'hem. d. I j d . ( L o n d o n ) p. 1358 (1961). 120. C. H. Hassall and E. hI. Wilson, J . Chrm. Soc. p. 2657 (1964). 121. 2. l'alenta, P. D~slongchamps,ZI. H. Kashid, K . H. Wight.man, and J. S. Wilson, Tetmhedrox Letters p. 1559 (1963). 122. K . A. Konowalova, B. S. Diskina, and 11. 6. Rabinovich, Z h . Obshch. K h i m . 21, 773 (1931). 123. R. T. Clarkc and 11.F. Grundon, J . C'hem. Soc. p. 41 (1960). 124. L'. Eisner and F. Sorm, C'ollection Czech. Chern. Comrnwz. 24, 2348 (1959); Chem. Abstr. 53, 22048f (1959). 125. I. L. Ka.rle arid J. Karle, Trtrahcdrow Letters p. 2065 (1963). 126. P. Kaegeli, R . Kaegeli, W. C. Wildman, and R. J. Highet., Tetrahedron Letters p. 2075 (1963). 127. P. Deslongchamps, J. S. Wilson, and Z . Valenta, Tetrahedron Letters p. 3893 (1964). 128. E. M. Wilson, Chem. & I n d . ( L o n d o n ) p. 472 (1965).

This Page Intentionaiiy Laft Blank

-CHAPTER

6-

QUINOLINE ALKALOIDS, OTHER THAN THOSE OF CINCHONA H. T. OPENSHAW T h e Wellcome Research Laboratories, Beekenham, Kent, England

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

I . Introduction.

223

B. Alkaloid of Choisya ternata D. Alkaloids of Evodin Species..

. . . . . . . . . 234 ............. 235

.........

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

IT’. Alkaloids of Lunasia amara and Balfouroden A. Introduction

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

236 236 239

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

247

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

V. Alkaloids of Oriza japonica.

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

VI. Alkaloids of Haplophyllum Species A. Occurrence ....................................... B. Haplophyllidine . . . . . . . . D. Khaplofoline

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

252

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

A. Introduction ........................ . . . . . . . ,256 B. Platydesmine ........................... 256 C. Pilokeanine ........................................... VIII. Alkaloids of Macrorungia longistrobus .

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

263

I. Introduction When the previous chapter ( 1 ) on the quinoline alkaloids was completed in 1957, the chemistry of the dictamnine group of alkoxyfuroquinolines was already well established. The present account records the isolation of already known alkaloids of this group from a much larger number of plant sources and the discovery and structural elucidation of 223

224

H. T. OPENSHAW

a few new members. Similarly, a number of new examples of simple quinolines and quinolones have been found in various plants. Greater interest attaches to the examination of a series of new quinoline alkaloids, occurring principally in Lunasia and Balfourodendron species, based on a 3-isopentylquinolone skeleton which may cyclize to either a dihydrofuroor a dihydropyranoquinoline ring system. An interesting feature of this group is the occurrence of some of the alkaloids in both dextro and lev0 forms. An entirely new type of alkaloid structure is exemplified in the quinolylimidazoles described in Section VIII. With the sole exception of the quinolylimidazole alkaloids, all the alkaloids described in this chapter occur exclusively in members of the Rutaceae ; Price ( 2 ) has discussed the taxonomic significance of the distribution of these and other alkaloids within this family. A summary of the chemistry of all the rutaceous alkaloids has been published ( 3 ) . The increasing use of spectroscopic measurements in the study of the structures of natural products has been strikingly portrayed in recent work on the quinoline alkaloids. I n addition to the many references to the specific use of these methods in papers on the chemistry of the alkaloids, more general studies of the value in this series of IR- (4-6), NMR- (7-9), and mass spectroscopy (10) have been made. A comprehensive review of the UV-spectra of alkaloids (11) includes much information on the quinoline group. Particular use has been made of UV- and IR-spectroscopy to distinguish between 2- and 4-quinolones (6, 12, 13) and hence between, for example, linear and angular furoquinoline ring systems. The NMR-spectrum also distinguishes between 2- and 4-quinolones, since, in the latter, the 5-proton gives a quartet at unusually low field due to deshielding by the 4-carbonyl group (7, 8 , 1 4 ) .

11. Simple Quinolines and Quinolones

A number of simple quinolines and quinolones have been isolated from various rutaceous plants, e.g., from angostura bark (Volume 111,p. 80) and from Lunasia amara Blanco (Volume VII, p. 241; this chapter Section IV,A). The leaves of Haplophyllum dubium Eug. Kor (15, 16) contain dubamine (mp 96"-97") which has been identified (17) as 2-(3,4-methylenedioxyphenyl)quinoline (I). Ruta graveolens L. contains, in addition to furoquinolines, the alkaloids graveoline (mp 205") ( 1 8 , 1 9 ) , and graveolinine (mp 115"-116") ( 2 0 ) ;the latter (11)is also found in L. amara, and the former is the related 1-methyl-4-quinolone (111). The seed (21) of the Mexican tree Casimiroa edulis LIave et Lex. contains eduline (IV) (mp 1S7"-18So), identified by synthesis ( 2 2 ) ;the

6.

225

QUINOLINE ALKALOIDS

bark ( 2 3 )contains the isomeric edulein (V) (mp 200”-201”) also found in L. umuru and L. quercifolia ( 2 4 ) ; casimiroin (VI) (mp 202”-203”) is found in both bark and seed, the former being the better source. The 0

R

I

I

I; R = H

111; RR=O-CHt-0, R’=R”=H 1IT; R = R “ = H , K’=OMe V ;R = R ’ = H ; R ” = O M e

11; R = OMe

structure of casimiroin was established by degradation (25). When treated with hot hydrochloric acid the alkaloid is demethylated t o a phenol, casimiroinol (VII), which is cleaved by alkaline hydrogen peroxide to a methylenedioxy-N-methylanthranilicacid. Decarboxylation gives 2,3-methylenedioxy-N-methylaniline, identical with material synthesized from 3-nitrocatechol. OR

OMo

TI;K = M e

VIII

1-11;R = H 0

R’ R I S ; R = H, R’= --CHzCHzCHs

S ;R = C H l O A r , R’ =--CH2CH2CH3 1 1 : R=K’=JIt.

X somewhat more complex 4-methoxy-2-quinolone is the alkaloid foliosidine (VIII) (inp 141”-143”) from Huplophyllum foliosum Vved. (see Section VI). The 2,3-dihydroxyisopentyloxy side chain, also found in evoxine and maculosine, was shown t o be present by periodic acid oxidation to acetone and an optically inactive aldehyde.

226

H. T. OPENSHAW

On heating with alkali, the side chain was eliminated, leaving an optically inactive phenol which on methylation yielded 4,X-dimethoxy1-methyI-2-quinolone.Since foliosidine is readily demethylated by dilute hydrochloric acid, and treatment of the product with diazomethane regenerates the alkaloid, it is assumed t,o be a 4-methoxy-2-quinolone, and hence has structure VIII (26, 2 7 ) . The leaves of Boronia ternata Endl. contain, besides skimmianine, an alkaloid, C15H17N03, which is very readily hydrolyzed by acid or alkali to give formaldehyde, acetic acid, and a product, C12H13NO. The I R spectrum of the original alkaloid has bands at 1740 cm-1 (ester carbonyl) as well as a t 1640 cm-1 (conjugated carbonyl) and the UV-absorption suggests a 4-quinolone structure. Permanganate oxidation of the hydrolysis product gives N-butyrylanthranilic acid, identifying it as 2-n-propyl-4-quinolone (IX).Hence the original alkaloid, which contains no active hydrogen, must be the 1-acetoxymethyl derivative ( X ) ; the NMR-spectrum is consistent with this structure (28). The simple 1,2-dimethyl-4-quinolone (XI)is a constituent of Platydesma campanulata Mann. (29) (see Section VI1,A).

111. Furoquinoline and Related Alkaloids

A. THEDICTAMNINE GROUP 1. Occurrence Dictamnine (XII) and its methoxy and methylenedioxy derivatives are widespread among the members of the Rutaceae, the most commonly occurring being skimmianine (XIII), which has now been reported in a total of 49 plant sources. Numerous new isolations of other known members of the group have been recorded; Table I summarizes all reported occurrences to date.

a 3 OMe

N’

XI1 Dirtamnine

0

RO 1

MPO XI11 ; R =Me, Skimmianirle S I V ; R = H, Haplopine

X V ; R=Mr?C(OH).CHOH.CHz,Evoxine

6.

227

QUINOLINE ALKALOIDS

TABLE I OCCURRESCE OF E’CROQUISOLISES

OF THE

Plant source

DICTAXSINE GROCP

Site

Reference

Dictamnine (XII) ,4egle mtrrmelos Correa Balfourodendron riedeliaiium Engl. Boenninghauscriin albijora illeissner, var. jnponica S . Suzuki Casimiroa e d u l i s Llavo et Lex. Dietamnus albus L. Evodia littoralis Endl. Flindersia acuminatn C. T. White F . dissospermu (F. Muell.) Domin. 3’.,maculosa Lindl. 3’.pubescens Bail. Glycosmis arboren (Roxb.) DC. Hortia arborea Engl. Phlebalium n u d u m Hook. S k i m m i a repens Xakai Zanthoxylum ailanthoidcs Sieb. et Zucc. 2. alatum Roxb. (2. planispiurn Sieb et Zucc.)

Heartwood Bark Leaves Leaves, stems, roots Bark Root Bark, leaves Bark Wood Wood Bark (trace) Root bark Bark Bark, wood Leaves Wood

30 31

Stem bark, roots

46-48

32 23 33, 34 35 36 37 37 38 39, 40 41 42, 43 44 45

6-Methoxydictamnine P l a t y d e s m campanulata Mann I’teleu. trifoliata L.

Root, stein bark Roots, fruit

29 49

Evolitrine (7-Methoxydictamnine) Leaves, stem Bark, leaves Root bark Bark Stem bark, root

Cusparia macrocarpa

Evodia littornlis Orixa japonica Thunb. Phlebalium nudurn Platydesma campanulata

50 35 51 42 29

7-Fagarine ( A-Methoxydictamninr) A e g l e marnielos Cnsimiroa edulis P a p m a coro (Gill) Engl. GEycosmis nrboren (Roxb.) DC. Hnptoph y l k m pedicellntum Bge. H . robustum Hortia arborea

Bark Bark Leaves Leaves, root bark Roots Roots

52 23 53 39, 40 16, 54 55

BaA

41

228

H. T. O P E N S H A W

TABLE I-continued

Plant source

Site

Reference

y-Fagarine (8-hIethox~dictamnine)-cotztii~ued Phlebalzuiri m d u m Ravenia spectcibzlis P1. Ruta gruueoleizs L. Zmtthoxylum ctkiturn (2. planaspiurn)

Bark Leaves All parts Roots

42 56 57 47

Kokusaginine (6,'i-Dimethoxydictamnine) Acronychia bnueri Schott Balfourodeiidroic riedelicmum Evodia aluta F. Muell. E . littoralis E. xunthoxyloides F. Muell. Fliizclersiu collina Bail. F . mnculosa F . pubesceru F . schottiana F. Muell. Clycosrnis petitnphylla (Rctz.) Correa Orixa jnponica Phlebulium nudum Platydesma campanulota Pteleu trifdiata Ruta qraveolens Vepris biloculnris

Leaves Bmk Bark Bark, leaves Bark Bark Leaves, bark, wood Leaves, wood (trace) Leaves, bark Leaves, root bark Root bark Bark, wood Stem bark, root Leaves, root Leaves, pericarps Stem bark

58 31 59 35 60 61 37, 62 38 38 63 64 42, 43 29 49 20, 65, 66 67

Maculositline (6,8-Diniethoxydictamnine) Balfourode,tdroii riedelia icum Eriostemotc brucei F. Muell. E . cocciizeus C. ,4.Gardn. E. difformis A . Cunn. E . thryptomenoides S. Moore E. torneiitrllus Diels Fliridersza m c u l o s a F.pubescens

Bark Leavcs, terminal branches Leaves, terminal branches Leaves, terminal branches Leaves, terminal branches Leaves, terminal branches Leaves, wood Leaves

13, 31 68 69 69 70 70 37, 62 38

Skimmianine (7,s-Dimethoxydictamnine) Acronychia buueri Aegle mnrnLe1o.s Bnlfourodendron riedelimzum Boroiiia ternnta Endl. Casimiroa edulis CIllo~ozylot1szcieteisin D.C.

Leaves Leaves, root, stem bark Bark Leaves

BRrk Bark

58 71, 72 31 28 23 73

6.

229

QUINOLINE ALKALOIDS

TABLE I-continued

Plant source ______

Site -

~

__._

Reference ~

____

Skimmianme (7,s-Dimethoxydictamnine)-continued Choisya ternatu H.B. et K. Citrus aurantium L. subsp. amriru Engl. C. uw-aiitium L. subsp. naisuduidaz Hayata C. u n s h i u Makino Dietamnus albus D. caucasicus Eriostemon coccineus E . thryptomenoides E . tomentellus Fugara angolensi3: Engl. P. cow F . viridis A. chev. P.zunthozyloides Lam. Fliridersia bennettianu F. Muell. P.bourjotiana F. Muell. F . dissosperma F . laeuicarpa C. T. White et Francis B’. mnculosn F . pubescens Glycosmis arborea G. pentuphylla Haplophyllum bucharicum Litwinow H . foliosurn Vved H . pedicellatum H . pcrforaturn Kar. et Ker. H . robustum Hortia urborea Lunusia amnra Blanco Mllclicope f u r e ~ n uEngl. J l u r r a y u omphnlocarpu Hayata Orixrr japonicn I’hl~bnliumnudurn Poricirus trifoliatu Rafinesquo Ptelea trifoliata Ruta graveolens Skirnmia nrisanensis Hayata 8. jtcporiica Thunb. 8. laureola Hook vepris bilocularis Znnthoxylum a ilanthoides Z . alatum (2.p l a n i s p i u m ) Z . rh?tsa DC. 2. schinifolium Sieb. et Zucc.

-

Leaves Stems Stems Leaves -

Leaves, terminal branches Leaves, terminal branches Leaves, tcrmirial branchcs Root bark Leaves Bark Root bark Bark Bark Leaves Wood Wood (trace) Bark (trace) Leaves, root bark Lcavcs (trace) -

Aerial parts Roots Leaves (not sceds) Roots Bark Leaves Leaves Leaves Root bark, leaves, fruit Bark, wood Leaf, stem Roots, leaves, fruit Roots, leaves, pericarps Leaves All parts Leavcs, bark Stem bark Wood Roots Heartwood Root, bark

74 75 75 75 3 4 , 7 6 , 77 78 69 70 70 79 53 80 81 82 83 37 84 37 38 39, 40 63 15 15, 85, 86 15,54 15, 87

55 41 12 88 89 90, 9 1 42, 4 3 75 49 20, 65, 66, 92 93 94 95

67 45 47 96

07, 98

230

H. T. OPENSHAW

TABLE I-continued

Plant sourcc -~

Site

Reference

-~

~~~

Acronycidino (5,7,8-Trimethoxydictamnine) Acronychia baueri Melicope fareanu

Bark Bark, leaves

58 88

Maculine (6,'i-Methylenedioxydictamnine) Flitidersia acuminatu F . be nnett in na F . dissosperme F . maculosa F . schottiana F. xanthoxyla Domin.

Bark Wood Bark Bark, wood Bark, wood, leaves Bark

36 82 37 37, 62 38 99

Kokusagine (7,8-i\.lethylenedioxydictamnine) Euodiu xanthoxyloides L u n a s i a arnara Orixa japonicu

Bark Leaves Leaves, root bark

60 12 64, 91

Flindersiamine (8-Methoxy-6,7-methylenedioxydictamnine) Balfourodendron riedelianurn Flindersiu bennettiuna F . bourjotiana 5'. collina F . dissosperma F . inaculosa F . pubesceizs F . xanthoxyla Teclea sudunicn A. Chev. Vepris bilocularis

Bark Bark, leaves Bark Bark Bark, leaves Bark, wood Bark (trace) Bark Leaves Stem bark

13, 31 82 83 61 37 37, 62 38 99

100 67

2. New Alkaloids 6-Methoxydictamnine (pteleine) (mp 134"-135") has been found in the and in the root and stem bark of Platydesma campanulata Mann roots, leaves, and fruit of Ptelea trifoliata L. (49); it has been synthesized (101)by the method of Tuppy and Bohm (102) (Volume VII, p. 237). Two phenolic members of this group have been isolated from Haplo~ ~ y l l species. um Haplopine (XIV) (mp 203"-204") occurs, together with the already known evoxine (XV),in the seeds of H . perforutum Kar. et Ker. (103).Skimmianine is obtained on methylation with diazomethane. The phenolic hydroxpl is shown to be a t the 7-position since haplopine is

(as),

6.

231

QUINOLINE ALKALOIDS

identical with the product of alkali fusion of evoxine (Volume VII, p. 240). Robustine (mp 147O-14tio), from the roots of H . robustum, forms a monoacetyl derivative with acetic anhydride, and is methylated by diazomethane to y-fagarine ; it is therefore formulated as 8-hydroxydictamnine (55).

3. Further Work o n Structure and Xynthesis The structure of maculosidine as 6,8-dimethoxydictamnine has been confirmed. Hydrogenolysis, followed by acid hydrolysis, gave F,8dimethoxy-3-ethyl-4-hydroxy-2-quinolone, identical with a synthetic specimen (104).The alkaloid has been synthesized (105)by the method of Tuppy and Bohm. Maculine (6,7-methylenedioxydictamnine)has been synthesized by Ohta and Mori (106, 107’) by a modification of Grundon’s method (108).3,4-Methylenedioxyanilinewas condensed with ethyl 2-benzyloxyethylmalonate and the resulting 4-hydroxy-2-quinolEtOOC, ,CH.CHzCH2OCHzPh

__f

EtOOC

I

J/ OMe I

Maculine

XVI

232

H. T. OPENSHAW

one was methylated with diazomethane aL the 4-hydroxyl group. Either the benzyloxyethyl or the derived hydroxyethyl compound may be cyclized with polyphosphoric acid to the dihydrofuro(2,3-b)quinoline (XVI) (dihydromaculine), which is converted to maculine by treatment with N-bromosuccinimide followed by dehydrobromination. Dihydrokokusaginine has also been synthesized by this (107) and a related method (66).Difficulty was experienced in its conversion to kokusaginine (6,7-dimethoxydictamnine) but this was later achieved by Kuwayama (109) (cf. I I O ) , who also developed an alternative synthesis of the dihydro alkaloids. The ethoxymagnesium derivative of a-acetobutyrolactone is condensed with an o-nitrobenzoyl chloride, and the product is deacetylated by ammonolysis. Diazomethane then gives the enol ether which may be cyclized to the dihydrofuro(2,3-b)quinolineby hydrogenation in acid solution. I n this way the dihydro derivatives of dictamnine, evolitrine, slrimmianine, haplopine, kokusaginine, and maculine were synthesized. C'OCHn

COCHn

Hz, Pd/C

I

MeOH-HCI

OMe I

Difficulty has also been experienced in the dehydrogenation of the dihydro derivative of acronycidine (5,7,8-trimethoxydictamnine), which was synthesized by Govindachari and co-workers ( I l l ) using Grundon's method, but kokusagine (7,8-methylenedioxydictamnine) (112) and flindersiamine (8-methoxy-6,7-methylenedioxydictamnine) (113)have been successfully prepared by this route.

6.

The

"

QUINOLINE

ALKALOIDS

233

4-dictamnine " synthesized by Asahina and Inubuse (Volume

111,p. 7 5 ; Volume VII, p. 236) has been shown by Ohta et al. (114)to be a mixture produced by an ineffective methylation procedure, and probably consisting mainly of the nor compound XVII.

XVII

4. Pharmacology Although a number of plants containing alkaloids of this group have been used medicinally, the alkaloids themselves have found no place in medicine. Only skimmianine appears to have been subjected to any detailed pharmacological study. According to Berezhinskaya and Trutneva (115),it potentiates adrenaline in cats, sensitizes spinal reflexes to stimuli, relaxes intestinal musculature, and raises the tonus of striated muscle ; it has much in common with ephedrine. Earlier pharmacological findings have been summarized by Schneider (92). Dictamnine strongly contracts smooth muscle and stops the isolated frog heart in diastole (116).

B. ALKALOID OF Choisya ternata Choisyine, C18H19N05 (mp 188"-189"), has beenisoIated, together with skimmianine and evoxine, from Choisya ternata H.B. et K. ( 7 4 , 117). It forms an 0-acetyl derivative (mp 231"-232") and with methyl iodide it is

XVIII

XIX Choisyine

isomerized to isochoisyine (mp 258"-259") which contains an N-methyl group. It also shows other reactions characteristic of a 4-methoxyquinoline. Hydrogenation leads t o a dihydro and a tetrahydro derivative and permanganate oxidation gives an aldehyde, C17H19NOs; a furo-

234

H. T. OPENSHAW

quinoline structure is thus suggested. Further oxidation yields ahydroxyisobutyric acid and the alkaloid is shown to possess the dihydropyranofuro(2,3-b)quinoline skeleton by its dehydration with sulfuric acid to acronidine (XVIII). Choisyine is therefore assumed to be a hydroxydihydroacronidine (XIX). OF Flindersia SPECIES* C. ALKALOIDS

Several further species of Flindersia have been examined for alkaloids and other extractives and the chemistry of this genus has been reviewed (118).The only new alkaloid found was ifflaiamine ([a]: - 0.6"; hydrate, mp 62"-63"; picrate, mp 207"-209"), the sole alkaloid of the wood of Flindersia iflaiana F. Muell. (119),which is a dihydrofuroquinoline (XX). I t s structure was largely elucidated by spectroscopic measurements. Its UV- and IR-spectra showed it to be a 2-alkoxy-4-quinolone, and the NMR-spectrum showed the presence of three C-methyl groups and one N-methyl (attached to aromatic ring N), a 1 ,Z-disubstituted benzene ring, and other evidence supporting the 2-alkoxy-4-quinolone structure.

xs

XXI

Ifflaiamine

On alkaline hydrolysis the alkaloid gave a phenolic compound (XXI), whose NMR-spectrum indicated a 4-hydroxy-2-quinolone structure and which gave an iodoform reaction. Attempts to synthesize ifflaiamine have not succeeded so far. OCH2 .CHOH .C(OH)Mr? I

CH?; XXII Maculosine

Maculosine (mp 229"-230"; [a]: + 36" in pyridine), from F . maculosa, originally (62) thought not to be a furoquinoline, has now been shown (104) to possess the structure XXII-an interesting variant of the

* Supplementary

t o Volume VII, p. 238.

6.

QUINOLINE ALKALOIDS

235

general type. The alkaloid, C I ~ H I ~ N Ocontains ~, a methylenedioxy group but no methoxy or methylimino group. It is optically active and the IR-spectrum shows the presence of hydroxyl groups; as phenolic properties are absent, the presence of alcoholic hydroxyl groups is indicated. The UV-absorption is very similar to that of a typical furoquinoline alkaloid. Periodic acid oxidation yielded acetone, formaldehyde, and a product which on hydrogenolysis gave the known 3-ethyl-4-hydroxy-6,7-methylenedioxy-2-quinolone, also obtained by hydrogenolysis of the alkaloid, followed by acid hydrolysis.

D. ALKALOIDSOF Evodia SPECIES* Evoxine (XXIII), originally isolated from Evodia xanthoxyloides F. Muell. (IZO),has also been found in Choisya ternata (7’4) and in the

I

Me0

SSIII Evoxine

* Supplementary t o Volume VII, p. 239.

236

H. T . OPENSHAW

seeds of Haplophyllum perforaturn (103). Evodine (mp 153"-154"; [a]: - 3" in chloroform), a base occurring in small amount in E . xanthoxyloides ( 1 2 4 , is isomeric with evoxoidine (XXIV), C18H19N05, but unlike the latter is not an artifact from the action of acid on evoxine. I t s structure was largely elucidated by physical means (121).The UVspectrum was similar to that of evoxoidine, but the IR-absorption indicated the presence of a hydroxyl group and a terminal methylene group. Analysis of the NMR-spectrum accounted for the functions of all nineteen protons and led to the proposal of structure XXV. Confirmation was achieved by a correlation with evoxoidine. Hydrogenation of evodine gave an optically active hexahydro derivative corresponding t o saturation of the ethylenic bond and hydrogenolysis of the furan ring; borohydride reduction of evoxoidine (XXIV) followed by hydrogenolysis gave a racemic product (XXVI) identical in IR-absorption with hexahydroevodine.

IV. Alkaloids of Lunasia amara and of Balfourodendron riedelianum

A. INTRODUCTION Although the presence of alkaloids in Lunasia amara Blanco has been long recognized and several bases were isolated and characterized during the first half of this century (Volume V, p. 316) the structures of only two had been elucidated by 1957 (Volume VII, p. 241) both of these being simple 2-arylquinoline derivatives (XXVII and XXVIII). Shortly

afterward an intensive study of the alkaloid content of :he leaves of this species was reported by Goodwin and her colleagues ( 1 2 )while Beyerman and Rooda (122) reexamined the alkaloids of the bark. Concurrently R,apoport and Holden (13) studied the alkaloids of Balfourodendron riedelianum Engl. which proved to be the optical enantiomers of some members of the Lunasia group.

TABLE II ALKALOIDS ISOLATED FROM Lunasia amaraa AND Balfourodendron riedeliarium'

Melting point ("C)

[a]%

(ethanol)

Reference

2-Aryl-4-methoxyquiriolines a n d 2 - a r y l - l - m e t h y l- 4 - ~u in o lo ~2 e s 4-Mcthoxy-2-phcnylquinoline ( X X V I I ) 4-Methoxy-2-(3',4'-mcthylonedioxyphenyl)quinoline (XXX) l-Methyl-2-phrnyl-4-quinolone (XXIX) 7-Mcthoxy-l-methyl-2-phenyl-4-quinolone (XXVIII)"~d "Luriasia I " ( X X X I ) Lunamarine (XXXII)

66-67 116-1 1 7 144-1 45 198-200 230-233 245-247

4-Methoxy-1-methyl-2-quinolones Lunacridine ( X X X V ) Hydroxylunacridine ( X X X V J I I ) Balfourolonr ( X X X V I I I ) Lunidine (XLIV) Hydroxylunidino (XLV) Lunidonine ( X L V I ) Luriulono (structure unknown)

85-86 100-1 02 99-100 65-66.5 124-1 23 118-119 100-103

0 0 0 0 0 0 t30.1" +31.5" - 36" +28"" +27.6" 0 +20.6"

123 I2 13 12 122,124 12.125 122, 125, 126 12, 127 I3 128 12 128 12

QT.XXOLIXE ALKALOIDS

-~

6.

Compound

TABLE 11-continued

Compound

Empirical formula

Dihydrofuro- and -pyrano-quinolines ( - )-Lunacrine (XXXIV)' (k)-Lunacrine (XXXIV) Hydroxylunacrine (XXXVII) Balfourodine (XXXVII) Lunine (XLII)" Hydroxylunine (XLIII) Lunacrinol (" Lunasia I1") (XLVII) Isobalfourodine (XLVII) Lunasine (XXXVl) 04-Methylbalfourodinium (LV)

Melting point ("C)

117-1 18 145-146 216-21 8' 188-189 228-229 228-230 201-203 204-205 143-;44y 124-125'

[a]*;

(ethanol)

Referrnce

- 50.4'

1 2 5 , 1 2 6 , 129, 130 122 12 13 12, 126 12 12,122 13 131 13

0 - 14.6"' + 49" - 38.5" - 5.9"

- 14'

+ 15" - 200g

+9"'

The furoquinolines skimmianine and kokusagine also occur in traces in the leaves ( 1 2 ) .

* The furoquinolines dictamnine, skimmianine, kokusaginine, maculosidine, and flindersiamine, and the acridone, cvoxnnthinc, are also present (13, 3 1 ) . Also isolated from the bark of L. quercifolia (Warb.) Lauterb. et K. Schum. ( 2 4 ) . Identical with cdulein from Casimiroa edulis bark (23). At 20". Perchlorate. Picrate.

'

6.

QUINOLINE

239

ALKALOIDS

The Lunasia and Balfourodendron alkaloids described thus far are listed in Table 11.They may be divided into three chemical groups. The first group consists of the simple 2-arylquinoline derivatives. The chemistry of the newly discovered members (XXIX, XXX, XXXI, XXXII) of this group resembles that of the previously studied examples (XXVII and XXVIII) and the assigned structures have been confirmed by synthesis (12, 124). Compounds of the second group have ringopened structures related to the tricyclic alkaloids of the third group. It is certain that some (and it is possible that all) of the compounds of the second group are artifacts, arising by the action of the alkali used in the extraction process on water-soluble, quaternary precursors existing in the plant.

Me XXX

XXXI; R’=OMe, R ” = H Lunasia I X X X I I ; R’=H, R ” = O M e Lunamarine

B. Lunasia ALKALOIDS: STRUCTURAL DETERMINATION 1. Lunacrine, Lunacridine, and Lunasine The major Lunasia alkaloid is ( - )-lunacrine, C16H19N03.Its structure was elucidated by Goodwin and Horriing (130).It contains one methoxyl and one methylimino group and Kuhn-Roth determination shows the presence of one C-methyl (or gem-dimethyl) group. The alkaloid is resistant to catalytic hydrogenation. The UV-spectral characteristics, particularly the hypsochromic shift of the long wavelength bands on acidification (313 and 326 + 300 mp), are consistent with a 4-quinolone structure. Hot aqueous alcoholic alkali converts the alkaloid into an alkali-soluble product by addition of the elements of water ;this product can be methylated by ethereal diazomethane to give a compound containing two methoxyl groups identical with the alkaloid ( + )-lunacridine. The UV-spectrum of lunacridine, which is unchanged in acid or alkali, is consistent with the presence of a 2-quinolone system; the bathochromic shift of the maxima a t 284 and 294 mp, in comparison with those of 4-methoxy-1-methyl-2-quinolone (268 and 278 mp), can be attributed

240

H . T. Ol’EXSHAX

t o the presence of a 3-substituent (130). The IR-absorption is also consistelit with a quinolone structure ( 1 3 1 ) . The formation of a 3substituted 4-methoxy-2-quinolone from the 4-quinolone lunacrine without loss of carbon requires t h a t the latter should contain a 5 - or 6-membered oxygen ring fused a t the 2,3-position ; the molecular formula

( - )-Lunarrine

(

(

+ )-Lunacridine

+ )-Lunacrine

and the resistance t o hydrogenation require this t o be a dihydrofuro- or dihydropyrano system. I n view of the prevalence of furoquinoline alkaloids in the Rutaceae, the five-membered ring was considered more likely.

6.

Q U I N O L I N E ALKALOIDS

241

When treated with a-toluenesulfonyl chloride in pyridine, ( + )lunacridine is converted in low yield into ( + )-lunacrine, the enantiomorph of the natural alkaloid. The cycle of reactions whereby ( - )lunacrine is converted through ( + )-lunacridine to ( + )-lunacrine thus includes a stereochemical inversion and requires that the alkaloids contain a single center of asymmetry which, in view of the reactions involved, must be adjacent to the ring oxygen. This leads to the representation (130)of the processes shown on p. 240. Cyclization of lunacridine can also be achieved more simply by fusion of its perchlorate which is thereby converted into a crystalline quaternary perchlorate corresponding to the intermediate XXXIII. The perchlorate anion is insufficiently nucleophilic to be capable of removing the 4-0methyl group of X X X I I I , but if the perchlorate is heated with lithium bromide in acetonitrile solution demethylation to ( + )-lunacrine occurs (130).Lunacridine can also be converted directly to ( + )-lunacrine by the action of strong acid (131). The structural elucidation was completed by the use of NMR-spectroscopy ( 7 ) to show that the Bz-methoxy group is attached at the 8position of the quinoline nucleus, and that the side chain C3H7 is an isopropyl group, as would be expected on biogenetic grounds. Thus the alkaloids lunacrine and lunacridine are XXXIV and XXXV, respectively.

XXXIV

XXXV

Lunacrine

Lunacridine

*aHMe2 C104-

Me0

Me

XXXVI Lunasine perchlorate

Price (131) has shown that the quaternary alkaloid lunasine perchlorate, isolated from L. quercifolia, is identical with methyllunacrinium perchlorate (XXXVI); on mild treatment with alkali, lunasine is

242

H . T. OPENSHAW

converted into lunacridine (XXXV). This is probably the source of the lunacridine isolated from the plant.

2. Hydroxylunacrine and Hydroxylunacridine A minor alkaloid, C16H19N04, had a UV-spectrum identical with that of lunacrine in both neutral and acid solution, and showed strong resemblance in its IR-absorption. As it contains one additional oxygen atom it was considered to be a hydroxylunacrine, and as the NMRspectrum showed the absence of the tertiary hydrogen atom of the

OH

Me

McO @!:k-C(OH)Mez M M O

Me0 XXXVIII Hydroxylunarridino

XXXVII Hydroxylunacrine

isopropyl group, the additional hydroxyl group was assigned to this position (XXXVII) ( 1 2 ) . Correspondingly, an alkaloid, C17H23N05, which had spectral characteristics similar to those of lunacridine, was shown by its NMR-spectrum to be hydroxylunacridine (XXXVIII) (127). The structure was confirmed by degradation. Periodic acid oxidation gave acetone and an aldehyde (XXXIX) (characterized as the dinitrophenylhydrazone) which was reduced by sodium borohydride to OMe

OMe

XL

XXXIX

t OH-

OMe I

I

OMe

I

6.

QUINOLIYE

ALKALOIDS

243

the crystalline alcohol (XL). The same alcohol was obtained from dihydro-y-fagarine (XLI) by alkaline fission of its methiodide (cf. conversion of lunasine to lunacridine, above).

3. Lunine, Ltcnidine, and Lunidonine ( - )-Lunine, C I ~ H ~ ~ N was O found ~, to contain no methoxyl group. The NMIt-spectrum ( 7 )shows that it possesses the same ring system and side-chain structure as lunacrine, but contains a methylenedioxy group attached a t the 7,8-position, and is therefore XLII. Ruegger and Stauffacher (128)isolated lunidine (XLIV) from L. amara var. repanda, and showed that it bears the same relation to Iunine as lunacridine does to lunacrine. Fusion of its perchlorate gave ( + )-0-methylluninium perchlorate, converted by lithium bromide in acetonitrile to ( + )-lunine. They also isolated lunidonine (XLVI), the ketone related to lunidine, and obtainable from it by chromic acid oxidation. 0

OMe

XLIV; R = H , Lunidine XLV; R=OH, Hydrox ylunidine

XLII; R = H, Lunine XLIII; R = O H , H ydroxylunine OMe

0 I

Me

H26-0

XLVI Lunidonine

Hydroxylunine (XLIII)and hydroxylunidine (XLV)are also found in the leaves of L. amara (12). 4 . Lunacrinol Lunacrinol, isolated in very small amount from L. amara leaves (12), is identical with “Lunasia 11”obtained from the bark (122).Beyerman and Rooda (122) have shown this to be a dihydropyranoquinoline

244

H . T . OPENSHA\V

( XLVIl), isomeric with hydroxyluiiacriiie (XXXVII),by comparison of its UV-spectrum with those of model compounds. On treatment u ith methyl sulfate it forms a quaternary salt which is decomposed hy alliali to racemic hydroxylunacridine (XXXT‘III ) ; as lunacrinol is opticallyactive the reaction must be accompanied by racemization.

*F Me.0

Me

XLVII

Me0

CHOH-C( OH)Mea Me

XXXVIII

Lunacrinol (“Lunasia 11”)

5. Pharmacology Some earlier reports on the pharmacological activity of Lunasiu extracts were vitiated by the use of incorrectly identified botanical material ; the position was reviewed by Dieterle and Bey1 (129).According to Steldt and Chen (125), lunacrine, lunacridine, and lunamaririe all cause a transient fall in blood pressure in cats, but show no digitalis-like action on the frog heart; they have no effect on blood sugar levels. Lunamarine moderately stimulated isolated rabbit intestine and uterus, but the other two alkaloids had little effect. I n acute toxicity tests in mice, lunacrine showed an intravenous LD50 of 78.7 2 3.8 mg/kg; because of their insolubility, lunacridine and lunamarine had to be given orally, the former giving an LD50 of 1097 2 167 mg/kg, the latter being nontoxic at 1000 mg/kg.

C. Balfourodendron ALKALOIDS : STRUCTURAL DETERMINATION The alkaloids of the bark of Balfourodendro?~riedelinnum Engl. ( B .eburneum Mello), a South American shrub used locally for treatment of stomach complaints, have bccn studied by Rapoport and Holdeii (I.?), The first two alkaloids isolated, balfourodine and balfourolone, showed a striking similarity in UV-absorption to luiiacriiie (XXXIV) and lunacridine (XXXV), respectively. Balfourodine, C l ~ H l & 0 4 (mp 188”-189”), contains one methoxyl and one methylimino group; balfourolone, CI7H23NO5(mp 99”-1 OO“), has an additional methoxyl group ; both alkaloids differ from their Lumsia counterparts by containing one additional oxygen atom which, since it does not influence the UV-

6.

245

QUINOLINE ALKALOIDS

absorption, cannot be on the quinoline nucleus. This suggested a glycol structure for balfourolone ; treatment with periodic acid produced acetone and an aldehyde which, assuming the analogy with lunacridine, should be XLVIII. Borohydride reduction gave an alcohol which was identified as XLIX by a synthesis following the route shown.

1. CHIXI

T

2. Hz/Pd

OH

The degradation products XLVIII and XLIX are identical with those ( X X X I X and XL) independently obtained from hydroxylunacridine (XXXVIII) by Goodwin et al. ; balfourolone in fact corresponds in properties to this alkaloid, with the exception that it has the opposite (levo) optical rotation ; i.e., it is ( - )-hydroxylunacridine. Balfourodine, like lunacrine, forms a methiodide which very readily undergoes ring fission by alkali, yielding balfourolone. Its UV-absorption resembles that of model linear dihydrofuroquinolines and it is therefore assigned the

XXXVII Balfourodine

L

246

H . T . OPENSHAW

structure XXXVII, [i.e., ( + )-hydroxylunacrine]. In support of this, dehydration by cold concentrated sulfuric acid converts balfourodine into a furoquinoline (L) which is hydrogenated to ( )-lunacrine (XXXIV). I n contrast, a third alkaloid isolated from the extracts, isobalfourodine, ClsH1gN04, has a UV-spectrum slightly different from that of balfourodine but identical with that of the model dihydropyranoquinoline L I and is accordingly ascribed the structure XLVII [i.e., ( + )-lunacrinol]. Isobalfourodine readily forms an 0-acetyl derivative (LII); acetylation of balfonrodine requires more vigorous conditions and is accompanied by rearrangement, the same product (LII) being obtained (in a partially racemized form). The UV-spectrum shows that the acetate contains the dihydropyran ring and on hydrolysis isobalfourodine is obtained.

Me

WR Me

Me0

Me0

LI

XLVII; R = H , Isohalfouroclinc 1,II: R = Ac

Rearrangement also occurs when balfourodine is treated with methyl sulfate, isobalfourodine methosulfate being formed. When the alkaloids or the methosulfate are treated with strong alkali, angular dihydrofuroand dihydropyrano-2-quinolones(LIII, LIV) are formed ; because of the occurrence of stereochemical inversions in some of these transformations both ( + ) - and (-)-forms of the rearrangement products can be obtained ( 1 3 ) .Similarly, Beyerman and Rooda, (122) have shown that Lunasia I1 is isomerized by alkali to LIV. The structures of these $-alkaloids were assigned by correlation of the UV-spectra with those of model compounds.

6. QCINOLINE

ALKALOIDS

247

As a %quinolone, balfourolone is virtually nonbasic and is readily extracted from aqueous acidic media by et,her. However, Rapoport and Holden ( 1 3 )noted that no balfourolone was obtained by ether extraction of the aqueous solution of the plant extracts until this had been brought to pH 10. By extraction with butanol at pH 7 they were able to isolate as perchlorate the expected quaternary precursor, 04-methylbalfourodinium (LV).Basification of the residual aqueous phase then gave only a negligible amount of balfourolone. When treated with alkali, the quaternary alkaloid was converted into balfourolone in good yield, clearly establishing the latter as an artifact. From a plant extract which had been kept in ethanol solution for a long time, the 04-ethyl analog of balfourolone (mp 137") was isolated. I t s identity was confirmed by its formation by alkali treatment of balfourodine ethiodide. It may be assumed that the cation LVI was present in the extract as a n artifact produced by alkoxyl interchange of LV with the ethanol solvent (132). OR I

I

Me0

Me LV; R = M e LVI; R = E t

D. SYNTHESIS The racemic forms of several of the Lunasia-Balfourodendron alkaloids have been synthesized by Clarke and Grundon (14, 133). Ethyl 3methylbut-2-enylmalonate (LVII)condensed with N-methyl-o-anisidine in the usual manner and the resulting 4-hydroxy-3-(3-methyIbut-2enyl)-2-quinolone (LVIII)was subjected to anti-Markovnikov hydration by the hydroboronation procedure ( 1 3 4 ) Methylation . with diazomethane then gave ( k )-lunacridine. Alternatively, methylation to LIX could precede the hydration process. The synthetic product was compared with ( )-lunacridine obtained by alkali treatment of the methiodide of natural ( k )-lunacrine (122); it was also cyclized by acid to give synthetic ( k )-lunacrine together with a large proportion of the angular isomer (LXI) ( 1 2 2 , 1 3 1 ) . When the unsaturated quinolone LTX was treated with sulfuric acid in cold aqueous dioxan, Markovnikov hydration to the tertiary alcohol L X I I took place ( l a ) ,and this could be cyclized by hot acid to a mixture

248

H . T. OPENSHAW

Me LVIII

CHaNe

EtOOC,

,CHCHzCH=CMez Me0

CHIN,

LVII LIX; R =Me LX;R=H BzHsIHaOz

J

( & )-Lunacrine

( & )-Lunacridine

qY

Me0

Me

LXI

of the linear and angular pyranoquinolines LXIII and LXIV. The structures of these products were unequivocally assigned by consideration of their spectroscopic (especially NMR) properties. The unsaturated quinolones (LVIII and LIX) can also be cyclized directly to the same mixture of pyranoquinolines (LXIII and LXIV). Treatment of the 4-hydroxyquinolone LVIII with peroxylauric acid gave, presumably through an intermediate epoxide LXV, a product which was identified as ( & )-balfourodine [( & )-hydroxylunacrine] by UV- and chromatographic comparison with natural ( + )-balfourodine.

6.

QUINOLINE

249

ALKALOIDS

On acetylation, followed by hydrolysis, it was converted into ( isobalfourodine [( & )-lunacrinol].

LXII

)-

LXIV

LXIII

@H -

cn;D,

@ T TMec M e z +

Me0

Me0

Me

1. A c t 0 2. O H -

A

CMe20H

( & )-Balfourodine

LXV

WH Me

Me0

( rf: )-Isobalfourodine

Similar oxidation of the methoxyquinolone L I X gave a water-soluble product, isolated as the perchlorate, which was identified as (k)-0methylbalfourodinium (LV) perchlorate. When the norquinolone LX was treated with peroxylauric acid, a mixture of the furo- and pyranoquinolines LXVI and LXVII was obtained; heating of the latter with methyl iodide furnished ( )-isobalfourodine, while the former similarly gave ( i )-balfourodine (135). OMe

I

Me0 LXVI

I Me0

LXVII

250

H . T. OPENSHAW

V. Alkaloids of Orixa japonica Besides skimmianhe, evolitrine, kokusagine, and kokusaginirie, the root bark of Orixa japonica Thunb. contains orixine (LXPIII), C17H21N06 (mp 152.5"; [.ID + 83.3') (136)and nororixine (51)(LXIX), C16H19NO6 (mp 199"-200") ; the latter is also produced by demethylation of orixine with ethereal hydrogen chloride (137).\;l'hen methylated with diazomethane nororixine is converted into isoorixine (LXX) which contains an N-methyl group; both these compounds have the UVabsorption of 2-yuinolones and isoorixine is identical with hydroxylunidine (XLV) from Lunasia amara (12)(see Section IV,B,3).

LXVIII

LXIX; R = H

Orixine

Sororixine

LXX; R = M e Isoorixine

OMe

I H2C-0

1 HzC-0

L

HC1-Eta0

@ J

0

Hz,P t O i ,

?@rCH3 H

I

H2C-0

H2C-0 Kokusagirie

LXXI

6.

QTJIXOLISE

251

ALKALOIDS

Oxidation of orixine with periodic acid gives acetone and an aldehyde ; hydrogenolysis of the ethylthioketal of the latter, followed by demethylation, yields LXXI which is identical with the hydrogenolysis product of kokusagine (138). Similar oxidation of nororixine, followed by borohydride reduction and methylation with diazomethane, gives the alcohol LXXII, which can also be obtained by the action of alkali on dihydrokokusagine methiodide (LXXIII) (see Section IV,B,2). LXIS

LXXIII

LXXII

When orixine or nororixine is warmed with aqueous hydrochloric acid (137, 139) it is converted into a mixture of orixidiiie (LXXIV), C15H13N04 (mp 195"; optically inactive), and orixidinine (LXXV),

0 I

LSXV

LSSITT Orixirline

Orixidinine

LXXVI

252

H . T. OPENSHAW

C15H15KO5 (mp 213"; [ c L ] ' " , ~ - 40.8'). The IR-spectrum of orixidine shows the absence of hydroxyl and methoxyl groups. The compound is unaffected by periodic acid and is resistant to catalytic hydrogenation in the cold, but with hydrogen and palladium at 35"-45" it gives dihydroorixidine, the UV-spectrum of which differs greatly from that of orixidine but resembles that of orixidinine. OzonoIysis of orixidine gives some isobutyric acid. Orixidinine contains a hydroxyl group (IR-spectrum) and concentrated sulfuric acid dehydrates it to orixidine. Treatment of isoorixine (LXX) with aqueous hydrochloric acid gives the h'-methyl derivatives of LXXIV and LXXV, which are also obtained by direct methylation with diazomethane. Under the influence of methanolic potash, N-methylorixidinine undergoes partial rearrangement to iso-Nmethylorixidinine (LXXVI). The structures assigned to these N-methyl compounds have been confirmed by NMR-studies ( 140).

VI. Alkaloids of Haplophyllum Species A. OCCURREPU'CE A number of species of Haplophylbum" (Rutaceae) growing in Uzbekistan and neighboring regions of Central Asia have been examined for alkaloids by Sidyakin, Yunusov et al., with the results shown in Table 111. Of these, mention has already been made of the 2-arylquinoline, dubamine (Section II), the 2-quinolone, foliosidine (Section II), and the phenolic furoquinolines, haplopine and robustine (Section III,A,2 ) . No structural investigation of foliosine, C17H15N03, has been described apart from the detection in it of an N-methyl and a methylenedioxy group.

B. HAPLOPHYLLIDINE This alkaloid, C18H23N04, is most conveniently obtained from H . perforatum seeds ( 0 .IS?/, yield) ; it crystallizes from light petroleum in colorless needles and is readily soluble in most other organic solvents. It contains one hydroxyl and two methoxyl groups and is not methylated by diazomethane ( 8 7 ) . On hydrogenation over platinic oxide it is converted to a tetrahydro derivative (143) which forms a diacetyl derivative ; together with the change in absorption spectrum this suggests the hydrogenolysis of a furoquinoline system (144).The alkaloid contains

* For a note on the nomenclature

of this genus see Volurrie V, p. 31 1.

Sptcies

H . buchnricurn Lit\. H . dubiurn Eug. Kor.

H . foliosum Vvecl

P a r t of plant

Alkaloids found

Aerial parts Aerial parts Leaves Leavcs

Skimrnianine ( X I I I ) An alkaloid Duhamine (I) Dubinine ( L X X X )

Leavcs

Dubinidine ( L X X I X )

Aerial Aerial Aerial Aerial

Skimmianine Dubinidine Foliosine Foliosidine ( V I I I )

parts parts parts parts

Physical properticss

-

mp 15I".~l520 m p 95"- $16' mp 185"- 186", [ a l l , - 59" ( E t O H ) mp 132"-133", [a]: - 63" ( E t O H ) -

mp 188"- 189" m p 141"-142", [a]? + 4 1 . 6 "

H . prdicc~lkitumBge. H . perjorrctum Kar. ct Kcr.

H . robustuin

H . vorsicolor Fisch.

Roots Aerial parts Aerial parts Leaves, stems Leavcs, stems, seeds Leavcs, stems, seeds

Khaplofoline ( L X X X I I I ) Skimrnianirie y-Fagarine ( = " haplophino ") Skimmianiric Evoxine ( = " haploperirie ") Haplophyllidine (LXXVII)

Seeds Roots Roots Roots Roots Aerial parts Aerial parts

Haplopine (XIV) Skimmianine y-Fagarine Robustine (8-Hydroxydictamnine) " Base I V " Haplopine Traces (0.01% total)

(EtOH)

m p 252"--2$4" -

-

__ mp 110"-111", [a]:: - 16.2" (acctont?) mp 203"-204" -

mp 147"-1.18" m p 930"- 23 I " -

254

H. T. O P E N S H A W

two C-methyl groups and the ease of formation of acetic acid on oxidation suggests the presence of a -CHOH-Me group. Oxidation of tetrahydrohaplophyllidine gives some propionic acid as well as acetic acid showing the presence of a C-ethyl group in this reduction product. Since no y-fagarinic aldehyde or acid could be detected on oxidation with permanganate in acetone, it was assumed that the second methoxy group is not in the 8-position, and i t was assigned the 7-position by analogy with the majority of similar alkaloids. Accordingly, the tentative structure LXXVII was proposed for haplophyllidine (144), but confirmation is clearly desirable. OMe

Haplophyllidine is a strong depressant of the central nervous system ; it synergizes the effects of hypnotic drugs in mice, rats, and rabbits, and antagonizes the action of analeptics (145). C. DUBINIDINEAND DUBININE Dubinidine is an optically active base, C15H17N04, containing two alcoholic hydroxyl groups (86, 146). Its IR-spectrum closely resembles that of a dihydrofuroquinoline alkaloid such as lunacrine ; with methyl iodide it gives a methiodide, which is isomerized by alkali to isodubinidine, containing a n N-methyl group-a behavior typical of a 4-methoxyquinoline. Confirmation is given by the formation of dictamnic acid (LXXVIII) on permanganate oxidation of the alkaloid ; chromic acid gives acetic acid but no acetone or isobutyric acid ( 8 6 , 1 4 7 ) Periodic . acid yields formaldehyde and an aldeliyde, dubinidinal, C14H13N03, showing the presence of a terminal glycol group in dubinidine. Clemmensen reduction of dubinidinal is accompanied by hydration, the product being C14H17NO3 and containing one hydroxyl, one methoxyl, one amide carbonyl, and two C-methyl groups. It is suggested (147)that dubinidine is LXXIX and that on reduction of dubinidinal (LXXXI) ring fission has occurred under the acidic conditions to give LXXXII. Further evidence for the correctness of structure L X X I X would appear to be required. Like haplophyllidine, dubinidine is a central nervous depressant and antagonizes the convulsant effects of strychnine and corazole (148).

6.

255

QUINOLINE ALKALOIDS

m;H H

LSXVIII

LXSIX; R = H r,xxx : R = A ~

OMe

OMP

LXXXI

LXXXII

Dubinine has been identified as the monoacetyl derivative LXXX of dubinidine, to which it is hydrolyzed by hot 5% hydrochloric acid (149). D. KHAPLOFOLINE The underground parts of H . foliosum contain khaplofoline, an optically inactive alkaloid which is oxidized by permanganate to N-oxalylanthranilic acid ; chromic acid oxidation gives acetone and 0.7 mole of acetic acid. Its UV-absorption is that of a 4-quinolone and treatment with methyl iodide and potassium carbonate in acetone produces an N-methyl derivative ; acetylation gives N-acetylkhaplofoline. The structure LXXXIII proposed for the alkaloid (142) C14H15N02,

EQ&

OH

arl, E

t

H

~L X~X X I I I Khaplofoline

256

H. T. OPENSHAW

has been confirmed through its synthesis by Bowman and Grundon (150).

VII. Alkaloids of Platydesma campanulata

A. INTRODUCTION The root and bark of the Hawaiian shrub Platydesma campanulata Mann contain evolitrine, kokusaginine, and the new alkaloids 1,2dimethyl-4-quinolone (XI) (Section 11),6-methoxydictamnine (Section 111,A,2), and platydesmine ; the leaves contain kokusaginine, 1,2dimethyl-4-quinolone, and the new alkaloid pilokeanine (29). B. PLATYDESMINE This alkaloid, C15H17N03 (mp 137"-138"; picrate, mp 107"-log"), has UV-absorption in neutral and in acidic ethanol identical with that of dihydrodictamnine. The mass spectrum shows only two major peaks, that of the molecular ion at 259 and a second peak at 200 m/e units, corresponding to a loss of C2H302 or C3H70.The former is unlikely, since the IR-spectrum shows no absorption in the 5.6 p region, indicative of an acetate or carbomethoxy group. A band at 2.79 p, however, suggests a. tertiary hydroxyl; if it is assumed that fragmentation is more likely to involve removal of a side chain than disruption of the dihydrofuroquinoline nucleus, the partial structure LXXXIV can be advanced for platydesmine. By analogy with the Balfourodendron and Lunasia alkaloids position 2 is the more likely point of attachment of the side ?Me

QMe

/

~~atydesmine

mTH2 OMo

I

CH=CMrz

H

6.

QUINOLINE ALKALOIDS

257

chain (29).The correctness of the structure LXXXV has been confirmed by synthesis (135) of the racemic base by treatment of the quinolone LXXXVI with peroxylauric acid (1.1)(see Section IV,D).

C. PILOKEANINE This oily base (picrate, mp 216" dec.) was isolated in small quantity from the leaves; the name is derived from the Hawaiian name of the plant, pilo-kea. Analysis indicates a formula C16H19-23N03, with one methoxyl and one N-methyl group. The UV-spectrum suggests a l-methyl-8-methoxy-4-quinolone showing the characteristic hypsochromic shift in dilute acid (130). The IR-spectrum also indicates a 4-quinolone structure but the absorption characteristic of a furan ring is absent ; a band a t 2.72 p suggests a primary or secondary alcoholic group. Oxidation with chromic acid gave a product which was isolated as a picrate (mp 187"-189"), analyzing for C16H1gN03*C6H3N407and having the same UV- but a different IR-spectrum from that of the alkaloid picrate. This is consistent with the oxidation of a secondary alcohol to a ketone in which the carbonyl is not adjacent to the quinoline nucleus. By analogy with other naturally occurring 4-quinolones the structure LXXXVII is proposed (29).

LSSSVII

VIII. Alkaloids of Macrorungia longistrobus Four new alkaloids-macrorine, normacrorine, isomacrorine, and macrorungine-have been isolated from the aerial parts of the South African shrub Macrorungia longistrobus C. B. Clarke (Acanthaceae) and have been shown to possess the novel quinolylimidazole structures LXXXVIII-XCI (151). The relationship between macrorine (mp 160") and isomacrorine, (mp 110') is shown by their formation of a common methiodide (mp 196") ; on thermal decomposition this gives macrorine and only a trace of isomacrorine. Methylation of normacrorine (mp 156"-157") with dimethyl sulfate gives a 2 : l mixture of macrorine and isomacrorine.

258

11. T . OPENSHAW

Sc' Isomacrorine

LXXXT'III;R=Ne Nacrorine

LXXXIX ; R = H Sorrnacrorine

SCI Macrorungine

The NMR-spectrum of macrorine shows, besides an AT-methyl group, only aromatically linked protons and the IR-spectrum contains only aromatic bands. Macrorine is stable to zinc dust distillation and to alkali fusion. With hydrogen and platinic oxide it gives a tetrahydro derivative which contains an NH group and has a IJV-spectrum resembling that of 1,2,3,4-tetrahydroquinoline-2-carboxyamide; NNR-spectroscopy also structure. suggests a 1,2,3,4-tetrahydroquinoline Oxidation of macrorine with permanganate gives quinoline-2carboxyamide and a second product, identified as the acylurea XCII by its spectral characteristics and by methanolysis with methanolic hydrochloric acid to methyl quinaldate and methylurea. Similar

SCII SCIII

oxidation of isomacrorine gives quinoline-2-carboxy-AT-methylamide as the main product. Macrorungine (mp 26'i0-2700 decomp.) is pale yellow, contains an amide carboiiyl group, and can be converted by reduction with lithium

6.

259

QUINOLIXE ALKALOIDS

aluminum hydride into macrorine. Location of the carboriyl group between two iiitrogeii atoms rests on the stability of macrorungine to acid or alkaline hydrolysis. Oxidation of macrorungine with permanganate produces the ureide XCII and a second product for which the structure XCIII has been proposed; chromic acid gives the terminal 3’-formyl derivative of XCII. Treatment of macrorine methiodide with alkali causes ring opening to a nonquaternary product formulated as XCIV and oxidized by chromic acid in pyridine to quinoline-2-carboxy-N-formyl-N-methylamide (XCV).

The structures of these alkaloids have been confirmed by the synthesis of normacrorine. 2-Acetylquinoline oxime was converted into 2-waminoacetylquiiioline hydrochloride by the Neber rearrangement and thiocyanate then gave the imidazole-2-thiol (XCVI), which was desulfurized with dilute nitric acid to yield normacroriiie (LXXXIX).

XCVI

H

IX. Biogenesis The biogeiiesis of the quinoline alkaloids found in the Rutaceae has been the subject of considerable speculation ; some earlier suggestions, concerned with the biogenesis of the simple 2-aryl- and 2-alkylquinolines, such as the angostura alkaloids, were discussed in Volume 111,Chapter 1 7 . It has generally bemi considered that the quinoline alkaloids of the Rutaceae, together with the acridine and quinazoline alkaloids which often occur alongside them, are all derived from an “anthraiiilic acid

unit" (152),but opinions have varied as to the precise nature of this precursor. For example, Scliopf and Thierfelder (153, 251) proposed a scheme for the biogenesis of the %substituted 4-quinolones or 4-methoxyquinolines in which o-aminobenzoylacetic acid (XCVII) condenses with an aldehyde, followed by dehydrogenation and methylation of the product. Robinson (155), however, considered the known oxidation product (XCVIII) of tryptophan as a more likely precursor; by its condensation with an acid. R .COzH, a 4-quinolone could be obtained directly. Several suggestions were put forward by Robinson for the origin of the furan ring in the furoquinolines ; it could be the residue of the tryptophan side chain existing in the intermediate XCVIII; it could be formed by

H

XCVII

0

a~5c0.COzH

I

+ HOzC-R

+

H

CHO XCVIII

degradation of an aromatic ring of the acridones; or it might arise by condensation of a suitable intermediate with a 2,4-dihydroxyquinoline derivative. This last suggestion has gained the most favor, since it may be considered as analogous to the probable biogenesis of the furocoumarins, many of which also occur in the Rutaceae; moreover, it is strongly supported by the more recent discoveries in the chemistry of this group of alkaloids. Aneja et al. (156) have drawn attention to the striking association of compounds having unsubstituted fused furan rings with those containing obvious isopentane attachments. This association is evident in both the furocoumarin and similar series and in the quinoline alkaloids ; thus Orixa japonica contains orixine and kokusagjne, while in acronidine and evoxine both features are found in the same molecule. Moreover, isopeiitanoid coumarins occur together with furoquinolines ; for example, Chloroxylon szcietenia, which contains skimmianine, also contains 7-demethylsuberosin (XCIX). This can be converted by

6.

261

QUINOLINE ALKALOIDS

p ~ m ~ . OMe cH(0H).'(0H)Mp2

0

0

1

I

HzC-0

H2C-0 Orixiric

Me0

Kokusaginc

MezC(0H) . C H O H .CHzO Me0 Acronidine

Evoxine

epoxidation and cyclization (157) into the dihydrofurocoumarin C, a procedure similar to that later used by Clarke and Grundon ( 1 4 )for the synthesis of balfourodine.

XCIX

C

Such analogies clearly lead to the supposition that the unsubstituted furan ring may arise by the fission of a 3-carbon fragment from the cyclized isopentane unit; this idea is far from new in the furocoumariii field (158),but its applicability t o the furoquinoline series became obvious only after the structures of alkaloids such as orixine, lunacrine, and balfourodine had been established ( 1 4 ) . Alternative suggestions for the construction of the furan ring have been made by Wenkert (154),who invokes a condensation of anthranilic acid with erythrose, and by Ghosal (159),who utilizes anthranilic acid and ornithine as precursors (see p. 262). Highly significant results have been obtained by Monkovii: and Spenser (160)from a study of the biosynthesis of dictamnine usiiig tracer methods. Mature plants of Dictanznus albus incorporate carboxyl-14Clabeled anthranilic acid to give radioactive dictamniiie, specifically labeled at C-4, strongly supporting the derivation of the alkaloid directly from anthranilic acid ; failure to incorporate radioactivity from tryptophaii-P-14C shows that the 4-hydroxyquinoline unit is not derived

26%

H . T. OPENSHAW

by the kynureiiine-kynurenic acid route or through XCi‘III as suggested by Robinson. The 0-methyl group of the alkaloid arises from methionine, and C-10 and C-11 from C-1 and C-2 of acetic acid, respectively. I n contrast. only a very low l e d of incorporation of acetate into C-2 and C-3 of the alkaloid was observed. According to the isopentanoid theory discussed above, these two carbon atoms should also be derived from acetate through the intermediate stage of mevalonic acid ; the low degree of incorporation of labeled acetate does not exclude this route, but may merely reflect a low rate of synthesis of mevalonic acid relative

+

I(‘HO

- axa C0.H

CHOH-CHOH CH20H I

,

Erythrose

H

CHzXH2

Hz

+

I

I oc ‘coo-

(CoA = coenzyme A)

H

(from ornithine)

OH I

H

OMe I

Dictamnine

to that of the quiiioline nucleus. Administration of labeled mevalonate t o D.ulbus has not yet been examined, but Floss and Alotlies (161) have shown that the cc-furan carbon atom of a furocoumarin, pimpinellin, is derived from C-4 of mevalonic acid. Thus tlie isopentarloid route to the furoquiiioliiie alkaloids seems the most probable. The alternative routes proposed by U’enkert and by Ghosal are excluded by the pattern of iiicorporatiori of acetate and by tlie failure of the plant to incorporate a-oxoglutaric acid-5-14C.

6.

QUINOLISE

ALKALOIDS

263

1. H. T. Openshaw, rllknloids 7, 229 (1960). 2. J . R . Price, i n “ChemicalPlant Taxonomy“ (T. Swain, ed.), p. 429. Academic Press, Sew York, 1963. 3. S. C. Pakrashi and J . Bhattacharyya, J . Sci. I n d . Kes. (Indim)24,226 and 293 (1965). 4. J. R. Price and J . B. Willis, Australian J . C‘hem. 12, 589 (1959). 5. L. H. Briggs and L. D. Colebrook, J . Chern. SOC. p. 2458 (1960). 6. S . J . BlcCorkindale, Tetrahedron 14, 223 (1961). 7. S. Goodwin, J. N.Shoolery, and L. F. Johnson,J. Am. C‘hem. Soc. 81, 3065 (1959). 5. A. V.Robertson, Australiuit J . Chern. 16, 451 (1963). 9. T. J. Batterham and J. A. Lamberton, Australian J . (:hem. 18, 859 (1965). 10. D. &I. Clugston and D. B. MacLean, Cali. J . Chem. 43, 2516 (1965). 11. A. W. Sangster and K. L. Stuart, Chern. Rev.65, 69 (1965). 12. S. Goodwin, A. F. Smith, A. A. Velasquez, and E. C. Homing, J . Am. Chena. Soc. 81, 6209 (1959). 13. H. Rapoport and K. G. Holden,J. Am. Chern. SOC.81,3738 (1959); 82,4395 (1960). 14. E. A. Clarke and M. F. Grundon, J . Chern. SOC. pp. 4190 and 4196 (1964). 15. S. Yu. Yunusov and G. P. Sidyakin, Z h . Obshch. Khirn. 22, 1055 (1952). 16. S. Yu. Yunusov and G. P. Sidyakin, Z h . Obshch. Khirn. 25, 2009 (1956). 17. G. P. Sidyakin, V. I. Pastukhova, and S. Yu. Yunusov, Uzbeksk. Khirn. Z h . 6, S o . 3, 56 (1962); Chem. Abstr. 58, 4608 (1962). 18. H. R. Arthur and H. T. Cheung, A u s t r a l i n n J . Chem. 13, 510 (1960). 19. H. R. Arthur and L. Y. S. Loh, J . Chem. Soc. p. 4360 (1961). 20. A. Chatterjee and A. Deb, Chem. & I n d . ( L o n d o n ) p. 1982 (1962). 21. F. A. Kincl, J . Romo, G. Rosenkranz, and F. Sondheimer, J . Chem. SOC. p. 4163 (1956). 22. H . C. Beyerman and R. W. R,ooda, K o n i n k l . X e d . A k a d . Wetenschap, Proc. B63, 432 (1960). 23. J. Iriarte, F. A. Kinel, G. Rosenkranz, and F. Sondheimer, J . Ghenc. SOC. p. 4170 (1956); F. Sondheimer and A. Meisels, J . Org. Chem. 23, 762 (1958). 24. R. Johnstone, J. R . Price, and A. R. Todd, AustrtrlicznJ. Claem. 11, 562 (1958). 25. A. Meisels and F. Sondheimer, J . Am. Chem. Soc. 79, 6328 (1957). 26. V. I . Pastukhova, G. P . Sidyakin, and S. Yu. Yunusov, Dokl. Akctd. S n u k . l T z .S S K 21, 31 (1964); Chem. Abstr. 62, 11864 (1965). 27. 5’. I. Pastukhova, G. P. Sidyakin, and S. Yu. Yunusov, Khim. Prirodn. Soedin., B k a d . X a u k l7z. SSR No. 1, p. 27 (1965); Chem. Abstr. 63, 8425 (1965). 28. A. M. Duffield and P. R. Jefferies, AustrciZici)r J . Chem. 16, 292 ( 1 963). 29. F. Werny and P. J. Scheuer, Tetrahedron 19, 1293 (1963). 30. A. Chatterjee and S. K. Roy, J . I n d i a n Chem. Soc. 36, 267 (1959). 31. 0. 0. Orazi and R . A. Corral, Anales Asoc. Quim. A r y . 51, 154 (1963); Chem. Abstr. 61, 959 (1964). 32. T. 0ht.a and T. Xiyazaki, Yakugctku Ztrsski 78, 1067 (1958). 33. H. Thorns, Ber. Deut. P h a r m . Ges. 33, 68 (1923). 34. W. Renner, Pharmarie 17, 763 (1962). 35. R . G. Cooke and H. F. Haynes, L 4 u s t m l i n u J . Chem. 7, 273 (1954). 36. E. Ritchie, W. C. Taylor, and S. T. K . Vautin, Australiun J . Chem. 14, 469 (1961). 37. Sylvia 1’. Binns, B. Halpern, G. K. Hughes, and E. Ritchie, Australiaiz J . Chem. 10, 480 (1957).

264

H. T . OPENSHAW

38. A. F. Hollis, It. H. Prager, E. Ritchie, and W. C. Taylor, Australian J . Chem. 41, 100 (1961). 39. D. P. Chakraborty and B. K. Barman, Trans. Bose Res. I n s t . (Calcutta) 24, 121 (1961). 40. S. C. Pakrashi and J . Bhattacharyya, J . Sci. Z n d . Res. ( I n d i a ) 21B, 49 (1962); Ann. Biochem. Ex$. M e d . (Calcutta) 23, 123 (1963); see Chem. Abstr. 59, 10466 (1963). 41. I. J. Pachter, R. F. Raffauf, G. E. Ullyot, and 0. Ribeiro, J . Am. Chem. SOC.82, 5187 (1960). 42. L. H. Briggs and R. C. Cambie, Tetrahedron 2, 256 (1958). 43. R. C. Camhie, New ZeaZandJ. Sci. 2, 254 (1959); C'hem. A b d r . 54, 3858 (1960). 44. Y. Asahina, T. Ohta, and M. Inubuse, Chem. Ber. 63, 2045 (1930). 45. N. Tomita and H. lshii, Yakugtaku Zasshi 78, 1441 (1958). 46. M. Tomita and H. lshii, Y a k u g a k u Zasshi 79, 1228 (1959). 47. H. Ishii and K. Harada, Y a k u g a k u Zasshi 81, 238 (1961). 48. A. Deb, B. Chaudhury, and A. Chatterjee, J . I n d i a n Chem. SOC.39, 493 (1962). 49. V. I. Frolova, A. D. Kuzovkov, and P . N. Kibal'chich, Zh. Obslrch. Khim. 34, 3499 (1964). 50. H. Rapoport and H. Tjan Gwan Hiem, J . Org. Chem. 2 5 , 2251 (1960). 51. M. Teresaka, K. Narahashi, and Y. Tomikawa, Chem. & Pharm. Bull. ( T o k y o ) 8 , 1142 (1960). 52. K. K. Chakravarty, J . I n d i a n Chem. SOC. 21,401 (1944). 53. V. Deulofeu, R . Labriola, and J . de Langhe, J . Am. Chem. SOC.64,2326 (1942). 54. S. Yu. Yunusov and G. P. Sidyakin, Dokl. A k a d . N a u k Uz.SSR No. 12, p. 22 (1953); Chem. Abstr. 50, 8691 (1956). 55. I. M. Fakhrutdinova, G. P. Sidyakin, and S. Yu. Yunusov, Khirn. Prirodn. Soedin., A k a d . h'auk Uz. SSR No. 2, p. 107 (1965); Chem. Abstr. 63,8423 (1965). 56. K. C. Das and P. K. Bose, T r a n s . Bose Res. Znst. (Calcutta) 26, 129 (1963). 57. G. Schneider, Naturwissenschaften 52, 347 (1965). 58. J. A. Lamberton and J . R . Price, Australian J . C'hem. 6, 66 (1953). 59. R. J. Gell, G. K. Hughes, and E. Ritchie, A u s t r a l i a n J . Chem. 8 , 114 (1955). 60. G. K. Hughes and K. G. Neill, A u s t r a l i a n J . Sci. Res. A2, 429 (1949). 61. F. A. L. Anet, P. T. Gilham, P . Gow, G. K. Hughes, and E. Ritchie, Australian J . S c i . Res. A5, 412 (1952). 62. R. F . C. Brown, P. T. Gilham, G. K. Hughes, and E. Ritchie, Australian J . Chcm. 7, 181 (1954). 63. A. W. McKenzie and J. R. Price, Australiaia J . Sci. Res. A5, 579 (1952). 64. M. Terosaka, Y a k u g a k u Zasshi 51, 707 (1931); 53, 1046 (1933). 65. T. Ohta and T. Miyazaki, Y a k u g a k u Zasshi 78, 538 (1958). 66. T. Ohta, Y. Mori, C. Noda, and T. Aoki, Chem. & Pharm. Bull. ( T o k y o ) 8,377 (1960). 67. T. R. Govindachari and V. N. Sundararajan, J . Sci. I n d . Res. ( I n d i a ) 20B, 298 (1961). 68. A. M. Duffield, P . R. Jefferies, E. X. Maslen, and A. I. M. Rae, Tetrahedron 19, 593 (1963). 69. A. 31. Duffield, P. R. Jefferies, and P. H. Lucich, Australian J . Chem. 15, 812 (1962). 70. A. 111. Duffield and P. R. Jefferies, AustraEian J . Chem. 16, 123 (1963). 71. A. Chatterjee and S. Bose, J . Z n t i i u n Chem. SOC.29, 425 (1952). 72. A. Chatterjee and B. Chaudhury, J . Zndian Chem. SOC. 37, 334 (1960). 73. A. Mookerjee and P. K. Bose, J . Indian Chem. SOC.23, 1 (1946).

6. 74.

QUINOLINE ALKALOIDS

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V.I. Frolova, A. I. Ban’kovskii, and M. B. Volynskaya, Med. Prom. SSSR 12,No. 7,

35 (1958); Chem. Abstr. 53, 11761 (1959). 75. T. Ohta, T. Miyazaki, and T. Yamakawa, Tokyo Y a k k a DaigGku Kenkyu Nempo 9, 237 (1959). 76. W.Renner, Naturwissensehaften 48, 53 (1961). 77. H. Gertig and H. Grabarczyk, Aeta Polon. Pharm. 18, 97 (1961); Chem. Abstr. 56, 7424 (1961). 78. T . G. Yakunina, Lekarstv. Syr’evye Resursy Irkutskoi Obl., Irkutskii Gos. Med. Inst., Sb. No. 3, 98 (1961); Chem. Abstr. 59, 14294 (1963). 79. K. H. Palmer and R. Paris, Ann. Pharm. Franc. 13, 657 (1955). 80. R. Paris and H. Moyse-Mignon, Ann. Pharm. Franc. 6, 409 (1948). 81. R . Paris and H. Moyse-Mignon, Ann. Pharm. Franc. 5, 410 (1947). 82. M. N. Galbraith, E. Ritchie, and W. C. Taylor, Australian J . Chem. 13, 427 (1960). 83. J. R . Cannon, G. K. Hughes, J. R. Price, and E . Ritchie, Australian J . Sei. Res. A5, 420 (1952). 84. G. J. W. Breen, E . Ritchie, and W. C. Taylor, AustralianJ. Chem. 15, 819 (1962). 85. M. Eskairov, G. P. Sidyakin, and S. Yu. Yunusov, Dokl. Akad. N a u k Uz. SSR No. 2, p. 21 (1957); Chem. Abstr. 52,2181 (1958). 86. G. P . Sidyakin, M. Eskairov, and S. Yu. Ynnusov, Zh. Obsheh. K h i m . 30, 338 (1960). 87. T. Shakirov, G. P. Sidyakin, and S. Yu. Yunusov, Dokl. Akad. Nauk U z . SSR No. 6, p. 28 (1959); Chem. Abstr. 54, 6035 (1960). 88. J. R . Price, AustrnlianJ. Sci. Res. 2, 249 (1949). 89. T. Ohta, H.-Y. Hsu, and C. Noda, Tokyo Y a k k a Daigaku Kenkyu Nempo 9, 244 (1959). 90. T. Obata, Yakugaku Zasshi 59, 136 (1939). 91. M. Teresaka, T. Ohta, and K. Narahashi, Yakugaku Zasshi 73, 773 (1953). 92. G. Schneider, Arzneimittel-Forseh. 14, 435 (1964). 93. T. Ohta, Tokyo Yakka Daigaku K e n k y u Nempo 8, 149 (1958). 94. J. Honda, Arch. Exptl. Pathol. Pharmakol. 52, 83 (1904); Chem. Zentr. 75, 11, 1511 (1904). 30,33 (1953). 95. A. Chatterjee and A. Bhattacharya, J . Indian Chem. SOC. 96. V. N. Gupta and T. R . Seshadri, J . Sci. I n d . Res. ( I n d i a ) 16C, 71 (1957). 97. R. Goto, Yakugaku Zasshi 61, 91 (1941). 98. H. Ishii, Yakugaku Zasshi 81, 1633 (1961). 99. E . Ritchie, W. C. Taylor, and D. V. Willcocks, AustralianJ. Chem. 13, 426 (1960). 100. R. R . Paris and A. Stambouli, Comnpt. R e n d . 248, 3736 (1959). 101. B. R. Pai, S. Prabhakar, P. S. Santhanam, M. Seetha, and V. Sudasarnam, Indian J . Chem. 2, 491 (1964). 102. H. Tuppy and F. Bohm, Monatsh. Chem. 87, 735 (1956). 103. G. P . Sidyakin and S. Yu, Yunusov, Dokl. Akud. Nauk U z . S S R 19,KO.4, 39 (1962); Chem. Abstr. 57, 15170 (1962). 104. R . H. Pragcr, E . Ritchie, and W. C . Taylor, AustralianJ. Chem. 13, 380 (1960). 105. T. Govindachari and S. Prabhakar, Indian J . Chem. 1, 17 (1963). 106. T. Ohta and Y. Mori, Tokyo Y a k k a Daigaku Kenkyu Nempo 10, 100 (1960); Chem. Abstr. 56, 4806 (1961). 107. T. Ohta and Y. Mori, Y a k u g a k u Zasshi 82, 549 (1962). 108. M. F. Grundon, N. J. McCorkindale, and M. N. Rodger, J . Chem. Soe. p. 4284 (1955); M. F. Grundon and S . J. McCorkindale, ibid. p. 2177 (1957). 109. Y. Kuwayama, Chem. & Pharm. Bull. (Tokyo) 9, 719 (1961); Yakugnku Zasshi 8 2 , 703 (1962); Y. Kuwayama and Y. Matsuda, Y a k u g a k u Zasshi 85, 731 (1965).

266

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110. H. Zimmer and R . IT’alter. 2. Snturforsch. 18b, 669 (1963). 11 1. T. R. Govindachari, B. R . Pai, S. Prabhakar, P. S. Santhanam, and 1’. Sudasarnam, I n d i a n J . Chem. 3, 5 1 (1965).

112. U. R’.Pai, 8 . Prabhakar, P. S. Santhanam, 31.Seetha, and I-,Sudasarnam, Indiun J . Chcm. 2, 449 (1964). 113. T. R. Govindachari and S. Prabhakar, I n d i u n J . Chem. 1, 348 (1963). 114. T. Oht.a, 1’. bIori, and XI. Cnieda, Chem. d- Phnrm. BuZl. (Tokyo) 7 , 547 (1959). 115. V. T’. Berezhinskaya and E. A . Trut.neva, Fm-makol. i Toksikol. 26, i 0 7 (1963); Chem. Abstr. 60, 13751 (1964). 116. V. S.Kovalenko,Farmutsiyu 9,S o . 5 , 2 0 (1946); Chem. Abstr. 41, 6989 (1947). 117. V. I. Frolova arid A. D. Kuzovkov, Zh. Obshch. K h i m . 33, 121 (1963). 118. E. Kitchie, Rev.Pure A p p l . Chem. 14,4 i (1964). 119. J. A. Bosson, M. Rasmussen, E. Ritchie, A. V. Robertson, and W. C. Taylor, Australiun J . Chem. 16, 480 (1963). 120. G. K. Hughes, K. G. Scill, and E. Ritchic, Austrrtlian J . Sci. Iies. A5, 401 (1952). 121. R . H . Prager, E. Ritchie, A . V. R,obertson, and W. C. Taylor, Australian J . Chem. 15, 301 (1962). 122. H. C . Beyerman and It. W. Rooda, Kowiiikl. Ned. A k a d . Wetenscha,p., Proc. B62, 187 (1969); 63, 154 (1960). 123. S . Goodwin, A. F. Smith, and E. C. Homing, J . Am. Chem. Soc. 79, 2239 (1957). 124. H. C. Beyerman and R. W. Rooda, h’ouinkl. X e d . A k a d . Weteiaschap., Proc. B63, 427 (1960). 125. F.a.Steldt and K. K. Chen, J . Am. Phurm. Assoc., Sci. Ed. 32, 107 (1943). 126. W. G. Boorsma, Bull. I n s t . Botccn. Buiteiizorg 6,15 (1900); 21,8 (1904); Chem. Zentr. 76,11,956 (1905). 127. S. Goodwin, J. N. Shoolery, and E. C. Homing, J . Am. Chem. Soc. 81, 3736 (1959). 128. A. Ruegger and D. St’auffacher,Helv. Chim. Actu 46,2329 (1963). 129. H. Dioterle and H. Beyl, Arch. P h u r m . 275, 174 and 276 (193i). 130. S. Goodwin and E. C. Homing, J . Am. Chem. Soc. 81, 1908 (1959). 131. J. R. Price, in “Current Trends in Heterocyclic Chemistry” ( A . Albert, G. M. Badger, and C. W. Shoppeo, eds.), p. 92. Butterworth, London and Washington, D.C., 1958; Australicrii J . Chem. 12,468 (1959). 132. H . Rapoport and I<. G. Holden, J . Org. Chem. 26, 3685 (1961). 133. E. 9. Clarke and &I. F. Grundon, Chem. & Iizd. (Loitdon)p. 556 (1962);J. Chem.Soc. p. 438 (1964). 134. H. C. Brown and G. Zweifel, J . A m . Ckem. Soc. 82,4708 (1960). 135. R. RI. Bowman arid M. F. Grundon, Chent. Commun. p. 334 (1965). 136. &I.Tercsaka, Y u k u g n k u Zusshi 51,507 (1931). 137. 31. Teresaka, Chem. d. Phnrm. Bull. (Tokyo) 8, 523 (1960). 138. RI. Tcrcsaka, T. Ohta, and K. Sarahashi, Phnrm. Bull. (Tokyo) 2, I39 (1954). 139. K. Sarahashi, C~UWL. 62 Phurm. Bull. (Tokyo) 10, i 9 2 (1962). 140. 11. Tcresaka, K. Yamamoto, and Y.Kawazoe, Cherrk. & Phurm. Bull. (Tokyo) 11, 108 (1963). 141. 31.Eskairov, G. P. Sidyakin, and S. Yu. Yunusov, DokI. Akctd. S n u k Cz. SSR KO.5 , p. 23 (1968); Chem. Abstr. 53, 9 5 i 4 (1959). 142. I. 31. Fakhrutdinova, G. P. Sidyakin, and S. Yu. Yunusov, Czbeksk. K h i m . Z h . 7, 41 (1063); C‘hem. Abstr. 59, 15331 (1963). 143. T. T. Shakirov, G. P. Sidyakin, and S. Yu. Yunusov, Dokl. A k u d . X a u k C z . SSR S o . 9, 13. 40 (1960); Chem. Abstr. 56, 11643 (1961).

6.

QUINOLINE

ALKALOIDS

267

144. T. T. Shakirov, G. P. Sidyakin, and S. Yu. Yunusov, Dokl. A k n d . S u u k 17z. SSR S o . 8, p. 47 (1961); Chem. Abstr. 57, 9902 (1962). 143. 11.A . Magrupova, I. K. Kamilov, and S . P. Polievtsev, Farwmkol. dlkctloidov, A4kud. Sauk 1,‘~. SNK, Inst. Khim. Bast. Veshchestv 1, 160 and 169 (1962); Chem. Abstr. 61, 11212 (1964). 146. G. P . Sidyakin, 11. Eskairov, and S. Yu. Yunusov, Dokl. Akrtd. Snuk LTz. SSB S o . 8, p. 2 i (1938); Chent. Abstr. 53, 20116 (19.59). 14i. I. A. 13essanova, G. P . Sidyakin, arid S. Yu. Yunusor, Dokl. Akctd. S n u k C z . SSR 19, S o . 1, 50 (1962); Chem. Abstr. 58, 4609 (1962); G. P . Siclyakin, I. A. Bessanova, V. I. Pastukhova, and S. Yu. Yunusor, Zh. Obslicli. Rliim. 32, 4091 (1962). 148. N. P . Polievtsev, I z v . A k a d . S u u k C z . SSI?, Ner. M e d . S o . 6, p. 66 (1959); Chem. Abstr. 54, 12479 (1960). 149. I. A . Bessanova, G. P . Sidyakin, and S. Yu. Yunusov, Dokl. A k a d . X a u k l“z. SSR 20, KO.2, 25 (1963); Ghem. Abstr. 59, 7572 (1963); Z h . Obshch. Khirn. 34, 347 (1904). 150. R. M. Bowman and ill. F. Grundon, .J. Chem. Soc. (C) p.1084 (1966). 151. R. R. Arndt, A. Jordaan, and V. P. Joynt, J . Chem. Soc. Suppl. 11. 5969 (1964); J . Chem. S o c . p . 3001 (1965). Luckner, I. Phurmazie 152. J. R. Price, li’ortschr. Chem. Org. Xuturstoffe 13, 302 (1956); & 18, 93 (1963). 163. C. Schopf and K. Thierfeldcr, Ann. Chem. 518, 127 (1935). 154. E. Wenkert, Experientin 15, 165 (1959). 155. R . Robinson, “The Structural R’elationsof Katural Products,” p. 92. Oxford Univ. Press (Clarendon), London and New York, 1955. 156. R. Aneja, S. K. Rlukerjee, and T. R. Seshadri, Tetrahedron 4, 236 (1958). 157. F. E. King, J. R. Housley, and T. J . King, J . Chem. Soc. p . 1392 (1954). 138. R . D. Haworth, Ann. Hept. I’rogr. Chern. (Chem.Soe. London) 34, 345 (1937). 159. S. Ghosal, S c i . Cult. (Calcuttu.) 30, 142 (1964). 160. I. Monkovii: and I. D. Spenser, Chern. Commun. p. 204 (1966). 161. H. G. Floss and U. Mothes, unpublished work quoted by I. Monkovid and I. D.

Spenser (IGO).

This Page Intentionaiiy Laft Blank

-CHAPTER

-i

THE TROPANE ALKALOIDS

Dcpflrt 1 n C ) l l of

Iiitrotluctiori .. . . . . . . .. . . . . . .. ............. .. . . . . . . . .. . . . . . . . . . . ............. .. .. .. .. . . . II.. Iiitrotluctiori

269 269 270 I1 . Structural Elucidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... .. . . . . . . . . . . 270 A . Phyllalbine .... ............ 270 13.. Valeroidirlc: Valeroidiric: .. ......... .. . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... . . . . . . . . 271 251 13 . . 273 C . E:cgoninols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 D . Conformation of Pseudot'ropine. . . . . . . . . . . . . . . . . . . . E . GP-Tigloyloxy-3n-tropanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 F . ( - )-BP-Hydroxyhyoscyaminc . . . ............ 277 I11 . Absolute Configuration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . . . . . 277 A.. Hyoscyamine Hyoscyamine and and Hyoscinr Hyoscine.. 277 277 A . . .................................... 2i8 B.. Correlation Correlation of of T'aleroidine Valeroidine wit'h wit’hS-( - )-Mcthoxysuceinic )-Mcthoxysuccinic Acid Acid.. . . .. .. .. .. .. . . . 278 B S-(-

I V . Total Syntheses . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

\’.

yoscyarnine .............................. B. Total Synthesis of Neteloidine. . . C. Total Synthesis of Oscine (Scopoline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D. Improved Synthesis of Hyoscine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E. Improved Synthcsis of Valeroidine. . . . . . . . . . . . . . . . . . F. Preparation of Trop-6-en-3-onc.. . . . . . . . . . . .. . . . . . . . ..... ..... The Stereochcmistry of the Ring Sitrog.cn in the Tropanes .

280 280 282

282 2881 285

VI. Fragmentation of the Tropanes including Mass Spectrometry. . . . . . . . . . . . . 290 VII. Biogenesis a n d 13iogcn~ticInterconversion of the Tropa.nrs. VIII. Pharrnacologically Active Synthetic Tropaniurn Salts. . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . 300

I. Introduction Subsequent to the appearance of Volume V I of this series, a number of reviews on the tropaiie alkaloids have appeared, dealing with chemistry (1, Z ) , biosyiithesis aiid biogenesis ( 3 , 4 ) , and pharmacological activity as a function of structure ( 5 , 6 ) . Dioscorine, which had been regarded as a tropane base, has been shown to be an isoquiiiuclidiiie ( 7 ) aiid will not be dealt with again. Notable progress has been recorded in the following areas: (a) The elucidation of t h e coiistitutioii of new bases and the reinvestigation of 269

250

G . FODOR

some of those formerly known: (b) the absolute configuration of ( - ) tropic acid, hence of hyoscyamine and hyoscine, and finally of valeroidine: ( c ) a direct total synthesis of hyoscyamine and an improved preparation of valeroidiiie and hyoscine ; (d) the stereochemistry of tertiary tropane bases and their selective quaternization ; (e) the fragmentation of tropanones and tropanols by mass spectrometry ; (f) the biogenesis of the tropane skeleton and the interconversion of the main bases in vivo; (g) a series of new quaternary Xepimeric tropanium salts were synthesized and their pharmacological activities were correlated with their configurations.

11. Structural Elucidation

A. PHYLLALBINE This alkaloid, isolated from roots of Phylluntus discoides Muell. Arg. by J. Manil, was investigated chiefly by modern physical methods (8). Its molecular formula, C16H2104N (calculated : 291.3), was corroborated by mass spectrometry (found: 291). The NMR-spectrum showed the same signals as tropine and its esters ; in particular, the triplet due to the C-3 proton a t 5.25 6 is very similar to that of atropine (5.00 6).Pseudotropine esters, e.g., tropacocaine (beiizoyl pseudotropine) show a quintuplet in almost the same region (5.27 6) for the 3a-proton. The methoxyl group appeared a t 3.94 ppm while the position of the signal of phenolic hydroxyl varied with the concentration and disappeared on deuteration. The IR-spectrum suggested the presence of a carbonyl H&,

H3C,

hh%

J’qH o-d&oH /I

OCH3

OH H

0

I

I1

joined to an aromatic nucleus so that a vanilloyl (I)or isovanilloyltropan3a-01 seemed very probable. Hydrolysis to tropine (11)and vanillic acid completed the evidence.

7.

271

THE T R O P A N E ALKALOIDS

The mass spectroscopic fragmentation of phyllalbine gave essentially the same species as did atropine and other tropeines studied by Djerassi et al. (8a,b)and controlled by the use of deuterated samples. This will be dealt with further in Section V I .

B. VALEROIDINE The product (mp 131") obtained on oxidation of valeroidine (111)with permanganate (9) was first formulated as a lactone (IV) on the basis of analytical figures, and then described later (10)as a cyclic carbonate (V) (see structure X L I V in Volume VI, p. 160) of norvaleroidine (VI). H3C I( h l I l 0 1

HO O-C-CHzCH(CH3)2 0

I1 I

v

0

O=C--9

0

\'I I

Recently it was subjected to spectroscopic examination (11); surprisingly, it has a strong band in the infrared at 3200 cm-1, pointing to a hydroxyl; in the NMR-spectrum it gives a proton signal at 8.05 6,

H3C

": CHz0 H

OH

H I-lIls

1

CH31

-OH

OH H

7. THE TROPANE

273

ALKALOIDS

evidence for a formyl proton; N,N-dimethyl formamide also has a typical signal a t 8.03 6. Thus N-formyl norvaleroidine (VII) would satisfactorily depict the constitution. The calculated C,H values for V and V I I differ too little to be detected by classic microanalysis. Obviously, the formation of N-formyl norvaleroidine (VII) instead of urethane V from the alkaloid does not provide any evidence as to the steric proximity of C-6 hydroxyl group and of ring nitrogen (Volume VI, p. 159). In spite of this the P-configuration of the same hydroxyl was ascertained by the lactonization of N-ethoxycarbonylmethyl dihydroxytropanium iodide (12).

C. ECGONINOLS An attempt was made to prepare the four epimeric ecgonines via the 2-hydroxymethyl-3-tropanols( 1 3 ) . By heating it alone or in aqueous medium, 2~-chloromethyl-3~-tropanol VIIIa was cyclized (14) t o a compound with an IR-spectrum (15) corresponding to an ammonium salt containing a four-membered ether ring. The methiodide VIIIb underwent a similar internal condensation leading t o an internal ether, leaving no alternative other than X. The chloride (IX) on reaction with alkali, gave two isomeric diols, one being ecgoninol (XI)while the other was deduced by ring opening a t C-3 t o be presumably the 2P-hydroxymethy1-3oc-tropanol(XIII). The isomerization of this hydroxyl by alkali gave another " tropanediol " H

3c\N I \

XIY

XI11 H

274

G. FODOR

described as the 2c~-hydroxymethyl-3c-tropanol (XIV)( 1 3 , 1 5 ) .However, these two alcohols could not be oxidized by silver oxide to the ,!-hydroxycarboxylic acids, although the same technique proved useful in oxidizing ecgoninol (XI) and pseudoecgoninol into ecgonine and pseudoecgonine, respectively. Furthermore, they were different from the lithium aluminum hydride reduction products of the two “new” epimeric ecgonine esters, synthesized by Findlay (16) (Volume VI, p. 157); thus, the formation of the ring ether from VIIIa demanded investigation ( 1 7 ) . Since the formation of a similar highly strained azetidinium salt (XV) from 1-tosyloxymethylquinolizidinewas proved recently ( l a ) ,structure I X was reconsidered also for the tropanium salt from Z/i-chloromethylSj?-tropanol. This salt, unlike those of tertiary tropane bases, cannot be liberated by bases; did not move in thin-layer chromatography; and finally, using high-resolution IR-spectroscopy, it showed a maximum a t 3260 cm-1 (although a t an unusually low wave number) for a hydroxyl. All these facts are strongly in favor of the nitrogen-, rather than the oxygen-containing four-membered ring. By inference, nucleophilic attack on the CH2 a t C-2 leads to ecgoninol (XI),while alternate cleavage between N and C-1 should afford an azabicyclononanediol (XII). This alcohol (XII) and its epimer, formed from it by the action of alkali, are not susceptible t o oxidation by silver oxide. Further support for this formulation, e.g., by degradation or NMR-spectroscopy, is in progress (17). The formation of I X from VIII corroborates the axial /i position of the hydroxymethyl group in ecgoninol and hence that of the carboxyl in ecgonine. This is in complete agreement with former configurational assignments. Furthermore, there is no doubt as to the cyclic ether structure of X, the nitrogen being blocked in the methiodide of V I I I ; this proves directly the cis axial-equatorial relationship between C-2 chloromethyl and C-3 hydroxyl groups. Compound XXXIII (Volume VI, p. 157),however, exists so far only as its methohalide, while formulas XXXVI and XXXVII (Volume VI, p. 157) do not describe adequately the cleavage of I X ; hence they have t o be replaced by the azabicyclononanediol XI1 and its epimer.

D. CONFORMATION OF PSEUDOTROPINE Acyl migration in N - and O-acylnorpseudotropines (19)involves the boat conformation in the transition state. Its presence in the ground state was indicated in an early infrared study (20) by a different ratio in bonded to nonbonded hydroxyls in the two epimeric 3-tropanols. An

7.

275

THE TROPANE -4LKALOIDS

independent infrared study by R)ussian authors (21) seemed to corroborate this assumption. However, a more recent systematic work (22a) completely disproves the existence of any sort of intramolecular hydrogen bonding in pseudotropine and, hence, its occurrence in the boat form. First, the IR-spectra of tropine and pseudotropine were recorded (in carbon disulfide, tetrachloromethane, and tetrachloroethylene) using a high-resolution grating spectrophotometer. In concentration below 2 x 10-3 M the bonded 0-H absorption is completely eliminated in both alcohols. The tropine absorption appears as a single, highly symmetrical band, while that of pseudotropine is unsymmetrical, i.e., an unresolved doublet. These facts correspond to an axial hydroxyl (XVIa) in the former and to an equatorial one (XVIb) in the latter, and prove the chair conformation for both epimers (226).Accordingly, less than 2 yoof either tropanol can assume a boat conformation. Relative pK, data show that tropine is the stronger base, as expected by analogy with piperidinols having the N electron pair and the hydroxyl both axial (22a).The glc retention data (2%)indicate the same axiallequatorial relationship for the pair of epimeric, a- and p-tropan-3-01s. More recent

SVItl

XVI b

X-ray crystallographic measurements (23) also prove the equatorial position of the hydroxyl and the chair form of the ring for the pseudotropine crystal. Acyl migration N --f 0 accelerates greatly the p-nitrobenzoylation of the 3p-tropanol tertiary base, in contrast with that of the 3a-tropanol ( 2 4 ) . The acid chloride gives an N-aroyltropanium chloride which rearranges spontaneously into the 0-aroyltropanium hydrochloride if a cis-hydroxyl is present, as is the case with pseudotropine. Here again the boat form must be present in the transition state to account for that marked stereospecificity ; N-aroyltropanium chloride with an axial hydroxyl can be converted to the ester only by an intermolecular mechanism, consequently a t a much lower rate. On the other hand, a novel transfer of hydrogen was discovered (25) by treating tropine with benzoyl chloride and alkali. The product,

276

G . FODOR

2,4-dibenzylidene-3-tropanone(XVII) is formed from tropan-3-one (LXXI) and benzaldehyde and suggests an intramolecular transfer of the C-3 /3-hydrogen to the benzoyl carbonyl group within A'-benzoyltropinium chloride (XVIII), entailing the occurrence of the boat form. As with acyl migration, the transition state might involve that conformation while the chair form is predominant in the ground state. Tropine was demethylated by potassium ferricyanide to nortropine in fair yields (26).

NaOH ___f

- I'hCHO

E.

~B-TIGLOYLOXY-~U-TROPANOL

This new alkaloid (XIX) was found (27) in Datura cornigera Hook. and was also obtained on partial hydrolysis of the ( - )-3cc,6/%ditigloyltropanediol (XX) found by the same team (28). The correct absolute configuration as 3R,6R follows from recent work on valeroidine (see Section 111,B).

I\

H

I

7.

THE TROPANE ALKALOIDS

277

F. ( - )-GP-HYDROXYHYOSCYAMIXE Isolated from Datum ferox L. (29), this product was hydrolyzed to ( - )-3cr,GP-tropanedioI and ( - )-tropic acid. A synthesis of XXI was achieved by hydrogenolytic cleavage (30) of AS'( - )-hyoscine ( X X I I ) ,

obtained by total synthesis, and followed by separation of the diastereoisomeric S(- )-tropoyltropanediols with dibenzoyltartaric acid. Feeding D. stramonium L. seedlings with hyoscyamine-(methylL14C) brought about its conversion to the GP-hydroxy derivative-(methyl-l4C) ( 3 1 ) .

H3C

"

XSSI

OH

XXIII

111. Absolute Configuration

A. HYOSCYAMINE AND HYOSCINE Both ( - )-hyoscine and ( - )-hyoscyamine are esters of levorotatory tropic acid, which represents the asymmetric moiety of these alkaloids. Freudenberg et al. (32) found that a series of derivatives of (-)-tropic acid showed a trend similar to derivatives of L-( +)-lactic acid, the L, configuration X X I I I being tentatively assigned on the basis of molecular rotation. Configurational correlation with alanine was achieved recently ( 3 3 ) . It was already known that ( + )-cr-methylphenylacetic acid (XXIVa) gave ( - )-cr-phenylethylamine (XXV) ( 3 4 )by a Curtius degradation with retention of configuration. Oxidative destruction of the aromatic ring in

278

G . F ODOR

XXV gave L-( + )-alanine (XXVI). Hence ( + )-methylphenylacetic acid has the absolute configuration depicted in XXIVa or, in modern terms, ( 3 6 ) the S configuration. On the other hand, ( - )-p-chlorohydratropic acid (XXVII)on hydrolysis gave ( - )-tropic acid ( 3 4 ) .The final correlation was achieved by hydrogenolysis of (,- )-p-chlorohydratropic acid to R-(- )-a-methylphenylacetic acid (XXIVb). Consequently, ( - )-tropic acid has the absolute configuration S according to Cahn, Ingold, and Prelog’s rules ( 3 6 );hyoscyamine is S-(- )-tropoyltropan-3a-ol (XXVIII), and hyoscine the S-( - )-tropoyl ester (XXII)of 6,7p-epoxytropan-3a-ol.

CHzOH

CHzCI

XXIII

CH3

XXVII

XXIVb

C6H5

C6H5

I

I

H&C-C-H

+

HzN-C-H

I

I

CH3

CH3

SXlVa

COzH

+

I CH3

xxv

d-

I

H2N-C-H

XXVI

CO-C-H

I

C6H.5 XS\’III

B. CORRELATIONOF VALEROIDINE WITH X-( - )-METHOXYSUCCINIC ACID Although the adoption of Hudson’s lactone rule allowed the tentative assignment of configuration, 3R,6R, to the ( - )-tropan-3oc,6/3-diol(37) (see Volume VI, pp. 161-162), corroboration by correlation seemed necessary. 6/3-Methoxytropinone (38) was resolved and correlated with ) . dextronatural valeroidine and with X-methoxysuccinic acid ( 3 9 ~ The rotatory ketone XXIX was converted into ( - )-3a,6p-diacetoxytropane

7. THE TROEANE ALKALOIDS

279

280

G . FODOR

(XXX) by reduction to XXXII and subsequent acetobromolysis, and this product was converted into the (-)-diol XXXI, identical with the alkamine of natural valeroidine (111).Inversely, partial methylation (39b) of that diol gave the methiodide (XXXIII) of ( - )-BP-methoxytropine so that no breaking of the C-6-0 bond occurred during demethylation; hence, the methoxyl and hydroxyl groups are both /3. The (39 a,b) degradation by nitric acid of the ( + )-2,4-dioximino-3-tropanone furnished 25 yo of 8-(- )-methoxysuccinic acid (XXXIV), earlier obtained by methylation of 8-(- )-malic acid. I n consequence, valeroidine is (38,68)-3a-isovaleroxy-6~-hydroxytropane (111), while 6~-tigloyloxy-3u-tropanol and 3a,BP-ditigloyloxytropane ( 2 7 ) ,both derived from dextrorotatory tropan-3,6-diol, have the 3R,GR configurations X I X and XX.

IV. Total Syntheses A. DIRECTSYNTHESIS OF ( - )-HYOSCYAMINE Atropine (XXVIII)had already been prepared from ( )-acetyltropoyl chloride and tropine (40) followed by resolution ( 4 l ) ,using D-camphorsulfonic acid, to obtain first the salt of dextrorotatory hyoscyamine. Recently dibenzoyltartaric acid was claimed to precipitate the salt of the ( - )-antimer first ( 4 2 ) . Direct synthesis of hyoscyamine (XXVIII) was realized by melting 8-(- )-acetyltropoyl chloride (XXXV), obtained for the first time in crystalline form, with tropine hydrochloride (XXXVI), followed by acid deacetylation of acetylhyoscyamine (XXXVII)

Y=C1-

[a]

1

-HCI 200

SST-III XXXVIII

7.

281

T H E T R O P A N E ALKALOIDS

( 4 3 ) .The main problem in acylatiiig bases like tropanols with this special acid chloride is the immediat'e loss of optical a.ctivity a t 25", for instance, by the action of triethylamine (44),to give a mixture of compounds, arising presumably from pheiiylacetoxymethylketene (XXXVIII), but yielding no tropoylated derivative. Hence the salts of the tropanols must be used. However, no adequate solvent has been found so far to prevent side reactions occurring from the excess of the liquid acid chloride upon the salt in suspension (45).By replacing the hydrochlorides byp-toluenesulfonic acid salts (e.g., XXXVIb) which, having low melting points, give eutectic mixtures with the acid chlorides a t low temperature, the yields have been increased ( 4 5 ) .

B. TOTAL SYNTHESIS OF METELOIDINE The route leading to dihydrometeloidine (Volume VI, p. 168) was not available for the alkaloid itself. In fact it involved a catalytic hydrogenolysis of the benzal group in the last step which affects the double bond in tiglic acid. Therefore, teloidinone-6,7-carbonate(XXXIX) was prepared ; the 3n-alcohol XL obtained therefrom on hydrogenation with Raney nickel was then acylated with tigloyl chloride. As a final step, the hydrochloride of tigloylteloidine-6,7-carbonate(XLI) was heated with methanol to eliminate carbon dioxide, thus yielding meteloidine (XLII) (46). H3C,

-

N

CHIOH

1. 2 H ' / N i

- CO,

2 . Tgrl

O C C 0h O

H SLI

XXSIS

H HO O--cO-C

\

0-Tg

282

G . FODOR

C . TOTAL SYNTHESIS OF OSCINE (SCOPOLINE) Heated t o 200" in wacuo, teloidine carbonate (XL) gave 3a,6a-oxidotropan-7p-01 (XLIII) (47). As a variation (as),6,7-ditosylteloidine (XLIV) was prepared from 6,7-ditosylteloidinone and solvolyzed in the presence of sodium methoxide to O-7-tosyloscine. Alkaline hydrolysis or hydrogenolysis with lithium aluminum hydride then afforded oscine (XLIII) in good yield.

YL

H H3C\ 1. GHIOHf

NaOCHJ

TsO

.H

TsO HO

XLIII

XLIV

D. IMPROVED SYNTHESIS OF HYOSCINE Prepared by Robinson condensation of 2,3,5-trimethoxytetrahydrofuran (38, 49) (available from furan), the ketone XXIX gave with subsequent reduction the 6-methoxytropan-3a-01 (XXXII) (see Section II1,B) which, in turn, was demethylated by aqueous hydrogen bromide (90%) to ( & )-tropan-3a,6/%diol (XXXI). As a condensing agent, p-toluenesulfonic anhydride gave good yields of 3a,6a-oxidotropane (XLVI). Cleavage with acetyl bromide (acetobromolysis) afforded the 6/3bromo-3a-acetoxytropane (XLVII) together with some 315-bromo-6aacetoxytropane (LXIX). Piperidine quantitatively converts XLVII into trop-6-enyl-3a-acetate (XLVIII). An acid deacetylation followed by S-acetyltropoylation of trop-6-en-3a-01 led to the 6,7-dehydrohyoscyamine (XLIX). Further

0

M z

7. THE TROPANE ALKALOIDS

x

z 0

.o

z

b'

283

284

G . FODOR

epoxidation of XLIX in aqueous 3076 Hz02 with sodium turigstate as catalyst leads to hyoscine hydrobromide (L). The over-all yield was approximately 15% based on furan (50).

E.

IMPROVED

SYNTHESIS O F VALEROIDINE

Partial Kuiiz hydrolysis of ( - )-3a,BP-diisovaleroxytroparie (LI), a t variance with the former finding (52), was achieved (54, yielding ( - )-3a-isovaleroxytropaii-B~-ol, to which the correct absolute configuration X X X I I was later allotted ( 3 1 ) .

aretone dil. N a O H

-H

HO

H

r

d-COCHzCH(CH3)z (-)

I11

F. PREPARATION O F TROP-6-EN-3-ONE The long-sought ketone (LII) recently was obtained (53)by oxidation of trop-6(7)-en-3a-ol (XLVIIIb) with chromic acid in pyridine. The product is quite stable and distillable and shows the carbonyl and the olefine bands in the IR-spectrum. Catalytic hydrogenation with 2 moles of hydrogen gives the tropan-3~-01(11). The picrate melts a t 151.5", in contrast with the mp of 191" of an alleged (54)tropen-3-one, which was obviously a contaminated tropan-3-one picrate (mp 210"). The latter ketone picrate was isolated from a Robinson-type condensation of maleic aldehyde which was itself formed during partial hydrogenation of acetylenic dialdehyde acetal ( 5 4 ) . I n any case, the authentic ketone L I I forms a methiodide LIlb, which by the action of alkali eliminates dimethylamine ( 5 3 ) to yield 100yo tropone (LIV).The methiodide XXIXb of 6P-methoxytropinone behaves in the same way (55). By polarography, the intermediate of the fragmentation had been indicated to be ( )-3-dimethylaminocyclohepta4,6-dien-1-one (LIII) (56).I t s dihydro derivatives have been detected by the same technique and also trapped (57).

7.

THE TROPANE ALKALOIDS

285

/ H

I1

LIIh

OH

LIII

V. The Stereochemistry of the Ring Nitrogen in the Tropanes Selective quaternization of tertiary tropane bases with different R halides leading to the R-equatorial tropanium salt has been described ( 2 , 58, 59). By first introduction of R and subsequent methylation the methyl-equatorial epimer was formed. Evidence was furnished by using a carboxymethyl for R with a tropane base having an adjacent hydroxyl either in the pyrrolidine or in the piperidine ring. Since lactones were

286

G . FODOR

formed between cis-carboxymethyl and hydroxyl, the relative and absolute configurations could be assigned for the first time in this way to a number of quaternary ammonium salts (58) (e.g., LV and LVI). However, oscine (3a,6~-oxido-7/!-hydroxytropane, XLIII) is an exception to this rule as it gives rise to a lactone salt both by "direct '' and '( reverse" quaternization sequence.

OH

OH

LVa; R =CH2C02R'

-

H

J>

+HICHzCOORHoJ>

-?

CHzCOOR

HO OH

OH

H 3 C \ e ,CHzCOOR

+

nolactone

H

HO

LVb

OH

The angle made by the plane /(C-l)-N-(C-5)/ and /(C-l)-(C-6)(C-7)-(C-5)/ has been calculated for nonbridged 3,6-tropanes as 126" while for oscine it was considered to be 141" (59) (see LVIIa and b). Notwithstanding, X-ray measurements (60) with LVIIIa indicated an angle of 136", due to methyl-hydrogen interactions in the five-membered ring. Accordingly, the nonclassic strain in the five-membered ring of the tertiary tropanes was held responsible for pushing the N-alkyl group into the axial position, thus making possible the equatorial access of the quaternizing cation. With oscine, where the H-H interactions are probably reduced in the pyrrolidine moiety due to the (C-B)-O--(C-3) bridge, the quaternization is less stereoseleetive.

7.

287

THE T R O P A N E ALKALOIDS

lac tone LVIS,

k

R'OOC-CH,

"/

CH3

CHzOH

XI

H

no lactone R = C'HaCOOR'

OH -.

LVIb

Investigations on N-ethylnortropine methobromide (LVIIIa) by X-ray crystallography (2, 60) proved the equatorial position of methyl, the opposite being true for tropine ethobromide (LVIIIb).Thus the rule K 126" 30'

LVIIa

LVII b

of an equatorial quaternization is corroborated. Similar stereoselectivity was observed in the case of codeines (61), morphines (62), and tetrahydroisoquinolines, but the interpretation of this phenomenon became a matter for argument. Nuclear magnetic resonance studies (63) with tropine deuterohalides (LIXa and b) indicated the presence of two N-methyl signals (2.90 and

288

G . FODOR

\

OH

LVIIIa

LTIIIb

3.03 6) the equatorial one in the higher field being more intense. With 6-substituted tropanes this preponderance was less marked. It was inferred that the stereoselectivity is more probably controlled kinetically than thermodynamically. However, further nuclear magnetic resonance investigations of the tertiary tropane bases seemed desirable.

LIXa

LIXb

A series of tropane bases, also partially deuterated, have been included in this study; 3u- and 3/3-cyanotropanes were submitted to a dipole moment study (64).The coupling constant for the C,,-proton in the 38substituted tropane bases correspond exactly with the expected values if the piperidine ring is in a chair form and if the N-methyl and C-3 hydroxyl (or CN) groups are both equatorial (LX).Dipole moment data found for 3p-cyanotropane (LX; Y =CN), 4.02 D, is very close to the calculated value, 4.04 D ; but 3cr-substituted tropanes (LXIa) indicate abnormal coupling constants for the C-3 ,&proton, particularly inconsistent with either classic conformation of the six-membered ring. Consequently, a distortion of the angle between the planes /(C-1)(C-2)-(C-4)-(C-5)/ and /(C-2)-(C-3 j-(C-4)/ was assumed to approach 30"-40". This is based on a hypothetical repulsion energy curve between bulky group a t C-3 and hydrogens on C-6 and C-7, which shows a minimum with an angle of 37" (symbolized by LXIb). These recent findings and calculations (64-70) seem to invalidate the previous hypothesis (58, 59) as to the preferred axial orientation of the

7.

LX Y = O H ; OAc; C N

289

THE TROPANE ALKALOIDS

LXIb

LXIa

N-alkyl groups pointing to a more favored equatorial position in the tertiary bases. I n the transition state of quaternization, however, the axial N-alkyl conformation with an equatorial incoming cation (LXII) seems more probable than the reverse (LXIII)where the entering group is axially approached. On the basis of the Curtin and Hammett hypothesis, the free-energy differences between the two transition states should determine the ratio of the products. This concept (71) must be true if the compression of the axial N-alkyl group by the C-2 and C-4 axial hydrogens (XLIII) is stronger than that between equatorial N-alkyl and the ,$-hydrogens in C-6 and C-7.

LXII

LXIII

Extensive studies by X-rays, IR-, and NMR-spectroscopy (65, 66, 68) on the stereoisomeric pairs of cyclic quaternary ammonium salts showed a preferable axial approach in the quaternization of the N-alkyl camphidine, 2-methylpyrrolidine, and piperidine series while for tropanes the equatorial approach has been substantiated. The increase of a band takes place in the higher region (885-900 cm-1) when the N-methyl is equatorial while the same change occurs in the lower region (840-885 cm-1) when N-methyl is axial (65). The NMR-spectra of a series of N-methyl and N-alkyl nortropanium salts show the signal a t 7 . 1 0 T for the equatorial position and a t 6.97 T for the axial one (66). Furthermore, sodium thiophenoxide reacts a t different rates in epimeric pairs of methyl ethyl nortropanium salts (67).When the ethyl group is equatorial, the ratio for thiophenetole : thioanisole is 2.5 :1 according to glc analysis. However, if the ethyl group is axial (LXV) the

290

G . FODOR

attack is directed toward the equatorial methyl rather than the axial ethyl. In other words, the nucleophilic attack by thiophenoxide removes an alkyl group from the tropanium nitrogen when it has the orientation it preferably adopts during its introduction in a quaternization of tertiary bases. Similar results were reported for the steric course of Emde degradation by lithium aluminum hydride (67). Recently the transquaternization between N-epimeric tropanium salts and strong tertiary bases has been studied ( 7 2 ) .

When heated in chloroform, some quaternary salts-e.g., N-methylN-benzyl cyclic ammonium iodides-do interchange their groups ; however, no similar interconversion has been reported for the corresponding tropanium salts (68). The preferred orientation of the N-methyl group in certain ketones derived from some tropanes is subject to other factors (73); hence it may assume a preferential, or even exclusive, axial conformation. For instance, the ketone formed from cis-cyclopentane-1,3-dialdehyde consists, as proved by dipole moment and NMR-analyses, of a mixture of conformakions LXVI and LXVII, both with an axial methyl opposite to the piperidine ring.

LSVI

LXVII

VI. Fragmentation of the Tropanes including Mass Spectrometry The first example of fragmentation was described by Willstatter (see Volume I, p. 287), i.e., alkaline cleavage of tropinone methiodide to

7.

291

THE TROPANE ALKALOIDS

“ dihydrobenzaldehyde ” and dimethylamine. The nitrogen-free fragment actually consists of a mixture of dihydrotropones ( 7 4 ) . Similarly, tropenone methiodide gives tropone on the action of NaHCO3 (see Section IV,F). On the other hand, as mentioned briefly in Volume VI, page 150, 3p-tropanyl chloride (LXIa; Y = C1) is converted by potassium cyanide into a pyrrolidine (LXVIII), while the 3a-epimer gives the Sa-cyanotropane due, presumably, to a transannular participation of the ring

LXIa

LXVIII

nitrogen atom (75).On the other hand, the 3/3-bromo-6a-acetoxtropane (LXIX) undergoes fragmentation to an oxygen- and halogen-free compound of low boiling point, probably having the constitution of 1,2-dimethyl-5-vinylpyrrole (LXX).

LXIX

LXX

A systematic study of the fragmentation of tropanes under electron impact was carried out (8a, b ) . As a control, the compounds were selectively deuterated either in C-6 and C-7 or in C-2 (C-3) and (3-4. When the mie of an individual fragment was shifted by 2, 4 (or 5 ) units, its original position in either the five- or six-membered ring was indicated. Ketones behave differently from alcohols of that series. The molecular ion LXXII, formed by removal of one electron from tropinone (LXXIa), undergoes homolytic cleavage either of bond C-1-(2-7 (or of the equivalent C-5-C-6) typical for ammonium salts, or of bond C-l/C-2 (its equivalent being C-4/C-5) as do simple ketones. I n the first case, a radical ion LXXIII is formed, to afford the N-methylpyrroleninium

292

f I

i

0

I

G . VODOR

+

I

It

I

0

I

7 2P

7.

293

THE TROPANE ALKALOIDS

radical ion LXXIVa of mie 83. This assignment is justified by the fact that deuteration on C-6 and C-7 does not cause any shift, while tropanone 2,4-d4 (LXXIb) affords a radical ion (LXXIVb) of m/e 87. Thus this fragment comes from the piperidine moiety. On the other hand, rearrangement of primary L X X I I I into the more stable secondary radical ion LXXV (H transfer C-4 to (2-7) followed by the loss of an ethyl radical (fission C-5jC-6) leads to the N-methyl-4-hydroxypyridinium ion (LXXVIa) (m/e 110) shifted by 4 mass units (LXXVIb) only if deuteration occurs in the 6-membered moiety of tropinone (LXXIb). I n the second case, fission C-l/C-Z gives an cc-substituted pyrroleninium ion (LXXVIIa) which loses ketene (cleavage 3/4) with formation of the a-methylene-N-methylpyrroleninium radical ion (m/e 97). This, in turn, eliminates a protoii and appears in the spectrum with m/e 96 (LXXVIII). The latter is probably a 2-methylene-N-methylpyrroliniumion since deuteration in either position [2D in C-6 and C-7 (LXXIc) or 4D in C-2 and C-4 (LXXIb)]is marked by a shift by 2 mass units.

P

H3C,'3

LSSIa

HzC

LXXVIIS,

LXXVIII (a)m/e 96

LSSIb

+

(b) m/e 98

>

(c) m/e 98

Alternately, the loss of acetone from LXXVIIb involves splitting off of one C-6-proton and leads to the AT-methylpyrroliumion LXXIX. A substitution in the tropane ring, e.g., the introduction of oxygen functions onto C-6 (and C-7), as with the 6-methoxytropinone X X I X , considerably changes the relative abundance of the species. Instead of cc-cleavage (C-ljC-a), the bond between the two hetero atoms will be

294

G. FODOR

H3C ' S

-CH&OCHz

,

LXXIX

broken, probably in eliminating methyl vinyl ether, so that the most intense peaks m/e 1 1 1 (LXXX) and m/e 94 (LXXXI) appear.

XXIX

LXXX

LXXXI

mje 1 1 1

m!e 94

The tropanols, i.e., tropine and pseudotropine (XVI),give a somewhat different picture. Besides a pronounced M-17 peak (OH), the radical ion m/e 113 (LXXXII, probably) is detected. Since no decarbonylation CH3

I

x@

OH LXXXII

XVI

m/e 113

D

OH XVIC

LXXXIII (a) m/e 96 (h) m/e 101

7.

295

THE TROPANE ALKALOIDS

can take place, the other species, m/e 96, might be the N-methylazabicyclo[2.2.0]hexane ion LXXXIII. This is substantiated by the fact that tropan-3-01-2,3,4-& (XVIc) furnishes a shift by 5 mass units-m/e 101. A similar bridged ion was very probably formed ( 8 ) , though not proved by deuteration, from phyllalbine (I). The introduction of a carboxyl group in C-2, in the case of ecgonine causes no major change, while insertion of a methoxyl in C-6, as well as of two hydroxyls in C-6 and C-7 gives the base peak a t m/e 113, corresponding to LXXXII and also its dehydroxylated product LXXXIII. All of these investigations allow the easy identification of new tropanes, when isolated on a microscale, by mass spectrometry.

VII. Biogenesis and Biogenetic Interconversions of the Tropanes An extensive use of radioactive tracer technique permits a deeper insight into the formation of the tropane skeleton in vivo. Hyoscyamine(methyl-14C) (76), atropine-l4C, tropic acid-14C (77), and succindialdehyde-2,3-14C (78) were synthesized. The last was not incorporated a t all by D . stramonium seedlings (78), while the former feeding experiments with ornithine-cc-14C proved its incorporation into hyoscyamine (79) by D . stramonium (see Volume VI, pp. 172-173). More recently two independent teams (80, 81) reported that this incorporation takes place asymmetrically. Hyoscyamine-14C (XXVIIIb)(from ornithine) was degraded following H3C N(CH3)Z 5

BkpJ

Ar-COOH

XXVIIIb

6" 0- 6 2steps

____,

LXXXV

LXXXVI

LXXXVII

ox.

141 Ar

COOH

296

G . FODOR

Willstatter’s method (Volume I, pp. 278; 285-286) to a-methyltropidine, i.e. ( & )-5-dimethylamino-l,3-cycloheptadiene (LXXXIV). Resolution of the latter with dibenzoyltartaric acid followed by (a)isomerization of each antimer into p-methyltropidines (LXXXV), (b) hydrolysis, (c) partial hydrogenation of the cycloheptenone, and (d) Grignard reaction with the cycloheptanones (LXXXVI) gave the phenyl-, and p-chlorophenyl-1-cycloheptenes(LXXXVII).The product of oxidation, arising from ( + )-LXXXIV, contained the whole radioactivity, while the benzoic and p-chlorobenzoic acids from the levorotatory form were radioinactive. This proved that the whole label from ornithine-a-14C was either in C-1 or in C-5 in hyoscyamine (80, 81). A correlation of configuration of ( + )-a-methyltropidine (LXXXIV) therefore gave a clue to the absolute configuration of labeled hyoscyamine. This was achieved by converting it (82) into the N-dimethylglutaminol antimer XCa, via the tetraol LXXXVIII and with periodate. The reduction of N,N-dimethyl-L-( + )-glutamic acid afforded its antimer XCb. Consequently, C-1 was radioactive in hyoscyamine, but, C-5 was not. This ultimate information concerning the biosynthesis of the tropane skeleton had not been anticipated.

HO

OH

LXXXVIII

LXXXIX

SCa

LXXXIV

SCh

The origin of C-2 and C-4 has also been proved by the tracer technique as coming from acetate methyl, while for C-3the carboxyl of acetic acid is the precursor (83),probably via acetoacetyl coenzyme A. The question still open is how ornithine reacts with that compound to account for the

7.

297

THE TROPANE ALKALOIDS

stereospecificity of the incorporation of radiocarbon. A two (or more)step addition-oxidation involving decarboxylations seems likely, e.g. XCI through XCV. COOH

I

H~C'--'CH

I '

SHz

-

+

+

HsC ,e,CHz-COOCoA

HZC-CH~NH~

E'\

H x

II

0

SSVIIIb

;

H~c,~,,CH-COOH

/I

O XCIII

XCII

SCI

p

-

Michael

11

/I

0

XCVb

XCIV

0

COOH

Most recently, however, it is reported (84) that a-N-methyl-14C ornithine is incorporated by Datura in the same way as ornithine. About 80% of the label was detected in the N-methyl group of hyoscyamine and hyoscine, while labeling of the methyl group in the 6 position of ornithine showed only 3-4% of the radioactivity in the N-methyl group of the main tropane bases. I n view of this fact the scheme XCI + XCV might be modified : a-N-methylation seems to precede condensation. N - and C-labeling is awaited to show whether or not the a-nitrogen is maintained during the biosynthesis. A surprising fact is that putrescine-1,4-14C may also serve as a precursor for tropanes, although it was shown only in the case of sterilized D. stramonium root or seeds (85). By degradation to N-methylsuccinimide-14C, it could be proved that the Iabel was present in the pyrrolidine moiety of hyoscyamine. The interconversion of tropane bases in vivo was already mentioned (see Volume VI, p. 173) for D . ferox scions on Cyphomandra betacea; so-called alkaloid-free plants were able to oxidize hyoscyamine (XXVIII) to hyoscine [( - )-XXII]. The course is highly stereospecific, since only 50 yo of atropine-i.e., of the levorotatory antimer-became oxidized (86).

298

G . FODOR

Feeding of the alkaloid-free plant with 6,7-dehydrohyoscyamine (XLIX) led as well to the formation of hyoscine ( - )XXII (87). Improvement of these investigations (88) was achieved by using very young, living Datura stramonium seedlings and feeding them with hyoscyamine-(methyl-l4C)(XXVIIIb). Thus 27.5% of the radiocarbon introduced with hyoscyamine was found in the form of hyoscine-(methyl14C), and S-9% in the form of labeled 6-hydroxyhyoscyamine (XXIb) (compare Section 11,F). When 6-hydroxy hyoscyamine-(methyl-14C) was introduced into the same seedlings, radioactive hyoscine was formed. Thus hyoscyamine is oxidized by an enzyme to 6-hydroxyhyoscyamine and this, in turn, is converted into hyoscine. The 6-dehydrohyoscyamine (XLIX) might well be an intermediate in this last step but it has not been trapped so far in the plant tissue. Therefore its role in the biogenetic pathway still remains hypothetical. Some attempts have been made to block the activity of the enzyme by using calcium nitrate and cysteine, respectively, to inhibit the introduction of the epoxide bridge, i.e., to stop a t the stage of dehydrohyoscyamine. However, only norhyoscyamine (XCV) was formed instead of the expected dehydrohyoscyamine (89).

H

OTr

XXVIIIb

XXIb

(-)

XXIIb

I H3C\N

XCV

XLIX

(-)

XXII

Feeding with labeled and unlabeled hyoscine, followed by paper chromatographic separation, showed no trace of labeled hyoscyamine. Hence no transmethylation occurred throughout this series of interconversions.

7.

299

T H E T R O P A N E ALKALOIDS

The hydrolysis of ditigloyltropanediol has been followed in vivo (90). The first suggestion regarding the biogenesis of tropic acid was that of a terpene origin (91) of this hydroxy acid. Since prephenic acid (XCVI) became known as a source of aromatic acids, the same intermediate was assumed for tropic acid. Notwithstanding, phenylalanine-3-14C(XCVII) gave radioactive hyoscyamine (XXVIII) and hyoscine (XXII) in feeding experiments (92) with D . stramonium. The whole label was contained in the tropic acid moiety and none in the alkamine. Hence, two mechanisms have been tentatively accepted : ( a )hydroxymethylation of prephenic acid (XCVI)by a biological equivalent of formaldehyde, followed by aromatization to XCIX and oxidation to XXIIIb, or ( b ) formation of phenylalanine (XCVIIa) from prephenic acid with subsequent oxidation to phenylpyruvic acid (XCVIII). The decarbonylation of that a-keto acid should give phenylacetic acid (C) which, by hydroxymethylation, gives tropic acid (XXIIIb). Unfortunately, feeding of Datura with either formate-14C or with formaldehyde resulted

“0 COOH

HO

CH-COCOOH

I

CHzCOCOOH

CHzOH CH20H

XCVI

H XCVIIa

XCVIII

XCIX

C

XXIIIb

both in an incorporation of the radiocarbon into the tropane skeleton, particularly in the N-methyl group, and without any trace of 14C in the methylol carbon (92). As a later development, feeding (93) of the same

&’Hk

IiH2 C H Z & Y ~ O H+

@

I

I4CHzO

n

XCVIIb

I

COOH XXIIIC

T

red. - C O ,

COOH XCVIIIb

CI

300

G . FODOR

plant with phenylalanine-2-14C (XCVIIb) conveyed the whole label into the methylol carbon of tropic acid (XXIIIc). The phenylpyruvic acid-2-14C (XLVIIIb) was probably carboxylated in C-3 to give CI which, in turn, was decarboxylated in C-1, with the formyl group reduced, leading to (methylol-14C)tropic acid (XXIIIc). The finding that tryptophan-2-14C (CII) may also serve as a precursor for tropic acid (94)labeled in the carboxyl group (XXIIId) seemed to be contradictory. However, it was interpreted later (93) by assuming tryptophan as a source for 14CO2, which becomes incorporated into phenylpyruvic acid; this acid is supposed to be formed from phenylalanine. However, this is an explanation but not a rigorous proof. KHz

I

H

GI1

XXIIId

VIII. Pharmacologically Active Synthetic Tropanium Salts Using the principle of direct and reverse quaternization ( 2 , 58, 5 9 ) ,a series of N-epimeric tropanium salts have been prepared (95, 96). Relative configurations have been tentatively allotted to them by analogy with the already known epimeric pairs, i.e., by deduction from the sequence of introducing the individual alkyl or arylalkyl groups onto nitrogen. Comparisons have been made, first, as to acetylcholine antagonists (atropine taken as 100) and second, concerning ganglion-blocking activity (tetraethylammonium bromide taken as 100). The strongest ganglion-blocking activity was shown by compounds with substituents in N , [for notation see Fodor et al. (59); also Volume VI, p. 1491 (axial) ethyl and in N b (equatorial) arylalkyl, in particular the p-phenylbenzyl group. REFERENCES 1. A. Lindenmann, PZanta Med . 9, 317 (1961). 2. G. Fodor, Chena. & Ind. ( L o n d o n )p. 1500 (1961). 3. A. Romeike, Pharnaazie 15, 655 (1960). 4. J. H. van Soeren, Pharna. WeekbZad 97, 721 (1962).

7.

T H E T R O P A N E ALKALOIDS

301

B. Issekutz, sen., Polski Iygod. Lekar. 18, 670 (1963). &.I.Tishler, Advan. Chem. Ser. 45, 1 (1964). A. Pinder, Chem. d2 I n d . (London)p. 1410 (1961). J. Parello, P. Longevialle, W. Vetter, and J. A. McCloskey, Bull. SOC.Chim. France p. 2787 (1963). 8a. H. Budzikiewicz, C. Djerassi, G. Fodor, E . Blossey, and M. Ohashi, Tetrahedron 20, 585 (1964). 8b. H. Budzikiewicz, C. Djerassi, and D. H. Williams, “Interpretation of Mass Spectra of Organic Compounds,” pp. 28-40. Holden-Day, San Francisco, California, 1964. 9. F. Martin and W. F. Mitchell, J . Chem. Soe. p. 1155 (1940). 10. W. F. Mitchell and E . M. Trautner, J . Chem. SOC.p. 1330 (1947). 11. G. Fodor, unpublished data (1966). 12. G. Fodor, J. T6th, and I. Vincze, Helv. Chim. Acta 37, 907 (1954). 13. 6. KovBcs, G. Fodor, and M. Halmos, J . Org. Chem. 22, 1699 (1957). 14. G. Fodor, 0.Kov&cs, and I. Weisz, Nature 174, 131 (1954); 8.KovBcs, G. Fodor, and I. Weisz, Helv.Chim. Acta 37, 892 (1954). 15. 6. Kovacs, I. Weisz, P. Zoller, and G. Fodor, Helv. Chim. Acta 39, 99 (1956). 16. St. P. Findlay,J. Org. Chem. 21, 711 (1956). 17. I. Weisz, N. Mandava, and G. Fodor, unpublished data (1966). 18. 0. E. Edwards, G. Fodor, and L. Marion, Can. J . Chern. 44, 13 (1966). 19. G. Fodor and K . XBdor, Nature 169,462 (1952); J . Chem.Soc. p. 721 (1953). 20. B. L. Zeuitz, C. M. Martini, M. Priznar, and F. C. Nachod, J . Am. Chem. SOC. 74,5564 (1952). 21. M. S. Bainova, G. I. Bazilevskaya, L. D. Mirosnichenko, and N. A . Preobrazhenskii Dokl. Akad. N a u k S S S R 157, 599 (1964). 22a. H. S. Aaron and C. P. Rader, J . Org. Chem. 29, 3426 (1964). 22b. H. S. Aaron and C. P. Rader, J . Am. Chem. Soc. 85, 3046 (1963). 23. C. H. MacGillavry, unpublished data (1966). 24. H. 0. House, H. C. Muller, C. G. Pitt, and P. P. Wickham, J . Org. Chem. 28,2407 (1963). 25. B. J. Calvert and J. D. Hobson, Proc. Chem. SOC.p. 12 (1962). 26. A. Sekera, Ann. Chirn. (Paris) [13] 7, 57 (1962). 27. W. C. Evans and W. J. Griffin, J . Chem. SOC. p. 4348 (1963). 28. W. C. Evans and M. Wellendorf, J . Chem. SOC. p. 1991 (1958). 29. A. Romeike, Naturwissenschaften 49, 281 (1962). 30. G. Fodor, I. Koczor, and G. Janzs6, Arch. Pharm. 295, 91 (1962). 31. A. Romeike and G. Fodor, Tetrahedron Letters No. 22, p. 1 (1960). 32. K. Freudenberg, J . Todd, and R . Seidler, Ann. Chem. 501, 206 (1933). 33. G. Fodor and Gy. Csepreghy, Tetrahedron Letters KO. 7, p. 16 (1959); J . Chem. SOC. p. 3222 (1961). 34. H. I . Bernstein and F. C. Whitmore, J . Am. Chem. SOC.61, 1324 (1939). 35. A. RIcKenzie and R. C. Strathern, J . Chem. Soc. 127, 82 (1925). 36. R. S. Cahn, C. K . Ingold, and V. Prelog, Ezperientia 12, 81 (1956). 37. G. Fodor, I . Vincze, and J . T6th, Ezperientia 13, 183 (1957). 38. A. Stoll, E. Jucker, and A. Lindenmann, Helv. Chim. Acta 37, 495 and 649 (1954). 39a. G. Fodor and F. S6ti, Tetrahedron Letters p. 1917 (1964). 39b. G. Fodor and F. S&i, J . Chem. SOC.p. 6830 (1965). 40. R.Wolffenstein and L. Mamlock, Chem. Ber. 41, 723 (1908). 41. M. Barrowcliff and F. Tutin, J . Chem. SOC.95, 1966 (1909). 42. Hungarian Patent 149,049 (1961). 5. 6. 7. 8.

302 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71.

72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84.

G . FODOR

G. Fodor, J. RBkbczi, and Gy. Csepreghy, Acta Chim. Hung. 28, 409 (1961). G. Fodor and P. Dob6, unpublished data (1957). J . Rak6czi and S. Kiss, unpublished data (1962). K. Zeile and A. Heusner, 2. A-citurforsch. 12b, 661 (1957). K. Zeile a.nd A. Heusner, L'JLem. Ber. 90, 2801 (1957). K. Zeile and A. Heusner, Chem. Ber. 90, 2809 (1957). A. Stoll, A. Lindenmann, and E. Jucker, H e h . C'him. Acta 36, 1500 (1953). G. Fodor, S. Kiss, and J. Ritkbczi, Chim. Ce- I n d . ( P a r i s ) 90, No. 3b, 225 (1963); I U P A C Meeting, London 1963 Abstracts p. 287. G. Fodor, I. Vincze, and J. Tbth, J . C'hem. SOC. p. 3219 (1961). A. Stoll, B. Becker, and E. Jucker, H e h . Chim.Acta 35, 1263 (1952). G. Fodor, S. Kiss, and A. Heusner, Chem. & I n d . ( L o n d o n ) p. 372 (1963). N. A. Preobrashenski, J. A. Kubtsov, T. F. Dankova, and V. P. Pavlov, Z h . Obshch. Khim. 15, 952 (1945). G. Fodor and F. Sbti, unpublished data (1964). V. Horak and P. Zuman, unpublished data (1963); G. Fodor, M a y y . T u d . A k a d . K i m . T u d . Oszt., KozZ6mny. 20, 337 (1963). V. Horak and P. Zuman, Tetrahedron Letters p. 746 (1961). G. Fodor, Bull. Soc. Chim. France p. 1032 (1956). G. Fodor, J . T6th, and I. Vincze, J. Chem. SOC. p. 3504 (1955). G. Fodor and C. H. MacGillavry, J . Chem. Soe. p. 597 (1964). K. Koczka and G . Bernbth, Chem. & I n d . ( L o n d o n ) p. 1401 (1958). R. Bognkr and S. Szab6, Tetrahedron Letters p. 2847 (1964). G. L. Closs, J. Am. Chem. SOC.81, 5456 (1959). R. J. Bishop, G. Fodor, A. R. Katritzky, F. S6ti, L. E . Sutton, and F. J. Swinbourne, J . Chem. SOC.(C), p. 74 (1966). J . McKenna, J. M. McKenna, A. Tulley, and J. White, J . Chem. Sac. p. 1711 (1965). J. K. Becconsall, R. A. Y. Jones, and J. McKenna,J. Chem. Sac. p. 1726 (1965). J. McKenna, B. G. Hutley, and J. White,J. Chern. SOC.p. 1729 (1965). J. McKenna and J. White, J. Chem. Soc. p. 1733 (1965). A. T. Bottini, B. F . Dowden, and R. L. VanEtten,J. Am. Chem. SOC. 87,3250 (1965). J. M. Eckert and R. J. W. LeFBvre, J . CILem. SOC. p. 3991 (1962). D. J. Cram, personal communication (1964). I. Weisz, unpublished data (1966). L. A. Paquette and J. W. Heimaster, J . Am. Chern. SOC.88, 763 (1966). J. Meinwald, S. L. Emermann, N. C. Yang, and G. Buchi, J . Am. Chem. SOC.77, 4401 (1955). S. Archer, & R. I. Bell, J. W. Schulenberg, and M. J. Unser, J . Am. Chem. Soc. 79, 6337 (1957); 80, 4677 (1958). G. Fodor, G. Janzs6, L. Otvos, and D. BBnfi, Chem. Ber. 93, 2681 (1960). G. Werner, H. L. Schmidt, and E . Kassner, Ann. Chem. 644, 109 (1960). G. Fodor and A. Romeike, I n d . Chim. BeZge 27,555 (1962); Lecture, 75th Anniversa.ry of the Sociktk Chimique de Belgique. E . Leete, L. Marion, and I. D. Spenscr, Can. J . Chem. 32, 1116 (1954). E. Leete, J . Am. Chem. SOC.84, 55 (1962). A. A. Bothner-By, R. S. Schutz, R. F. Dawson, and M. L. Solt, J. Am. Chem. SOC. 84, 52 (1962). E. Leete, Tetrahedron Letters p. 1619 (1964). K. Mothes, J. Kaczkow-ski,and H. R. Schiitte, Biochim. Biophys. Acta 46,588 (1963). D. Neumann and H.-B. Schroeter, Tetrahedron Letters p. 1273 (1966).

7. THE TROPANE 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.

ALKALOIDS

303

H . W. Liebisch, H. R. Schutte. and K. Mothes, A n n . Chem. 668, 139 (1963). A. Romeike, Flora ( J e n a ) 143, 67 (1956); 148, 306 (1959). G. Fodor, A. Romeike, G. Janzso, and I. Koczor, Tetrahedron Letters KO.7, 19 (1959). A. Romeike, Katurwzssemchujtften 47, 64 (1960); A. Romeike and G. Fodor, Tetrahedroia Letters S o . 22, p. 1 (1960). A. Romeike, ~ ~ ' c l t u r w i s s e n s c h n e49, n 426 (1962); Florn ( J e m ) 154, 163 (1964). W. C. Evans and W. J. Gtiffin, Phytochemzstry 3, 503 (1964). E. Wenkert, E x p r i e n t i a 15, 165 (1959). E. Leete,J. Am. Chem. Soc. 82, 612 (1960). E. Leete and M. L. Louden, Chem. & I n d . ( L o n d o n )p. 1405 (1961). A. M Goodeve and E. Raamstad, Experientia 17, 124 (1961). M. Doda, L. Gyorgy, and K. Sbdor, Arch. Intern. Pharmacodyn. 145, 264 (1963). C. G. Haining and R. G. Johnston, Brit. J . I'harmacol. 18, 275 (1962).

This Page Intentionaiiy Laft Blank

-CHAPTER

8-

STEROID ALKALOIDS: ALKALOIDS OF APOCYNACEAE AND BUXACEAE V. CERNPA N D F. SORN Iiistitute of Organic Chemtstry n)id Biochemistry, Crechoslovuk Academy of Scieitce, Prcigue, C ~ e c h o ~ d o v n k m I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Alkaloids of Apocynaceae. . . . . . . . . ................. A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Mass Spectra of Holnrrhenn a n d Related Alkaloids. .................... C. Pregnane and 17aa-Methyl-D-homoandrostane Deribatives. D. Conanino Derivatives. ..................................... E. Total Syntheses in the C Group. ................ F. Paravallarine-Type Alkaloids. ......................... .... G. 18-Substituted Analogs of Steroid Hormones from Alkaloids. . . . . . . . . . . . 111. AlkaloidsofBuxaceae. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Introductlon. ..................................... B. B u m s Alkaloids. . . . . . . . . . . . . . . . . . . ............... C. Sareocoecn Alkaloids. . . . . . . . . . . . . . . D. Pachysandra Alkaloids. . . . . . . . ............

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

IV. Biogenetic Xotes. References

305 307 307 308 310 330 358 367 350 376 375 378 406 410

417

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

419

I. Introduction Since the publication of the summary of Holarrhenu alkaloids by 0. Jeger and V. Prelog in Volume V I I of this series (I),much attention has been paid to these bases for two reasons. One was the unique substitution a t C-18 of the steroid skeleton characteristic of then known Holarrhencc alkaloids, which promised to be a suitable starting material for the preparation of the adrenocortical hormone aldosterone and its analogs. The other was the possibility of applying some simple alkaloids of this group to the industrial production of steroid hormones. In the given period Holarrhena alkaloids were studied chiefly in France by Goutarel and Janot, in Germany by Tschesche, and in Czechoslovakia by the authors of this article. It is to the credit of the French authors that they proved the presence of the same types in other genera of the family 305

v. ERN+

306

A N D F. ~ O R M

Apocynaceae namely, in Funtumia and Malouetia. These bases are either simple pregnane (I)derivatives, or are derived from conanine (11) ( 2 ) . Simple pregnane derivatives were also found in Conopharyngia, Chonemorpha, and Dictyophleba. The latter genus also contains alkaloids (111); their immediate derived from 17acr-methyl-~-hornoandrostane precursors, however, are undoubtedly bases with pregnane skeleton. Finally, an interesting group of basic steroid lactones derived from the basic types I V and V was discovered in Paravallaris and Kibatalia by Le Men.

Me

I

---:1;--. H

I1

I

5a-Conanine

Ba-Pregnane

@ H

I11 17aa-Methyl-~-homo-

CCp H

IV (20R) V (20s)

Ba-androstane

@ Z

&-) H

IX VI;Z = C N z VII;Z = H , M e VIII;Z =Me, M e

8.

ALKALOIDS O F

Al’OCYNhCEAE A N D

BUX-&CEAE

307

The occurrence of pregnane-type alkaloids, however, is not restricted t o certain Apocynaceae. I n some Buxaceae, namely, in Sarcococca and Pachysandra, there were found pregnane-type alkaloids some of which are identical with those of Apocynaceae ; both foregoing genera differ in this respect from Buxus, the most important genus of the family. Structure elucidation of the main types of the Buxus alkaloids is an important achievement of the given period, made possible by the establishing of the structure of cyclobuxine-D and other alkaloids by Kupchan and co-workers. His work, together with the results arrived at by Goutarel, Nakano, Arigoni, Stauffacher, Marini-Bettblo, Votickf, Tomko, and others, showed that Buxus alkaloids represent new types of steroid alkaloids (except for the simple pregnane derivative irehine) which can be derived from the structures expressed by the formulas VI-VIII or IX.

11. Alkaloids of Apocynaceae A. INTRODUCTION The study of Holarrhena alkaloids resulted in structure elucidation of numerous alkaloids which were either newly isolated or subjected to reinvestigation. For example, the structure of conkurchine and related bases was thus definitively established. I n newly isolated alkaloids new findings are restricted chiefly to broadening of the knowledge of the character of skeletal substitution, e.g., isolation of mononitrogen bases, alkaloids substituted by the 3a-amino group, pregnane derivatives lacking the substituent in position 18, and a-amino alcohols. A more significant finding was the isolation of kurcholessine, which is substituted by a methyl group in position 4,thus resembling Buxus alkaloids in this particular structural feature. Steroid alkaloids were also found in Funtumia and Malouetia. The genus Funtumia comprises tropical trees indigenous to equatorial and West Afrika. Alkaloids found therein belong to types I and 11. Many contain only one atom of nitrogen and an oxygen function in positions 3 or 20; in comparison Holarrhena alkaloids exhibit this type of substitution much less frequently. The genus Malouetia occurs in both Africa and South America. It is distinguished by the same types of alkaloids as Funtumia and Holarrhena. Of particular intercst is the isolation of the quaternary alkaloid malouetine with curarizing effect in the African Malouetia bequaertiana Woods. It is probable that the same effect produced by the Venezuelan drug guachumaca can be attributed to some alkaloids of the South American Malouetia ( 3 ) .

v. E E R N . ~A N D

308

F.

SORM

The genus Malouetia was described in detail, both from the botanical and chemical point of view, by F. Khuong-Huu-Lain6 et al. ( 3 ) . The results of extensive investigations of steroid alkaloids of dpocynaceae have been reviewed in several articles (4-8) and in the excellent monograph by Goutarel (9).

B.

MASS

SPECTRA OF Holarrhena

AND

RELATED ALKALOIDS

The mass spectrometric investigation of a series of Holarrhena alkaloids was independently undertaken by two groups ( 1 0 , l l ;see also 12, 13).Their work resulted in practically identical conclusions and also demonstrated the immense diagnostic value of mass spectrometry in this field of alkaloid chemistry.

1. 3-Aminopegnane Derivatives Depending on the number of N-methy1 substituents of the amino group, the inass spectra exhibit characteristic intense peaks, the masses of which form the homologous series 56, T O , and 84 corresponding to primary, secondary, and tertiary amino functions ; the intensity of the peaks increases in the same order. This fragmentation was rationalized

8.

ALKALOIDS O F APOCYNACEAE AXD BUXACEAE

R

R

P

__f

309

*

*CH2-N=CH-CH,

X X I I a ; m/e 56 + R

I@

CH2=N--CH--GHa

XXIIb

+D XXITI

b

+ HzC-CH=NRIRz XXIV

XXV; m/e 42

(f)

+ R I + Rz

(10, 11) by the mechanism ( a ) .The validity of these considerations was confirmed by deuterium labeling (14).The presence of a 5,6-double bond considerably promotes the fragmentation ( a ) , since both dissociating bonds occupy allylic positions. On the other hand, t h e presence of an exomethylene group a t C-4, encountered in some Buzus alkaloids, quenches this fragmentation almost completely. The alkaloids which do not contain a 5,G-double bond exhibit additional characteristic fragmentation occurring at m/e 80 + R1+ Rz. The proposed mechanism ( b ) (11, 12) was supported by establishing that hydrogen is transferred from C-4 ( 1 4 ) . If 4-hydrogen is lacking, as in 4,4-dimethyl steroids, the fragmentation does not occur ( 1 5 ) ;it is also almost totally suppressed in 5,6-unsaturated steroids. The presence of a 9,19-cyclopropane ring or a 4-methylene group gives rise to other fragmentation types, fragmentation ( a ) being greatly

310

v.

~ E R AKN D ~ F. . ~ O R M

reduced. Thus, the peak at m/e 57 in the spectrum of cyclovirobuxine-D (partial formula : XVII ; R1= H, Rz =JIe) is due to rupture of the 1,2bond activated by the cyclopropane ring, fragmentation (c) (15,16). I n the spectrum of cyclobuxine-D, the 3-methylamino group is characterized by the peak a t m/e 44. The fragmentation process ( d ) probably commences by the fission of the 2,3-linkage and transfer of the hydrogen atom from position 1 (16). Thus, the presence of the exomethylene double bond influences the course of the fragmentation more strongly than does the cyclopropane ring.

2. Conanine Derivatives The alkaloids of this group are characterized by two important peaks : the intense peak a t mje 56 + R (R = H or Me), due to fragmentation ( e ) , and at 31-15. Both fragmentations arise from the fission of the linkages adjacent to the 18,20-imino group (13,lX- and 17,20- or 20,21-linlrages) (10, 11, 13). Simultaneous presence of both intense peaks is highly characteristic of the conanine type. It is pertinent to note that the abundance of M-15 ions is strongly dependent on the extent of other fragmentations, particularly on fragmentation (a). This type of cleavage is not suppressed in 20-(h7)-pyrrolines(10).

3. 20-Aminopregnune Derivutives These structures are characterized by intense ions of mass m/e 42 + R1+ Rz owing to fragmentation ( f ) .The alternative fission of the 20,21-linkage leading to 111-15 ion generally occurs to a much smaller extent than in the conanine type ( 1 0 , l l ) .

C.

PREGNANE AND 17aa-&IETHYL-D-HOMOANDROSTANEDERIVATIVES

1. Fu?atuphyllumines-A,-B, und -C These alkaloids were first isolated from insoluble oxalate fraction from Funtuiniu ufricnna (Benth.) Stapf. (17, 18). Both the primary amine funtuphyllamine-A (XXVI) and the secoiidary base funtuphyllamine-B (XXVII) gave funtuphyllamine-C (XXVIII) 011 Eschweiler-Clarke methylation. The structure of funtuphyllamine-B follows from the result of the Ruschig degradation (conversion of a primary or secondary base to a ketone via chloramine and ketimine) (19), which furnished 3P-hydroxy-5a-pregnan-20-one. O-hcetylfuntupliyllamine-C proved to be identical with the known (20) 3/3-acetoxy-20a-dimethylamino-5a-pregnane. Funtuphyllamine-B is

8. ALKALOIDS O F APOCYNACEAE

HOS

N H

R

XXVI; XXVII; XXVIII; XXIX:

l

R

RI

Rz

H H Me H

H Me Me CHO

2

AND BUXACEAE

311

o&NR1R2 H

XXX; XXSI;

RI R2 -___ Me Me Me

H

identical with the known 20a-methylamino-5a-pregnan-3P-01 (21). Funtuphyllamine-A was converted to funtuphyllamine-B by way of the N-formyl derivative XXIX and reduction of the latter with lithium aluminum hydride. The structure of funtuphyllamine-A was confirmed by its synthesis from 3p-hydroxy-5a-pregnan-20-one oxime by catalytic hydrogenation over platinum in acetic acid solution. On chromic acid oxidation funtuphyllamine-B and funtuphyllamine-C yielded the corresponding ketones, identical with the natural alkaloids funtumafrine-B and -C, respectively (17).

2. Funtumafrine-B and -C Funtumafrine-B (XXX) and funtumafrine-C (XXXI) were obtained from the leaves of Funtumia africuna via the soluble oxalates. The IRspectrum of both alkaloids disclosed the presence of a carbonyl group (1706 cm-1) and their structure was established by the preparation from funtuphyllamine-B (furnishing funtumafrine-B) and funtuphyllamine-C (furnishing funtumafrine-C) on chromic acid oxidation (17, 18). 20cr-Dimethylamino-5cr-pregnan-3-one had been previously reported as a product of partial synthesis (20).

3. Funtumine This alkaloid (XXXII) was isolated from the leaves of Funtumia latifoEiu (Stapf) Stapf ( 2 2 ) . The presence of a keto and a primary amino group was revealed by the spectral behavior of the free base, its hydrochloride, and its Wacetyl derivative and was further confirmed by the result of Eschweiler-Clarke methylation, yielding a n N, N-dimethyl derivative which could be reduced by Wolff-Kishner method to give the known (23) 3a-dimethylamino-5a-pregnane. Ruschig degradation of funtumine gave 5a-pregnan-3,20-dione, thus locating the oxygen function in position 20.

v.

312

ERN$ A N D F.

SORM

Funtumine (together with funtumidine) is of practical use as suitable starting material for the production of some steroid hormones ( 7 ,2 4 ) .

4. Guntumidine Funtumidine (XXXIII) was isolated along with funtumine from the leaves of Puntumia latifolia. I n contrast with funtumine, it contains no carbonyl group ; instead, the IR'-spectrum showed the presence of a hydroxyl group. On chromic acid oxidation funtumidine yielded funtumine ( 2 2 ) .The configuration of the hydroxyl group was established by Ruschig degradation to a ketone, the IR-spectrum of which proved to be identical with that of 20~hydroxy-5a-pregnan-3-one. Funtumine was converted to funtumidine by reduction with sodium and ethanol. On the other hand, reduction of funtumine with potassium borohydride (or catalytic hydrogenation) resulted in the formation of the 20P-hydroxy derivative, isofuntumidine (XXXIV) (mp 170°, [.IU - 6"in chloroform), which on Ruschig degradation yielded 20P-hydroxy-5cc-pregnan-3-one. Both epimeric 20-hydroxy-5a-pregnan-3-ones on acetylation showed shifts in molecular rotation characteristic of 2Oa- or 20P-configuration, respectively (25, 26).

XXXII

XXXIII

XXXIV

Microbiological hydroxylation of funtumine and funtnmidine by Aspergillus ochraceus was reported to yield 1 Icc- and 12/3-hydroxy derivatives ( 2 7 ) .

8.

ALKALOIDS OF APOCYNACEAE A N D BUXACEAE

313

Several 20-oxygenated alkaloids, including funtumidine and 20-ketopregnane derivatives funtumine, holaphylline (LV), holaphyllamine (LVI), and holamine (LXIII), were subjected to a detailed pharmacological investigation (28-32). They exhibited no effect on gonads. All of them showed antigonadotropic, corticotropic, and antiinflammatory activity. Holaphyllamine and holamine proved to be strong local anesthetics. Except for holaphylline, they showed hypotensive and antipyretic or hypothermic activity ; funtumine and funtumidine have a stimulating while holaphylline, holaphyllamine, and holamine have a depressing effect on respiration. Diuresis in rats was observed after application of holaphylline, holaphyllamine, or holamine ; holaphyllamine and holamine caused retention of sodium. Funtumidine and funtumine lowered serum cholesterol and raised phospholipids.

5 . Chonemorphine Chonemorphine (XXXV) was first isolated from the roots of Chonemorpha fragrans (macrophylla)G. Don (33, 34) and C. penangensis Ridl. (35)and was later found in other Apocynaceae ( 3 , 35a). Initially, it was considered to be a quaternary base CllH23NO3 (33, 34). This alkaloid contains a dimethylamino and a primary amino group as demonstrated by the spectral properties of the acetyl derivative and by the formation ofa benzylidene derivative. Based on end absorption in the UV-spectrum, a double bond was presumed (35)to be present; it was tentatively located in the 8,g-position of the steroid skeleton and the formula C23H40N2 was adopted ( 3 6 ) .However, this assumption was disproved by later work (37) showing that the alkaloid has a saturated skeleton. Decisive information as to its structure was provided by treatment of chonemorphine with nitrous acid yielding a hydroxy derivative which was found to be The identical with the known (80) 20a-dimethylamino-5cc-pregnan-3P-01. structure of this deamination product was further confirmed by subjecting it to Hofmann degradation followed by catalytic hydrogenation to yield 5a-pregnan-3P-01 ( 3 7 ) . Definitive confirmation of the assigned structure was provided by establishing the identity of chonemorphine with 3P-amino-2Oa-dimethylamino-5~-pregnane prepared synthetically from the oxime of 20cc-dimethylamino-5~~-pregnan3-one by reduction with sodium in ethanol (18)or in amyl alcohol (38).

6 . N-Acetylchonemorphine This a,lkaloid (XXXVI) was isolated from Malouetia bepuaertiana R. E. Woodson ( 3 ) .

v. ERN^

314

A N D F. ~ O R M

7 . Dictyophlebine Dictyophlebine (XXXVIII) was isolated via the corresponding acetyl derivative C ~ ~ H ~ ~(mp N Z198"; O +15" in chloroform) from the roots of Dictyophleba lucida (K. Schum.) Pierre. Its structure was indicated by mass (peaks a t m/e 70, 96, 72) and NMR-spectrometry [presence of one secondary and two tertiary C-methyls, NHCH3, and N(CH3)z groups] and confirmed both by degradation by the Ruschig method to 20a-dimethylamino-5a-pregnan-3-one, and by synthesis : treatment of chonemorphine with ethyl chloroformate led to 3-Ncarbetlioxychonemorphine (XXXIX) which upon reduction with lithium aluminum hydride yielded 3P-methylamino-20a-dimethylamino-5a-pregnane, identical with dictyophlebine (35a, 39, 40). I

Ri

R2

Me Me XXXVII; Me H XXXVIII; Me Me XXXIX; COOEt Me XXXV; XXXVI;

H Ac

I

2x

XL; X=OH XLI;

X=Cl

8. Dictyodiamine This alkaloid (XXXVII)was isolated indirectly, by way of its diacetyl derivative, C Z ~ H ~ (mp ~ N 240"; ~ O ~ ["ID - 16" in chloroform), from the roots of Dictyophleba lucida (35a)and was only obtained by cleavage of the diacetyl derivative with lithium in diethylamine. Its structure was indicated by the mass spectrometric fragmentation pattern (peaks a t m/e 70, 96, and 58), NMR-evidence (methyl groups), and chemical behavior (formation of a neutral diacetyl derivative), and received full confirmation by a synthesis of the diacetyl derivative, using N-acetyldictyophlebine as starting material : on reaction with hydrogen peroxide, it was converted to the 20-N-oxide which suffered decomposition on heating with acetic anhydride to yield diacetyldictyodiamine. Dictyodiamine is identical with epipachysamine-C found previously by Kikuchi and collaborators in Pachysandra terminalis Sieb. et Zucc., but isolated and reported only as its N,N'-diacetyl derivative (mp 242'-243" ;

@

8.

ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

315

[aln - 16" in chloroform) (41). The Japanese authors established the structure of this diacetyl derivative on the basis of its empirical formula, neutrality, and spectrographic properties, and supported this assignment by correlation with epipachysamine-X (see Section 111,D).This allialoid was degraded with cyanogen bromide to a secondary base the acetylation of which afforded A7,X'-diacetylcpipacliysamine-C.

9. Malouetine 3lalouetine (XL) was isolated (by means of ion exchange technique) from the roots and bark of Malouetia beguaertianu ( 4 2 ) .This alkaloid is responsible (at least in part) for the curarizing activity of tlie plant extract. On pyrolysis malouetine lost one molecule of trimethylamine to yield malouetimethine. The IR-spectrum demonstrated in the latter the presence of a vinylic (side chain) double bond and hydrogenation led to the known (43)3/i-dimethylamino-5a-pregnane.Reduction of malouetine chloride (XLI) with lithium aluminum hydride furnished the already known (20) 3/i,20a-bisdimethylamino-5a-pregnane. The structure XL, established (18) on the basis of the foregoing experiments, was further confirmed by synthesis from funtumafrine-C (XXXI) by way of the corresponding oxime, reduction with lithium aluminum hydride to a primary amine, identical with chonemorphine (XXXV), methylation with formic acid-formaldehyde, and quaternization with methyl iodide followed by ion exchange. I n addition, syntheses of all three remaining 3- and 20-isomers of malouetine are described in the original paper (18).

10. Malouphylline Malouphylline (XLII) was isolated from the leaves of ilfulouetia beqzcaertiana (18).The presence of an aldehyde and an acetylamino group mas disclosed by I R - and NNR-evidence (bands a t 1720, 1580, 1642, and 1653 cm-1, and singlets a t 0.30 and 8.04 T). The 1720 cm-1 band was absent in the hydrochloride, indicating an interaction between the aldehyde and the amino group. The structure of malouphylline was proved (44) by chemical correlations as outlined by the sequence XLII-XLVII. The alkaloid was reduced by lithium aluminum hydride to yield tlie secondary-tertiary base XLIII which by Ruschig deamination a t C-3, followed by Hofmanri degradation, yielded tlie cyclic ether XLVII which proved to be identical with the known ($5) (20K)-18,20oxido-5a-pregnan-3-one. Alternatively, the base XLIII was rnethylated with formaldehydeformic acid to yield the ditertiary base XLIV which on Hofmanii degradation yielded a mixture of tetramethyldihydroliolarrhimine

316

8. ALKALOIDS O F APOCYNACEAE

AND B U X A C E A E

317

(XLV) and a monoamine XLVI which could be converted to XLVII by cyanogen bromide and Ruschig degradation. The formation of the cyclic oxide XLVII settled the stereochemistry a t C-SO in X L I I since this conversion is known to involve an Sx2-displacement at this center (23, 4 6 ) .

11. ~ ~ a ~ o u p h ~ l l i n i n e This alkaloid (XLVIII) was isolated from Nalouetia beyuaertiana and was shown to be identical with malouphyllinol, obtained from malouphylline by reduction with potassium borohydride ( 3 ) .

12. Funtudiamine-A and -E Isolation of funtudiamine-A (XLIX) and funtudiamine-B (L) from Funturnia ZatifoLia was announced but no paper on this work has as yet appeared (35a). 13. Holafebrine and Conopharyngine Conopharyngine was isolated from the roots of Conopharyngia pachysiphon G. Don and was shown to be SOm-aminopregn-5-en-3P-y1-~~-glucoside.The proof of this structure was obtained by acid hydrolysis affording D-glucose and a n aglycone identical with 20m-aminopregn-5en-3p-01,which was confirmed by the synthesis of conopharyngine. This glucoalkaloid possesses a high hypotensive activity on intravenous, but low activity on oral, administration ( 4 7 ) .The aglycone was found to be

LI; LII; LIII; LIV:

Ri

Rz

H H H Me

H COOEt Me Me

identical with t,he compound LI prepared from t,he known (48) O-acetyl derivative. Its presence in a Conopharyngia species is interesting since Conopharyngiae belong to the subtribus Tabernaenaontana which is characterized by the presence of the iiidole alkaloids ; e.g., Conopharyngia

318

v. ERN$ AND

F. ~ O R M

durissirna Stapf afforded iboga bases ( 4 9 ) . ZOa-Amino-3/3-hydroxypregn-5-ene (LI) was later found in Holarrhena febrifuga Klotzsch and named holafebrine. Its structure was proved by the Ruschig degradation and by catalytic hydrogenation to 3/3-hydroxypregn-5-en-ZO-one furnishing funtuphyllamine-A (XXVI) (50). 14. Irehamine Irehamine was isolated (39) from the leaves of Funtumia elastica (Preuss.) Stapf. The structure LIII of this alkaloid follows from its via the N-carbpreparation from 20a-amino-3/3-hydroxypregn-5-ene ethoxy derivative LII and reduction of the latter with lithium aluminum hydride. In accord with this structure irehamine was converted to funtuphyllamine-B XXVII on catalytic hydrogenation (39).

15. Irehine This alkaloid was isolated from the leaves of Funtumia elastica; its formation by Eschweiler-Clarke methylation of 20a-aminopregn-5-en3/3-01 provided proof of its structure (LIV) which was further confirmed (39) by the result of the catalytic hydrogenation of irehine leading to funtuphyllamine-C (XXVIII). Noteworthy is the isolation of irehine, initially named buxomegine, from the leaves of Buxus sempervirens (51, 52). This finding is of interest from the biogenetic point of view since this is the only case where a simple pregnane derivative was found among Buxus alkaloids.

16. Holaphylline Holaphylline (LV) was isolated from the leaves of Holarrhena africana A. DC. (Jloribunda) advantage being taken of the insolubility of its oxalate in ethanol ( 5 3 ) .This alkaloid was found to contain a double bond, an N-methyl, and a keto group. On Wolff-Kishner reduction it yielded the known (23) 3/3-methylaminopregn-5-ene; Ruschig reaction led to progesterone. Independent evidence was obtained by correlation with isofuntumidine : holaphylline on reduction with potassium borohydride, catalytic hydrogenation on palladium, and Eschweiler-Clarke methyla(LVII) which was tion afforded 3P-dimethylamino-5cc-pregnan-2O~-ol also prepared from isofuntimidine (XXXIV) by replacing the 3a-amino group by a keto group (Ruschig reaction), converting the product to an oxime followed by reduction with sodium in ethanol, and subsequent methylation ( 5 3 ) . 17. Holaphyllamine This amorphous alkaloid was isolated from the leaves of H . africana (JEoribunda)by way of its ethanol-insoluble oxalates ( 5 3 ) .Its structure

+

f

8. ALKALOIDS OF APOCYNACEAE AND BUXACEAE

x

319

320

v. ERN^ AND

F. ~ O R M

(LT'I) was proved (5-2) by Eschweiler-Clarke methylation to methylholaphylline and was further confirmed by a synthesis from pregnenolone (LIX) via 3~-tosyloxy-2~~-oximinopregii-5-ene (LX)which on treatment with sodium azide in methanol yielded a mixture of 3P-azido-20-oximinopregn-5-ene (LXI) and the 3a,5~-cyclo-BP-azidoisomer. Selective reduction with lithium aluminum hydride followed by acid hydrolysis yielded holaphyllamine along with its 3,5-cyclo isomer which could be separated by chromatography ( 5 5 ) .

18. Holuphyllidine The isolation of this base from the leaves of H . africuna (floribunda) was announced (56).It is assigned the structure 3P-methylaminopregn5-en-20a-01but no details have been published.

19. Holamine This alkaloid was isolated ( 5 4 ) from the leaves of H . africana ($or;bunda).It contains a keto group and a primary amino group ; its structure, 3a-aminopregn-5-en-20-one (LXIII), was deduced from the following transformations : the R'uschig reaction yielded progesterone in 40 yo yield and hydrogenation led to funtumine (XXXII). The position of the double bond was established by conversion to the known ( 5 7 ) 3adimethylaminopregn-5-ene on Eschweiler-Clarke methylation followed by Wolf-Kishner reduction ( 5 4 ) .This structure was later confirmed ( 5 5 ) by a synthesis of holamine from pregnenolone (LIX). Pregnenolone tosylate was treated with sodium azide in dimethylsulfoxide; in this dipolar aprotic solvent the reaction proceeded without participation of the double bond to yield the 3a-azide (LXII) by the Sx2 mechanism. Reduction with lithium aluminum hydride, followed by Oppenauer or chromic acid oxidation, yielded holamine.

20. Kzcrchiline Kurchiline (LXIV), along with kurchiphylline, kurchiphyllamine, kurchaline, holadysine, and holadysamine, was isolated from the leaves of Holurrhena antidysenterica (Roxb.)%'all. ( 5 8 ) .The structural similarity of all these alkaloids suggests a biogenetic relationship. However, those containing oxygen in position 16 may be artifacts produced during the isolation procedure. The presence in kurchiline of a secondary-tertiary double bond, a methylketo, a hydroxyl, a dimethylamino, and two tertiary C-methyl groups was disclosed by IR- and NMR-spectra, respectively. The hydroxyl group is Lapable of acetylation but is

321

8. ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

resistant to common oxidation procedures ; this latter observation together with the strong intramolecular hydrogen bonding observed in the IR-spectrum indicated the structure of a 1,2-amino alcohol. The occurrence of an intense peak a t m/e 100, instead of a t m/e 84 as encountered in steroids carrying an isolated dimethyl amino group in position 3, was in accord with position 2 for the hydroxyl. The same evidence was provided by the presence of an 11-44peak attributable to splitting off of a molecule of acetaldehyde. This assignment was confirmed and completed by a configurational proof of both substituting groups in the following manner : kurchiline on catalytic hydrogenation followed by Wolff-Kishner reduction afforded a tetrahydrodeoxykurchiline which was identified as 3P-dimethylamino-5cc-pregnan-2~~-01, prepared from 2a-acetoxy-5u-pregnan-3-one oxime by lithium aluminum hydride reduction and subsequent Eschweiler-Clarke methylation.

21. Kurchiphylline This alkaloid (LXVII) is isomeric with kurchiline and shows close similarity to it in spectral data except for those pertaining to the ketone group. The position of the carbonyl band in the IR-spectrum (1748 cm-1) demonstrated the keto group to be a part of a five-membered ring. This fact, in conjunction with strong negative optical rotation shown by the base, led to location of the ketone group in position 16. Both kurchi-

LXIV

LXV

LXVI; LXVII;

R=H R=Me

v.

322

&ERN+ AND F. ~ O R M

phylline and kurchiline yielded the identical product LXV on WolffKishner reduction, which resulted in formulation of kurchiphylline as 2a-hydroxy-3P-dimethylaminopregn-5-en-16-one (58, 59).

22. Kurchiphyllamine Kurchiphyllamine (LXVI) is hT-demethylkurchiyhyllineas shown by methylation with formic acid-formaldehyde to kurchiphylline (58, 59). 23. Kurchaline The presence of two hydroxyls (one of them allylic), one dimethylamino group, and two secondary tertiary double bonds in the pregnane skeleton of this alkaloid was established from I R - and NMR-spectra. Comparison of the NMR-spectrum with those of the stereoisomeric 3,16-dihydroxypregna-5,17(20)-dienes reported in the literature (60) showed that the signal of the 18-methyl occupied the position (9.24 T ) which was in agreement with the C( orientation of the 16-hydroxyl and trans configuration of the olefinic side chain as expressed in the formula LXVIII (59).

LXVIII

LXIX

LXX

24. HoEadysine This strongly levorotatory secondary base contains a trisubstituted double bond and, similar to kurchiphylline, exhibits a carbonyl maximum at 1742 em-1 in the IR-spectrum. The presence of the 16-keto group was confirmed by the mass spectrum in which the fragments a t m/e 298 and m/e 213 were identical with those reported as characteristic (61)of this keto group. The structure LXIX was proved by correlation with holaOn Wolff-Kishner reduction acetylmine (3~-aminopregn-5-en-Zo-one).

8.

ALKALOIDS OF APOCYNACEAE A N D BUXACEAE

323

holadysine furnished 3u-methylaminopregn-5-ene which proved to be identical with the product prepared from dihydrodeoxoholamine by reaction with ethyl chloroformate followed by reduction with lithium aluminum hydride. Holadysine is thus 3cc-methylaminopregn-5-en-16one (58, 59).

25. Holadysamine This alkaloid (LXX) (58) contains a methylamino and a hydroxyl group. The NMR-spectrum disclosed further two trisubstituted double bonds, the first located in the usual 5,A-position (4.65 T). Information regarding the position of the second double bond was also provided by the NMR-evidence since the signal of the u-proton in the secondary hydroxyl group appeared as a quartet. Taking into consideration further evidence locating this hydroxyl group in position 20, the above quartet implies the absence of a proton a t (2-17. This fact, together with the occurrence of completely analogous splitting patterns in 3,20dihydroxypregna-5,IA-dienesreported in the literature (62), led t o location of the second double bond in position 16,17. This assumption was further strengthened by the course of hydrogenation of holadysamine in acetic acid solution over palladium catalyst which furnished a mixture of products containing 16- and 20-ketones (bands a t 1740 and 1710 cm-I), a result which was interpreted as due t o allylic rearrangement and/or prototropic shift. The Wolff-Kishner reduction of the ketonic fraction yielded 3a-methylamino-5u-pregnane, the structure of which was confirmed by synthesis from funtumine. Finally, the configuration of the 20-hydroxyl was deduced from the negative increment of the molecular rotation observed on acetylation (59). 26. Irehdiamine-A This alkaloid (LXXI) was isolated from the leaves of Funtumia elastica (63).The NMR-spectrum disclosed the presence of two primary amino groups, one olefinic proton (multiplet a t 4.7 T), one secondary, and two tertiary methyl groups. On Ruschig deamination the alkaloid afforded progesterone and on methylation with formic acid-formaldehyde it yielded a tetramethyl derivative which proved to be identical with the known (64) 3/?,20a-bisdimethylaminopregn-5-ene.

27. Irehdiamine-B, Kurchamine, and Kurchimine Irehdiamine-B (LXXII) occurs in the leaves of 3’.elastica (63).The presence of the functional groups was inferred from its NMR-spectrum.

324

v. EERNPA N D

F.

SORM

As in the case of irehdiamine-A, Ruschig deamination afforded progesterone and methylation furnished 3/3,20a-bisdimethylaminopregn-5ene. The proof of the location of the methylamino group in position 3 was provided by the partial synthesis of dihydroirehdiamine-B from dihydroholaphylline which, after conversion to the oxime, was hydrogenated over Adams' catalyst in acetic acid solution to yield a mixture of 2 0 ~ -and 20p-amines, from which the preponderant 20a-epimer was isolated via the corresponding isopropylidene derivative (63).

LXXI; LXXII; LXXIII;

Ri

Rz

H

H

H Me

Me Me

Recent investigation showed the identity of irehdiamine-B with kurchamine, C22H38N2 (mp 115"-117°; [aID - 16" in chloroform). This alkaloid, along with isomeric kurchimine (mp 104"-106"; - 21" in chloroform), was isolated from the bark of H . antidysenterica (65, 66). Both kurchamine and kurchimine were found t o contain a primary amino and a methylamino group. Both of them undergo methylation to yield kurchessine. Initially, they were assumed to have the empirical formula C22H36N2, and a conan-17,20-ene structure (65, 66). Since the structure of kurchessine was later established as 3p,20~-bisdimethylaminopregn-5-ene ( 6 7 ) , the above assignments were thus shown to be incorrect. The melting point of kurchamine suggested possible identity with irehdiamine-B and a direct comparison of both alkaloids confirmed this assumption (8, 35a, 68). The optical rotation given for kurchamine is, in fact, the value for the isopropylidene derivative formed on crystallization from acetone. By exclusion it thus follows that the structure of kurchimine is 3/3amino-20~-methylaminopregn-5-ene (8).

28. Irehdiamine C Isolation of this alkaloid from FuntuinicL latifolia and the structure 3~-dimethylamin0-20a-aminopregn-5-ene (LXXIII)has been announced

(35a).

8. ALKALOIDS OF APOCYXACEAE A N D BUXACEAE

325

29. Kurchessine Kurchessine was prepared as a methylation product of kurchamine (65) and isolated from a methylated alkaloid mixture from the bark of H . antidysenterica (66); its presence in the bark as a natural base was demonstrated later (67). It was also found in Pachysandra terminalis and designated “alkaloid E ” (69); it is identical with saracodinine (mp 136”) from Sarcococca pruniformis Lindl. (70). The initially assumed pyrroline structure (65, 66) was not verified and the alkaloid was shown (67). to be 3/3,20a-bisdimethylaminopregn-5-ene 30. cr-Kurchessine a-Kurchessine (LXXXI) (“ epiheteroconessine ”), was isolated from the methylated alkaloid mixture from the bark of H . antidysenterica (66) and was later found in the bark of this plant as a naturally occurring alkaloid (67). Characteristic behavior on catalytic hydrogenation led to the assignment of the 3cr-dimethylamino-5,6-unsaturatedsystem. Initially the alkaloid was considered to be isomeric with conessine; on the basis of optical rotatory properties it was tentatively assigned the structure 3-epiheteroconessine (3cr-dimethylamino-20-isoconan-5-ene) (66) but was later found (67) t o be identical with the known (64) base LXXXI. 31. Holarrhidine The isolation of holarrhidine (LXXIX) from H . antidysenterica was based on the sparing solubility of its cinnamate in ethanol ( 7 1 ) . As demonstrated by conversion to N,N,N’,iV’-tetramethyl derivative on Eschweiler-Clarke methylation and by oxidation of this ditertiary bast to an aldehyde it contains one primary hydroxyl and two primary amino groups. The presence of the pregnane skeleton including the substitution pattern at C-18 and (2-20 was established by selective Hofmann degradation furnishing the diene LXXX, which proved to be identical with ’30cr-dimethylaminopregna-3,6-diene-lS-ol obtained from N,N,N’,N‘tetramethylholarrhimine (LXXVII) in an analogous manner. This behavior in conjunction with the evidence obtained from optical rotational increments resulted in the formulation LXXIX for holarrhidine ( 6 4 , a conclusion which was later confirmed by synthesis of conkuressine from holarrhidine ( 7 2 ; see Section 11,D). Holarrhidine is the first steroidal alkaloid in which the presence of a Scr-amino group was found. 32. 3-hT-Methylholarrhi?nineand 20-N-Methylholarrhimine 3-N-Nethylholarrhimine (LXXV) and 20-N-methylholarrhimine (LXXVI) were found in the bark of H . antidysewterica by Tschesche and

326

v. &ERN+

is x 4

AND F.

SORM

x 0-

x x

5

8.

X

c-l

ALKALOIDS O F APOCYNACEAE AND BUXACEAE

I

A

0

H

5 x x x

i;l

327

328

v. ~ E R NAND P

F. ~ O R M

Wiensz (65).LXXVI was obtained as its hydrochloride and was characterized as a picrate; LXXV was isolated by way of its salicylidene derivative and also described as a free base. Both alkaloids were converted into LXXVII on methylation with formaldehyde-formic acid. Similar to the methylation of holarrhimine, methylation of LXXVI was attended by the formation of a trace amount of conessine, whereas no conessine was detected following the same reaction on the second isomer. From analogy with the behavior of holarrhimine, which also gives some conessine on methylation, this observation was interpreted as indicating the presence of a primary amino group a t C-20 in LXXVI, designated monomethylholarrhimine I by the German authors, and the alternative structure containing a primary amino group a t C-3 was proposed (65)for the isomeric alkaloid named monomethylholarrhimine 11.However, this assumption was rendered untenable by later investigation : the correct structure of these alkaloids could be established unambiguously by a synthesis starting from holarrhimine ( 7 3 ) . I n the synthesis of 20-Nmethylholarrhimine, the hydroxyl group in holarrhimine was selectively formylated using formic acid in the presence of perchloric acid; the resulting 0-formyl derivative (LXXXIII) suffered acyl migration on heating in tetrahydrofuran solution to yield the 20-N-formyl derivative LXXXV ; subsequent reduction with lithium aluminum hydride yielded the base LXXVI (mp 163.5"-166"; [.ID - 19" in chloroform). In similar manner 20a-acetylamino-18-acetoxy-3~-aminopregn-5-ene (LXXXVI) was prepared (74) which on formaldehyde-formic acid methylation afforded the 3P-dimethylamino derivative LXXXVII. Treatment of this base with cyanogen bromide, followed by alkaline hydrolysis, afforded 3-N-methylholarrhimine LXXV (mp 160"-163" ; [ a ] = - 1 7 " in chloroform). Although both isomeric bases show a close resemblance in physical constants, the respective IR-spectra differ fundamentally, and their comparison with natural monomethylholarrhimine I1 showed identity of the latter alkaloid with 3-N-methylholarrhimine (LXXV). By exclusion, the monomethylholarrhimine I has to be formulated as 20-N-methylholarrhimine (LXXVI).

33. N ,N,N',N'-Tefrarnethylholarrhirnine This alkaloid (LXXVII) was isolated from the bark of H . antidysenterica by chromatography, advantage being taken of its poor solubility in acetone (65). 34. Dictyolucidine and Dictyolucidarnine These alkaloids were isolated from the roots of Dictyophleba lucida. Dictyolucidine (XCII) according to IR-, NMR-, and mass spectro-

8.

ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

329

metric data, contains a methylamino group located a t C-3 of a steroid skeleton lacking the 5,6-double bond, and containing three tertiary C-methyls, a secondary, and a tertiary hydroxyl group. Dictyolucidamine (XCIII) is N-methyldictyolucidine. On methylation with formic acid-formaldehyde both dictyolucidine and dictyolucidamine furnish the identical product XCI, the synthesis of which from l7u-hydroxyprogesterone served as a proof of the structure of the above alkaloids. Under alkaline conditions, 17a-hydroxyprogesterone LXXXVIII underwent D-homosteroid rearrange.ment ; treatment of the product with dimethylamine converted it to the enamine LXXXIX which on reduction with sodium borohydride gave rise to a mixture of 1 7 and ~ 17p-epimeric diols. Subsequent treatment of this mixture with formic acid-formaldehyde converted the cis-diol XC to the methylenedioxy derivative which on catalytic hydrogenation over palladium gave XCI identical

#

0

___f

<-tj'i-::.

(Me)ZN

LXXXVIII

xc

'

\ LXXXIX

XCI

XCII; XCIII;

R=H R=Me

+

330

v. ERN$ A N D

F.

BORM

with a substance prepared by the same methylation reagent from dictyolucidine or dictyolucidamine. These alkaloids are not likely to be artifacts produced during the isolation procedure. I n such case, the presence of 17-hydroxyl could not be understood since, on D-homosteroid rearrangement, a 17-ketoneshould be expected. In all probability, dictyolucidine and dictyolucidamine arise in the plant from the respective 17a-hydroxy-20-ketopregnane precursors (39, 40).

D. CONANINE DERIVATIVES

1. Reactions of Conessine Some well-known reactions of conessine or closely related compounds were reinvestigated. I n addition, several new reactions were reported. a. Conessimethine. The cyclization of conessimethine (XCIV) under the influence of acetic acid (99) was reinvestigated in detail by Jewers and McKenna (100).This study showed that the prevailing product is the less-stable (20s)-quaternaryacetate (XCV).The equilibrium between methine and quaternary salts is obviously attained very slowly in acid solution.

XCIV

XCV

b. Dehydrogenation Experiments. Janot and Goutarel (101) reported an interesting transformation which conessine undergoes on treatment with iodine in tetrahydrofuran solution in the presence of sodium bicarbonate. This t,ransformat,ion, leading t,o C, was plausibly int,erpreted as involving oxidation with iodine to an iminium compound XCVII corresponding to XCVIII. Iodination of the acetyl side chain in XCVIII is followed by cyclization to C. The structure of this six-membered ketone was largely established from its NMR-spectrum. Another enlargement of the heterocyclic ring was reported by Kasal et al. (102)in the course of a study on mercuric acetate dehydrogenation of dihydroconessine. This latter reaction was previously studied by

8. ALKALOIDS O F APOCYNACEAE

331

AND BUXACEAE

Me

XCVI

XCVII

XCVIII

I

Me I

NHMe

C

CHzI

XCIX

Favre and Marinier (103), who obtained a dehydrogenation product giving a stable perchlorate for which the iminium structure was established on the basis of spectral properties. Since the identical salt resulted under the same conditions from dihydroheteroconessine, the Canadian authors could thus demonstrate unambiguously that conessine and heteroconessine differ from each other in configuration a t C-20. The Czech authors showed that the reaction product, obtained after liberation of the base from the above perchlorate with alkali, behaved like the pyrrolidine CI. In line with this constitution are both the IR-data and the result of osmium tetroxide hydroxylation followed by periodic acid oxidation, this treatment furnishing the lactam CII. Schotten-Baumann benzoylation of CI yielded the tetrahydroazepinone CIY. The reaction was rationalized (102) as an initial opening of the heterocyclic ring to CIII followed by Camps’ (104)reaction.

CII

CI

CIII

CIV

v. EERNPAND

332

F.

SORN

c. Isoconessine and Neoconessine. Both isomers of conessine, isoconessine Cz4H40N2 ([a]= + 97" in EtOH), and neoconessine C24H40N2 +97" in EtOH), were obtained from conessine (mp 128"-129"; [.In either by treatment with sulfuric acid (105)or with a mixture of sulfuric and acetic acids (106)and were regarded as arising from conessine by a simple migration of the double bond (99, 107). Later reinvestigation (108) showed that the formation of isoconessine involves Westphalen rearrangement which is followed by double bond migration. Me

cv

CVI; CVII;

R=OAc R=H

Me

CVIII

This was proved by subjecting 6/3-acetoxy-3/3-dimethylamino-5aconan-5-01 (CV) t o the conditions of Westphalen rearrangement and removing the 6P-acetoxy group in the rearranged product (CVI) by hydrolysis, oxidation, and Wolff-Kishner reduction. The noncrystalline product, C24H40Nz (CVII), was designated alloconessine and was converted to isoconessine (CVIII) by treatment with sulfuric acid. The tetrasubstituted nature of the double bond in isoconessine was derived from the absence of an olefinic proton in the NMR-spectrum and by application of the Castells and Meakins method (109): hydroxylation with osmium tetroxide followed by oxidative cleavage with lead tetraacetate which afforded a diketone. The formation of neoconessine appears to involve more complicated changes since the NMR-spectrum reveals the presence in its molecule of two secondary methyl groups.

8. ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

333

d . a-Hydroxyconessine. This substance, C24HmN20 (mp 157"; ["ID in EtOH-chloroform 1: l), arising by selenium dioxide oxidation of conessine (110)was attributed the structure of 4-hydroxyconessine (107) or 5~-hydroxy-3P-dimethylamiiioconan-6-ene ( 2 ) . Recent reinvestigation (111)made it possible to decide between these two formulas in favor of the former view. The structure CIX was confirmed by NMR-spectrum, revealing the presence of one olefinic proton (at 4.28 T ) and the secondary character of the hydroxyl function (the signal of the proton adjacent to hydroxyl at 5.85 T shifted to 6.23 T in the dihydro derivative), and by the mass spectrum of the acetyl derivative, CzsH42hTzO2 (mp 127"; [.ID - 75" in chloroform), which showed a peak a t M-60 but no molecular peak. This ready splitting off of a molecule of acetic acid was attended by a total suppression of the fragmentation leading to m/e 84 ions; such cleavage is, of course, ruled out in the structure CX.

+ 20'

Me

I

OH CIX

cx

The P-configuration of the hydroxyl group was inferred from the small coupling constant (J 2.5 cps) corresponding to axial-equatorial coupling.

-

2. 3a-Aminoconun-5-ene This alkaloid was isolated as a chromatographica!ly homogeneous substance (mp 95"-100°; [.ID + 2 7 " in EtOH), from the bark of H . antidysenterica ( 7 7 ) . Although crystalline, it resisted all attempts at recrystallization from a variety of solvents. Its structure was indicated by mass spectrometry showing a fragmentation pattern characteristic of the h'-methylpyrrolidine moiety of the conanine type (peaks a t m/e 71, 31-15) and of a primary amino group in position 3 (peak at m/e 56). The pure compound was prepared synthetically by Jarreau (75) and shows mp 94"; ["Iu + 1 1 " (in E t O H ) ; comparison of the acetyl derivatives of the synthetic and natural bases established their identity (77).

334

v. EERNPAND

F.

SORM

3. Conamine The structure of conamine CXIII (112-114) was confirmed (92,97)by a partial synthesis from 3~,5~-cycloconan-6a-ol by a route outlined in the sequence CXI-CXIII. Me

+ 1111111111111111

OH CXI

CXII

Me I

CXIII

The reaction of 3a,5a-cyclo-B-hydroxy steroids with azoimide in the presence of boron fluoride represents a general preparative method for steroids which can be thus the preparation of 3/z-amino-5,6-unsaturated obtained in excellent yields. The intermediate in this reaction is S/zazido-3~,5a-cycloconanine which undergoes homoallylic rearrangement t o yield 3/z-azido-5,6-unsaturatedsteroid (115). By this procedure conamine was prepared in pure condition for the first time (76). 4. Conkuressine

This alkaloid was isolated from the mixture of methylated alkaloids from the bark of H . antidysenterica (66, 67). It also occurs in the bark as a natural alkaloid (67). Conkuressine was recognized as an isomer of conessine containing one double bond ; the apparent resistance of the latter to hydrogenation led to the tentative assumption that this alkaloid might be 3-dimethylaminoconan-7-ene (66). However, later reinvestigation (67) demon-

8 . ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

335

strated the identity of conkuressine with 3a-dimethylaminoconan- 5-ene (CXVI)which had been prepared synthetically both from conessine and from holarrhidine (72). I n this synthesis, N,N,N',N'-tetramethyIholarrhidine(CXIV) was treated with tosyl chloride to give a tosyloxy derivative which underwent spontaneous cyclizatiori to the quaternary tosylate CXV. The latter on heating with ethanolamine according to the Hunig method (116, 117) was converted to conkuressine. This alkaloid was also synthesized by another route using conessine as starting material. Following the known (97) procedure, conessine (XCVI) was first converted t o the N-cyano derivative CXVII, the tosylate of which was treated with

Me

I

CXVI

CXIX

v. ERN.^ A N D P. ~ O R M

336

sodium azide in dimethylsulfoxide. Since these conditions favor the SXZ mechanism (55, 118), the 3a-azide CXIX constituted the main component of the reaction mixture. Lithium aluminum hydride reduction, followed by Eschweiler-Clarke methylation, afforded conkuressine CXVI.

5. Conessimine Two syntheses of this alkaloid (119) have been reported. I n one of them (120), starting from conessine (XCVI), the more reactive 3pnitrogen was protected by a selective reaction with 1 mole of hydrogen peroxide to form the 3-mono-N-oxide CXX ; subsequent treatment with cyanogen bromide yielded N-cyanoconessimine-3-N-oxide(CXXI) which on reduction of the AT-oxide grouping with sodium borohydride and aluminum chloride followed by alkaline hydrolysis yielded conessimine. I n the second synthesis (77) isoconessimine (CXXIII) was converted to its 3-N-formyl derivative, and the latter was treated with cyanogen bromide to yield the 20-N-cyano derivative (CXXIV) which on reduction with lithium aluminum hydride afforded conessimine. Me

H Ri Cxx; CXXI; CXXII; CXXIII; CXXIV;

Rz

O+N(Me)z Me O+N(Me):! CN HNMe H HNMe Me NMeCHO CN

CXXV; CXXVI;

R=H R=Me

6 . Dihydroisoconessimine This base (CXXV),first prepared by hydrogenation of isoconessimine, was later found to occur as a natural alkaloid in the bark of H . antidysenterica (77, 81).

7 . Dihydroconessine This base (CXXVI) was isolated only from the methylated alkaloid mixture from the bark of H . untidysenterica (66)but probably also occurs

8.

ALKALOIDS O F APOCYNACEAE A N D B U X A C E A E

337

as a natural alkaloid, as indicated by mass spectrometric investigation of a fraction corresponding in polarity to dihydroconessine ( 7 7 ) .

8. Malouphyllumine This minor alkaloid from the leaves of Malouetia bequaertiana was shown ( 4 4 ) to contain an acetylamino group by IR- (bands at 1580, 1642, 1653 cm-l) and NMR- (singlet of a COCH3 group at 8.03 T ) evidence. The conanine structure, strongly indicated by further NMRdata, was confirmed by mass spectrometry (peak at M-15 and the base peak a t m/e 71). The structure CXXVII was thus derived from the above evidence and proof of its correctness was provided by the following degradation and synthesis : malouphyllamine was first reduced with lithium aluminum hydride to give the 3p-ethylamino derivative CXXVIII which on Ruschig deamination furnished the known 5a-conan3-one CXXX. Malouphyllamine was resynthesized from this ketone via the oxime CXXXI which was reduced with sodium in ethanol and the reaction product acetylated to malouphyllamine ; it differed from the 3a-epimer which was prepared from dihydrolatifoline tosylate via the Me

CXXVII: CXXVIII; CXXIX;

R=Ac R=Et R=H

CXXX; CXXXI;

CXXXII : CXXXJII;

R=O R=XOH

X = OTs X=I

338

v.

ERN$ A N D F.

SORM

3m-azido-5a-conanine. I n addition, an interrelation with malouphylline (XLII)was accomplished by the reduction of this alkaloid to malouphyllinol, which on tosylation underwent internal self-cyclization to yield a quaternary tosylate (CXXXII); this was converted to the quaternary iodide (CXXXIII)identical with malouphyllamine methiodide prepared from the natural alkaloid (96). 9. 3 ~Di- meth ylamino -5~-conanine This base was isolated from the methylated alkaloid mixture from the bark of H . antidysenterica and proved to be identical with the minor product of hydrogenation of conkuressine (CXVI). Its presence in the nonmethylated alkaloid mixture was evidenced by thin-layer chromatography but the pure alkaloid could not be isolated (67).

10. 7a-Hydroxyconessine This base was isolated from the bark of H . antidysenterica (88)but was first prepared along with its 7-epimer by microbiological hydroxylation of conessine by Aspergillus ochraceus (87); the same result was obtained with Cunninghamella echinulata (86). I n all three cases, its structure was established in essentially the same way. The NMR-signal of the olefinic C-6 proton (at 4.38 T ) appeared to be shifted toward the lower field (as compared with the C-6 proton in conessine) and to be split into a doublet ; oxidation of the alkaloid with chromium trioxide gave a product characterized by spectroscopic evidence as a six-membered cyclic ketone conjugated with a secondary-tertiary double bond in a homoannular system (A",:' 236.5 mp, E 13,200) which thereby must have been 7-ketoconessine, C24H38N20 (mp 160"-162" ; [a]= - 57") (86-88). Additional proof of the assigned structure was provided by the preparation of both epimeric 7-hydroxyconessines by allylic oxidation of conessine with tert-butyl perbenzoate (88). The possibility that 7 ~ conessine is an artifact, arising by air oxidation of conessine in the course of the isolation procedure, was excluded by a model experiment. On the other hand, the possibility cannot be excluded that it may have been formed from conessine by the action of microorganisms in the bark (88).

11. 7~-Hydroxyconessine The presence of this base in the bark of H . antidysenterica was indicated by chromatographic evidence but the alkaloid could not be isolated in pure condition (88).

8. -4LKALOIDS O F A P O C Y N A C E A E

4NI) BUXACEAE

339

12. Holaline Holaline was isolated from the bark of H . africana (jloribunda)(85). As evidenced by IR- and NMR-data, it contains a tertiary hydroxyl, a methylimino, and a dimethylamino group. The presence of a conanine skeleton became obvious from mass spectrometric (peak a t mje 71) and NMR-data, the latter showing characteristic signals of 19- and 21-methyl groups and of the 18-methylene group. The peak a t m/e 110 in the mass spectrum was absent; instead, a n intense peak was found a t m/e 126 which indicated the hydroxyl to be situated in the C-3 to C-7 part of the molecule. The result of a dehydration experiment with acetic anhydrideboron fluoride leading to conessine made it possible to locate the tertiary hydroxyl in position 5. The structure CXXXVII was confirmed by a synthesis from dihydroxydihydroconessine (CXXXIV)prepared according to a known procedure (2, 121) by oxidation o f conessine with potassium iodate and dilute sulfuric acid. The monomesylate (CXXXV) of this compound on treatment with sodium methanolate yielded the 5cc,6c(oxide CXXXVI. This compound on reduction with lithium aluminum hydride furnished the 5cc-hydroxy derivative CXXXVII which proved to be identical with holaline (85).

13. Holarrhenine The 12p-configuration of t h e hydroxyl group in t h i s alkaloid (CXXXIX)(122,123)was confirmed by the Emde reduction of apoholarrhenine methiodide with lithium in liquid ammonia t,o yield a mixture of neutral products (along with the basic ones) which on cata,lytic hydrogenation gave a compound identical with 12P-hydroxy-5a-pregnane prepared from hecogenine (124,124a). 14. Holarrheline The isolation of this alkaloid from H . africana (jloribunda) and establishment of its structure CXXXVIII have been announced (85).

15. Funtessine This alkaloid, occurring in the bark of F . lntifolin, was isolated by way of its 0,N-diacetyl derivative furnishing the free base on alkaline hydrolysis (82). It contains a secondary hydroxyl, a primary, and a tertiary amino group and its mass spectrum indicated the conanine skeleton (peaks at m/e 71, M-15) with a primary amino group in position 3 (peak at m/e 56). The characteristic doublet of the methylene group (at 7.25 r , J = 10 cps) of the conanine heterocycle constituted further evidence in favor of the conanine skeleton. I n the 0,N-diacetate the

v. €!ERN+ AND F. ~ O R M

340

CXXXIV; CXXXV;

CXXXVI

R=H RIMS

Me I

CXXXVII

CXXXVIII; CXXXIX; CXL;

H Me Me

H H Ac

Me

I

CXLI

8. ALKALOIDS OF APOCYNACEAE A N D RUXACEAE

34 1

position of the signal due to methyl of the acetoxyl group and the signal exhibited by the proton adjacent to this group were reminiscent of those occurring in funtuline and were hence suggestive of a 12P-acetoxyl group. Furthermore, the equatorial position of the 3-acetylamino group was indicated by a broad multiplet of the a-proton a t 6.25 T ; hence, the above data resulted in the formulation CXLI for funtessine. The proof of the correctness of this structure was given by the result of EschweilerClarke methylation of funtessine which afforded dihydroholarrhenine. Conversely, dihydroholarrhenine was converted to funtessine by successive von Braun and Ruschig degradations leading to the %ketone CXLII, the oxime of which gave funtessine on reduction with sodium in ethanol.

16. Xurcholessine This alkaloid was isolated from H . antidysenterica using fractionation with phosphoric acid in ethanol combined with adsorption chromatography. It contains three N-methyl groups, one secondary, and one tertiary hydroxyl group. The empirical formula C24H40N202 and a pyrroline structure were initially assumed for this base (66) but later reinvestigation (90) led t o the correction of the formula to C25H44N~02. The structure CXLIII was derived largely from physical properties of the alkaloid. The mass spectrum demonstrated the presence of the N-methylpyrrolidine moiety (peak at m/e 7 1) characteristic of the conanine type. This received confirmation by the NMR-evidence (signals of 19- and 21-methyl groups).The presence in the mass spectrum of a base peak at m/e 84 showed that the C-1 to C-3 part of the A ring is only substituted with a dimethylamino group in position 3. The presence of a peak at mje 156 instead of at 110 indicated that both the hydroxyl and methyl group are located in the C-3 to C-7 part of the molecule. Since the NMR-signal of the additional methyl group occurred as a doublet, position 5 was thus ruled out; it also became obvious that it could not be attached to the same carbon atom as the tertiary hydroxyl. Biogenetic considerations made position 4 the most likely as the point of attachment of this methyl group; this view was supported by a marked downfield shift in the NMR-spectrum due to the presence of nearby nitrogen and oxygen functions. I n agreement with this assumption, the NMR-spectrum of the dehydration product of kurcholessine monoacetate showed the presence of a trisubstituted (5,6-) double bond. The product thus formed did not have the character of an enol acetate, which ruled out position 6 for the secondary hydroxyl and, by exclusion, located this group in position 7.

v. &RN$

342

AND F.

SORM

The stereochemistry of the funct,ional groups could be deduced from the absence of any intramolecular hydrogen bonds which excluded 1.2 or 1,3-cis-diol groupings; the same is true of the diaxial position of dimethylamino and hydroxyl groups.

17. Latifoline This alkaloid was isolated (91)from the bark of F . lufnifolia. It contains one acetylable hydroxyl and one N-methyl group ; on Hofmanii degradation it yielded a iiitrogen-containing product, C23H37NO (mp 142" ;)1I.[ - 39" in chloroform), resisting all attempts at further Hofmann degradation. Latifoline was therefore suspected to contain a conaiiine skeleton; the proof of this assumption was given by a synthesis of the alkaloid from conan-4-en-3-one (latifoliniiie) (CXLIV) which was converted to the enol acetate CXLV; subsequent reduction with sodium borohydride and alkaline hydrolysis led to latifoline (CXLVII) (91). This compound had been prepared previously from conessine (92, 97, 125). >I e

&-a'

0

AcO

CXLIV

'' CXLV

I

CXLVI; CXLVIT;

R=H

__f

1

CXLIII

R=3le

18. Latifolinnine This base (CXLIV) was isolated in oily condition from the bark of F. latifoliu (93) and was characterized as its crystalline oxime (mp 255"; ,1I.[ + 190" in MeOH). The presence of an +unsaturated keto

8 . ALKALOIDS O F APOCYNACEAE A N D RUXACEAE

343

group was disclosed by the IR-spectrum (band at 1675 cm-1); the conanine skeleton and position of the keto group were recognized from mass spectrometric properties of the ethylene ketal derivative (mp 124"; [a],) + 15" in chloroform) : the peak at m/e 71 is characteristic of the N-methylpyrrolidine moiety of conanine type ; the peak at m/e 99 is owing to an ethylene ketal grouping in position 3 of a 5,B-unsaturated steroid. Preparation of conan-4-en-3-one (mp 1O8.5"-1lO0) (94,126)had been reported earlier by several investigators (92, 94, 107, 126);the identity of the oxime of the natural latifolinine with that prepared synthetically (92, 94) confirmed the above conclusion ; independent evidence was also adduced by hydrogenation of latifolinine to dihydrolatifoline (93).

19. Norlatifoline This alkaloid was isolated from the bark of P. latifolia. The mass spectrometric evidence (peak a t m/e 5 7 ) led to the norconanine structure CXLVI which was unambiguously confirmed by converting N-carboethoxynorlatifoline to latifoline by lithium aluminum hydride reduction (93). Norlatifoline had been previously synthesized (97)from conessine via 3,f-hydroxyconan-5-ene by cyanogen bromide degradation or, alternatively, from 3a,5a-cycloconan-A-one by von Braun degradation and re-formation of the 3,f-hydroxy-5,6-unsaturated steroid system.

20. Funtuline This alkaloid (CL) from the bark of F . latifolia ( 8 4 , 93) contains two acetylable hydroxyl groups. The presence of a conanine skeleton was indicated by the mass spectrum (peak a t m/e 71). I n line with the mass spectrometric evidence, the NMR-spectrum displayed signals of the 19and 21-methyls. It also proved the presence of an olefinic proton. The secondary nature of both hydroxyl groups was inferred from the NMRspectrum of the 0,O'-diacetate which at 5.0 T and 6.7 T displayed signals of the protons adjacent to the same carbon atom as the respective acetoxyl groups. Since the signal of one acetoxyl showed a close similarity to that in O-acetylholarrhenine, one hydroxyl group was suspected to be located in the 12/3-position. This assumption was fully confirmed by a synthesis of funtuline from holarrhenine (CXXXIX). O-Acetylholarrhenine (CXL) was subjected to eyanogen bromide degradation t o yield the secondary base CXXXVIII which on Ruschig deamination afforded the ,+unsaturated ketone CXLVIII. Conversion of this compound to the en01 acetate CIL followed by reduction with sodium borohydride

344

v.

&ERN+ A N D F.

BORM

and alkaline hydrolysis gave funtuline. In analogous manner, dihydroholarrhenine was converted to dihydrofuntuline ( 8 4 ) .

CXLVIII Me

Me

I

CL

CIL

iEIe

;Me

I

I

f"Y

CLI

CLII

21. Holudienine This alkaloid was isolated from the bark of H . africana (Joribunda) and the establishment of its structure CLI has been announced (85).

22. Puntudienine This amorphous base was isolated from the bark o f F. latifolia (83) and was characterized as a crystalline oxime, CZZH~ZNZO (mp 190"; [WID - 228" in chloroform). The UV-spectrum (A?;:: 280 mp, E 22,000) characterized it as a heteroannular dienone with one disubstituted and

8. ALKALOIDS O F APOCYNACEAE

A N D RUXACEAE

345

one trisubstituted double bond. The mass spectrum indicated a conanine skeleton (peaks at m/e 71, 31-15) which was found to be in conformity with the NMR-data revealing the presence of one tertiary and one secondary C-methyl, the 18-methylene group, and three olefinic protons (singlet a t 4.40 T and a two-proton multiplet a t 3.90 T ) . Catalytic hydrogenation over palladium catalyst yielded an amorphous tetrahydro derivative which was shown to be a six-membered ketone by IRevidence. The above data indicated the structure of cona-3,5-diene-7-one for funtudienine; this view received strong support in the result of the Wolff-Kishner reduction yielding cona-3,5-diene. The structure CLII was confirmed by a synthesis from acetyllatifoline which on chromic acid oxidation afforded the corresponding ?'-ketone ; subsequent elimination of acetic acid on heating with p-toluenesulfonic acid in benzene solution led to funtudienine (83).

23. Conkurchine (Irehline)and Conessidine As has been shown by earlier work summarized in Volume V I I ( l ) , conessine and its congeners are closely related to the alkaloids of conkurchine type, the only difference being the presence of a double bond in the E ring of the latter group. Bertho postulated (127)dl-pyrroline structure (CLVIII in the old formulation) for conkurchine. However, structures CLIX and CLX were later assigned by Tschesche and Roy (114)to conkurchine and conessidine, respectively. The main argument in favor of these A 2-pyrroline formulas was the finding that conessidine yielded acetic acid on ozonolysis (and subsequent hydrolysis). However, the strain present in such structure would be extreme; an alternative structure with exocyclic 20,2 1 -double bond was considered by Jeger and Prelog (1)but, as demonstrated later (102),this structure appeared to be unstable as well. Besides, in view of the ascertained knowledge of the stability of simpler systems of this type, the imine structure should be the preferred one (128, 129). I n line with this evidence is the finding of CernJ; and Sorm (98),who demonstrated that the elimination of the hydrochloric acid from the chlorainine corresponding to N-demethylconaiiine led to the 20(AT)-pyrroline(see Section 11,G). Thus, the double bond in conkurchine could not be in the 17,20- or 20,21-positions. Jarreau et al. (74a,75,130)ruled out the BO(N)-positionby the synthesis of 3/3-methylamino-N-demethylcona-5,20(N)-dieneand 3/3-aminodemethylcona5,(20)N-diene which are not identical with conessidine and conkurchine, respectively. The problem was solved by Janot et al. (74a, 78, 130) in connection with the study of the alkaloid irehline, C21H32N2 (mp 150"-151";

346

V . 6 E R N 9 A N D F. 5 O R N

- 51" in chloroform). One amino group in this alkaloid was found to be primary and the presence of two double bonds was established. The NMR-spectrum revealed the presence of two olefinic protons, one of them (at 4.67 r ) clearly belonging to the 5,B-double bond whereas the

..

CLVIII CLTII; CLIV;

R=H R=Me

W N H C C X X V I IO P h CLVII Ac

I

AcHN

&H

I / H

I

CLV

CLvlRHK

& CLIX; CLX;

R=H R=Me

position of the second signal (at 2.42 r ) is characteristic of a proton in the grouping R-CH = N-R'. I n accord with formula CLIII, indicated by this finding, was the fact that the signal at 2.42 T was split into a doublet (J= 3 cps) due to long-range coupling with the C-20 proton; this and the occurrence of a doublet of the 21-methyl at 8.65 r proved the presence of a proton in position 20 and confirmed the above formula for irehline. This formula was confirmed by the following chemical trans-

8.

ALKALOIDS OF APOCYNACEAE AND BUXACEAE

347

formations : irehline on treatment with acetic anhydride in pyridine solution yielded the diacetyl derivative CLV which on heating lost one molecule of acetic acid to give the pyrroline CLVI. This compound could be transformed to malouphyllamine (CXXVII) by potassium borohydride reduction, hydrogenation, and methylation. Alternatively, the pyrroline ring was opened by Schotten-Baumann benzoylation to give the aldehyde CLVII which on reduction with potassium borohydride followed by energetic alkaline hydrolysis yielded holarrhimine (LXXIV). A still simpler proof was provided by a synthesis of irehline by chromic acid oxidation of holarrhimine in acetic acid solution (80). Comparison of the physical constants of irehline, conkurchine, and the respective derivatives demonstrated their identity. It was proposed that the older designation conkurchine be retained for this alkaloid (74a,130). Similarly, the structure of conessidine (114, 131) was established by a synthesis from 3-N-methylholarrhimine (LXXV) on chromic acid oxidation (80).Another base of this group, the so-called conkurchinine (132) was identified (74a) as N-isopropylideneconkurchine and was thereby recognized as an artifact arising by crystallization of conkurchine from acetone. The reported (114) formation of acetic acid on ozonolysis of conkurchine was confirmed by later reinvestigation ( 7 9 ) . Obviously, ozonolysis is unsuitable for structure determination of pyrrolines. This is in accord with Witkop’s conclusion (133)that ozonolysis cannot be applied for structure determinations in imine-enamine systems. The last remaining moot point was the formation of so-called trimethylconkurchine on methylation of conkurchine and conessidine (114) which result would be inconsistent with the structures CLIII and CLIV. However, later reinvestigation demonstrated conkurchine to yield a mixture of conessine and dimethylconkurchine on Eschweiler-Clarke methylation ( 7 9 ) and thus the claimed formation of “ trimethylconkurchine ” must have rested on error. A pharmacological study on conkurchine hydrochloride demonstrated a hypotensive and vasodilatory activity of this alkaloid (134).

24. Holonamine Holonamine was isolated from the bark of H . antidysenterica from a fraction of sparingly soluble perchlorates (88). The structure of holonamine was established (89) largely on the basis of the spectrographic evidence. The alkaloid was shown to contain one acetylable hydroxyl and a conjugated keto group. Strong evidence in favor of the 1 ,l-dien-3-one structure was obtained from the occurrence of characteristic absorption at 1656, 1613, and 1597 cm-1 and the

TABLE I ~

Compound

~

Molecular formula

~

~

~~~~

Melting point ("C)

~

ID ~

~

_

Sourcea

Reforcricc

_

_

_

Pregnano-type alkaloids ~.

Choriernorphine Dihydroehlorida Dihydroiodidc Chloroplatinate

K -Acetylchonemorphino S-Uenzylidcne derivative X-Carbethoxy derivative Dihydro bcrizylidene derivative Dirncthylchoneinorphine dimethoiodide Conopharyngino ( = holafebrine-nglucosidc) Dictyodiaminc ( = epipac:hysamine-C)b 20-N-Acetyl derivative X,X'-Diacetyl derivative Dictyophlebirio N-Acctyl dorivativc Buntudiamine-A Furitudiarnine-13 Funtumafrinc-13 Funturnafrinc-C Funtumidine

.-

~~

~~~

148 418-420 3 12-3 14 > 300 (decamp.) 276-279 184 270 156

+ ZS(CHCl3) -

18, 35, 3 5 ~ 1J8 , 35 35

-

3 ,i

-

+ 15(CHC13)

3, 18, 3:i, 35rr, 35 35 35(1 35

-

-

-

115-116

+22(CHC13)

35u, 41

204 242 151

- lO(CHC13)

35Cf

- lG(CHC13)

350, 41 35/l, 39 35Cl 350 35fL

198 80 98-100 1 60 176 182

+ SO(CHC13) + lS(CHC13) + G(CHC13) + 20(CHC13) +43(CHC13) + 45(CHC13) + lO(CHC13)

+ 3(CHzCl2-MeOH, 1 : 1 )

d, f, l , m f

-

17 17 22 24

~

8.

ALKALOIDS O F APOCYNACEAE A N D E U X A C E A E

I70

173 184 214-2 15 172 173 120 177 > 310 242 250 199-201 166 285-288 259-260 173 174-175 135-136 137 205

+ 95(CHC13)

f

+ 60(MeOH) + 9S(CHC13)

+ 95(MeOH) + 26(CHC13) + 93(CHC13) + 110(MeOH)

- G(CHC13)

+ 13(CHC13) + 78(MeOH) + 24(CHC13) + 24(CHC13) - 78(CHC13) - ISS(CHC13)

- 61.5(CHC13) - 56.5(CHC13) -

- 42(CHC13)

-

-

b

-66.6(Py-H20, 9 : l )

+ lO(CHCl3) +23(CHC13) 17.5(CHC13) - $8.6(CHC13)

1

+

-

-

320

+ 20(MeOH) ___

-

~

22 22 22, 24 24 22 26‘ 24 24 22 26 17,18 18 17, 42 17 58 58 50 50 50 50 47 30 47 47

50 47 54 64 55 53 55

-

ALKALOIDS O F APOCYNACEAE A N D E U X A C E A E

Holarnirie A’-Dimethyl derivative Holaminol Holaphyllamirro Hydrochloride

123 280 247 167 22 1 163 128 270 163

8.

Funtumine Hydrochlorido A-Acetyl derivative N-Trifluoroacetyl derivative Oxiuie Hydrazone N-Dimethyl dnrivativo N-Dimethyl dorivativn rncthiodide Dihydrodeoxy derivative Isofuntumidino Funtuphyllamine-A X-Uenzylidene derivative Funtuphyllaminn-B Funtuphyllarnine-C Holadysamine Holadysine Holafehrino Hydrochlorido ~‘-p-~itr.o))enzylidene derivative N,O-Diacetyl derivative XTrifluoroacetyl derivative N-Carbot,hoxy dorivativo p-1)Glucoside (conopharyngine) p-D-Glucoside hydrochloride Dihydro derivative (=funtuphyllamino-A)

0 8

W + CD

w

TABLE I-continued

cn 0

-

Compound

X-Dimethyl derivative ( = m e t h y l holaphyllinc) Holaphyllidirie Holaphylline N-Acetyl derivative "Methyl derivative Dihydro derivative Dihydrodeoxo derivative Holaphyllinoi Holarrhidine N , N , N ' , N -Tetramethyl derivative N,N,,~',N'-Tetramcthyl-5u-dihydro derivative

N,N,N',N'-Tetramethyl-5/3-dihydro derivative Dehydro-N,N,N',N'- tetramethyl derivative Deoxy-N,N,N',N'-tetramcthyl derivative HolarrhimineC 3-N-Acetyl-20-S-benzoylderivative Irehamino N-Acetyl drrivative N,O-Acetyl dsrivativc Irehdiamirie A Dihydrochloride

Molecular formula

~~

Melting point ("C)

121

[UID

+ 30(CHC13)

-~

Sourcea

-

Reference

-

54 56 53 53 53 53 53 53 71 71

+ lS(CHC13)

-

66

87-89

+ lS(CHC13)

-

66

164-165

+ lB(CHCI3)

-

64

148-149.6

- 31(CHC13)

-

64

-

74n 39 39 39 63 63

-

-

+ 24(CHC13) + 17(CHC13) + 30(CHC13)

128 205-206 121 123-124 136 226 181-182 163-164

-57(CHC13) - 73(CHC13) - 23(CHC13) - 34(CHC13)

156-159

180/238 230 237 224 148 > 300

+ 64(CHC13)

-

- 33(CHC13)

- 47(CHC13)

i i -

g

c, e , f -

- GO(CHC13)

-

- 47(CHC13-MeOH) - 44(MeOH)

-

e

N,N’-Diacetyl dorivative N,N‘-Dicarbethoxy derivative N,N’-Diisopropylidcne derivative N,N’-Bisdimcthyl derivative Dihydro derivative Irehdiarnine-B ( = kurchamine) Dihydrochloride N,N’-Diacetyl derivative N-Isopropylidene derivative Dihydro derivative Irehdiamine-C Irehine Kurchaline Kurchamine ( = irehdiamine-B) Kurchcssine

Picrate

-

Perchlorato

-

a-Kurchcssine (“ 3-epihrteroconessine ”) C25H4432 Kurchiline 0-Acetyl derivative Dihydro derivative Kurchimine Picrate Perchlorato N,N’-Diacetyl derivative Kurchiphyllamine Kurchiphylline 0-Acetyl derivative

270 186 169 139 154 115-117 295 231 134 128 105-106 174 185

-49(MeOH) - 35(CHC13) - 26(CHC13) - 40 13(CHC13) - 56(CHC13) -27(MeOH) - 48(CHC13) - lG(CHC13) lS(CHC13) - 47(CHC13) - 46 - 37(CHC13)

63 63 63 63 63 63, 65 63 63 63 63 35n 39 59

132-133

- 36(CHC13) - 17(MeOH)

140-141 228-230 277-279 146.5-147.5 148-150 219 139 154 1 04-1 06 137-1 40 294-295 239-245 161 184 125

- 37(CHC13)

65 65 67 65 65 66 67 58 58 58 66 66 66 66 58 58 58

+

+

-

- 31(CHC13)

- 28(CHC13)

+ 46(CHC13) - lS(CHC13)

+ 84(CHC13) - 21(CHC13) -

-2lI(CHC13) - 173(CHC13) - 194(CHC13)

4

0 M

+

M

2

U

tC cl

P Q

M 9

M

w

TA131,E I--conti)~ucd

C'I tG

~

Molecular formula Ma1ouct in c Uichlorido Diiotlitle Dipcrchloratc Dipicrato Malouct irnothinc Malouphylline Illalouphylliriol ( = inalouphyllinint Malouphy llinine (inalouphyllinol) 3-N-Mcthylholarrhirnirie Hydrochloride Picrato A'-Sal icy1i dcrie dcri vat ive

20-A'-Methylholarrhimine Hydrochloridr Picrato ~'-p-Sitroheiizyliclenederivative N,N,l~',N'-TetramcthylholarrhimineC

-

. ...._

Melting point ("C)

lic\fctrmrr

-

JX. 4 2

> 300 > 300 > 300 2F4 88-90 259-261 257 163-164 293-294 98-99 264 (decomp.) 163.5--166 360 133-135 237-240 227-229

42 J8 42 42

~

- l(CHC13)

JX

+ 32(CHC13)

44

- ll(CHC13)

1

- lS(CHC13) - l7(EtOH)

w

-

-

3 , 44 6.5, 7.i 6.; 65 65 6.i

73

- 28(McOH)

65 6.i 73 66

-

- 35(CHC13)

-

w

Conanine-type alkaloids 95-100 94

0 ?3

- lg(CHCI3)

~~~

3a-Aminoconan-5-one

o r

+ 27(EtOH)

77

- 7.5(CHC13)

75

+ 1l ( E t 0 H )

76

x

Hydrochloride N-Acetyl derivative ConamitieC Dihydrochloride N-Isopropylidene derivative N-Acetyl derivative Conarrhiminec Dihydrochloride 3-N-Acctyl derivative N-Ralicylidene derivative Conkuressine

Dihydroconkuressine ConkurchineC (irehline) N-Dimethyl derivative Monoacetyl dcrivative Diacetyl derivative AT-Benzylidcnederivative N-Salicylidene dcrivat ive

h'-Isopropylidene derivative ( = conkurchinine) Dih ydroisoconessirnine Funtessine N-Acetyl derivative 0,N-Diacctyl derivative

285 191

> 330 128 214 222 135-1 36 > 300 251-252 195 86.5-87.5

93-94 93-94 150 159-160 246-248 194

210 245 260 247 164 97-98.5 194-1 95 248 > 300 (decomp.)

+ 3(MeOH)

-

- 29(CHCly)

-

+ 7(MeOH)

-

- 6.6(CHC13) - 13(CHC13) - lG(CHC13) - 26(CHC13) - 28(MeOH) - 57(CHC13)

+ 45(CHC18) + 'i(CHC13) + 18(EtOH) O(CHC13) + 48(CHC13)

- 51(CHC13)

-

Synthetic -

6

g

e, k

- GO(CHC13) -48(EtOH) - 56(CHC13) - 5(CHC13) - 12(CHC13) lB(CHC13) +81(CHC13) 14(CHC13)

-

- 44(EtOH) - 58(CHC13) -

-

+

-

+

+ 49(CHCl3) + 22.5(CHC13) + 25(CHC13)

75 75

76 76 74a 76 740 74n 74n 74rk 66 66 67 67 7 4 ~ 178 , 79 71) 78 78 74n, 78 74n 78

0

r

80

P f -

-

74i1, 7 8 74n, 78

7 7 , 81 82 82 82

w cn w

TABLE I-continued

Compound A'-Dimcthyl derivative N-Salicylidene derivative N-Isopropylidene derivative Funtudieriine Oxime Funtuline 0,O'-Diacetyl derivative Dihydro derivative Holadienine Holaline Holarrheline 7a-Hydroxyconessine

Molecular formula

Melting point ("C) 186 275-278

0-Acetyl derivative Holonaminc

215-216 Amorphous 190 235 237 230 110 267 190 171-172 175-1 76 176-178 127.5-1 2 8.5 206-208 208-210 210-212 173-174 257-259

Diacetyl derivative Triacetyl derivative Kurcholcssine

232-234 178-180 21 8.5-22 1.5

0-Acetyl derivative 7P-Hydroxyconessine

Hydrochloride

255-265 (decomp.)

CO ID +42(CHC13) 52(CHC13) 45(CHC13) -247(CHC13) - 228(CHC13) - G(CHC13-MeOH8: 2) - 15(CHC13) 6O(EtOH) 80(CHC13) 38(CHC13-MeOH 1 : 1) 18(EtOH) -43(EtOH) - 60(CHCl?) - BI(CHC13) - 168(EtOH) +57(EtOH) 42(CHC13) 32(CHC13) 103(EtOH) - 14.8(EtOH) - 2.3(CHC13) I27(CHC13) 194(CHC13) 5(EtOH) - 4(CHC13)

+ +

+ + + +

+ + +

+ + +

-

Sourcea

Reference 82 82 82 83 83 84 84 84 85 8s 85

86 57 88 86

86 87 88 86 89 89 8.9 8$1

66,!I0 66

217-220 > 360 129 160 170 142 Oil 108.5-110

Picrate Perchloratc Latifoliiir 0-Acetyl dwivative Dihydroderivative Latifolinrmothine Latifolininc Tetrahydro derivative (SF-conanine3a-01) Oxime Ethylenedioxy derivative Conan-4-on-3/3-01 Malarboreinc Malarborine Malouphyllamine Methiodidc Norlatifoline N-Acetyl derivative 0,N-Diacetyl derivative N-Carbethoxy derivative Dihydro derivative

C21H33NO C~3H~sNOz C25H37NO3 Cz4H37NO3 CziH35NO

137 225 124 186 169-177 164-1 65.5 2 19-220 235 (decomp.) 189-190 192 181 124 160 174 171-172

-

GG

-

66 91

- 4(CHC13)

m

91 91 91 92,93

- lB(CHC13)

+ 54(CHC13)

- 39(CHC13) -

9 F

x

94

+ 56(CHC13) + 19O(MeOH) + lB(CHCl3) + 96(CHCl3)

0 Y

93 93 93 93 95 95 96 96

+ 57(EtOH) -

+ 42(CHC13) + 22(MeOH)

b

9 Z

c

97 93 93 93 93 93

- 31(CHC13)

- 26(CHC13)

+ lG(CHC13) + 12(CHC13) + 3 1(CHC13) + 33(CHC13) + 39(CHC13)

W

c!

98 ~~

-~ W 01 01

w

01

TABLE I-continued

Compound

Molecular formula

a

Melting point ("C)

ID

Sourcc'

Reference

17aa-Methyl-D-homoandrostane-type alkaloids ...

Dictyolucidamine

C23H41x02

0-Acotyl derivative Dictyolucidinc A'-Acetyl derivative

CzdhN03 C22H39N02 CdLiN03

N,O-Diacrtyl derivative - -

.~~... -

198 205 228-229 198 278 220

Cz6Hd04 ~~

~~~~

5

+ 7(CHC13) ++G(CHC13) 30(CHC13)

C

-

+ 30(CHC13)

C

+ S(CHC13)

-

+ 18(CHC13)

~

~

39

40 40 39, 40 40 40 ~~~

~

0 M 9

*,+ 2

Z

U .

r

0

Key to lettors: a . Buxus sempervirens L.; b. Conophuryngia pachysiphon G . Don.; c. Uictyoph,leba lucida (K. Schum.) Pierre.; d. F u i i / u mia africnntz (Benth.) Stapf. ; e. F u n t u m i a elostica (Preuss.) Stapf. ; f. Funtumia latifolicx Stapf.; g. HoZnrrhena untidysentericrc (Itoxb.) Wall.; h. Holarrhenn febrifuga Klotzsch.; i. Holarrhena africana A. DC. ; j. Kibatalia arborea (Bl.) G Don.; k . Mtclouctia nrborecr Mic:rs.; 1. Maloueticr bequaertiarui Woods. ; m. Malouetia glandulifera Miers. ; n. Pachysandra terminalis Sieb. e t Zucc. ; 0 . Snrcococctr pruniforniis Lindl. See Tahle V. Reviewcd in Volume V I I ( 1 ) .

s

8. ALKALOIDS O F APOCYNACEXE

A N D BUXACEAE

357

absence of the maximum of the methylene group adjacent to the keto group. The same conclusion was drawn from the UV-spectrum ( X " ' , S ~ ~ 245.8 mp, E 18,000)and from the conversion of holonamine to a mixture of aromatic products on heating with hydrochloric acid. The position of the hydroxyl group was inferred from a comparison of physical properties with those of 1la-substituted and unsubstituted pregna- 1,4-dien-3-onederivatives. The introduction of the 11a-hydroxyl into the dienones of this type results in characteristic changes in the UV- and NMR-spectra observed also in holonamine. The most important evidence of this kind was drawn from the positive Cotton effect exhibited by holonamine as contrasted with the negative effect observed in unsubstituted 1,4-dien-3-ones. The NMR-splitting pattern characteristic of conkurchine-type alkaloids (74a) disclosed the presence of an 18(N)-double bond and the structure of holonamine was thus ascertained (89) to be CLX.

25. Malarboreine Malarboreine was isolated in minute quantity from Malouetia arborea (95).The UV-spectrum (AT,",: 283 mp, E 24,700) was consistent with the presence of a 4,6-dien-3-one moiety which was confirmed by the ORDcurve closely resembling that of ergosta-4,6,22-trien-3-one (135, 136) and by the NMR-spectrum revealing the presence of protons in the conjugated system a t C-4: (4.32 T ) and C-6 and C-7 (3.88 T ) . Signals characteristic of the 18-proton (doublet at 2.46 r ) and of a tertiary and a

CLX

CLXI

CLXII

358

v. &ERN+

A N D F. ~ O R M

secondary methyl group together with the molecular weight (309) permitted the assignment of structure CLXI to this alkaloid.

26. Malarborine This alkaloid was isolated from Malouetia arborea (95).Its molecular weight (313) and the presence of a nonconjugated keto group suggested the formula CLXII which was confirmed by direct comparison with a synthetically prepared (137)sample.

E. TOTALSYNTHESES IN

THE

CONANINEGROUP

Since the appearance of a summary of Holarrhena alkaloids in Volume VII of this series, several partial and thrse total syntheses of conessine (or related bases) have been published. It should be noted that the starting compounds for all partial syntheses of conanine bases are accessible from steroids whose total syntheses were already accomplished. Irrespective of the formal difference in definition, both kinds of synthetic approach are dealt with in this chapter. The partial synthesis of 5a-conanine was published by Jeger and Arigoni’s group simultaneously with the partial synthesis of dihydroconessine by Corey and Hertler. Starting material for the synthesis of 5a-conanine (11) was 20amethylamino-5cc-pregnan-3-one (CLXIII) which had been prepared in several steps from 3fl-acetoxy-5a-pregnan-20-one via the corresponding oxime. The ketone CLXIII was subjected to Wolff-Kishner reduction to give the base CLXIV which was converted to the chloramine CLXV on treatment with N-chlorosuccinimide. The action of concentrated sulfuric acid in acetic acid solution generated 5a-conanine ( 2 1 ) . As in the case of 5a-conanine, the Loeffler-Freytag reaction was applied in the synthesis of dihydroconessine by Corey and Hertler (138, 139). Starting from 3fl-acetoxy-20a-aminopregn-5-ene (48) they obtained 3fl-dimethylamino-20a-methylamino-5a-pregnane (L) by obvious reactions. The base was converted to chloramine CLSVI which upon irradiation with UV-light afforded the 18-chloro derivative CLXVII cyclizing readily to dihydroconessine (CXXVI). A partial synthesis of conessine, the principle of which was later applied in a total synthesis of this alkaloid, was accomplished by Johnson and his co-workers (94). The starting conan-4-en-3-one (107, 126) was prepared by a novel synthesis from isoconessimine by a Ruschig reaction. The a,ji-unsaturated ketone CXLIV reacted readily with

8.

359

ALKALOIDS O F APOCYNACEAE AND B U X A C E A E

CLXIII; CLXIV; CLXV;

0 Hz Hz

H H Cl

CLXVII

Me

I

CXXVI

anhydrous dimethylamine in the presence of magnesium sulfate and a trace ofp-toluenesulfonic acid to give the enamine CX. The enamine double bond in this compound was selectively reduced with sodium borohydride to give conessine (XCVI). Barton and Morgan described another synthesis of conessine (140, 141) based upon photolytic cyclization of alkyl azides to pyrrolidines. They explained this reaction by the assumption that alkyl azide gives an activated nitrene which may react in different ways-one of the possibilities being, if necessary steric requirements are satisfied, 1,5hydrogen abstraction followed by cyclization to pyrrolidine. They prepared from the applied this principle to 3P,20u-diazidopregn-5-ene,

360

v. ~ E R X +A N D

F.

SORM

Me

a3 -

&+

0

(Me)ZN

\

\

cx

CXLIV Me

I

XCVI

corresponding 3/3,20/3-ditosylate and lithium azide, and obtained conessine in low yield. However, later attempts a t repetition of this experiment were unsuccessful and the exact conditions needed for the synthesis remain still to be defined (142). Barton and Starrat (142) later reported a synthesis of norlatifoline which constitutes a formal synthesis of conessine since a conversion of the former alkaloid to conessine had been accomplished previously (94, 143-145). The synthesis started from 3/3-acetoxypregn-5-en-20p-o1 Rz I

Rz R3 __ Me H CH=NOH H CH=NOH H Ms CN H CHzNH2 H CH~NHAC CHzNHAc Ms

RI

Rz

~

CLXVIII; CLXIX; CLXX; CLXXI; CLXXII; CLXXIII; CLXXIV;

Ac Ac

H Ms H Ac Ac

CLXXV; CXLVI;

Ac

Ac

H

H

8.

ALKALOIDS O F APOCYNACEAE AND BUXACEAE

CLXXVI

361

C1,XXVII

CLXXIX

CLXXVIII

CLXXXI

CLXXX

CLXXXII

CLXXXIII

Me

I

"

( J \\\"

aP

-

CXLIV

+

C' 'f J -

(Me)ZN

CX

H

CLXXXIV

Me

xcvr

362

v. EERNB AND

F.

SORM

(CLXVIII)which was converted into its nitrite on reaction with nitrosyl chloride in pyridine. The subsequent photolysis of the nitrite gave the 18-hydroximino derivative CLXIX which was converted to the 3hydroxy derivative CLXX ; subsequent treatment with mesylchloride afforded the 13-nitrile CLXXI. Energetic reduction with lithium aluminum hydride converted this compound into the 18-amine CLXXII which on partial acetylation with acetic anhydride in pyridine gave the diacetyl derivative CLXXIII. Treatment with mesylchloride led to the mesyl ester CLXXIV cyclizing spontaneously t o the tertiary amide CLXXV which on deacetylation with calcium in liquid ammonia gave norlatifoline CXLVI. In the total synthesis of Marshall and Johnson (143) the tetracyclic ketone CLXXVII was used as starting material. This compound had been prepared from 5-methoxy-Z-tetralone (CLXXVI) by successive condensation with ethyl vinyl ketone followed by methyl vinyl ketone and was then stereoselectively converted into the hydroxy ketone CLXXVIII (146). This compound was treated with methyllithium to afford a diol which after protective acetylation of the hydroxyl function in position 3 was dehydrated with phosphorus oxychloride in pyridine to yield a mixture of olefins rich in isomer CLXXIX. Subsequent ozonolysis yielded the diketone CLXXX which smoothly cyclized under alkaline conditions to the a,P-unsaturated ketone CLXXXI; addition of the elements of hydrogen cyanide by treatment of the latter with potassium cyanide and ammonium chloride led to the formation of both epimeric 13-cyano derivatives which could be separated by chromatography. Protection of the 20-keto group by ketalization was followed by reduction of the cyano group with lithium aluminum hydride, acid hydrolysis, partial hydrogenation of the pyrroline CLXXXIII (formulated with 17,20-double bond in the original paper, see Section II,G), and methylation with formaldehyde-formic acid which afforded the hydroxy derivative CLXXXIV. This compound, after oxidation to the 3-ketone, bromination, and debromination (147), yielded the +unsaturated ketone CXLIV whose conversion to dl-conessine was accomplished in the same way as above. In Stork’s synthesis (1481, 5 - methyl - 6 - methoxy - 1 - tetralone (CLXXXIV)was converted into the tricyclic intermediate CLXXXVII in several steps involving condensation with dimethyl carbonate, addition of methyl isopropenylketone, and cyclization to the a,/i-unsaturated ketone CLXXXVI, followed by catalytic hydrogenation, replacement of the hydroxyl group in the resulting dihydro alcohol by a chlorine atom on treatment with phosphorus oxychloride in pyridine solution, and elimination of hydrogen chloride by methanolic sodium methoxide.

8. ALKALOIDS OF

APOCYNACEAE A N D BUXACEAE

363

Transformation of the D ring was carried out by ozonolysis to the keto aldehyde which was then cyclized in acetic acid containing hydrogen chloride to the a$-unsaturated ketone CLXXXVIII. After protection of the methyl keto group by dioxolanation, the carbomethoxy group was reduced with lithium aluminum hydride t o give the 18-hydroxy derivative. Tosylation to CLXXXIX, hydrogenation on palladium, and treatment with hydroxylamine gave the nitrone CXC which by hydrogenation on rhodium furnished the compound CXCI already containing the pyrrolidine ring with the required stereochemistry. Cleavage of the phenolic ether with hydrobromic acid, selective acetylation, hydrogenation, and oxidation gave the ketone CXCII. I n order to build up the A ring, acrylonitrile was added using Triton B as catalyst. The following steps were then necessary to transform the 8a- t o the required Sgconfiguration. Bromination, aqueous base hydrolysis to the a-ketol, and mild oxidation with Benedict reagent gave the enolic a-diketone which was methylated to CXCIV and treated with aqueous sodium hydroxide t o achieve inversion at C-8. The double bond and methoxyl were then removed by successive catalytic hydrogenation on palladium and reduction with calcium in liquid ammonia : acetylation on nitrogen and oxidation of the sodium salt of the resulting hydroxy acid with chromtrioxide-pyridine gave the keto acid CXCVI. Treatment with acetic anhydride and sodium acetate yielded the corresponding enol lactone CXCVII which was treated with methylmagnesium iodide to give the 4,5-unsaturated 3-ketone CXLIV. Conversion of this compound into 3P-dimethylaminoconan-5-enederivative was achieved essentially in the same manner as in Johnson's synthesis and deacetylation with calcium in liquid ammonia followed by formaldehyde-formic acid methylation gave racemic conessine. The third total synthesis of conessine was published by Nagata et al. (144, 145). The Japanese authors started their synthesis from the tricyclic ketone CXCVIII whose preparation was previously described by Howell and Taylor (149) and which on Birch reduction with lithium and ethanol in liquid ammonia gave the enol ether CXCIX. Acid hydrolysis followed by benzoylation afforded the a,P-unsaturated ketone CCI which was alkylated with 5-bromopentan-2-one ethylene ketal in the presence of sodium hydride in boiling xylene. This reaction followed by alkaline hydrolysis resulted in the formation of CCII in which the double bond was reduced with lithium in liquid ammonia; acid hydrolysis of the resulting product yielded the hydroxy diketone CCIII which under the influence of dilute alcoholic sodium hydroxide cyclized to the +unsaturated ketone CCIV. The introduction of the angular substituent was achieved by the addition of hydrogen cyanide

v. ~ E R N I ?AND F . BORM

364

C00Me

-

0 Me0

+

/’

0 CLXXXIV

CLXXXV

CLXXXVI

+ cLxxxvm

cxc

CLXXXIX

H

CLXXXVII

Ac

CXCII

CXCI

+

__f

CXCIII

OMe CXCIV

?J3 CXCVII

OM0

-

+

HOOC

CXCVI

cxcv

xcvl

CXLIV

catalyzed with triethylaluminum in tetrahydrofuran solution. The resulting product CCV was converted to the ketal CCVI which by reduction with lithium aluminum hydride and subsequent methylation afforded dl-dihydrolatifoline (CCVII). For the introduction of the double bond the route via the 4,5-unsaturated 3-ketone was chosen. This objective was achieved by the application of the Rosenkranz method currently used in steroid chemistry (147) which included : oxidation, bromination to 2,4-dibromide, treatment with sodium iodide, and subsequent reduction with chromous chloride. The conversion of

366

8. ALKALOIDS OF APOCYNACEAE AND BUXACEAE

CXLIV to latifoline was achieved by the application of a general method *

(150, 151) based on conversion of an a,&uns&urated ketone to its onol ether and reduction of the enolic double bond in the latter with soclium borohydride. Since the a,B-unsaturated ketone CXLIV waa converted to coneseine previously (94) the total synthesis of latifoline also constitutes a formal total synthesis of conessine.

-

0

HO

H

H

CXCIX

CXCVIII

CCII

CCIV Me

CCIII

I

N

w - fJt7

H

CCVI

CCV

CCYII

Me

I

N

0

&CXLIV

A

c CXLV O

m

&OH

CXLVII

*

W

TABLE I1

Q,

a2

PARAVALLARINE-TYPE ALKALOIDS

Compound

Molecular formula

(20 R)-3~-Dimethylamino-20-hydroxypregn-5-en-l8-oic acid lactone (18 -+ 20) 5a-Dihydro derivative Kibataline 5a-Dihydro derivative 5P-Dihydro derivative Paravallaridine Hydrochloride N-Monoacetyl derivative N,O-Diacetyl derivative N-Methyl derivative Dihydro derivative Paravallarine Hydrochloride N-Acetyl derivative N-Methyl derivative Dihydro derivative

Melting point ("C)

191 168 171 150 116 231 280 261 240 200 233 181 295-298 258-260 140 166

Key to letters: a. Kibatalia gitingensis (Elm.) Woods; b. Paravallaris microphylla Pitard.

Source"

- 33(CHC13)

157

+ 4(CHCk)

157 158 158 158 154

- 42(CHC13) -4.6(CHC13) 9.5(CHC13) - 48(CHC13)

+

- 65(CHC13) - 36(CHC13) -49(CHC13) - 19.6(CHC13) - 52(CHC13) - 36(EtOH) - 25(MeOH) - 45.4(CHC13) - 37.7(CHC13) - 5(CHC13)

Referencc

-

b

154 154 154 154 154 152 152 152 152 152 152

4

A< z*, * M

~

U

w m.

8.

ALKALOIDS OF APOCYNACEAE A N D BUXACEAE

367

F. PARAVALLARINE-TYPE ALKALOIDS

1. Paravallarine This secondary base (CCVIII) is the principal alkaloid of Paravallaris microphylla Pitard. (152). The presence of a lactone group, indicated by a carbonyl band a t 1766 cm-1, was confirmed by lithium aluminum hydride reduction to a diol, CzzH37N02, and hydrolysis to a hydroxy acid, characterized as a methyl ester. Catalytic hydrogenation yielded a dihydro derivative which on Ruschig degradation gave rise to a ketone that proved to be identical with the known (45) ( 2 0 X)-S-keto20-hydroxy-5a-pregnan-18-oic acid (18+20) lactone (CCXVI). The 5,6-position of the double bond follows from the expected dextrorotatory shift on hydrogenation and from the conversion of paravallarine to a A4-3-ketone by Ruschig degradation method. The formation of a 5aderivative on hydrogenation constitutes a strong argument in favor of the p-configuration of the 3-methylamino group, since otherwise a considerable proportion of the 5/3-isomer should be found in the hydrogenation mixture. I n addition, optical rotation data are in conformity with the Sfhonfiguration.

2. Paravallaridine This base is a minor alkaloid ofP. microphylla. Aside from an additional hydroxyl, the functional groups in this alkaloid were established analogously to those in paravallarine. The product CCXIII arising by oxidation of N-methyldihydroparavallaridine (CCXI) was recognized as a five-membered ketone owing to the position of the carbonyl maximum in the IR-spectrum. An attempt was made to interrelate paravallarine and paravallaridine by removing the keto group in CCXIII by means of Clemmensen reduction method. Albeit the reaction took a different course, furnishing a 15,16-unsaturated derivative, catalytic hydrogenation of the latter resulted in the formation of the desired N-methyldihydroparavallarine CCXV. It was inferred that the oxygen function must be located in the 16-position since a strong levorotatory shift accompanying the introduction of the keto group into the molecule of paravallarine is only consistent with this position. The same conclusion was also drawn from the formation of an a$-unsaturated ketone prepared by the following reaction sequence oxidation of N-acetyldihydroparavallaridine CCXII to a keto derivative CCXIV, protection of the keto group by ketalization, reduction of the lactone ring with lithium aluminum hydride, and acid hydrolysis followed by dehydration with thionyl chloride. The resulting u,p-unsaturated ketone exhibited relevant IR- and UV-characteristics expected of the structure CCXVIII

368

I

8 x

XO .^

II II FZP;

v. ~ E R NAND P

N

F.

SORM

.^

E

u

8.

ALKALOIDS OF APOCYNACEAE A N D BUXACEAE

369

and identical with the spectrographic data reported for an analogous 3-hydroxy derivative (153). The above transformations can thus be formulated as proceeding through the intermediate CCXVII. The remaining question of the configuration of the hydroxyl group could be answered by taking into consideration the characteristic negative molecular rotation increments accompanying the introduction of the hydroxyl into the molecule as well as furt,her levorotatory change on acetylation. Thus the structure of paravallaridine was completely established (154)as CCIX. Dehydration of the epimeric 16-hydroxy derivatives was investigated (155). The free alcohols were found to be resistant or undergo chiefly substitution upon the action of a variety of reagents ; 15,16-unsaturated steroids could be obtained on heating of the corresponding tosylates with bases. The easily accessible 16-ketones served as starting material (156)for the preparation of paravallarine derivatives substituted with an amino group in position 16.

3. 20-Epi-N-methylparavallarine This alkaloid (CCXX) was found in Kibatalia gitingensis (Elm.) Woods. A steric arrangement at C-20, differing from that of paravallarine, was indicated by paramagnetic shift of the 21-methyl and 20-hydrogen signals in the NMR-spectrum. This assumption received confirmation by a synthesis of the alkaloid from paravallarine. Alkaline hydrolysis of paravallarine, followed by esterification of the free acid with diazomethane, and subsequent oxidation with chromic acid, yielded the ketone CCXIX. Reduction of the latter substance with sodium borohydride furnished a mixture from which, after methylation with formic acid-formaldehyde, 20-epi-N-methylparavallarine could be isolated (157). 4. Kibataline This alkaloid was isolated from K . gitingensis. The presence of identical functions in this alkaloid and in N-methylparavallarine was demonstrated by IR- and NMR-data. The mass spectra of both compounds were found to be qualitatively identical, which indicated that N-methylparavallarine and kibataline are stereoisomeric. Formation of two isomeric dihydro derivatives upon catalytic hydrogenation (5a and 5 8 ) and the lesser polarity of kibataline, as compared with N-methylparavallarine, led to the assumption that the alkaloid bears a 3a-amino function as visualized in the formula CCXXI. This assumption was confirmed by the synthesis of the 5a-dihydro derivative CCXXII by

370

v. ERN$ A N D

(Me)&

\""

F. ~ O R M

:.-1.13& \C C X X I

R

/

CCXXII

H

CCXXIII; R =0 CCXXIV; R = N O H

ccxxv; R=--OH C C X X V I ; R =-OTs C C X X V I I ; R = IIIIIIN~

three independent routes. The 3-ketone CCXXIII was converted to the oxime CCXXIV which on catalytic hydrogenation followed by methylation furnished a mixture of two C-3 isomeric amines, the less polar of which proved to be identical with CCXXII. Stereospecifically, the 5adihydrokibataline was prepared from the 3P-tosyloxy derivative CCXXVI which on treatment with dimethylamine in benzene solution yielded directly CCXXII. Alternatively, by reaction with sodium azide, the tosylate CCXXVI was converted to the 3a-azide CCXXVII, which on hydrogenation followed by methylation also gave CCXXII (158).

G. 18-SUBSTITUTED ANALOGS OF STEROID HORMONES FROM ALKALOIDS The fact that most of the Holarrhena alkaloids are characterized by substitution in position 18 was utilized for preparation of a series of nitrogen-free, 18-substituted steroids, which are of interest in relation to the adrenocortical hormone aldosterone. A detailed description would be beyond the scope of this summary. However, since some steps in these syntheses constitute interesting reactions of Holarrhena alkaloids, a brief outline, dealing with the principles of these procedures, will be presented here.

8.

37 1

ALKALOIDS OF APOCYNACEAE AND BUXACEAE

The first such transformation was the synthesis of 5a-pregnan-3P,18diol-20-one (in its hemiketal form, partial structure CCXXXI) by LBbler and Sorm (159, 160). Dihydroholarrhimine can be acetylated selectively in acetic acid in the presence of perchloric acid to give the 0-acetyldihydroholarrhimineperchlorate CCXXIX. The free base, when liberated from this salt, easily undergoes acyl migration to furnish 20-AT-acetyldihydroholarrhimine. This made a selective protection of the 20-amino group possible and the following replacement of the amino groups could be accomplished either successively (159, 160) or simultaneously (161). With holarrhimine (LXXIV)the method of choice was the successive replacement of the amino group in position 3 by nitrous acid deamination whereas the 20-amino group was best removed by means of the Ruschig method. This procedure afforded 18-hydroxyprogesterone represented

&;go4-

OH

OAc

SHz

& OH

NHAc --f

CCXXVIII

__f

CCXXIX

CCXXX

I 0 &OH

CCXXXI

CCXXXII

WR CCXXXIII

by the hemiketal formula CCXXXII (74, 162). The extension of these results then led to a formal synthesis of aldosterone (163).A later paper reported a simple preparation of 18-hydroxyprogesterone based on simultaneous deamination of both basic functions in LXXIV by means of the Ruschig reaction under carefully controlled conditions (164). Another very simple approach to 18,20-oxygenated steroids is nitrous acid deamination of pyrrolines of the type CCXXXVI. I n this manner, Buzetti et al. (165) prepared 18-hydroxyprogesterone CCXXXII. The pyrrolines (CCXXXVI) are readily accessible from the demethylconanine type (CCXXXIV) by the Ruschig method. The position of the double bond was established (98) in a model pyrroline from the absence

v. ~ E R NA P ND

372

F.

SORM

of the v(NH)frequency in the IR-spectrum, active hydrogen determination, and from the result of Schotten-Baumann benzoylation leading to the methylketone represented by the partial structure CCXXXVII. R I

NHCOPh

CCXXXIV ; R = H CCXXXV : R = CI

CCXXXVI

CCXXXVII

The isomeric 18(N)-pyrrolines cannot be prepared in this way. Opening of the pyrroline ring under acylating conditions was utilized for the preparation of some steroid hormone analogs, e.g., 18-benzoylaminoprogesterone (CCXXXVII) (166). More detailed investigation of the deamination of 20(N)-pyrrolines demonstrated that under a variety of conditions the procedure affords the substitution product to only a minor extent, whereas the principal reaction product is represented by a rearranged compound (97, 167) which was later found (168-170) to contain a 14p, 18-cyclopregnane skeleton (CCXXXIII). Another route to 18-hydroxyprogesterone was published by Pappo (171, 172). In this synthesis the 18,20-methylimino group was replaced by oxygen functions, as i h s t r a t e d by the sequence CCXXXVIIICCXXXII.

CCXXXVIIl

CCXXXIX

CCXLIV

CCXL; X = OTS CCXLI;X=OH

CCXLII ; R = H CCXLIII; H = T s

CCXLV

The Hofmann degradation product CCXXXIX was hydroxylated by osmium tetroxide to give a diol which on treatment with methyl p -

373

8. ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

toluenesulfonate afforded the quaternary salt CCXL ; pyrolysis of the corresponding ammonium base resulted in elimination of the quaternary function to yield the cyclic ether CCXLII. Obvious transformations, via the tosylate CCXLIII, 2 1-dimethylamino derivative, and the corresponding h7-oxide led to the enol ether CCXLV which on acid hydrolysis furnished the required hemiketal CCXXXII. Compounds containing the (20)N-pyrrolinesystem may be converted to 18,20-oxygenated steroids by a further route which is illustrated in the example of the pyrroline CCXLVI, yielding an oxazirane CCXLVII

& +g k0 -

t-

+

__f

O

H

CCXLVII

CCXLVI

CCXLVIII

~o

CCXLIX

1

CZJ

+ CCLII

CCLI

CCL

on reaction with p-nitroperbenzoic acid. Treatment with an additional mole of peracid resulted in oxidation of CCXLVII to the oximino derivative CCXLVIII, convertible to the nitrile CCL under the influence of phosphorus oxychloride. Reduction of CCL with sodium borohydride resulted in a mixture of 20-epimeric hydroxy derivatives which on acid hydrolysis of the nitrile group yielded the respective lactones CCLI and CCLII (173, 174). Nitrile CCL was also used for the synthesis of 18norsteroids (175). Displacement of a quaternary function in position 20 by an anion situated a t C-18 constitutes a further approach to the synthesis of 18,20-oxygenated steroids. Thus, quaternized 3P,20~-bisdimethylamino-5~-pregnan-l8-al (partial structure CCLIII) under the conditions of Hofmann degradation yielded a cyclic hemiacetal (CCLIV),convertible ( 4 6 )by oxidation to the corresponding lactone (CCLV); similar treatment of homologous

methylketones of the type CCLIX yielded enol ethers represented by the formula CCLXI. Identical products also resulted from cyanogen bromide treatment of a tertiary base of this type (176).These reactions bear close similarity to a well-known reaction leading to (20 R ) -18,20-oxidopregna3,j-diene (partial structure CCLYIII) on Hofmann degradation of S,S,S’,X’-tetramethylholarrliimine( 2 3 ) ; the identical oxide results from the action of cyanogen bromide on 20K-dimethylaminopregns3,5-dien-lX-o1 (176).

CCLIII

CCLIV

wi

CCLV

CCLVIII

CCLVI; R = M e CCLVII; R = C N

S(R1e)z

CCLIX; R = M e CCLX; R = C N

H

z

C

D

+ CCLXI

l’articipation of the 18-hydroxyl function was observed (164, 177) in nitrous acid deamination of holarrhimine and its derivatives resulting in the formation of (20 Rj-18,BO-oxides of the type CCLVIII. Another attractive possibility is offered by using paravallarine as starting material since this alkaloid already contains oxygen functions in both position 18 and 20 (152).The (20 22)-oxidesof the type CCLVIII can be prepared from 18,20a-diols, easily accessible by the reduction of the lactone ring in paravallarine-type alkaloids, by acid catalyzed dehydration (178).

8 . ALKALOIDS O F A P O C Y N A C E A E

-1ND B U X A C E A E

375

111. Alkaloids of Buxaceae

A. INTRODUCTIOX

BUXUS sempervirens L. has been used in medicine since ancient times. I n the Middle Ages it was used for many disorders, including skin and venereal diseases. I n the nineteenth century the extract of this plant gained a reputation as a remedy for malaria. The plant was first subjected to chemical investigation in 1830 in France by FaurB, who succeeded in' isolating an impure alkaloid which he designated " buxine " (179).Later, several authors claimed the isolation of various " buxines " and other alkaloids (parabuxine, buxinidine, parabuxinidine, buxinamine, buxeine) from the leaves or bark of B. semperrvirens. Ho vever, none of these preparations (with the possible exception of parabuxinidine) was obtained in pure condition (for detailed citations of the older literature see Schlitter et al., 180). It was not until 1949-1950 that the Swiss chemists Schlittler, Heusler, and Friedrich succeeded in isolating seven individual bases (A, B, C, D, L, Af, N) from the leaves of this plant (180-183). Their investigations resulted in the conclusion that the skeleton of the Buxus alkaloids is formed by a polycyclic unsaturated system. The turning point in the investigation of this group of alkaloids was the work of Brown and Kupchan (184, 185) which led to the structural elucidation of the alkaloid-A designated as cyclobuxine. This alkaloid was recognized as " a prototype of a new class of steroidal alkaloids which contain a cyclopropane ring and which liave a substitution pattern at C-4 and C-14 which is intermediate in the biogenetic scheme between lanosterol and cholesterol-type steroids " (184). The subsequent investigations were conducted by several groups (Kupchan, Stauffacher, Arigoni, Goutarel, Kakano, Marin-Bettdo, Voticl@, Tomko) and showed that the substitution at C-4 by methyl, methylene, hydroxymethyl, or alkoxymethyl, and at C-14 by a methyl group, is a characteristic common to all (except for irehine) BZLX'LLS alkaloids. The variety of the alkaloid types included in this group made it necessary to adopt an adequate nomeiiclature to avoid confusion in the designation of the many new alkaloids. According to a convention accepted by Kupchan, Nakano, Arigoni, and Goutarel a t IUPXC symposium in Kyoto, 1964 (see Brown and Kupchan, 186) the chosen trivial name designates the skeletal type whereas the substitution a t nitrogen atoms in positions 3 and 20 is expressed by a letter suffix according to Table 111. The use of this nomenclature was extended to alkaloids with a heterocyclic system joined to the steroid skeleton in

376 TABLE I11

SOVEVCLATI R E OF D I V I I I I Buxus ~ E.XSES

suffix

A B C

D E F G H

I

C-3 s

CH3 CH3 H H CH3 H H H H

CH3 CH3 CH3 CH3 CHB H CH3 H H

c-20 x

C& H CH3 H H CH3 H H H

CH3 CH3 CH3 CH3 H CH3 H C133

H

positions 3 and 4 but cannot be applied to the designation of monoacidic bases. Depending on the nature of the skeleton and substitutioii in positions 4 and 14, the Buxus alkaloids containing 2 atoms of nitrogen can be divided into several groups which are represented by formulas CCLXIICCLXXI and designated by the respective trivial names. The several mononitrogen alkaloids isolated to date correspond in their substitution pattern a t C-4 and C-14 with the above dibases. alkaloids, this was conducted by As concerns the isolation of BUXUS extraction of the plant material with a suitable organic solvent directly (15) or after previous treatment with acetic acid (52, 180, 187) or after basification with ammonia or soda (188).The total alkaloids were often fractionated into weak and strong basic portions by extraction from aqueous solutions of alkaloid salts a t appropriate pH and then subjected to separation by means of adsorption or partition chromatography (189). A histochemical investigation also established the presence of alkaloids in Pachysandra, Xarcococca, and Simrnondsia (190).The alkaloids found in Sarcococca and Pachysandra are simple pregnane derivatives lacking the alkyl substitution at C-4 and C-14. The alkaloids isolated from Sarcococca pruniformis Lindley show close similarity in structure t o alkaloids typical of pregnane-type alkaloids of Apocynaceae ; some of them were found in both families. Though the same is true of Pachysandra alkaloids, many of them are distinguished by the presence of a hydroxyl group in position 4 and/or by the amidic character of one of the nitrogen functions, particularly in position 3.

8. ALKALOIDS O F APOCYN-ACEAE

A X D BUXACEAE

CCLXII

CCLXIII

Cycloprotobuxines

Cyclovirobuxines

CCLXIV 7 ; Cyclovirobuxeines

CCLXVII

CCLXV

Cyclobuxines

Cyclornicrophyllines

CCLXVI 6-H, 7-H; Dihydrocyclomicrophyllines

CCLXVIII

CCLXIX

R1= H ; C'prlobuxoxazines

Cyclobuxnmiries

('CLXX R1= Me; Cyclomethoxazines

CCLXXI Buxttmines

377

378

v. ~ E R XAPN D

F. ~ O R M

The Pachysunclrci alkaloids have been intensively studied in Japan by Kikuchi and Cyeo.

B. Buxus ALKALOIDS

1. Cyclobuleine-D Cyclobuxine-D, C25H42Xs0,was isolated from the acetone insoluble portion of the strong bases of B. senipervirens leaves, is the principal alkaloid of this plant (181, 187), and is most probably identical with Schlittler's alkaloid A (181). It yields an O,K$ '-triacetyl derivative owing to the presence of two S-methyl groups and a hydroxyl group, the corresponding splitting pattern in the NRIR-spectrum being in accordance with the -CH&HOHCHgrouping. The NMR-spectrum further revealed the presence of one secondary and two teritiary Cmethyls, a cyclopropyl methylene, and a terminal methylene ; this latter was also confirmed by the IR-spectrum. After modification of the molecule by means of appropriate reactions, the spectral data of the corresponding compounds proved to be useful in providing additional information concerning mutual relations of the respective functional groups. Thus, cyclobuxine-D could be easily methylated with formic acid-formaldehyde mixture to give an N,N-dimethyl derivative exhibiting a marked shift of the NMR-signal of the secondary C-methyl group ( 9 . 1 3 T as compared with 8.92 T in cyclobuxine-D). This provided strong evidence for the proximity of one basic function to the secondary C-methyl. Further important information was gained from the restricted internal rotation of one AT-acetyland both AT-methylgroups in the triacetate, and of one N-acetyl and one N-methyl group in the AT,hT'diacetyl derivative, as inferred from the respective NRIR-spectra ; if the terminal methylene in the triacetyl derivative was degraded by ozoiiolysis, the NNR-spectrum of the resulting ketone (CCLXXIV) proved free rotation of the Ar-acetyl and one %methyl group. It appeared that the terminal methylene and one basic function are in close proximity. The same conclusion was arrived at on the basis of the Hofmann degradation of N,AT'-dimethylcyclobuxiiie-D moiiomethoiodide which led to a product having the composition CzsH39NO (mp 169"-170"; [CC]~) + 170" in chloroform), and containing the original terminal methylene in conjugation with a newly formed double bond. This behavior was in accord with another experiment in which ozonolysis of cyclobuxine-udi-p-iiitrobenzylcarbamate, followed by hydrogenolysis. resulted in the formation of an unstable amino ketone CCLXXII. Oxidation and hydrolysis uiider alkaline coiiditioiis led to a diosphenol the UV-spectrum

TAI3LE I V

Buzus ALKALOIDS Cotnpound

Alkaloid A ( = cyclobnxiiic-D) Balnabuxitliiic Ualr~abuxiric nchuxinc ( = cyclovirohuxiiic-D) Buxamiiic-14; T-Isopropylidene clerivativo OGalnte Uishytlrogon tartrate Buxnmiric.-(: ( = buxcxiim-G, norbuxamine) S-Isol,ropylitlcne tlcrixrative

Molecular formula

Molting point ("C)

357 258-259 Ainorphous 187 263 -267 210 (tlccornp.) -

193 1!)4-196 21 6-820 300 (deromp.) 200 209 210 176-178 172-1 78 181-183 178-1 8 1 213-215 21 1-213 193-197

+ Tl(CHC13) + 115(CHC11)

2

a

218 15

+ 32(CHC13) +.I~(CHCIJ) + 18(50°,,MvOH) + 2ii(50°,,EtOH) 20(CHC13) 30(CHClj) + 31 (CHCI j ) 130(CHCI3) + 86(30",EtOH) +38(CHCI() !)T,(CHC'13) + 14(50",,EtOH)

+ + +

+

+ lO~5(CHCI,~)

+ l.X(CHCl3) + IT,i(EtOH) + IB!)(C*HC'I3) + 132(CHC13) + Xi(CHC"11 )

+ !)2(CHC'13)

+ 9<>(CHCI,j)

W 4

W

c3

TABLE IV-continued

c/)

0

Compound ___

~-

~

~

~

Molecular formula _

_

Dihydrobrornide Dihydroiodide N,N’-Bisphenylthiourea Diperchlorate Dioxalate 3-LV-Acetylderivative S,N’-Diacetyl derivative

Sourcc“ Refcrencc

_

Oxirne Dihydrobuxtauine Dihydrocyclobuxoxinc-a Dihydrocyclobuxoxirie-b “Diol 111” Cyclobaleabuxine ( = cyclomicrophylline-I) Cyclobuxamine-H A‘-Isopropylidene derik ative N,N’,O-Triacetyl dcrivative N,N’-Diformyl derivative N,S’,O-Triformyl derivative K,A’,S’-Trirnethyl derivative 3-AT’-Isopropyl derivative Cyclobuxine-D ( =alkaloid A)

Melting point (“C)

235-238 169-172 198-200 192-194 187-190

248-250 (decomp.) 261-263 330-331 (decomp.) 275-276 (decomp.) 215-218 267-269 (decomp.) 24‘ 245-247 248-249 288-292 (decomp.) 274-2 78 2 76-27 8 180-1 82/216-2 19 244-245 (decornp.) 264-267 (decomp.) 187-192 283-285 (decornp.)

-

+ Sl(CHC13) + 100(CHC13) + GO(CHC13) + 67(CHC13)

+ 30(CHC13) + 67(CHCl3) -

+ 33 -

+ 125(CHC13) + SR(CHC13) + 96(CHCl3) -

-

-

+ 41(CHC13) + lO(CHC13)

52 213 214 214 52

5 0

206 206 206 206 206 206 206 180 184, 185 209 I84 181 187 181 187 187 191 185

M

0

Z ++

5.

Z U

h:

rn< 0

E

H

N,N’,O-Triacetyl derivative

C3iH48Nz04

3-N-Methyl derivative A‘,”-Dimethyl derivative Dihydro derivative

CzsH44Nz0

Cyclobuxoxazine-A Cyclobuxoxazine-C N-Acetyl derivative N,O-Diacetyl derivative N-Methyl derivative Cyclobuxoxine ( = buxtauine) Cyclomalayanine Cyclomethoxazine-B Cyclomicrobuxinc ( = buxpiine)

-

- 12(CHC13)

+ 104(CHC13) -

+99(CHC13) -

+ 46(CHC13) + 45(CHC13) + 29(CHC13) - 28(CHC13) - 35(CHC13)

+ 40(CHC13)

181 184 200 181 184 181 184

Po P F

205 212 212 212 212

FF

8 0

0

170 195 178-1 80 173 232-233

0-Acctyl derivative Cyclomicrobuxininc ( = buxtauine) Cyclomicrophyllidine-A Dihydroderivative Cyclomicrophylline-A O,O’-Diacctyl derivative 0,O’-Dibenzoyl derivative Monotosyl derivative Monomethiodidc Dimethiodide DihydrocyclomicrophJ.Iline-A ( = cyclorolfeibuxine-A)

16-Dehydroderivative

246-248 256-258 (decomp.) 233-234 193-194 204-206 (decomp.) 217 208-209 197 245-246 284-285 240 201-202

- 6 1(CHC13)

+ 54(CHC13) + 172(CHC13) + 158(CHC13) + 146(CHC13)

w

201 205 200, 209

P

52 200, 209

Z

w

0 Q

#

& M

Amorphous Amorphous 232-233 Amorphous 105-113 176-177 265-270 (decomp.) > 320

CZSH~GNZOZ

265-266 271-272 266 156-157 (decomp.)

- lGO(CHC13) - 33(CHC13) -93(CHC13) - lOO(CHC13) - 94 lB(CHC13)

+

-

+ 37(CHC13)

20!) 209 208, 209 209 209 208 211 211

+ 44

208 209 205

- 170(MeOH)

208 -

F M

F Z 0

2 F

0

M

P

M

w

00

c

3

w

TABLE I\'+ontinued

rn

E3

Compound

Molecular formula

Molting point ("C)

11.11 ...

Cyclomicrophylline-B ( = cyclobalcabuxine) N-Acetyl derivat,ive N,O-Diacetyl derivative N,O,O'-Triacetyl derivative N,O-Diacetyl-0'-tosyl derivative N-Methyl derivative ( = cyclornicrophylline-A) Dihydro derivative 16-Dehydroderivative Cyclomicrophylliric-C N,O,O'-Triacetyl derivative Monomcthiodidc Dihydrocyclomicrophyllinc-C ( = cyclorolfeibuxine-C) 16-Dehydro derivative

Cycloprotobuxine-A

Cycloprotobuxinc-C (=alkaloid L)

Hydrochloride

251-252 254 272 228 196 202-203 202-203 232 247-248 247 162-164 283-284 Amorphous > 320 265 256 160-164

207 207-208 208-21 1 212 198-203 200-202 > 320

-

-~

- 65(CHC13)

- 67(CHC13)

- 157(CHC13)

- 185(CHC13)

- 156(CHC13)

Sourceo Reference .

~~

201,208 15 15

15 15

- IBl(CHC13) - lOO(CHC13)

209

4

15

0

- 74(CHC13)

I5 209

m

+ 26(CHC13) + 59(CHC13)

- 156(CHC13)

- 40(CHC13)

- 132(CHC13) -

+ 52(CHC13)

+ 74

- 14O(CHC13) -

$. 7S(CHC13)

+31(CHC13) f

78(CHC13)

+ 77(CHC13) + 76(CHC13) -

15

209 208 209 209

M

*\ *Z Z

C

r

Cn< 0

PJ

z 209 205 209 15, 201 15 200 203 15 180 200 I83

Dihydroiodidc Diperchlorate X.Acety1 derivative iV,N’-Uiacotyl derivative iV,N’,O-Triacctyl derivative N,N’-Diincthyl derivative ( = cyclovirobuxine-A) n’,h”-Di.p-nitrobcnzylox~carbonyl derivative Dihydrocyclornicl.ophyl1 inc-F ~‘.Monoacctylderivative N,O,O’-Triacetyl derivative N-Isopropylidcne derivative Norbuxaminc ( = buxamine-G)

222-235 220-229 198-200 140-142 276-278

253 235 239 220 203 172 220 221-224 (decomp.) 313-3 15 (dccomp.) 249-252 (decomp.) 215 265-266 231 240-241 (decomp.) 244 227-229 260 278-279 298-300 229-230

-

183 183

-

183 203 203

+ llS(CHC13) -

+ llS(CHC13) - 34(CHC13)

+ lOB(CHC13) - 87(CHC13)

- 75(CHC13) - 153(CHC13)

+ 63(CHC13) + B3(CHC13) -

205 205 205 201 201,204n 201 201 52, 186 186

-43(CHC13) - 52(CHC13)

186 205 186 201

+ 44(CHC13) + 38(CHC13)

I86 20 1

+ 14(CHC13)

- 8(CHC13)

+ 4.6(CHC13) + 3.6(CHC13) + lS(CHC13) + vB(CHC13)

186

209 209 209 209

8. l L K d L O I D S O F APOCYNACEAE AYKI RUXACESE

Monoacctyl derivative C29H50xZ0 Monobcwzoyl derivative C34H~izNz0 N-Monomethyl derivative ( = cycloprotobuxine-A) Dihydro derivative C27H50N2 Cycloprotobuxine-D CZ~HMNZ N,iV‘-Diacetyl derivative C~OH~ONZOZ N,N’-Uimothyl derivative ( = cycloprotobuxine-A) Cyclorolfcibuxinc-A ( = dihydrocyclomicrophylline-A) Cyclorolfcibuxine-C ( = dihydrocyclomicrophylline-C) Cyclorolfcinc N-Acctyl derivative Cyclorolfoxazine Cyclovirohuxcirle-A Cyclovirobuxeinc-B N,O-Diacetyl derivative Cyclovirohuxine-D ( = bcbuxine)

-

TABLE IV-continued _ _ _ _ ~ _ _ _

-

-

w CI)

k P

Compound ~

- -

._____

Molecular formula

Melting point ("C)

[@ID

Source" Reference

~ ~ _ _ _ _ _ _ _

-

-

Alkaloids of unknown structure -

Alkaloid B Alkaloid C Alkaloid D Alkaloid M Alkaloid N ( = buxtauinr?) Minor alkaloids 1 2 3 4

5

205-207 212-214 182-183 203-205 178-1 79 199 195 281 177 156

-

-

+

e e e e e

+ + + +

e e e e

+56(CHC13) 61 ( E t O H ) Sl(CHC13) 49(CHC13) 93(CHC13)

e

+ GO(CHC13) + BO(CHC13) - SO(CHC13) 150(CHC13) +31(CHC13) 92(CHC13) 68(CHC13) 147(CHC13) 40(CHC13)

e

-

~

180 180 180 182 I82 188 188 188 188 188

5 0

M

%

*\ + Z Z

Buxalfine Dihydro derivative Octahydro derivative Buxazine Oxalate Buxdeltine Buxetine Buxidine Buxomegine 0-Acetyl derivative Dihydro derivative

202-205 244-249 152-155 2 38-2 39 257-260 (decornp.) 275 263-265 254-2 5 8 172-173 182 170

+ + + +

-

+79(EtOH) - 30(CHC13) 76.5(CHC13) - 48(CHC13) -45(CHC13) +31(CHC13)

+

-

52 52

0

0

e

52 52 2220

-

222n

e e

52 52 222n 52 52 52

-

e

e -

-

Key toletters: a. Buxus balenrica Willd.; b. BuxusmalayanaRidl.; c. Buxusmicrophylln Sieb. e t Zucc. var.suffruticosa Makino; d. Buxus rolfei Vidal; e. Buxus sempervirens L.

rcnc

k!

8.

ALKALOIDS OF APOCYNACEAE AND BUXACEAE

385

of which disclosed extended conjugation (A::: 296.5 mp as compared with 278 mp in the known steroidal 3,4-diosphenols). It could be demonstrated that the above shift is due to the cyclopropane ring since the action of hydrogen chloride upon this diosphenol CCLXXV resulted in

I

OH CCLXXV

RI Rz R3 CCLXXII; H H CCLXX1II:Ac Ac CCLXX1V;Ac Ac

H H Ac

(+.,pp?

HMe

CCLXXXII

a":i- H cxr".

CCLXXVI

/

CCLXXVII

CCLXX I x

CCLXXX

CCLXXVIII

CCLXXXI

another diosphenol lacking the cyclopropane ring and exhibiting a normal position of its UV-maximum A(E$: 277 mp). This behavior provided valuable evidence in favor of the proximity of the exocyclic methylene and one methylamino group to the cyclopropane ring and,

386

v. 6 ~ ~ AND x 9F. SORN

more specifically, for the 9,8,19-position of the three-membered ring. Such reasoning found support in biogenetic considerations and was buttressed by additional chemical evidence. Thus, decyclization of the cyclobuxine-D derivatives under the influence of hydrogeii chloride resulted in a mixture of unsaturated compounds the double bond of which resisted hydrogenation. Such behavior is typical of 8,9- or 7,8unsaturated steroids. On selenium dehydrogenation, cyclobuxine-D yielded a complex mixture of aromatic hydrocarbons derived from anthracene (CCLXXVIIT, CCLXXIX) and phenanthrene (CCLXXVI, CCLXXVII). I n contrast, dehydrogenation of the decyclized cyclobuxine-D furnished exclusively phenanthrene derivatives. The formation of the anthracenoid products is thus related to the presence of the cyclopropane ring; moreover, these results are suggesti-:e of the 9,19-cyclopregnane structure since the production of the anthracenoid hydrocarbons can be plausibly explained by assuming the initial cleavage of the 1,10- or 9 , l l bond followed by recyclization onto C-6 or C-7 and elimination of the cyclopropyl methylene. Oxidation of a series of cyclobuxine-D derivatives with protected amino functions furnished compounds characterized as five-membered ring ketones by their IR-spectra and positive response t o the Zimmermann test. When the protection of the nitrogen functions was omitted, the ketones arising from the oxidation readily eliminated methylamine on treatment with alkali t o give cis- and trans-cisoid or$-unsaturated ketones CCLXXX and CCLXXXI. Apart from its stereochemistry, the above results allowed the establishment of the structure of cyclobuxineD as CCLXXXII ( 1 8 4 , 1 8 7 ) . The confirmation of this structure and proof of the stereochemistry of the skeleton was provided by the following correlation of dihydrocyclobuxine-D with cycloeucalenol (185, 191). Cycloeucalenol acetate (CCLXXXVI) was degraded to the ester CCLXXXVIII applying the reported procedure (192),which included ozonolysis to the ketone CCLXXXVII, reduction of the ketone function followed by dehydration of the alcohol thus formed, ozonolysis, oxidation with chromic acid, and esterification. For further degradation, recourse was taken to the Meystre-Miescher method (193-196) ; treatment of the ester CCLXXXVIII with phenylmagnesium bromide led to a tertiary alcohol which suffered dehydration on heating with acetic anhydride. Subsequent allylic brornination with h'-bromosuccinimide followed by dehydrobromination with dimethylaniline yielded a diene CCXC which after hydrolysis of the acetoxyl group was oxidized with chromic acid to the 3,20-ketone CCLXXXV identical with the substance obtained

8.

ALKALOIDS OF APOCYNACEAE AND BUXACEAE

387

B l e H S L ; H CCLXXXIII

CCLXXXIV

2

ddPh CCLSXXIX

AcO

g

k

CCLXXXVI 0

CCLXXXVII

CCLXXXrlII

from dihydrocyclobuxine-D by Ruschig degradation followed by hydrogenation (191). The configuration of the 3-methylamino group follows from the fact that N,N'-dimethylaminodihydrocyclobuxine-D is remarkably resistant to Hofmann degradation, analogous to other saturated steroids carrying a dimethylamino group in the equatorial 3P-position. This behavior is owing to the impossibility of the coplanar trans-diaxial elimination which, in contrast, occurs easily with 3a-epimers ( 4 3 ) . The same conclusion was drawn from the weak negative Cotton effect of the ozonolysis product (CCLXXIV) of O,N,N'-triacetylcyclobuxine-D comparable to

388

v. ERN+ A N D

F.

SORM

that of 5a-cholestan-4-one and therefore not affected by the 3-acetylmethylamino group. This may be expected if the 3-substituent is equatorial. The a-orientation of the 16-hydroxyl group was inferred from the negative shift of the molecular rotation observed on acetylation, and from the NJIR-signal of the 16-proton, which is split by the nearly opposing (J = 9.5 cps) proton. The 20a-configuration of the methylamino group in the side chain is strongly favored a priori on biogenetic grounds since all known natural 20-aminosteroids possess a-configuration at this position. Chemical evidence was provided by the observed facilitation of alkaline hydrolysis of the 20-N-acetylmethylamino group which finds its analogy in the reported increase in the saponification rate of the 20a-acetoxy group in 3p, 16a,20a-triacetyIpregn-5-ene (197) due to the participation of the 16-hydroxyl in the hydrolysis process. The structure of cyclobuxine-D is in agreement with the results obtained by the X-ray analysis of cyclobuxine-A and its monomethobromide (198).

2. Cycloprotobuxine-C Cycloprotobuxine-C was first isolated from Buxus sempervirens by Schlittler and co-workers (180-183) and was designated “alkaloid L.” It was later found in other Buxus species (15, 199-201). Its structure (CCXCIII) was established by Calame and Arigoni (202), who reported its synthesis from cycloartenol in a preliminary communication, and independently by Nakano and Hasegawa (199, ZOO), who correlated this base with cyclomicrophylline-A (CCCXIX). The NMRspectrum of cycloprotobuxine-C revealed the presence of one methylamino and one dimethylamino group, one secondary and four tertiary C-methyl groups, and one cyclopropyl methylene. On methylation it furnished an iV-methyl derivative (cycloprotobuxine-A) which was also prepared from dihydrocyclomicrophylline-A (CCXCV) in the following manner : the latter alkaloid was tosylated to yield the ditosylate CCXCVI which on treatment with sodium benzyl mercaptide in dimethylformamide furnished the bisbenzyl t,hioether CCXCVII. Desulfurization of this substance generated the base CCXCII identical with the methylation product of CCXCIII. Proof of the position of the methylamino group in cycloprotobuxine-C was provided by the result of the Ruschig degradation which yielded a ketone containing no methylketo group and exhibiting a weakly positive Cotton effect. These facts are only in accord with the formulas CCXCI and CCXCIII for the ketone and the starting base, respectively.

8.

389

ALKA4LOIDSO F AEOCYNACEAE A N D B U X A C E A E

CCXCII; RIe CCXCIII; H CCXCIV: H

CCXCI

Me Me H

\

CHzR

CCXCVIII

CCXCV; R = O H CCXCVI ; R = OTs CCXCVII; R = SCHzPh

3. Cycloprotobuxine-A Cycloprotobuxine-A (CCXCII) was found in B. balearica Willd. (15) and in B. maEayana Ridl. (201). 4. Cycloprotobuxine-D Cycloprotobuxine-D (CCXCIV) was isolated from the acetone soluble portion of strong bases of B. sempervirens (203). The NMR-spectrum revealed the presence of two A-methyl groups, one secondary and four tertiary C-methyl groups. and one cyclopropyl methylene. On acetylation, the alkaloid gave an N.3'-diacetyl derivative. These data, coupled with the similarity of the IR-spectrum of cycloprotobaxine-D to that of cyclovirobuxine-D (CCXCIX), indicated the alkaloid t o be deoxycyclovirobuxine-D (CCXCII'). This assumption was fully confirmed by Ruschig degradation of C C S C I V to the known diketone CCXCVIII (186, 2Od) and by formic acid-formaldehyde methylation to cycloprotobuxine-A (183).

5 . Cyclovirobuxine-D Cyclovirobuxine- D (CCXCIX) was isolated from the acetone insoluble alkaloid fraction from B. sernperwirens (186)and from B. malayana (201).It is identical with bebuxiiie (16,52).This alkaloid both in chemical

390

V. &ERN* A N D F. g O RM

behavior and in spectral properties shows close similarity with dihydrocyclobuxine-D : the IR-spectrum is essentially superimposable on that of dihydrocyclobuxine-D and also the respective NMR-spectra are similar, disclosing the presence of the same functional groups except for the presence of two tertiary methyl groups in cyclovirobuxine-D instead of the secondary one in dihydrocyclobuxine-D. The Ruschig degradation, conducted under similar conditions as with dihydrocyclobuxine-I), furnished the a,p-unsaturated ketone CCC which on selective hydrogenation yielded the diketone CCXCVIII identical with the substance obtained by degradation of cycloartenyl acetate (CCCI) (204). This result settled the stereochemistry in positions Ti, 8, 9, 10, 13, and 14. As in the case of cyclobuxine-D, the 16-ketone derived from CCXCIX suffered a base catalyzed elimination of methylamine to givc a mixture of cis- and trans-isomeric unsaturated ketones analogous to CCLXXX and CCLXXXI. This behavior coupled with the above results confirmed the positions of the hydroxyl group and of the side chain amino function. The a-configuration of the 16-hydroxyl group was inferred from the NMR- and optical rotatory data on the basis of the same arguments as

CCXCIX

CCCII

CCC

CCCILI

8.

ALKALOIDS O F A P O C Y N A C E A E AND B U X A C E A E

39 1

in the case of cyclobuxine-D. The essential identity of the curves of X,AT’-dibenzoyldehydrodihydrocyclobuxine-D (CCCII) and N,X’-diacetyldehydrocyclovirobuxine-D (CCCIII) is only consistent with the steric identity of both compounds in position 17. Since a variety of chemical transformations conducted in both series are attended by parallel changes in optical rotation, the 3/3,20cc-configurations of the respective amino functions are well founded.

6. Cyclovirobuxeine-A and B , Cyclomalayanine These alkaloids were isolated from the leaves of B. malayana (201). Cyclovirobuxeine-B was also obtained from B. sempervirens (204a). The spectral characteristics established the close relationship of cyclovirobuxeine-A, CzaH48Nz0, (CCCV), to cyclovirobuxine-A : the substantial difference being the presence of a disubstituted double bond in the former. Indeed, catalytic hydrogenation of CCCV gives cyclovirobuxine-A. The double bond in cyclovirobuxeine-A is located in the 6,7position which accounts for the marked shift of the cyclopropyl methylene signal to higher field in the NMR-spectrum and is consistent with the large negative change in optical rotatory power accompanying the passage from the unsaturated alkaloid to the saturated one (201).The structure CCCIV of cyclovirobuxeine-B, C Z ~ H ~ ~ was N ~ analogously O, indicated by physical methods (201, 2043) and by the result of methylation converting it to cyclovirobuxeine-A. The 20-position of the secondary amino group was established by the Ruschig reaction furnishing the 20ketones CCCVI and CCCVII ( 2 0 1 , 2 0 4 ~ ) . Catalytic hydrogenation of cyclovirobuxeine-B yielded cyclovirobuxine-B which has not been found in nature to date (201, 204a). Cyclomalayanine, C36H5&203, isolated from the same source, proved to be the coumaric acid ester of cyclovirobuxeine-B.

CCCIV ; R = H CCCV; R = M e

CCCVI

CCCVII

7 . Cyclorolfeine Cyclorolfeine occurs in B. rolfei Vidal. Its spectroscopic properties reveal the presence of a methylamino group in position 3 and a methylketo group in position 17, a cyclopropyl methylene, four tertiary Cmethyls, and one hydroxyl group which easily suffers dehydration t o an

392

v. ERN+ AND

F. ~ O R M

c+unsaturated ketone. These data suggested the formula CCCX which received confirmation by interrelation with cyclovirobuxine-D. O,hT,N‘Triacetylcyclovirobuxine-D (CCCVIII) on selective deacetylation furnished CCCIX which, by Ruschig degradation, was converted to Nacetylcyclorolfeine (CCCXI) (205).

RI Rz R3 -~ CCCV1II;Ac CCCIX; Ac

Ac H

Ac H

CCCX; R = H CCCXI ; R = Ac

8. Cyclobuxamine-H Cyclobuxamine-H was isolated from the acetone insoluble portion of the strong bases from B. sempervirens by way of its isopropylidene derivative (187, 189). Spectroscopic (IR-, NMR-) properties of the isopropylidene derivative showed its close similarity to dihydrocyclobuxine-D and revealed the presence of two secondary and two tertiary C-methyls, one cyclopropyl methylene, and one hydroxyl group, the NMR-splitting pattern demonstrating identical ( 16,) configuration of the hydroxyl group as in cyclobuxine-D. N,N,N’-Trimethylcyclobuxamine-H (cyclobuxamine-A) is not identical with dihydrocyclobuxine-A; considerable difference in the positions of the signals of the 19-cyclopropyl methylene indicated that both bases may differ in the configuration of 4-methyl groups. Useful information concerning this point was provided by the study of hydrogenation of the cyclobuxine-D and some of its derivatives. Dihydrocyclobuxine-D (CCLXXXIII) arising by direct hydrogenation of cyclobuxine-D (CCLXXXII)yielded an N,N’-diacetyl derivative which proved to be different from the substance obtained by the catalytic hydrogenation of N ,N’-diacetylcyclobuxine-D (206). The comparison of the molecular rotation increments of both acetyl derivatives led to the conclusion that the 4-methyl group in dihydrocyclobuxine-D is O! oriented. Examination of the molecular models indicated that the catalyst can approach the L-shaped molecule of cyclobuxine-D from the /3 side whereas the presence of an acetylmethylamino group makes this approach less likely. Further evidence was drawn from the difference in the position of the NMRsignals of the 4-epimeric 3-acetyl derivatives which was interpreted as a

8.

393

ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

blocking effect by the 4P-methyl group on the long-range deshielding influence exerted by the 3p-acetylamino group on the 19-methylene. Noteworthy also is the result of the Ruschig degradation of dihydrocyclobuxine-D which yielded an u,P-unsaturated ketone, further hydrogenated to the diketone CCLXXXV with the 4 ~ m e t h ygroup; l inversion at C-4 in the course of the degradation is unlikely in view of the known (207) stability of 4P-methylcholestan-3-onetoward strong basic conditions. Difficulties arising from different hydrogenation courses rendered the interrelation between cyclobuxamine-H and cyclobuxine-D somewhat difficult. It was accomplished in the following manner: cyclobuxamine-H was formylated t o the triformyl derivative CCCXV which could be saponified partially (albeit in poor yield) under basic conditions to yield the 3-formyl derivative CCCXVI. Reduction of this compound with lithium aluminum hydride, followed by acetylation, furnished the acetyl derivative CCCXIV identical with that obtained by catalytic hydrogenation of O,N,N'-triacetylcyclobuxine-D(CCCXII); the structure of cyclobuxamine-H was thus established to be CCCXIII.

f'

/'O,

OAc

CH2

CCCXII

CCCXIII

CCCXIV

i'

R1 CCCXV; H CCCXVI; H CCCXVII; H

RZ

R3

CHO CHO CHO H Me H

R4

R5

Me Me Me

CHO H H

9. Cyclomicrophylline-A Cyclomicrophylline-A (CCCXIX) was isolated from Buxus microphylla Sieb. et Zucc. var. sufruticosa nlakino by Nakano and Terao (208,209). The IR-spectrum of this alkaloid disclosed a hydroxyl group, whereas

v.

394

&ERN+ A N D F.

SORRI

the NMR-spectrum demonstrated the presence of the grouping -CHz-CHOH-CH(septet a t 5.90 T ) and -CH-C-CHZOH doublet a t 6.30 7,J = 1 0 . 5 cps), four N-methyl groups, three tertiary

CCCXVIII

1 J

Ri

Rz

CCCX1X;Me CCCXX; Me CCCXX1;H

Me H Me

\

gyd0 fl(h CCCXXII

(Me)zN

,.'

(I1Ze)zN

CHzOH CCCXXIV

CHzOH CCCXXIII

C-methyls, and one cyclopropyl methylene. The NMR-spectrum also proved the presence of one disubstituted double bond which could be also demonstrated by hydrogenation. Information concerning the position of the double bond was provided by isomerization of cyclomicrophyllineA (CCCXIX) under the influence of hydrogen chloride. This reaction resulted in the opening of the cyclopropane ring to furnish a substance (CCCXXII) containing an additional trisubstituted double bond which on prolonged treatment with the reagent yielded the conjugated diene 236, 243.5, CCCXXIII with absorption in the UV-spectrum: : ;A:(

8 . ALKALOIDS O F APOCYNACEAE

AND BUXACEAE

395

2 5 2 mp) characteristic of steroidal 7,9(1l)-dienes. Only the 6,7-position

of the double bond in cyclomicrophylline-A accounts for all these facts. The relative positions of the methylamino and hydroxymethyl groups are illustrated by the result of the Ruschig degradation of cyclomicrophylline C (CCCXXI) leading to the ketone CCCXXV which on mild alkali treatment suffered a retroaldol loss of formaldehyde t o give CCCXXVI. Chromic acid oxidation of this product resulted in the production of the diketone CCCXXVII which readily eliminated dimethylamine in alkaline solution to furnish a mixture of a,P-unsaturated cis- and trans-ketones CCCXXVIII and CCCXXIX which on hydrogenation gave CCCXXX (206, 207). The identical diketone was prepared from cyclobuxine-D (206,207)via the amino ketone CCCXXXI by catalytic hydrogenation and subsequent Ruschig reaction. This interrelation established the absolute configuration a t six (5a,8P, 9B, lop, 13p, and 14a) of the eleven asymmetric centers in the molecule.

CH~OH

CCCXXVI

CCCXXV

CCCXXVII

CCCXXX

cccxxrx

CCCXXVIII

CCCXXXI

T

CCLXXXIJ

396

v. I ~ E R NAPN D

F.

SORM

The configuration of the hydroxymethyl group in position 4 was derived from the position in the NMR-spectrum (at 6.30 T ) of the quartet of two protons due to the CHzOH group. This observation is only consistent with the axial position of this group since the signal of an equatorial hydroxymethyl group should be expected a t higher field (209-211). The same conclusion was drawn from the strong intramolecular hydrogen bonding of the hydroxyl group to the 3-dimethylamino group in the compound CCCXVIII, the equatorial /&configuration of this dimethylamino group being well founded on the resistance of the cyclomicrophylline-A monomethiodide toward Hofinann degradation (43, 211). The 17P-configuration of the side chain was derived from the strongly negative Cotton effect exerted by the 16-ketone CCCXVIII. The a-configuration was attributed to the 16-hydroxyl group on the basis of a strongly negative shift in molecular rotation observed on acetylation. Finally, the 20a-configuration of the dimethylamino group in the side chain could be assigned from the course of the pyrolytic (cis) elimination of dimethylamine from the amino ketone CCCXVIII furnishing the cis-cyclopentenone CCCXXIV.

10. Dihydrocyclomicrophylline-A This base (CCXCV), obtained from cyclomicrophylline-A by catalytic hydrogenation, was also isolated from B. microphylla (209). 11. Cyclomicrophylline -B and Cyclomicrophylline- C These alkaloids were isolated from the same source (209). Both cyclomicrophylline-B (CCCXX) and cyclomicrophylline-C (CCCXXI) generate cyclomicrophylline-A on methylation with formic acid-formaldehyde ; their structures follow from the above mentioned Ruschig degradation, from the result of alkali catalyzed elimination of the 2 0 ~ amino function in the respective 16-ketones, and from the relationship to cyclomicrophylline-A further illustrated by the following transformations : cyclomicrophylline-A 0,O'-diacetate could be converted to cyclomicrophylline-B on treatment with cyanogen bromide followed by alkaline hydrolysis, and cyclomicrophylline-C could be methylated selectively to a monomethiodide which after conversion to the corresponding quaternary base and subsequent pyrolysis yielded cyclomicrophylline-A (209). I n independent work, cyclomicrophylline-B was isolated by Goutarel's group from B. balearica (15) and B. malayana (201) and named cyclobaleabuxine. The French authors established the substitution pattern in

8.

ALKALOIDS

OF APOCYNACEAE AND BUXACEAE

397

positions 3, 4, and 20 by mass spectrometric evidence, the presence of a hydroxyl group in position 16 from the Ruschig degradation resulting in the formation of an U,jl-unsaturated ketone, and the jl-configuration of the basic function in position 3 from its resistance toward Hofma,nn degradation. All these facts, together with the NMR- (useful correlations with cyciobuxine-D are in the original paper) and other spectroscopic data, led (25) to a formulation identical with that established by the Japanese authors.

12. Dihydrocyclomicrophylline-C Dihydrocyclomicrophylline-C (CCCXXXIX) (mp 265' ; [a]= + 52' in chloroform) (209), is identical with cyclorolfeibuxine-C (mp 256" [aID + 74" in chloroform), the principal alkaloid of Bums rolfei (205).

73. Dihydrocyclomicrophylline-F The structure CCCXXXVIII of this primary-tertiary minor alkaloid )f B. microphylla rests on the following transformations : selective bddition of one molecule of methyl iodide to the isopropylidene dihydro:yclomicrophylline-F and subsequent pyrolysis of the corresponding paternary base yielded dihydrocyclomicrophylline-C(209).

@y+Me)z: (Me)&

$

'"/'ORz

/

p(M

+ (MeW

$

-

C H z OR l

CHzOTs

RI C C C XI X ; H CCCXXXII; H C C C X X X I I I ; Ts C C C X X X I V ; Ts

cccxxxv

Rz H COPh H COPh

CHzOR CCCXXXVI ; R = H CC CX X X V II ; R = T s

v. GERN.~.

398

AND F. ~ O R M

@

R2/h’ @-(Me)z R1\ $ =

(Me)zN

CHz

CHzOH

Ri Rz

CCCXL

CCCXXXVIII ; H CCCXXXIX; H

ccxcv;

H Me M e Me

14. Cyclomicrophyllidine-A This amorphous alkaloid from B. microphyllu (209) is cyclomicrophylline-A 16-benzoate (CCCXXXII). I n accord with this structure it yields cyclomicrophylline-A and benzoic acid on alkaline hydrolysis ; cyclomicrophyllidine-A monotosylate (CCCXXXIV) is identical with the compound obtained from cyclomicrophylline-A by selective tosylation followed by benzoylation. The 16-position of the benzoxy group was demonstrated by oxidation of the free hydroxyl group in the monotosylate CCCXXXIII to a five-membered ketone which, in typical manner, readily eliminated dimethylamine on alumina to yield an a,P-unsaturated ketone. On benzoylation the dihydro derivative CCCXXXV yielded the base CCCXXXVII identical with dihydrocyclomicrophyllidine-A tosylate. Dihydrocyclomicrophyllidine,4 (CCCXXXVI) is a natural alkaloid isolated from B. microphyllu (209).

15. Cyclobuxoxuzine-C Cyclobuxoxazine-C (CCCXLII) is a minor alkaloid from B. microphylla very similar to dihydrocyclomicrophylline-A (CCXCV). Apart from a secondary amino group in cyclobuxoxazine-C and a tertiary amino group in dihydrocyclomicrophylline-A, the only significant difference revealed by the NRIR-spectrum involved the absence of protons of the hydroxymethylene group. Instead, a pair of quadruplets centered at 6.48 T (J=11cps) and 5 . 5 5 T ( J = l O cps) indicated the presence of a pair of methylene protons both located in proximity t o an oxygen atom, one of them being further deshielded by an adjacent nitrogen function; in accord with this assumption the position of the second signal proved sensitive to the addition of monochloracetic acid. The same effect was achieved by acetylation. The formula CCCXLII, suggested by the above properties, was confirmed by chemical behavior and, eventually, by synthesis, Thus, reduction of cyclobuxoxazine-C

8. ALKALOIDS O F APOCYNACEAE

AND BUXACEAE

399

with lithium aluminum hydride yielded dihydrocyclomicrophylline-C (CCCXXXIX); Eschweiler-Clarke methylation of cyclobuxoxazine-C yielded a n N-methyl derivative (CCCXLIII) (cyclobuxoxazine-A)which on reduction with lithium aluminum hydride furnished dihydrocyclomicrophylline-A. The synthesis of cyclobuxoxazine-C was accomplished starting from dihydrocyclomicrophylline-F (CCCXXXVIII).On treatment with three equivalents of formaldehyde in dioxane solution, this base yielded (via an intermediary azomethine) the methyl ether CCCXLI which, on filtration in methylene chloride solution through a column of alumina, cyclized to cyclobuxoxazine-C. A similar cyclization was also observed on attempted methylation of dihydrocyclomicrophylline-F with formaldehyde-formic acid which gave rise to cyclobuxoxazine-A (212).

CHzOH CCCXLI

CCCXLII R = H CCCXLIII; R = M e

16. Cyclobuxoxazine-A Cyclobuxoxazine-A :CCCXLIII) was isolated from the strong base fraction of B. rolfei. I t s structure follows from the mode of its formation on treatment of dihydrocyclomicrophylline-C with formic acid-formaldehyde mixture, and from spectrometric characteristics (205). 17. Cyclomethoxazine-B Cyclomethoxazine-B was obtained from B. rolfei. I n contrast with cyclobuxoxazine-C, the NMR-spectrum of this alkaloid displays a single AB-system corresponding to a C-CH20R grouping, but contains signals The formula characteristic of the grouping -N--CH(CH3)-OR.

CCCXLIV ; R = H CCCXLV; R = M e

CCCXLVI

400

v. ~ E R NAND P

F.

SORM

CCCXLIV derived from the spectrometric data was confirmed by preparation of the cyclomethoxazine-A (CCCXLV) from dihydrocyclomicrophylline-C (CCCXXXIX) on treatment with acetaldehyde in acetic acid solution ; the relevant NMR-data characterizing the heterocyclic system proved identical with those of cyclomethoxazine-B. A direct interrelation could not be achieved since attempted methylation of cyclomethoxazine-B resulted (205) in the production of CCCXLIII.

18. Cyclorolfoxazine The structure CCCXLVI of this minor alkaloid from B . rolfei was established on the basis of typical NMR-, IR-, and mass-spectrometric data (205). 19. Buxtauine (Cyclobuxoxine, Cyclomicrobuxinine) Buxtauine (mp 172"-178"; [a]D + 154" in chloroform), and cyclobuxoxazine (mp 181"-183"; [aID + 169" in chloroform), are synonyms for the same alkaloid (CCCXLIV) isolated independently by Tomko et al. (52,213)and by Kupchan and Abushanab (214)from the weak base portion of B . sempervirens. This base represents the first Buxus alkaloid recognized as containing an acetyl grouping as side chain; later investigation showed that the presence of a 20-keto group is common to all mononitrogen alkaloids occurring in this genus. It is noteworthy that Schlittler's alkaloid N (182)shows closely similar physical constants (mp 178"-179"; + 150" in chloroform). The elementary analysis of the alkaloid N (76.07% C, 10.10% H, 4.03% N by the Swiss authors presumed to indicate the formula CzzH35NOz) is in fair agreement with the figures for methanol-solvated cyclobuxoxine (75.92"/0C, 10.14% H, 3.61% N) (214).I n an independent work, Nakano la and Hasegawa (200)reported isolation from B. ~ ~ c r o p ~of~anl identical alkaloid which they named cyclomicrobuxinine (mp 178"-181" ; [a]= + 152" in chloroform). IR- and NMR-spectra of buxtauine, cyclobuxoxine, and cyclomicrobuxinine revealed the presence of an exomethylene, a hydroxyl, a cyclopropane methylene, a methyl keto, an N-methyl group, and two tertiary methyl groups (200,213,214).The presence in the mass spectrum of a peak a t m/e 44 indicated the N-methyl group to be situated in position 3. The double bond in the alkaloid was shown to add hydrogen readily (213, 214) ; in the hydrogenation product, designated dihydrocyclobuxoxine-b, the presence of a secondary C-methyl group was demonstrated. This group must therefore have arisen by the addition of hydrogen to the methylene double bond. The hydroxyl group

8. ALKALOIDS O F APOCYNACEAE

40 1

AND BUXACEAE

of the alkaloid is readily eliminated; formation of anhydro products was observed on attempted alkaline hydrolysis of its diacetyl derivative and on attempted oxidation (213) as well as Eschweiler-Clarke methylation of the alkaloid (200, 213). These anhydro products were recognized as a&-unsaturated ketones, which together with the observed facility of the reaction led to the conclusion that the hydroxyl and keto group occupy a P-position to each other. On biogenetic grounds, the keto group was assumed to be located a t position 20 and, consequently, the hydroxyl group was placed in position 16 (213). The correctness of these conclusions was confirmed by correlation with cyclobuxine-D by essentially identical methods reported independently from two laboratories (214, 215). The dihydroalkaloid CCCXLVII was degraded by the Ruschig method to the a,p-unsaturated ketone CCLXXXIV which on selective

CH2

R i Rz CCCXL1V;H H CCCXLV; Ac Ac CCCXLVI; hle H

CCCXLVIT

1 CCLXXXIV

.1 CCLXXXV

hydrogenation afforded a saturated ketone identical in properties (213, 215, 216) by direct comparison (214) with the known (191) ketone CCLXXXV. The remaining stereochemical features, on biogenetic analogy presumed to be 36, 16a, and 17p for the respective substituents, were confirmed by the weak positive Cotton effect exhibited by the ketone

402

v. E E R N . ~ A N D

F. ~ O R M

CCCXLVIII, by the negative shift of molecular optical rotation on acetylation of the 16-hydroxyl, and by the positive Cotton effect exhibited by the alkaloid (215, 217).

20. Cyclomicrobuxine Cyclomicrobuxine, C25H39N02 (CCCXLVI) (mp 178"-180" ;

[.ID

+ 172" in chloroform), was isolated from B. microphylla. It contains one nitrogen atom which is present as a dimethylamino group. The NMRspectrum showed, further, the presence of a cyclopropane and terminal methylene, two tertiary methyl groups, a methyl keto group, and a secondary hydroxyl. The positive Cotton effect demonstrated the isconfiguration of the side chain, whereas the negative change in optical rotation upon acetylation was taken as a proof of the a-configuration of the 16-hydroxyl. (The reported shift is too low, presumably owing to an erroneous value for ["ID of the acetate.) Dehydration of the alkaloid both under acetic and basic conditions led to the a,p-unsaturated ketone CCCL prepared from cyclobuxine-D by a synthesis involving selective methylation to cyclobuxine-B followed by Ruschig degradation of the secondary amino function in the side chain (200). Alkaloid buxpiine, C25H39N02 (mp 173"; [aID + 158'), is identical with cyclomicrobuxine as follows from preparation of buxpiine by Eschweiler-Clarke methylation of buxtauine oxime, although the melting points of the diacetates differ considerably. [Cyclomicrobuxine diacetate mp 232"-233'; [ a ] D + 146' (in chloroform), buxpiine diacetate mp 205'-207'; [.ID + 99" (in EtOH) and + 95" (in chloroform).]

21. Baleabuxine Baleabuxine (CCCLI) was isolated from B. balearica (15).The I R - and NMR-spectra of this alkaloid demonstrated the presence of a -CH2COgrouping in a 6-membered ring. The latter method proved the presence of one dimethylamino group, four tertiary, and three secondary Cmethyls. The presence of the cyclopropyl methylene is easily distinguishable only after hydride reduction of the keto group. On treatment with boron fluoride baleabuxine was converted to the a,p-unsaturated ketone CCCLII. This behavior is consistent with the presence of a cyclopropane ring adjacent to the keto group. Mass spectrometric evidence indicated the dimethylamino group to be situated in position 20 and proved the presence of an isobutyramide grouping (peaks at M 87 and a t m / e 88, 71, 43) (15).The structure CCCLI received confirmation by correlation with cycloprotobuxine-A (CCXCII) as indicated by the sequence CCXCII + CCCLVII (218).

8.

403

ALKALOIDS O F A P O C Y N A C E A E AND B U X A C E A E

CCCLl I CCCLIII

R Y R7

CCCLI

CCCLIV; H CCCLV; H CCCLVI; Me

C C C L X ; IOa-H C C C L X I ; lop-H

COCH(Me)z

H Me

CCCLVII

1. IfCl

2.

CCXCII

(1103

__j

CCCLVIII

CCCLIX

22. Bnleabuxidine Baleabuxidine. isolated from B. brileuricn. was formulated as CCCLIII on the basis of mass spectrometric, IR-. and KJIK-data. Acetylatioii to O,O'-diacaetyl cleris-ative is coiisisteiit with this formulation. However, no further chemical evidence is available (218). The above mentioned isomerization of CCCLI to CCCLII constitutes a route from the Ifp,ln-cyclosteroids to a iiem skeletal type which is characteristic of a small group of Buxzis alkaloids and will be dealt with in the subsequent text. Another reaction applied to an analogous structural type and leading to cleavage of the cyclopropane ring was reported by Kupclian and Xbushanab (219) who had subjected 9p, 19eyclo-5a-pregnane-3,l I ,~0-trioiie-3,%0-tliethyleiie ketal to Wolff-Kishner reduction and obtained a mixture of 10-epimeric ketals CCCLX and CCCLXI.

23. Buxamine-G (Buxenine-G) This alkaloid (CCCLXIII) was isolated from the strong base fraction from B. sempervirens by Stauffacher (188)and named norbuxamine (it should be renamed buxamine-G) and, independently, by Kupehan and Xsbun (220) who proposed the name buxenine-G. The alkaloid is amorphous but gives a well-crystallizing isopropylidene derivative (mp 193"; [.ID +30° in chloroform) (188). Having applied a variety of physical methods both the Swiss and the American authors arrived a t essentially identical conclusions. The NMR-spectra of both the free base and its isopropylidene derivative revealed the absence of a cyclopropane ring, the presence of two vinylic protons (singlet a t 4.17 7 and a multiplet at 4.5.5 T ) , one A7 methyl group, one secondary, and four tertiary Cmethyl groups. The UV-spectrum proved the presence of a heteroannular conjugated dielie system which result, when considered in conjunction with the NMR-evidence, led to the part structure -CH2-CH=CCH-. In accord with this assignment, the alkaloid yielded a tetrahydro derivative on catalytic hydrogenation over Adams catalyst in acetic acid solution. The American authors selectively degraded the primary amino group by Ruschig method, using one equivalent of ~r-chlorosuccinimide, and obtained the methyl ketone CZ5H39KO.This demonstrated the priniary amino group to be in position 20. The a-configuration for this group was deduced from a positive circular dichroism maximum of buxenine-G salicylidene derivative (220, 221). The above physical a i d chemical data together with biogenetic coilsiderations led to the proposition of alternative formulas (188, 220) CCCLXII or CCCLXIII (220) for the structure of buxamine-G.

8. ALKALOIDS O F APOCYNACEAE

CCCLXII

A N D BUXACEAE

405

CCCLXIII

The problem was recently decided in favor of structure CCCLXIII by X-ray analysis of buxenine-G dihydroiodide ( 2 2 1 ~ The ) . same conclusion was drawn from the conversion of buxaminol-E t o buxpsiine on Ruschig deamination (68).

24. Buxamine-E Buxamine-E (CCCLXV) was isolated by Stauffacher from B. sempervirens (188). This alkaloid could be obtained only in amorphous condition but its isopropylidene derivative is a well-crystallizing compound (mp 187"; [.ID + 48" in chloroform). Buxamine-E and buxamine-G were interrelated by reduction of the respective isopropylidene derivatives with sodium borohydride to the corresponding isopropylamines which upon methylation with formic acid-formaldehyde yielded the identical product CCCLXIV; the primary amino group hence occupies the same position in both alkaloids.

CCCLXIV

CCCLXV; R = H CCCLXVI; R = O H

25. Buxuminol-E This alkaloid (CCCLXVI), obtained along with buxamine-E and buxamine-G from B . sempervirens (188)was related to buxamine-E in the following manner. Buxaminol on catalytic hydrogenation afforded tetrahydrobuxaminol which by short treatment with acetic anhydride was converted to N-acetyltetrahydrobuxaminol. This substance was oxidized to a ketone which was subjected t o Wolff-Kishner reduction to give a product which proved to be identical with N-acetyltetrahydrobuxamine-E. Buxaminol is hence hydroxybuxamine-E. The 16-position of the hydroxyl group follows from the fact that oxidation of tetrahydrobuxamiiiol with chromic acid yielded a 5-membered ring ketone which

readily elimina,ted the primary amino group to give an ccJ-unsaturated ketone (188).By analogy with other alkaloids the cc-configurationof the hydroxyl group is very probable.

26. Buxpsiine Buxpsiine, isolated from B. sempervirens, is an +unsaturated ketone the NMR-spectrum of which disclosed the presence of three olefinic protons. h positive multiple Cotton effect is in conformity with the presence of a A16-20-keto moiety. These data together with the UVevidence are consistent with the structure CCCLXVII which was confirmed by the occurrence of an intense peak at mje 84 in the mass spectrum.

CCCLXVII

CCCLXVIII

CCCLXIX

CCCLXX

Since the formation of the ion of mje 84 involves cleavage of the C-1 to C-10 linkage, the alternative structure CCCLXX is thus excluded. This conclusion is also supported by the fact that the peak a t m/e 71 became a base peak of the spectrum as is easily understood on the basis of the structure CCCLXVII. Similarly, the formation of the ion of m/e 267, stabilized by three conjugated double bonds, was interpreted as shown above (CCCLXIX) and constitutes another support for formula CCCLXVII (222). C. Xarcococca ALKALOIDS

1. Alkaloid A and Alkaloid B Alkaloid 4, C ~ ~ H ~ ~(mp N Z 2-15"-246") O and alkaloid B. C26H44N20 ( 2 ) (mp 232"-233"), were both isolated from Sarcococcapruniforrnis (223).

TABLE V

ALKALOIDS FROM Pachysandra

Compound

Molecular formula

AND

Sarcococcu

Melting point ("C)

Source" Reference __

~

Alkaloid A Alkaloid D Alkaloid E ( = kurchessine)b Saracodinine (3P,20a-bisdimethylaminopregn-5-ene) Base XI Epipachysamine-A Deacyl derivative Epipachysamine-B Epipachysamine-C ( = dictyodiamine)b Epipachysamine-D Epipachysamine-E Epipachysamine-F S-Acetyl derivative Pachysamine-A N-Acetyl dcrivative AT-Methylderivative (3a,20a-bisdimethylamino5u-pregnane) Pachysamine-B Dihydro derivative Pachysandrinc-A 0-Deacyl derivative N,O-Deacyl derivative Pachysandrine-B 0-Deacetyl derivativc

245-246 109-110 135-138 201-202 203-205 96-98 260-262

b

a

- 37(CHC13) - GO(CHC13)

- 17(CHC13)

+ BO(CHC13) + lS(CHC13)

223 69

a

69 228 228 228 41

a a

226 226

a a

226 225 225

a a a -

0 9 0

0 K!

245-248 2 10-2 12 250-253 167-168 150-152 165.5-167 171-1 73 138-139 235-236 195 226-227 187-189 184-1 85

+ 13(CHC13) + BO(CHC13) + G(CHC13) + 20(CHC13)

kM

5.

M

-

+ lG(CHC13) + 67(CHC13) + 54(CHC13) + 80(CHC13) + Sl(CHC13) +28(CHC13) + 93.4(CHC13) + 127(CHC13)

z

-

a

a -

a

-

225 225 225 229 229 229 229 229

TABLE V-continued

ip ~~

~~~~

Compound

Molecular formula

Melting point ("C)

[nID

~

0

__

-

0

3

Sourcen Reference

~

2 12-2 14 184-185 181-182 260-263 25s-261 225-260( ? ) 220-224 256-258 235-236 190-192 136 243-244 202-204

Pachysandrine-C Pachysandrine-D Dihydro derivative Pachysantermine-A N-Methyl derivative Dihydro derivative Pachystermine-A Pachystermine-B Saracocine Saracodine ( = epipachysamine A?) Saracodinine ( = kurchessine,b alkaloid E) Terminaline 0,O'-Diacetyl derivative

-

+ z(CHC13) - 8(CHC13)

a

a

+ 43(CHC13) + 30(MeOH)

-

+24(CHC13) - lB(CHC13)

a a

a -

-

b

-

b b

-

+-+ 29(CHC13-MeOH 1 :1 ) 40(CHC13)

a -

228 228 228 232 232 232 231 231 70 70 70 41 41

Alkaloids of unknown structure Alkaloid B Base IV Base V Base VI Base XV Base X V I Base X I X

a

CZ~H~~NZO(?) C23H41;?J02

232-233 2 10-21 5 2 18-221 290-295 260-263 252-276 243-244

Key to letters: a. Pachysandra terminalis Sieb. et Zucc.; b. Sarcococca pruniformis Lindl. See Table I.

b a

a a a a a

223 228 228 228 228 228 228

4 0

M

LZ

2

6

*z

U

r

8. ALKALOIDS OF APOCYNACEAE

AND BUXSCEAE

409

Structure CCCLXXI was tentatively proposed for the alkaloid A on the ground of the molecular weight determination (mol. wt. 402; mass spectrometry) and a degradation study which is not clearly described.

CCCLXXI

CCCLXXII

Alkaloid B is claimed to be 5,6-dehydroalkaloid A but the molecular weight 398 given in the original paper (223)is not consistent with this formula.

2. Saracodine Saracodine, Cz6H&zO (mp 190"-1 92'), isolated from 19.pruniformis, contains a dimethylamino and an acetylmethylamino group. On acid hydrolysis and methylation it yielded dimethylchonemorphine. Mass spectrometry proved the location of the dimethylamino group in position 3 (peaks a t m/e 84 and 110) and of the acetylmethylamino group in position 20 (peaks a t m/e 58 and 100). Saracodine should thus be identical with epipachysamine-A ( 7 0 ) .

3. Saracocine This alkaloid (CCCLXXII) was found in 8. pruniformis. The I R spectrum disclosed the presence of a n amide carbonyl. I n agreement with this finding, the alkaloid liberated acetic acid on acid hydrolysis. The Hofmann degradation gave an unsaturated compound showing characteristic absorption of steroidal 3,5-dienes in the UV-region. The NMRspectrum proved the presence of one secondary and two tertiary Cmethyl groups and confirmed the presence of one dimethylamino and one acetylmethylamino group. On the basis of these data, the alkaloid was assigned the structure 3/i-dimethylamino-20/i-acetylmethylaminopregn-5-ene (224).Later investigation (70)rendered the 20fi-configuration untenable since catalytic hydrogenation converted saracocine to saracodine. The position of the double bond was inferred from the mass spectrum in which the peak a t m/e 110 was missing. 4. Saracodinine Saracodinine was isolated ( 7 0 )from the same plant and proved to be identical with 3/?,20a-bisdimethylaminopregn-5-ene (kurchessine).

410

v. EERNL A N D

F. ~ O R M

D. Pachysandra ALKALOIDS* 1. Alkaloid E Alkaloid E contains, according to NMR-spectrum, one secondarytertiary double bond, two dimethylamino groups, two tertiary, and one secondary C-methyl group. The bisdimethylaminopregnene structure is thus indicated and comparison (69) with the authentic sample proved the identity with 3fi,20a-bisdimethylaminopregn-5-ene (kurchessine) (64). 2. Alkaloid D Alkaloid D was found to be identical with 3/3,20a-bisdimethylamino5a-pregnane (69). Two additional closely related alkaloids, named A and B, could not be separated from each other but the NMR- and chromatographic analysis of the acetylated and/or methylated mixture suggested that they are 80-N-demethyl alkaloids D and E, respectively (69).

C C C L X X I I I ; R =H CCCLXXIV; R = COCH=C(Me)z

5Rz CCCLXXV ; CCCLXXVI ; CCCLXXVII; CCCLXXVIII; CCCLXXIX; CCCLXXX; CCCLXXXI ; XXXVII;

R3

H Me Me Me Me COPh H COCH=C( Me)z Me Me H COC5H4N Me Me Me Me Me Me H H 1RIe

Me Me H

* From Pachysuitdra terminalis Sieb. et ZUCC.

R4

H Et Me Me Me AC H Me

8. ALKALOIDS O F APOCYNACEAE

AND BUXACEAE

411

3. Pachysamine-A The presence of one methylamino and one dimethylamino group in this alkaloid (CCCLXXIII)is disclosed by its NMR-spectrum which also reveals two tertiary C-methyl groups. On methylation, pachysamine-A ; Ruschig degradation furnishes 3a,20a-bisdimethylamino-5a-pregnane to ZOa-dirnethylamino-5a-pregnan-3-one(funtumafrine-C, XXXI) proves the location of the secondary amine function in position 3 (225). 4 . Pachysamine-B The structure (CCCLXXIV) of this alkaloid was largely derived from spectral data indicating the identity of the amide moiety in this base with that of pachysandrine-B. The confirmation of this assignment was provided by the synthesis of pachysamine-B from pachysamine-A and ,8,,8-dimethylacrylyl chloride (225). 5. Epipachysanzine-F This alkaloid (CCCLXXV) was isolated in the form of its N-acetyl derivative from the strongly basic alkaloid fraction. In the mass spectrum of this derivative the presence of important peaks a t m/e 84 and 110 indicated 3-dimethylaminopregnane skeleton with saturated A and B rings : the peaks a t 345 (M-CH3CO)and a t mje 302 (M-CH3CHNHCOCH3) suggested the presence of a 20-acetylamino group. Confirmation of these results and the necessary stereochemical proof were obtained by reducing N-acetylpachysamine-F with lithium aluminum hydride followed by Eschweiler-Clarke methylation to give the base CCCLXXVI identical with that obtained from epipachysamine-A by the same hydride reduction (226).

6 . Epipachysamine-D This alkaloid (CCCLXXVII) furnished chonemorphine (XXXV) on acid hydrolysis. Conversely, chonemorphine regenerated epipachysamine-D on benzoylation (226).

7 . Epipachysamine-E The structure CCCLXXVIII of this alkaloid was established analogously by hydrolysis to chonemorphine and by its synthesis from chonemorphine and P,P-dimethylacrylyl chloride (226).

8. Epipachysamine-B This base, furnishing chonemorphine on hydrolysis, contains a dimethylamino and a secondary amide group. The structure CCCLXXIX,

indicated by KlLK-data, was confirmed ( 4 1 ) by a synthesis from choiiemorphiiie and ilicotiiiic acid using the mixed anhydride method

(227). 9. Epipchysrrm ine-A The amide group in this alkaloid (CCCLXXX) is resistant to hydrolysis. However, deacetylatiori could be achieved by treatment with phenyllithium. The deacyl dcrivative thus formed regenerated epil'acliysamiiie--I on acetylatiori. -illthough the constants of the deacyl (*ompound CCCLXXXI were fouiid to be close to those of 3~-dimetliylamino-~(~cc-metl?ylamino-~~-pregriaiie, no direct comparison was reported in the original paper (228). The same is true of the I\'-methyldeacetyl epipachysamine-,I obtained from CCCLXXXI by Eschu eiler-Clarke methylation. However. its identity with 3/3,20abisciimethylamino-5wpregnane was mentioned later in Reference 1 2 ( 7 0 ) . Epipachysamine-,2 is probahly identical with saracodine.

10. Epipnchysamine - C The diacetylderivative of this alkaloid, C27H46N202 (mp 242";

[.In

- 16" in chloroform), was isolated from the acetylated products of the

strongly basic alkaloid fraction. The free base (XXXVII) is identical with dictyodiamine (35a, 41).

11. Pachysnnclrine-A The structure of this alkaloid was found to represent an interesting example of the cr-aminoalcohol type (229). The NMR- and IR-spectra disclosed the presence of an acetoxyl in the grouping -CH-CHOCOCH3-CH-, a conjugated amide carbonyl, a phenyl group, a methylamide, a dimethylamino group, one secondary, and two tertiary C-methyls. Mild alkaline hydrolysis afforded an 0 deacyl derivative which on acetylation regenerated the parent alkaloid. Using more vigorous conditions, benzoic acid and the 0,N deacyl derivative CCCLXXXIV could be obtained, which on oxidation yielded a ketone CCCXC with a negative Cotton effect, similar to that of 5a-cholestan-4one. Huaiig-blinlon reduction of this ketone led to 20a-dimethylamino5cc-pregnanc whose structure was confirmed by synthesis. On treatment with ethanolic potassium hydroxide the ketone CCCXC readily underwent oxidative cleavage to yield the diosphenol CCCXCII identical with the substance obtained by air oxidation cjf 20a-dimethylamino5/3-],regiiaii-3-oiie. Evidence for 3a,4/3-configuration was provided as follows : treatment of 0-deacylpachysandrine-A (CCCLXXXIII)

I{ ith phosphorus oxychloride in pyridine solution. follo.vr-ed by alkaline hydrolysis resulted in a new hydroxy derivative ; its structure C'CCLXX X'I-I1 \\as unambiguously proved by oxidation to the ketone C'CCXC. The acyl migration under the influence of phosphorus oxychloride was thus accompanied by inversion of the configuration at (3-4. Such type of aryl migration has been intcrlreted as proceeding via an oxazoline intermediate (230) the formation of Tvhich involves nucleophilic backside attayk a t C--$ by the S-acyl group and. ronseyuently, can only occur in a 1 ,?-diaxial arninocycloalkanol system. This assumption 1% as further supported by NJIR-evidence, by the presence of an intramolecular hydrogen bond in the epimeric compound CCCLXXX'I71, and by formation of an oxazolidine derivative from it on Eschu-eilerClarke methylstion. Pachysandrine-A is thus CCCLXXXI.

ORz R, CCCLXXXI ; CCCLXXXII ; CCCLXXXIII; CCCLXXXIV; CCCLXXXV;

COPh COCH=C(Mc)2 COPh

H COCH=C(Me)2

R B

A4c

AG H H H

CCCLXXXVI. CccLxxxvII; CCCLXXXVIII: CCCLXXXIX;

COPh H H COCH=C(hle)z H H COCH=C'( Me)z H

0 CCCS('; CCCXCI;

R=H K=Me

12. Pachysaizdrine-B The structure (CCCLXXXII) of this alkaloid, indicated by spectral properties and formation of acetone and formaldehyde on ozoiiolj s'is,n-as confirmed by the synthesis of 0-deacylpachysandrine-B (CCCLXXXV) by treatment of O.S-deauylpacliysandrine-A (CCCLXXXI\') n.ith p.pdimethylacrylylchloride in pyridiiie followed by mild allialitie hydrolysis (229).Pachpsandrine-B shows behavior analogous to that of pachysandrine-A. T

114

C'CCSC'III

CCCXCII

OH

cccxcv 13. Pachysandrine-C This alkaloid is identical with 3a-methylamino-20a-dimethylamino5a-pregnaii-4x-ol (CCCLXXXVII) obtained from pachysandrine-A

(228). 14. Base X I This compound is identical with the oxazolidine derivative of pachysandrine-C (228).

15. Pachysanclrine-D The structure (CCCLXXXIX) of this alkaloid as indicated by the spectral data u7as confirmed by its conversion to pachysandrine-C on mild alkaline hydrolysis. Further proof is the identity of dihydropachysandrine-D with the acyl migration product of 0-deacyidihydropachysandrine-B (228).

16. Terminaline This alkaloid (CCCXCIII) contains two hydroxyl groups capable of acetylation and a dimethylamino group for which the 20-position was indicated by the occurrence of the peak at m/e 7 2 in the mass spectrum. On oxidation with periodic acid terminaline yields a dialdehyde. By analogy with the alkaloids of the pachysandrine type the a-glycol moiety WAS located in position 3.4. This assumption proved to be correct since terminaline o n oxidation with periodic acid followed by sodium boro-

8. ALKALOIDS O F AP O CYNACEAE A N D BUXACEAE

415

hydride reduction and acetylation was converted to the same diacetate CCCXCIV which was prepared from the diosphenol CCCXCII by sodium borohydride reduction to CCCXCV and oxidation by periodic acid followed by the same steps as above. Configuration of terminaline is based on its unreactivity towards acetone and on the fact that the signal of C-19 methyl is found in the standard region which rules out proximity of this angular methyl and an axial hydroxyl group ( 4 1 ) .

17, Pachystermine-A and -B Pachystermine-A is one of the major alkaloids of P. terminalis. It was isolated from the weak base fraction along with pachystermine-B. The alkaloids are mutually interconvertible : pachystermine-A gives pachystermine-B on sodium borohydride reduction and, in turn, pachystermine-B can be oxidized with chromic acid to pachystermine-A. Pachystermine-A (CCCXCVI) exhibits two carbonyl bands at 1735 and 1715 cm-1 in the IR-spectrum and its ORD-curve shows negative Cotton effect comparable to that of 5a-cholestan-4-one. The NMRspectrum revealed the presence of a dimethylamino group, a n isopropyl group, one secondary, aiid two tertiary C-methyl groups. PachystermineB (CCCXCVII) exhibits only a plain, negative ORD-curve. Treatment of pachystermine-A with ethanolic potassium hydroxide resulted in the formation of the diosphenol CCCXCII ; Huang-Minlon reduction of pachystermine-A yielded 20a-dimethylamino-5wpregnaneand 5apregnan-4-one. Alkali degradation of pachystermine-B under the conditions of Huang-Minlon reduction furnished an amino alcohol (CCCXCVIII)which on methylation and oxidation gave rise to the amino ketone CCCXCIX obtained from the previously prepared epimeric ketone CCCXCI (229) by alkali or acid treatment. This proved the substitution in positions 3 and 4. Xtereochemistry of the hydroxyl group in the amino alcohol CCCXCVIII follows from displacement of the NMR-signal of the 19-methyl group towards lower field. On aluminum hydride reduction both pachystermine-A and -B gave an amino alcohol which was assigned the structure CCCC on the basis of the mass spectrometric behavior of its derivatives. Alkaline hydrolysis of pachystermineB resulted in the formation of two diastereomeric acids containing the same number of carbon atoms as the starting compound. All these results are consistent with the p-lactam structures CCCXCVI and CCCXCVII which received confirmation by conversion of the amino alcohol CCCC to CCCCIII and unambiguous synthesis of the latter from CCCXCVIII. The monotosykite of the methylated diol CCCCI was subjected to reduction with lithium aluminum hydride t o give the base CCCCIII. Reaction of the amino alcohol CCCXCVIII with methyl

416

v. ERN+ A N D F. SORM

8.

ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

417

isopropyl acetaldehyde (obtained by ozonolysis from ergostenone) resulted in a Schiff base which was successively reduced with sodium borohydride and methylated with formic acid-formaldehyde to furnish an amino alcohol identical with CCCCIII (231).

18. Pachysantermine-A This base is a minor alkaloid from P. terminalis. The presence of a conjugated lactone group was indicated by a band a t 1710 cm-1 in the IR-spectrum and confirmed by the course of reduction with lithium aluminum hydride which afforded a diol. The positive plain curve demonstrated that the carbonyl group is not a part of the skeletal ring system. The NMR-spectrum revealed the presence of two allylic hydrogens and two allylic methyl groups. The structure CCCCIV was confirmed by converting the N-methylpachysantermine-8 (CCCCV)to the methylester CCCCVI which on reduction with lithium aluminum hydride yielded the diol CCCCII prepared previously from pachystermine-B (232). IV. Biogenetic Notes Evidence has been accumulated that the biogenesis of plant steroids proceeds by the same scheme as in animals; this sequence was proved up to squalene and recently squalene has been shown t o be a precursor of @-sitosterol;evidence was also adduced that this conversion includes lanosterol as an intermediate (233).Goutarel assumes that the sequence squalene, lanosterol, zymosterol, and desmosterol may be implied also in the biogenetic pathway of Apocynaceae alkaloids (205).It may be assumed that biogenetic intermediates from sterol or triterpene precursors of Apocynaceae or Buxaceae allraloids, respectively, are 3and/or 20-ketones which may give rise to mono- and diamines. Consistent with this assumption is the existence of mono bases containing an oxygen function in one of the above-mentioned positions. Among Buxus alkaloids there were found several such bases containing a keto group in position 20. Moreover, in several cases nitrogen-free substances were found to accompany the alkaloids in plants and constitute their oxygenated analogs. Thus, Potier et al. (234) isolated compounds CCCCVII-CCCCIX from Paravallaris microphylla. Tschesche et al. (235, 236) found holadyson CCCCX in the bark of H . antidysenterica. Leboeuf et al. (56)isolated progesterone from the leaves of H . africana (fioribunda),where it occurs along with the steroidal monoamines holaphylamine (LVI),holaphylline (LV),and holamiiie (LXIII). The French authors presumed progesterone to be the precursor of the former two

v.

418

&RN+

AND F.

SORM

alkaloids. This interesting finding prompted a more detailed study of these problems by means of feeding experiments. It was demonstrated (237) that after administration of cholesterol-4-14C to the leaves of H . africana (Jloribunda)radioactivity was found in holaphylline and holaphyllamine. On the other hand, experiments conducted with labeled progesterone showed that this steroid was not a precursor of the above mentioned alkaloids ; pregnenolone-4-14C was converted to holaphyllamine and holaphylline by the leaves of H . africana (Jloribunda) (238) but no radioactive pregnenolone could be detected after administration of cholesterol-4-14Cto the leaves (237).The above results do not permit any conclusion as to the nature of the C-21 precursor(s); nor do they necessarily imply that cholesterol is the true precursor of the alkaloids. The conversion of cholesterol to holaphyllamine and holaphylline may be also explained by the assumption that it undergoes degradation analogous to that of the true precursor which may differ from cholesterol only in the structure of the side chain. The biosynthetic pathway will then proceed via the C-21 precursor (possibly pregn-5-en-3,20-dione) which according to Janot et al. (78) will be followed by the sequence CCCCXI-CCCCXV. This appears to be a very plausible explanation involving a series of obvious conversions, the first step being the only point which cannot be easily interpreted. Goutarel considers functionalization of C- 18 by a biosynthetic mechanism invoIving activation of the amino group analogous to reported radical cyclizations (81, 139, 140). An alternative hypothesis postulates amination at C-20 to be preceded by introduction of the oxygen function into position 18. This consideration is supported by the occurrence of holadysone and holonamine in the same plant. Tschesche (89) assumes oxidation of the

CCCCIX

CCCCVII; R = H CCCCVIII ; R = O H

OH &

y

N

CCCCXI

(

CCCCXII

CCCCX

fyN(fJ5 I

CCCC'XIII

CCCCXIV

CCCCXV

8.

ALKALOIDS O F APOCYNACEAE A N D BUXACEAE

419

angular methyl group to an aldehyde function since hydroxylation a t this carbon atom would lead to 18-hydroxy-20-ketone known to exist in the cyclic hemiketal form (159, 160) which is unlikely to undergo amination a t C-20. Consideration was also given to other possibilities, e.g., the order D + B (74a)or B + E (89) in the above sequence. To date, no direct evidence is available to warrant a decision between the above hypotheses. As an alternative amination reaction an enzymatic mechanism was considered (78, 96) comparable to that responsible for the formation of 2 1-N-acylaminocortisol derivatives on incubation with Streptomyces roseochromogenus (239). However, it may be noted that considerable structural differences between the compared types cannot be disregarded. One structural feature which illustrates the stereospecific character of the amination a t C-20 should be mentioned here. In all known alkaloids of both the Apocynaceae and Buxaceae families bearing an amino group in position 20 this function possesses a-configuration. No attempt as yet has been made to study the biogenesis of Buxus alkaloids. Indirect evidence gave rise to the presumption that in the biogenetic scheme lanosterol is followed by cycloartenol (or similar triterpene type). Goutarel(205) tentatively proposed a possible pathway via lanosterol, cycloartenol, 9/3,19-cycl0-4,4',14a-trimethyl-5a-pregnan3p-01-20-one, 9/3,19- cyclo -4,4',14c(trimethyl - 5wpregnan - 3,20-dione, mono-, and diaminosteroids. It is pertinent to note that the two groups are mutually related by common types. In the one case kurcholessine, which contains a methyl group in position 4, was isolated from H . antidysenterica; in the other, Votick9 and Tomko demonstrated the presence of the simple pregnane derivative irehine in B. sempervirens (51). The occurrence of such anomalous types may indicate the operation of aberrant biogenetic pathways in some species. No investigation dealing with the biogenesis of Pachysandra or Sarcococca alkaloids has been reported, However, their close similarity to Holarrhena alkaloids permits the assumption of analogous biosynthetic pathways. It may be noted that important questions concerning the biogenesis of steroidal Apocynaceae and Buxaceae bases remain still open. REFERENCES 1. 0. Jcger and V. Prelog, Alkaloids 7, 319 (1960). 2. R . D. Haworth and M. Michael, J . Chem. Soc. p. 4973 (1957). 3. F. Khuong-Huu-Lain&,N. G. Bissct, and R.Goutarel, Ann. Pharm. Frunc. 23, 396 (1966).

420

v. ~ E R X +A N D F . SORM

R. Goutarel, Bull. Soc. C‘liim. France p. 569 (1960). R. Goutarel, Tctruhedron 14, 126 (1961). It. F. Raffauf arid 11.B. Flaglcr, E J c o ) ~ . Bolrrxy 14, 37 (1960). R. Gout.arc1,BuU. Soc. Chim. Frcrnce p. 1665 (1964). R . Tschesche, Bull. Soc. C‘him. Frcrtice p. 1219 (1965). R. Goutarel, “Les Alcaloides stkroidiques dcs Apocynac&cs.” Hermann, Paris, 1964. L. Doleji, V. H a n d , V. Cernj., and F. Sorm, Collvctiori Czech. C h e m . Commun. 28, 1584 (1963). 11. W. Vetter, P. Longevialle, F. Khuong-Huu-Laine,Q. Khuong-Huu, arid K . Goutarel, Bull. Soc. Chim. France p. 1324 (1963). 12. H. Budzikiewicz, C. Djerassi, arid D. H. Williams, “Interpretation of Nass Spectra of Organic Compounds,” p. 74. Holden-Day, San Francisco, California, 1964. 13. H. Budzikiewicz, T e t m h e d r o u 20, 2267 (1964). 14. Z. Pelah, Sf. Kielczcwski, J . M. Wilson, M. Ohashi, H. Budzikiewicz, and C. Djerassi, J. Am. Chrm. Soc. 85, 2470 (1963). 15. D. Herlem-Gaulier, F. Khuong-Huu-Lain&,E Stanislas, and K. Goutarcl, Bull. S O C . Ghim. Franc(: p. 657 (1965). 16. L. Doleji, V. HanuR, Z. Votickj., and J. Toinko, Collection Czech. Chem. Conbnzun. 30, 2869 (1965). 17. M.-M. Janot, Q. Khuong-Huu, and R. Goutarel, Compt. R e n d . 250, 2445 (1960). 18. M-RI. Janot, F. Lain& Q. Khuong-Huu, and R. Goutarel, Bull. Soc. Cltirn. F r a n c e p. 111 (1962). 19. H. Ruschig, N. Fritsch, J . Schmidt-Thoind, and W. Haede, Chem. Ber. 88,883 (1955). 20. V. Cerny, L. LBbler, and F. Sorm, GollectioiL Czech. Chem. Cornmutb. 22, 76 (1957); Chem. Listy 50, 1126 (1956). 21. P. Buchschacher, J. Kalvoda, D. Arigoni, and 0. Jeger, J . Am. Chem. Soc. 80, 2905 (1958). 22. M.-M. Janot, Q. Khuong-Huu, and R.Goutarel, Compt. Rend. 246, 3076 (1958). 23. H. Favre, R. D. Haworth, J. WcKenna, R . G. Powell, and G. H. Whitfield, J . Chem. Soc. p. 11 15 (1953). 24. M.-M. Janot, Q. Khuong-Huu, and R.. Goutarcl, Bulb. Soc. L‘iiim. Frame p. 1640 (1960). 25. M.-M. Janot, Q. Khuong-Huu, X. Lusinchi, and R. Goutarel, C‘ompt. Ketid. 248, 982 (1959). 26. M.-M. Janot, Q. Khuong-Huu, X. Lusinchi, and K . Goutarel, Bull. Soc. C ’ h i m . France p. 1669 (1960). 27. G. Greenspan, R. Kees, L. L. Smith, arid H. E. Alburn,J. O r g . Chem. 30,4215 (1965). 28. A. Quevauviller and 0. Blanpin, Therap., Semcritze Hop. 36, 899 (1960); Chein. Abstr. 55, 8637 (1961). 29. A. Quevauviller and 0. Blanpin, Compt. Rciid. Soc. Biol. 153, 1728 (1959); Chem. Abstr. 54, 13412 (1960). 30. 0. Blanpin and A. Quevauviller, Therap., Semuirte H o p . 36, 909 (1960); Chem. Abstr. 55, 8638 (1961). 31. 0. Blanpin, Compt. Rend.S‘oc. BioZ. 154, 1860 (1960); Chena. Abstr. 55, 23806 (1961). 32. 0. Blanpin, Compt. Retid.Soc. B i d . 154, 1587 (1960); Chem. Abstr. 55, 11641 (1961). 33. K . G. Das and P. P. Pillay, J . Sci. I d . Res. ( I n d i r i ) 13B, 602 (1954). 34. K. G. Das and P. P. Pillay, J . Sci. Itid. Kes. ( I n d i n ) 13B, 701 (1954). 35. A. Chatterjee and B. Das, Chena. & I u d . ( L o n d o n ) p. 1445 (1959). 3%. Q. Khuong-Huu, 5 . Monseur, RI. Truong-Ho, Et. Kocjan, and R. Goutarel, Bull. Soc. Chim. Frtcnce p. 3035 (1965). 4. 5. 6. 7. 8. 9. 10.

8.

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42 1

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422

v. &ERN$

AND F.

SORM

73. A. Kasal, A. PolbkovB, A. V. Kamernitzky, L. LBhler, and V. Cernj., Collectioii Czech. Chem. Commun. 28, 1189 (1963). 74. L. LBhler and F. Sorm, Collection Czech. Chem. C o m m u n . 25, 265 (1960). 74a. M.-M. Janot, F. X. Jarreau, M. Truong-Ho, Q. Khuong-Huu, and R. Goutarel, B u l l . Soc. Chim. France p. 1555 (1964). 75. F. X. Jarreau, Ph.D. Thesis, University of Paris (1965). . 76. F. X. Jarreau, Q. Khuong-Huu, and R . Goutarel, Bull. Soc. C h i m . France p. 1861 (1963). 77. V. Gem$, L. DolejR, and F . Sorm, Collection Czech. Chem. C o m m u n . 29, 1591 (1964). 78. M.-M. Janot, M. Truong-Ho, Q. Khuong-Huu, and R. Goutarel, Bull. Soc. Chim. France p. 1977 (1963). 79. Q. Khuong-Huu, M. Truong-Ho, L. Lbhler, R. Goutarel, and F. Sorm, Collection Czech. Chem. Commun. 30, 1016 (1965). 80. Q. Khuong-Huu, L. LBhler, M. Truong-Ho, and R . Goutarel, Bull. SOC.C h i m . France p. 1564 (1964). 81. R . D. Haworth, J. McKenna, and G. H. Whitfield, J . Chem. Soe. p. 1102 (1953). 82. Q. Khuong-Huu, J. Yassi, C. Monneret, and Ic. Goutarel, B u l l . Soc. Chim. France p. 1831 (1965). 83. Q . Khuong-Huu, C. Monneret, J. Yassi, and R. Goutarel, Bull. Soc. Chim. France p. 2169 (1964). 84. M.-M. Janot, Q. Khuong-Huu, J. Yassi, and R . Goutarel, Bull. Soc. Chim. France p. 787 (1964). 85. M.-M. Janot, P. Devissaguet, Q . Khuong-Huu, and R . Goutarel, Compt. Rend. 260,6631 (1965). 86. E. L. Patterson, W. W. Andres, and R. E. Hartman, Ezperientia 20, 256 (1964). 87. S. M. Kupchan, C. J. Sih, S. Kuhota, and A. M. Rahim, Tetrahedron Letters p. 1767 (1963). 88. R. Tschesche and H. Ockenfels, Chem. Ber. 97, 2316 (1964). 89. R . Tschesche and H. Ockenfels, Chem. Ber. 97, 2326 (1964). 90. R . Tschesche, W. Meise, and G. Snatzke, Tetrahedron Letters p. 1659 (1964). 91. M.-M. Janot, Q. Khuong-Huu, and R. Goutarel, Compt. Rend. 254, 1326 (1962). 92. R . Pappo, U.S. Patent 2,913,455 (1959); Chem. Abstr. 54, 3527 (1960). 93. Q. Khuong-Huu, J. Yassi, and R . Goutarel, Bull. Soc. Chim. France p. 2486 (1963). 94. W. S. Johnson, V. J. Bauer, and R. W. Franck, Tetrahedron Letters p. 72 (1961). 95. F. %ti, V. (?ern$, L. DolejR, and F. Sorrn, Tetrahedron Letters (1967) (in press). 96. M.-M. Janot, F. Khuong-Huu-Lain&,and R . Goutarel, B u l l . Soc. Chim. France p. 641 (1963). 97. J . Hora and V. Cernj., Collection Czech. Chem. C o m m u n . 26, 2217 (1961). 98. V. Cern$ and F. Sorm, Collection Czech. Chem. Commun. 24, 4015 (1959). 99. R. D. Haworth, J . McKenna, R. G. Powell, and P. Woodward, J . Chem. Soc. p. 1736 (1951). 100. K. Jewers and J. McKenna, J . Chem. Soc. p. 1575 (1960). 101. M.-M. Janot and R . Goutarel, Bull. Soc. Chim. France p. 2234 (1962). 102. A. Kasal, V. Cern$, and F . Sorm, Collection Czech. Chem. C o m m u n . 27, 2898 (1962). 103. H. Favre and B. Marinier, Can. J . Chem. 36, 429 (1958). 104. R . Camps, Chem. Ber. 32,3228 (1899). 105. S. Siddiqui, Proc. I n d i a n Acad. Sci. A2, 426 (1935). 106. S. Siddiqui and S. K. Vasistha, J . Sci. Iizd. Res. ( I n d i a ) 3, 559 (1945). 107. A. Bertho and M. Gotz, Ann. Chem. 619, 96 (1958).

8.

ALKALOIDS O F A P O C Y N S C E A E A N D B U X A C E A E

423

108. P. Devissaguet, M. Pais, F. X. Jarreau, Q. Khuong-Huu, and R. Goutarel, Tetra!t~di-vflLetters p. 1073 (1966). 109. J. Castells and G. D. Meakins, Chem. & Ind. (London)p. 248 (1956). 110. A. Bertho, A n n . Chern. 557, 220 (1947). 111. R. Goutarel, C. Conreur, and J. Parello, Bull. SOC. Chim. France p. 2401 (1963). 112. S. Siddiqui,J. Indian Chem.Svc. 11, 283 (1934). 113. 8. Siddiqui, Proc. Indian Acad. Sci. A3, 249 (1936); Chem. Abstr. 30, 4866 (1936). 114. R. Tschesche and A. C. Roy, Chem. Ber. 89, 1288 (1956). 115. F. X. Jarreau, C. Monneret, Q. Khuong-Huu, and R. Goutarel, Bull. SOC.Chim. France p. 2155 (1964). 116. S . Hiinig and W. Baron, Chem. Ber. 90,395 (1957). 117. S. Hiinig and W. Baron, Chem. Ber. 90,403 (1957). 118. D. N. Jones, Chem. & Ind. (London)p. 179 (1962). 119. S. Siddiqui and P. D. Pillay, J . Indian Chem. SOC.9,553 (1932). 120. P. K. Bhattacharyya, B. D. Kulkarni, S. Kanthamani, and C. R. Narayanan, Chem. & I n d . (London)p. 1377 (1962). 121. H. Warnecke, Arch. Phurm. 26, 248 (1888). 122. F. L. P y m a n , J . Chem. SOC.115, 163 (1919). 123. A. Uffer, Helv. Chim. Acta 39, 1834 (1956). 124. L. van Hove, Tetrahedron 7, 104 (1959). 124a. G. Vandewoude and L. van Hove, Tetrahedron Letters p. 2657 (1966). 125. J. Laos a n d R . Pappo, U.S. Patent 2,933,511 (1960); Chem. Abstr. 54, 17477 (1960). 126. J. de Flines, A. F. Marx, W. F. van der Waard, and D. van der Sidje, Tetrahedron Letters p. 1257 (1962). 127. A. Bertho, Ann. Chem. 573, 210 (1951). 128. J. H. Burckhalter and J . H . Short, J . Org. Chem. 23, 1278 (1958). 129. M. C. Kloetzel, J. L. Pincus, and R. M. Washburn, J . Am. Chem. SOC.79, 4222 (1957). 130. M.-M. Janot, F. X. Jarreau, M. Truong-Ho, Q . Khuong-Huu, and R. Goutarel, Compt. Rend. 258, 2089 (1964). 131. A. Bertho, G. von Schuckmann, and W. Schonberger, Chem. Ber. 66, 786 (1933). 132. A. Bertho, Arch. Pharm. 277, 237 (1939). 133. B. Witkop,J. Am. Chem.Soc. 78,2873 (1956). 134. J. Shankar, N. C. Neogi, and N. K. Basu, Proc. Rajasthan Acad. Sci. 8, 94 (1961); Chem. Abstr. 58, 11872 (1963). 135. R . van Moorselaar, Ph.D. Thesis, University of Leiden (1962). 136. P. CrabbB, “Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry,” p. 226. Holden-Day, San Francisco, California, 1965. 137. L. Lbbler, to be published. 138. E. J. Corey and W. R. Hertler, J . Am. Chem. SOC. 81, 5209 (1959). 139. E. J. Corey and W. R. Hertler, J . Am. Chem. Soc. 80, 2903 (1958). 140. D. H. R. Barton and L. R. Morgan, J . C h e n . Soc. p. 622 (1962). 141. D. H. R . Barton and L. R. Morgan, Proc. Chem. Soc. p. 206 (1961). 142. D. H. R. Barton and A. N. Starrat, J . Chem. SOC.p. 2444 (1965). 143. J . A. Marshall and W. S. Johnson, J . Am. Chem. Svc. 84, 1485 (1962). 144. W. Nagata, T. Teresawa, and T. Aoki, Tetrahedron Letters p. 865 (1963). 145. W. Nagata, T. Teresawa, and T. Aoki, Tetrahedron Letters p. 869 (1963). 146. W. S. Johnson, W. A. Vredenburgh, and J. E. Pike,J. Am. Chem.Soc. 82,3409(1960). 147. G.Rosenkranz, 0. Blancera, J. Gatica, and C. Djerassi, J . Am. Chem. SOC.72,4077 (1950).

424

v. ~ E R NASD P

F. . ~ O R M

148. G. Stork, S. D. Darling, I. T. Harrison, and P . S. Wharton, J . A m . C’hem. Soc. 84, 2018 (1962). 149. F. H. Howcll and D. A. H. Taylor, J . Chem. Soc. p. 1248 (1958). 150. W. G. Dauben and J. F. Eastham, J . Am. Chem. Soc. 73, 3260 (1951). 1-51, B. Belleau and T. F. Gallagher, J . Am. Chem. Soc. 73, 4458 (1951). 152. J . Le Men, Bull. Soc. Chim. F r a m e p. 860 (1960). 153. Huang-Minlon and Chung-Tungshun, Tetruhedron Letters p. 666 (1961). 154. J . Le Men, C. Kan, and R. Beugelmans, Bull. Soc. Chim. France p. 597 (1963). 155. H. P. Husson, R. Beugelmans, P. Potier, and J. Le ;Men, Bull. Soc. C’him. Frcince p. 1930 (1965). 156. H. P. Husson, P. Potier, and J. Le Men, Bull. Soc. C h i m . F r a n c e p. 1721 (1965). 157. A. CavB, P. Potier, and J. Le Men, Bull. Soc. Chim. Frrciice p. 2502 (1965). 158. A. C a d , P. Potier, A. C a d , and J. Le Men, Bull. S o c . Chim. France p. 2415 (1964). 159. L. Labler and F . Sorm, Chem. & I n d . (London) p. 1661 (1958). 160. L. Labler and F. Sorm, Collection Czech. Chem. C o m m u n . 24, 2975 (1959). 161. L. LBbler and F. Sorm, Collection Czech. Ch,em. C o m m u n . 24, 4010 (1959). 162. L. Labler and F. Sorm, Chem. & I n d . (London) p. 598 (1959). 163. L. LBbler and F. Sorm, Collection Czech. Chem. C’ommun. 27, 276 (1962). 164. D. D. Godse, M. Ram, and P. K. Bhattacharyya, Tetrahedron 19, 783 (1963). 165. F . Buzetti, W. Wicki, J. Kalvoda, and 0. Jeger, Helu. Chim. Acta 42, 388 (1959). 166. A. Kasal, V. Cernjr, and F. Sorm, Collection Czech. Chem. C o m m u n . 25, 2849 (1960). 167. V. Cernj. and F. Sorm, Collection Czech. Chem. C o m m u n . 25, 2841 (1960). 168. J. Hora, V. cernjr, and F. Sorm, Tetrahedron Letters p. 501 (1962). 169. W. G. Dauben and P. Laug, Tetrahedron Letters p. 453 (1962). 169a. W. G. Dauben and P. Laug, Tetrahedron 20, 1259 (1964). 170. J. Hora, V. Cernj., and F. Sorm, Collection Czech. Chern. Cornmuit. 27, 2771 (1962). 171. R. Pappo,J. Am. Chem. Soc. 81, 1010 (1959). 172. R. Pappo, U.S. Patent 2,907,758 (1959); Chem. Abstr. 54, 2430 (1960). 173. M.-M. Janot, X. Lusinchi, and R. Goutarel, Bull. SOC.Chim. Prance p. 1566 (1964). 174. M.-M. Janot, X. Lusinchi, and R. Goutarel, Compt. Rend. 256, 2627 (1963). 175. M.-M. Janot, X. Lusinchi, and R. Goutarel, Compt. Rend. 258, 4780 (1964). 176. V. Cernj., A. Kasal, and F. Sorm, Collection Czech. Chem. C o m m u n . 31, 1752 (1966). 177. M. Ram, D. D. Godse, and P . K. Bhattacharyya, Tetrahedron 18, 1457 (1962). C h i m . France p. 136 (1964). 178. R. Beugelmans. H. P. Husson, and J . Le Men, Bull. SOC. 179. M. FaurB, J . Pharm. 16, 428 (1830) (cited in Schlittler et al., 180). 180. E. Schlittler, K. Heusler, and W. Friedrich, Helu. Chim. Actu 32, 2209 (1949). 181. K . Heusler and E. Schlittler, Helv. Chim. Acta 32, 2226 (1949). 182. W. Friedrich and E. Schlittler, Helv. Chim.Acta 33, 873 (1950). 183. E. Schlittler and W. Friedrich, HeZw. Chim. Acta 33, 878 (1950). 184. K. S. Brown and S. M. Kupchan, J . Am. Chem. SOC. 84,4590 (1962). 185. K. S. Brown and S. M. Kupchan, J . Am. Chem. SOC.84, 4592 (1962). 186. K. S. Brown and S. M. Kupchan, Tetrahedron Letters p. 2895 (1964). 187. K. S. Brown and S. M. Kupchan, J . Am. Chern. SOC.86,4414 (1964). 188. D. Stauffacher, Helv. Chim.Acta 47, 968 (1964). 189. K. S. Brown and S. M. Kupchan, J . Chromatog. 9, 71 (1962). 190. E. Martin-Sans, Compt. Rend. 191, 625 (1930). 191. K. S. Brown and S. M. Kupchan, J . Am. Chem. Soc. 86, 4424 (1964). 192. J . S. G. Cox, F. E. King, and T. J. King, J . Chem. Soc. p. 1384 (1956). 193. C. Meystre, H. Frey, R. Neher, A. Wettstein, and K. Miescher, Helv. Chim. A c t n 29, 627 (1946).

8.

ALKALOIDS O F AP O CYNACEAE A N D BUXACEAE

425

C. Meystre, H. Frey, A. Wettstein, and K. Miescher, Helu. C'him. d c t n 27, 1815 (1944). C. Meystre, A. Wettstein, and K. Miescher, Helu. Chim. Actn 30, 1022 (1947). C. S. Barnes, Austtulim J . Chem. 9 , 228 (1956). H. Hirschmann and F. B. Hirschmann, J . Biol. Chem. 184, 259 (1950). C. G. Casinovi, G. B. Marini-Bettblo, M. Bonamico, and A. Vaciago, Ric. S c i . 33(3), I1 A, 1028 (1963). 199. T. Sakano and M. Hasegawa, Tetrahedron Letters p. 3679 (1964). 200. T. Sakano and M. Hasegawa, J . Chem. SOC.p. 6688 (1965). 201. P. Khuong-Huu-Lain&,&I.J. Magdeleine, N. G. Bisset, and R. Gout.are1, Bull. SOC. Chin&.Frtrnce p. 758 (1966). 202. J. P. Calame and D. Arigoni, Chimirc ( A a r a u ) 18, 185 (1964). 203. S. M. Kupchan a i d E . Kurosawa, J . Org. Chem. 30, 2046 (1965). 204. J. P. Calame and D. Arigoni, Helu. Chirn. Acta (1966) (in press). 204a. S. M. Kupchan and G. Ohta, J . Org. Chem. 31, 608 (1966). 205. F. Khuong-Huu-Laine, A. Milliet, N. G. Bisset, and R. Goutarel, Bull. SOC.Chim. Frrcnce p. 1216 (1966). 206. K. S. Brown and S. M. Kupchan, J . Am. Chem. Soc. 86, 4430 (1964). p. 753 207. J. L. Beton, T. G. Halsall, E . R. H. Jones, and P. C. Phillips, J . Chem. SOC. (1957). 208. T. Sakano and S. Terao, Tetrahedron Letters p. 1035 (1964). p. 4512 (1965). 209. T. Nakano and S. Terao,J. Chem. SOC. 210. E . Wenkert and P. Beak, Tetrahedron Letters p. 358 (1961). 211. T. Nakano and S. Terao, Tetruhedron Letters p. 1045 (1964). p. 4537 (1965). 212. T. Sakano and S. Terao,J. Chem. SOC. 213. Z. Voticky, J. Tomko, L. DolejB, and V. Hanui, Collection Czech. Chem. Commun. 30, 3705 (1965). 214. S. M. Kupchan and E . Abushanab, J . Org. Chem. 30, 3931 (1965). 215. Z. Votickj. and J . Tomko, Tetrahedron Letters p. 3579 (1965). 216. J . Tomko, private communication (1966). 217. Z. Voticky and J. Tomko, Tetrahedron Letters p. 4160 (1965). 218. F. Khuong-Huu-Lain&,D. Herlem-Gaulier, and R. Goutarel, Compt. Rend. 261, 4139 (1965). 219. S. M. Iiupehan and E. Abushanab, Tetrahedron Letters p. 3075 (1965). 220. S. M. Kupchan and W. L. Asbun, Tetrahedron Letters p. 3145 (1964). 221. D. Bertin and M. Legrand, Compt. Rend. 256,960 (1963). 221a. R. T. Puckett, G. A. Sim, E. Abushanab, and S. M. Kupchan, Tetrahedron Letters p. 3815 (1966). 222. J. Tomko, 0. BauerovA, Z. Votickj., R. Goutarel, and P. Longevialle, Tetrahedron Letters p. 915 (1966). 222a. W. Dopke and B. Muller, Naturwissenschaften 52, 61 (1965). 223. J. M. Kohli, A. Zaman, and A. R. Kidwai, Tetrahedron Letters p. 3309 (1964). 224. K. L. Handa and 0. E. Edwards, Abstr. Papers, I U P A C Symp., Kyoto, J a p a n , 1964p. 120. 225. M. Tomita, S. Uyeo, and T. Kikuchi, Tetrahedron Letters p. 1641 (1964). 226. T. Kikuchi, S. Uyeo, and T. Nishinaga, Tetrahedron Letters p. 3169 (1965). 227. J. R. Vaughan and R. L. Osata,J. Am. Chem. Soe. 73, 3547 (1951). 228. T. Kikuchi, S. Uyeo, M. Ando, and A. Yamamoto, Tetrahedron Letters p. 1817 (1964). 229. M. Tomita, S. Uyeo, and T. Kikuchi, Tetrnhedron Letters p. 1053 (1964). 230. J. Attenburrow, D. F. Elliot, and G . F. Penny, J . Chem. SOC. p. 310 (1948). 231. T. Kikuchi and S. Uyeo, Tetrahedron Letters p. 3473 (1965). 194. 195. 196. 197. 198.

426 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244.

V . 6 E R N P A N D F. gORM

T. Kikuchi and S. Uyeo, Tetrahedron Letters p. 3487 (1965). R. D. Bennet and E. Heftmann, Phytochemistry 4, 47.5 (196.5). P. Potier, C. Kan, and J. Le Men, Tetrahedron. Letters p. I671 (1964). R. Tschesche, L. Miirner, and G . Snatzke, Anti. Chem. 670, 103 (1963). R. Tschesche, V. Knittel, and G. Snatzke, Chem. Ber. 98, 1974 (1965). R . D. Bennet and E. Heftmann, Arch. Biochern. Biophys. 112, 616 (1965). R. D. Bennet and E . Heftmann, Phytochemistry 4, 873 (1965). L. L. Smith, M. Marx, H. Mendelsohn, T. Ewell, and J . J . Goodman, J . Am. C’heni. Soc. 85, 1977 (1963). M.-M. Janot, P. Devissaguet, M. Pais, F. X. Jarreau, Q. Khuong-Huu, and R. Goutarel, Tetruhedron Letters p. 4375 (1966). T. Kikuchi, S. Uyeo, and T. Nishinaga, Tetrnhedron Letters p. 1749 (1966). T. Nakano, S. Terao, andY. Saeki,J. Cheni. Soc. (C), p. 1412 (1966). L. Labler, Z. Samek, J . Smolikova, and F. Sorm, Collection Czech. ChenL. C ” o m m u ~ . 31, 2034 (1966). H. P. Husson, P. Potier, and J . Le Men, Bull. Soc. Chim. France p. 948 (1966).

Note added in proof: The structures of neoconessine ( 2 4 0 ) ,epipachysandrine-A ( 2 4 l ) , several new alkaloids from Buxus microphylla ( 2 4 2 ) , and of artifacts arising on methylation of the alkaloids from Holnrrhena ckntidysenterica ( 2 4 3 ) have been established. The reactions of Eschweiler methylation productsof 16/3-arninoparavallarine derivatives have been studied ( 2 4 4 ) .

-CHAPTER

9-

THE STEROID ALKALOIDS : THE SALAMANDRA GROUP* GERHARDHABERMEHL I nstitut f u r Orgonische Chemie, Teehnisrhe Hocharhule, Darmstadt, Germany

........... ...................... Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... A. Alkaloids with an Oxazolidine System. .............................. B. Alkaloids with a Carbinolamine System. ............................. Biosynthesis ........................................................ Toxicology ......................................................... References .........................................................

I. Introduction.. ................................

427

11. Isolation and Purification of Salamandra Alkaloids

427

111.

IV.

V.

429 429 435 436 438 439

I. Introduction It has long been known that salamanders are venomous animals; just a century ago Zalesky (1)isolated a poisonous substance from the skin glands. This substance behaved like an alkaloid and was named samandarine though it is now known to be a mixture of alkaloids. 11. Isolation and Purification of Salamandra Alkaloids The isolation, separation, and purification of the alkaloid mixture was achieved by Schopf and co-workers about 1930. The animals are narcotized with gaseous carbon dioxide and the skin glands are sucked out by means of a glass tube connected t o a water pump. Then the animals are washed ; about 20 minutes later they regain consciousness. The crude secretion is digested by a pepsin/hydrochloric acid solution a t 37' to hydrolyze the proteins and then, after basification, is extracted by ether and chloroform ( 2 ) .According to a newer method ( 3 )the crude secretion is ground with sand and extracted with 80% ethanol or isopropanol. On evaporation of this solution there remains a nearly colorless sirup from which the alkaloids are dissolved with dilute acetic acid. This

* Supplementary to Volume V, page 321. 427

TABLE I

PROPERTIES O F Salumundra ALKALOIDS Melting

Name

Formula

Occurrence

Alkaloids with ozazolidine system Samandarine S.m.t. Samandarone S.m.t.; S.m.m. Samandaridine S.m.t. ; S.m.m. 0-Acetyl-samantlarine S.m.m. ; S.m.t. Samandenone

S.m.t.; S.m.m.

point ("C)

188 190 290 159 191

S.m.m.

R

0.42 0.52 0.20 0.55 0.35

170

0.68

Alknloids with cnrbinolamine system Cycloneosamandione S.m.t. ; S.m.m. S.m.t. ; S.m.m. Cycloneosamandaridine

119 282

0.08 0.75

Alkaloids not yet inveetignted Samanine

197

Samandinine

S.m.t.

Functional groups

a

-NH-NH-NH-NH-NH-

CHOH CO

0 @

2

-1actone

kt!

CH-0-CO-CH3

-0-

C=C-C=O

-CH

AH3 'CH3

z

> d

t; N-C-OH N-C-OH

C=O

-NH-

-CHOH

a

-0-0-0-0-

Paper: SiOz-paper Schleicher/Schull, No. 289; soivent : Cyclohexane-diet,hyIamine 9 : 1.

-1actone

9.

THE STEROID ALKALOIDS: T H E

Salnnzandra

GROUP

429

acidic solution is basified and the alkaloids are extracted with ether (alkaloids with oxazolidine system) and then with methylenechloride (alkaloids with carbinolamine system). The main alkaloids, samandarine and samandarone, can be separated by virtue of the sparing solubility of the hydrochloride of the former and as the ether-insoluble semicarbazone of the latter ( 2 , 4 ) .The minor alkaloids remaining in the mother liquor can easily be separated by preparative thin-layer chromatography on silica gel (5). It is to be noted that there is a difference in alkaloid content between the two subspecies of Sala,nandra, namely, S. rnaculosa faeniata (S.m.t.) endemic to western Europe and A'. inaculosa waaczilosa (S.m.m.)endemic to south-eastern Europe ( 3 ) . An outline of the alkaloids and their occurrence in the two subspecies are given in Table I ; the table emphasizes the two groups of alkaloids which will be discussed in the following sections.

111. Structure

A. ALKALOIDS WITH

AN

OXAZOLIDINE SYSTEM

I . Sarnandarine The main alkaloid of S . rriaczclosa taeniata is samandarine, a saturated N O a~secondary , hydroxy group. Chromic secondary amine, C ~ ~ H ~ I with acid oxidation converts it to the corresponding ketone, samandarone ( 2 , 4 ) The . second oxygen atom is present as an ether bridge and there are two C-methyl groups. These data together with the molecular formula show that samandarine contains three rings. Hofmann degradation of N-methylsamandarine methiodide (I)yields a desbase (11)which still contains all of the carbon atoms, thus proving that the nitrogen atom of samandarine belongs to a ring. The double bond of the desbase can be hydrogenated to yield the dihydro-desbase (111).The desbase is stable to alkali but on warming with dilute sulfuric acid it adds I mole of water, forming the oxydihydro-desbase (IV) and thus indicating that it is an enolether. It (IV)can be oxidized to yield the lactone samandesone (V) and on boiling with acetic anhydride it gives two reaction products : the desbase and the quarternary starting material, which is now the aretate. The formation of the latter can be rationalized as an alkylation of the tertiary amine by an intermediate acetate (VI) in the way that trimethylamine can be alkylated with methylacetate to yield tetramethylammonium acetate. These reactions indicate that the nitrogen and the ether oxygen are attached to the same carbon.

430

GERHARD HABERMEHL

I

I-

I1

I

r OH

HzjPt

MezN

OHC--CH<

IV

il'

/r

P

MeCO .O.CH-CH<

I\.IezCl

I

HzC-CH,

/

111

-

I1

VI

Whereas samandarine is stable toward lead tetracetate, samandiole

(VII) reacts with 1 mole of the reagent with the elimination of 1 mole of formaldehyde and the formation of compound X. Samandiole must therefore possess the -NH-CHz-CHOHgrouping, the hydroxyl of which comes from the ether oxygen. The evidence so far presented leads to the partial formula V I I I for samandarine ( 6 ) . The carbon skeleton of samandarins was elucidated by selenium dehydrogenation of samandiole (VIIa) a t 320"-340". This reaction ( 7 ) yields an oily mixture of hydrocarbons which was separated by means of addition compounds with trinitrobenzene and with trinitrofluorenone. The main product was a crystalline hydrocarbon, C15H16, which proved to be l,Z-dimethyl-5,6-cyclopentenonaphthalene (XI). By combining structures V I I I and X I it is reasonable to assume a steroid skeleton for samandarine, ring A being enlarged with an oxazolidine nucleus. Three probable structures (XII, XIII, XIV) can then be

9.

THE STEROID ALKALOIDS : THE

/-P

Salamandra GROUP

F-TH\

Li.%IHa

OH

HS

*H s

'CH2--CH< VIII

VII

340"

OH

HN

431

Me

XI

VIIa

envisaged for samandarine. The position of the secondary hydroxyl must be on the five-membered ring D because the carbonyl band in the IRspectrum of the corresponding ketone, samandarone, occurs a t a position ( 1740 cm-1) characteristic of five-membered cyclic ketones.

&IOH

&IOH

HX

HN

XI11

XI1

XIV

The structure and the location of the hydroxyl group were determined by an X-ray crystal structure analysis of samandarine hydrobromide which crystallizes from methanol in monoclinic prisms. Its space group

432

GERHARD HARERMEHL

is Pdl, with two molecules per unit cell, and the cell constants are: a=12.98 8;b = 6 . 2 8 A ; c=12.43 8 ;p=95". Structure XV was arrived at, and the given configuration was confirmed by a three-dimensional X-ray analysis. Accordingly samandarine possesses a steroid skeleton in which ring A is enlarged by an NH group. The introduction of the ether bridge results in the formation of an oxazolidine ring which is the first representative of such a system in the steroid alkaloids (8). The configuration is the same as that of cholic acid. Me

XV

2. Samandarone Samandarone (XVI) is the main alkaloid of 8. maculosa maculosa ; in S. maculosa taeniata it is one of the minor alkaloids. It can readily be obtained from samandarine by oxidation with chromic acid ; conversely, samandarone is reduced stereospecifically to samandarine by sodium and alcohol or by sodium borohydride. Me

XVI

From the optical rotatory dispersion curve of samandarone its absolute configuration, and consequently that of samandarine, can be determined

(8). 3. Samandaridine Another alkaloid with the oxazolidine system is sainandaridine (XVII),C21H31N03, also a secondary amine. Chemical reactions ( 9 )and IR-spectra indicate that it possesses a five-membered lactone ring. Its structure was also elucidated by X-ray analysis. Samandnridine hydrobromide crystallizes from methanol in monoclinic prisms ; its space group is C2 with four molecules in the unit cell. The cell constants are : a = 14.50 A, b=6.15 A, ~ = 2 2 . 5 28,p=94" (10).

9.

THE STEROID ALKALOIDS

: THE Salamandra GROUP

433

H XVII

The absolute configuration of samandaridine was determined by partial synthesis (11).Condensation of N-acetylsamandarone (XVIII) with glyoxylic acid yields a mixture of the two carboxylic acids X I X and XX. Reduction of the former, first with sodium borohydride and then catalytically generates samandaric acid (XXI), which on boiling with dilute mineral acid lactonizes to samandaridine (XVII).

MeCO .N&()

s1-111

XIS

+

XS

4 . 0-AcetyEsumandarine The structure of this base follows from the fact that hydrolysis of it yields samandarine and acetylation of the latter regenerates the O-acetyl-

434

GERHARD H A B E R M E H L

Me

samandarine (XXII). IR-data are consonant with this formulation ( 3 ) .

5. Xumaizdenone The IR-spectrum indicated an oxazolidiiie ring in this alkaloid. Elementary analysis and mass spectra determined the empirical formula CzzH3302N. The partial structure X X I I I was arrived at by UV-, IR-, and NMR-spectra and the fragments of the mass spectrum proved that the skeleton was that of samandaroiie; hence the structure XXIV is that of samandenone ( 2 2 ) .

XXIII

XXIV

6 . Xamaizdinine This base is present in only very small amounts so that evidence for its structure (XXV)is limited to spectral data. I t s IR-spectrum is consonant with the oxazolidine system (828/845 cm-1) ; with an 0-acetyl group

xsv (1240/1725 cm-1); and with an isopropyl group (pattern at 1370 cm-1). The mass spectrum evidences the same groups, differing from that of 0-acetylsamandarine only in features associated with the isopropyl group ( 1 3 ) .

9.

THE STEROID ALKALOIDS : THE

Salamandrci

GROUP

435

B. ALKALOIDS WITH CARBIKOLS31ISE S Y S T E M 1. Cycloneosarnandione

Cycloneosamandione is an isomer of samandarone but differs characteristically by the absence of the oxazolidine system. The IR-spectrum proves that one oxygen atom belongs to a carbonyl group in a fivemembered ring. The second one belongs to an aldehyde-ammonia group which can react in two tautomeric forms:

I I

> N-C-OH

>NH

OC<

I n the free base as well as in the salts the cyclic form is present. Acetylation of cycloneosamandioiie yields a neutral substance, derived from the second tautomeric “open” form ( 1 4 ) .I t s IR-spectrum shows, besides the band a t 1732 cm-1 for the carbonyl group in the fivemembered ring, a band a t 1620 cm-1 for the N-acetyl group, and a t 1714 cm-1 one for a carbonyl group in an unstrained system. That this carbonyl band comes from an aldehyde is proved by the band at 2705 cm-1 for the aldehyde-v-CH vibration. The same conclusion follows from a comparison of the NMR-spectra of samandarone, cycloneosamandione, and N-acetylneosamandione ( 1 5 ) . While the spectrum of samandarone shows the signals for the C-18 and C-19 methyl groups a t 9.1 and 9.2 T , the NMR spectrum of cycloneosamandione possesses the signal for the C-18 methyl group at 9.1 7 only. But there are two additional signals for the protons of a CHOH group, at 5 . 5 T for CH and a t 3.25 T for OH. I n the spectrum of N-acetylneosamandione the signal a t 9.1 T is also present, but instead of the two signals of the CHOH group, there is a doublet a t 0.09 r for the proton of an aldehyde group. These spectra thus show uiiambigously the presence of an aldehyde group instead of the C-19 methyl group.

XSVI

The structure of cycloneosamandione was finally elucidated by X-ray analysis of its hydroiodide ( 1 5 ) which crystallizes from water in orthorhombic prisms; the space group is P212121 with four molecules per unit

436

GERHARD HABERMEHL

cell. The cell constant,s are: a = 10.87 8,b = 9.59 8,c = 19.51 8.Two- and three-dimensional electron-density calculations proved the correct formula t o be XXVI. Cycloneosamandione possesses the same C-N skeleton as samandarone with the essential difference that there is an a-aldehyde group a t C-10 instead of a P-methyl group. This anomalous configuration a t C-10 (otherwise not yet found in the naturally occurring steroids) was also determined by means of the ORD-curve of N-methylneosamandione methiodide; it is practically the mirror image of the ORD-curve of corotoxigenine which has the opposite 5 ~ ( ,10P-configuration. The absolute configuration was also established by the ORD-curve of cycIoneosamandione. This curve shows a strong negative Cotton effect a t 31 5 mp; thus the absolute configuration of cycloneosamandione is in accord with that of the other naturally occurring steroids.

2 . Cycloneosamandaridine A second alkaloid without the oxazolidine ring, but with the carbinolamine system is cycloneosamandaridine (XXVII). The IR-spectrum evidences a five-membered lactone ring (band at 1780 em-1) as well as the carbinolamine group (bands at 1050/1180 cm-1). The IR-spectrum of the hT-acetyl compound no longer shows these bands at 1050-1 180 cm-1, but an additional carbonyl frequency a t 1735 em-1 for an aldehyde group. The mass spectrum confirms the molecular formula as well as structure XXVII(I6).

XSVII

IV. Biosynthesis Recent investigations concerning the biosynthesis of Snla?nandra alkaloids ( 1 7 ) involving in vitro and in vivo experiments showed that these alkaloids are formed like other steroids from acetate via cholesterol. The alkaloids substituted a t C-17 (samandaridine, samandenone, and samandinine) might be considered as intermediates on the way from cholesterol (XXVIII) to the alkaloids without side chains. A cholic acid intermediate (XXIX) could be postulated as one route to the isopropyl

9.

THE STEROID ALKALOIDS

: THE Salamandra GROUP

437

side chain ( X X X ); another route by way of P-oxidation to a malonic acid ( X X X I ) followed by decarboxylation could generate the side chain of

XXXI

E'"'" +m XXXII

XXXIII

samaridaric acid (XXXII). In a similar manner the skin glands of Uufo (toad)could generate the bufotaline dienolide ring (XXXIV)from X X I X without loss of carbon atoms, It, is also possible to rationalize the anomalous configuration at (3-10of cycloneosamandione. The enlargement of ring A may proceed after a fission between carbon atoms 2 and 3 (XXXV and XXXVI). Compound XXXVI could undergo a Michael fission yielding XXXVII, which could be epimerized to give XXXVIII. A Michael addition could bring the aldehyde group a t (3-10 in the &-position(XXXIX). That these reactions with other steroids are never observed can be

438

GERHARD HABERJIEHL

based on the argument that the decaline system of the rings A and B does not show any tendency to change into the unfavored cyclodecane system. CHO

XXX\'

CHO

XXXVI

XXXPII

OHC

XXXIX

XXXVIII

V. Toxicology Toxicological and pharmacological examinations of Xuluamandra alkaloids have been made by Faust ( 1 8 ) and later by Gessner (19-23). Gessner also found the secretion to contain hemolytically active peptides in addition to the alkaloids. Poisoning with samandarine first causes convulsions followed by irregular palpitation and finally paralysis. Samandarine affects the central nervous system. The vasomotor center is stimulated, causing an increase in blood pressure. Death occurs within a few hours because of primary respiratory paralysis without damaging the heart. Samandarine is toxic to all higher animals ; fishes, amphibia, birds, and mammals. Even the salamanders themselves die of their own venom if it seeps into the blood. The lethal dose is 19 mg/kg for the frog, 3.4 mg/kg for the mouse, and 1 mg/kg for the rabbit. There is a characteristic difference between the Salamandra and the Digitalis venoms insofar as the arrest of the heart in diastole is not compensated for by atropine. Remarkable is the potent local anesthetic action of samaiidarine. Therapeutically, however, it is not used because of its toxicity.

9.

THE STEROID ALKALOIDS : THE

Sulamandra GROUP

439

KEFERESCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

20. 21. 22. 23.

S. Zalesky, M e d . C h e m Cpiteres. Hoppe-Seyler 1, 85 (1866). C. Schijpf and W.Braun, d 7 i n . C’hem. 514, 69 (1934). G. Habermehl, - 4 n ~(’hem. . 679, I 6 4 (1964). C. Schijpf and K. Koch, .4)771. C‘hem. 552, 37 (1942). G. Habermehl and G. Haaf, Citein,. Ber. 98, 3001 (1965).

C. Schijpf, H. K. BlBdorn, D. Klein, and G. Seitz, Chem. Ber. 83, 372 (1950). C. Schopf and D. Klein, C‘hem. Ber. 87, 1638 (1954). E. IVolfel, C. Schopf, G. Weitz, and G. Habermehl, Chem. Ber. 94, 2361 (1961). C. Schijpf and K. Koch, AnTi. C”he)n.552, 6-3 (1942). G. Habermehl, Chem. Ber. 96, 143 (1963). G. Habermehl, (,%?)I.. Ber. 96, 8-10(1963). G. Habermehl, C h e m Ber. 99, 1439 (1966). G. Habermehl, G. Haaf, and G. Volkwein, unpublished C. Schiipf arid 0. W. MIiiller, A7s7i. Chem. 633, 127 (1960). G. Habermehl, and S. Gottlicher, Che71s. Ber. 98, 1 (19(i5). G. Habermehl and G. Haaf, Chein. Ber. 98, 3001 (1965). G . Habermehl, G. ‘olkwein, and A. Haaf, CImm Ber. 100 (1967) (in press). E. S. Faust, Arch. Exptt. Pnticol. Phnrmakol. 41, 229 (1898). 0. Gessner, in “Handbuch der experimentellen Pathologie” (Erg. W). Vol. 6 , p. 66. 0. Gessner, Ber. Ges. Bef. Snturwiss. Marburg 61, 138 (1926). 0. Gessner and F. hlollenhoff, Arch. Exptl. Puthol. Phorinukol. 167, 638 (1932). 0. Gessner and W. Esser, Arch. Exptl. Pathol. Pharmakol. 179, 639 (1935). 0. Gessner and G. Urban, Arch. Exptl. Prtthol. Phurmnkol. 187, 378 (1937).

This Page Intentionaiiy Laft Blank

-CHAPTER

10-

NUPHAR ALKALOIDS J. T. W R ~ B E L [J?iiversity of Warsaw, Wnrsaw, Polnnd I . Occurrence and History.

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

11. Nupharidine and Deoxynupharidine .................................. A. Structure ............................... B. Absolute Configuration. .................. . . . . . . . . . . . . . . . . . . . . . . . C. Synthesis ............................... 111. Nupharamine ..................... A. Psructure ...................................................... B. iibsolute Configuration. ......................................... C. Synthesis ................................. .................. IV. Deliydrodeoxynupharidine ..................... .................. Structure . ................................................... V. Nuphamine ................................................... Structure ........................................................ VI. Neothiobiuupharidine .............................................. Structure ........................................................ VII. Thiobinupharidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

....................... .................. References.. ......................................................

VIII. Castoramine

444 450

454 458 458 460 460 461 462 462 463 463 464

I. Occurrence and History The genus Nuphar belongs to the family Nymphaeaceae, which contains about one hundred species, the more common being Nuphar luteum Sibth. et Sm., N . japonicum DC., Nymphaea alba L. ( N . candida J. et C. Presl), Nelumbium speciosum Willd. ( N . caspium Eichw.; N . nuciferum Gaertn. ; N . nelumbo Karst.), and Euryale ferox Salisb. Alkaloids were first detected in these plants by Dragendorff ( 1 ) ,who found them in 1879 in the rhizome of N . luteum. Soon thereafter Griiiiing ( 2 )isolated nupharine, an amorphous alkaloid to which he ascribed the formula C18H2402N2. Not until 40 years later did &4rimaand Takahashi ( 3 ) obtain from Nuphar japonicum another alkaloid, which had the formula C15H2302N and which they named nupharidine. I n 1913 Kotake et al. isolated another alkaloid, deoxynupharidine, C15H230N. I n 1934 Bures and Hoffmann ( 4 ) reported nympheine, C I ~ H ~ ~ O ~ N , from Nymphaea alba. 441

TABLE I NYMPHAEACEAN ALKALOIDS AND THEIRPROPERTIES

NO.

Compound

Formula

Melting point ("C)

Boiling point

("C)

[.ID

Melting point ("C) of the salts

_ _ _

-

1 2

Nupharidine Deoxynupharidine

3

a-Nupharidine

222 21-22 -

4

/'!-Nupharidine

-

5

Nupharamine

-

6

Dehydrodeoxynupharidine

-

7

Nuphamine

8 9 10 11

Reference

Methyl et'her of nupharamine Ethyl ether of nuphararnine Nupharine Nympheine

48-50

65 76-77

+ 14.5 -112.5

HCI: 262, picrak: 176 HC1: 262, picrat,e: 153, methiodide: 146 121/2 mm - 112.1 Met'hiodide: 185-187, HCI: 258-259, H J : 301-302, picrate: 165-167 HCI: 269-370, 140/2 mm H J : 273-275, picrate: 152-153 - 35.4 Picrolonate : 168, 130-134/1 mm methiodide: 203.5 110-120/3 mm Perchlorate: HBr: 199-201, -130.1 (CHC13) HC104: 159-161 150-153/3 mm - 60.5 (C€IC13) Picrolonate: 159-160, methiodide: 1A4 -52.5 ( E t OH) HC104: 197-198 -448.25 (EtOH) HC104: 183-184 -

112-115jS mm

-

-

HC1: 230

3 12, 13

5

4

5

6 7

8

TABLE I1

SULFUR-CONTAINING ALKALOIDS AND THEIRPROPERTIES

Melting point Compound

Formula

("C)

Thiohinupharidine Neothiobiriupharidine Pseudothiobinupliaridine

C30H4202N2S 129-1 30 C30H4202NzS 159-160 C ~ ~ H ~ O O ~ N~ S

Thiobideoxyriupharidine

C~OH~OON~S

A1lot.hiobinupharidine

C ~ O H ~ ~ O Z N Z S-

~

[.ID

+ 49.4 - 93.09

Perchlorate : 186.2 Perch1orat.e :

+

Melting point ("C) of the salts

2 HC104: 283-284 2 HC104: 320 2 HClOa: 173-175

in

2 HC104 : 224-225

10

2 HC104: 320-325

10

+ 26.6 -

Reference

11 10

444

J . T. W R ~ B E L

In thc 1!KIO's. investigations of Sztphcv h t ~ i u nby A4dimatonicz and ?tlollOn-na (5) resulted ill t h c isolation of two isomeric alkaloids. a- and ,L-nu]iharidinc, of the empirical formula C15H23ON. The a-isomer is probably identical u itli the cieoxynupharidine of Kotake et ( 1 2 . In I !)37-1963 -4rata and Ohashi isolated another three alkaloids from Suphnr jnpo~zicz~n? : nupharamine, C15H2502nT (6); dehydrodeoxynupharidinc, ClsH2lOK ( 7 ): and nuphamine. C15H2302N (8). Kotake et al. (9)found among the minor alkaloids of the same species the methyl and ethyl ethers of nupharamiric. The known alkaloids of Nymphaeaceae and their properties are compiled in Table I. X novel type of sulfur-containing alkaloids in these plants was reported by Achmatowicz and Bellen (10)in 1962. The novelty was that in these compounds, unlike in those previously known, the sulfur was incorporated not in a side chain but in the ring structure. They were found in II'. luteuin (collected in northern Poland) which yielded the crystalline thiobinuphariciine, C ~ O H ~ O O ~ and N ~ Sthe , perchlorates of three other suIfur-containing alkaloids : pseudothiobinupharidine, C30H400&2S, thiobideoxynupharidirie, CSOH~OOPJ~S, and allothiobinupharidine, C30H420~NzS.Two years later Achmatowicz and JYrhbel (11) isolated yet another alkaloid with heterocyclic sulfur-neothiobinupharidine, C ~ O H ~ ~ O ? N Z S . These novel sulfur alkaloids and their properties are given in Table 11. Structural studies have demonstrated for all the known A'uphar alkaloids shown in Tables I and I1 either the sesquiterpenoid or the triterpenoid structure incorporating the quinolizidine and furan systems, with the tetrahydrothiophene system in the sulfur-containing alkaloids. 11. Nupharidine and Deoxynupharidine

-'II) vH3T A. STRUCTURE

('(HJ

I

I

I

I

1

I1

The structure of these two alkaloids was investigated simultaneously by two groups of Japanese researchers: Kotake et al. and Xrata et al.

10. Xuphar

445

ALKALOIDS

A t a relatively early date (12, 13) nupharidine was identified as an S-oxide and its deoxyderivative as the deoxynupharidine isolated from S.jnponicum. There remained only the problem of determining the structure of deoxynupharidine. Chart I

Me

I

v

/

\

HOOC?

COOH VIII

I S

1V

SYTlI

I

I

J

M0

XVI

XI

? Grraniol

.XIS

COOH

446

J. T. W R ~ B E L

Arata (14)and Kotake et al. (15)reported their results almost a t the same time, showing deoxynupharidine to have a novel sesquiterpenoid structure of the quinolizidine type. The problem was resolved essentially by stepwise degradation of the molecule to furaii-3-carboxylic acid, pyridine-2,5-dicarboxylic acid (Y), nupharidinic acid ( S V I I I ) , and anhydronupharanediol, C15H30O (XV), with the structure of the last-named supplying the key to that of deoxyiiupharidine (15, 16). Chart I shows the main steps of the degradation.

1. T h e %Oxide Group in h’upharidine Nupharidine can be reduced with sulfur dioxide or hydrogen iodide to deoxynupharidine, which can be reconverted to the former alkaloid by oxidation with hydrogen peroxide. Consequently nupharidine is an N-oxide (12, 13, 17).

2. Reduction of Deoxynupharidine Catalytic reduction of deoxynupharidine (11)leads to the tetrahydro (111)and the hexahydro derivative (IV) (13, 2 2 ) . Both were important

I11

IV

starting compounds for further degradation. Hofmann’s degradation, reduction, and treatment with methyl iodide converted I11 to the methiodide of I V .

3. Presence of the Piperidine Ring \?‘hen dehydrogenated on palladium the hexahydroderivative I V afforded C15H230K which could be converted to pyridine-2,5-dicarboxylic acid (1’)by oxidation with permanganate (13, 18, 19). The acid V was also obtained when deoxynupharidine was dehydrogenated with palladium to C15HlgON and this was oxidized with permariganate ( 1 5 ) . 4. Presence of the 3-Substituted F u r a n Ring Hofmann’s degradation of tetrahydrodeoxynupharidine (111)afforded

10. Nuphur

447

ALKALOIDS

the derivative %‘I,which was oxidized by ozone to tetrahydrofwane-3aldehyde and the corresponding acid (14, 16, 22).

Deoxynupharidine yielded in the same sequence of reactions furan-3aldehyde and furan-3-carboxylic acid (15). The characteristic maxima at 3135, 1499, and 874 cm-1 in the IRspectra indicate the presence of furan (19).

5. Position of the Methyl Groups (13, 14, 22) Two C-methyl groups are present in deoxynupharidine; in order to determine their positions the hexahydro derivative I V was subjected twice to Hofmann’s degradation according to the following scheme :

Compound V I I on ozonolysis gave four products : isovaleric acid, acid C9H170* COOH, ketone C12H23O CO -CH3, and formic acid ; hence the inference that product VII is a mixture of V I I I and I X .

TI11

IS

This enabled position 3 t o be assigned to one of the methyl groups in the piperidine ring :

448

J . T. W R 6 B E L

Twofold Hofmann degradation of I V without hydrogenation in the first stage, followed by ozonolysis, led to the products X I and X I I ; hence it was inferred that the intermediate X is a mixture of XI11 and XIV. (C~HI~O)CH(CH~)COOH

XI11

XIV

6. Xtructure of Anhydronupharanediol Anhydronupharanediol, C15H300 (XV), was obtained by hydrogenation of VII. Compound XV was degraded in several stages to 1,6dimethylpelargonic acid (XVI) which was synthesized independently from geraniol.

XVI

This indicated structure XVII for anhy dronupharanediol (16).

10. Nuphar

449

ALKALOIDS

I

XVII

7 . Presence of the Quinolizidine System (15, 21, 23) Oxidation of deoxynupharidine leads to nupharidinic acid (XVIII) which on distillation with soda lime affords 1,7-dimethylquinolizidine (XIX).

COOH XVIII

XIX

This crucial observation, together with the data previously presented, determines the structure of nupharidine (I).

8. Mass Xpectrum of Deoxynupharidine The mass spectrum of deoxynupharidine ( 2 4 ) contains key fragments a t masses 94, 98, and 136. Their presence may be understood on the following basis. Cleavage of a carbon-carbon bond next to a nitrogen is strongly favored because the electron pair of a nitrogen atom may stabilize a positive charge of a neighboring carbon. Further stabilization of the positive charge obtained by hyperconjugation makes a preliminary fission of the bond between C-1 and C-10 understandable. Ion XXI, still having the mass of the molecular ion 233 (XX), is now cleaved between the nitrogen and C-4 with a simultaneous shift of the hydrogen atom, resulting in the appearance of the key fragment of the mass 98 (XXII). The preliminary fission combined with this shift seems to be possible in this case owing only to the presence of the furan ring because other quinolizidine alkaloids are usually cleaved between C-3 and C-4 (25). The second fragment formed by the cleavage of the deoxyiiupharidine molecular ion has 136 mass units; no suggestions are made concerning its structure since the character of the rearrangement which must occur to stabilize the fragment is not known.

450

J . T. W R ~ B E L

I1

xx

(233)

(233)

XXII 98

XXI (233)

XXIII 94

The third key peak in the deoxynupharidine spectrum corresponds to the mass 94. Fragments of this mass are often found in the spectra of compounds containing a furan ring with a side chain. Its structure may be of the type represented by XXIII.

B. ABSOLUTECONFIGURATION The absolute configuration of nupharidine and deoxynupharidine was established in a variety of ways. The first to solve this problem were BohImann et al. (23). Their method rested on the synthesis of 1,7-dimethylquinolizidone-4 (XXIV) and its subsequent chromatographic separation into the four possible stereoisomers. Me

0

XSIV

Reduction of the particular stereoisomers with lithium aluminum hydride afforded four stereoisomers of 1,7-dimethylquinolizidine, whose configurations were determined from IR-spectra compared for this

10. Nzcphar ALKALOIDS

45 1

purpose with those of authentic stereoisomers obtained from hydroxymethyl derivatives of known configuration. With their configuration now known the four 1,7-dimethylquinolizidones-4 were used t o prepare the corresponding stereoisomers of deoxynupharidine by the method of Murakoshi ( 2 6 ) . Only four stereoisomers were obtained, instead of the possible eight, and their IR-spectra served for comparisons with that of natural deoxynupharidine which on this evidence had Configuration XXV ascribed to i t :

* (a) Me ( e )

O (el

Wa)

xxv

Kotake et al. established the same absolute configuration on different evidence, having proved configuration AS(- ) for the a-methyladipic acid obtained by degradation of deoxynupharidine ( 2 7 ) and compared the NMR-spectra of 1,7-dimethyl- and 1,4,7-trimethylquinoIizidinesobtained from the alkaloid with those of mono- and dimethylquinolizidines of known configuration (28). With the 1- and 3-methyl derivatives the maxima for axial methyl groups were a t a lower field than for the equatorial, whereas with the 4-methyl derivative the reverse was true (28). Arata (29) independently also established the same absolute configuration on the basis of IR-studies of 4-hydroxymethyl-l,7Me I

CHzOH

XXVI

dimethylquinolizidine (XXVI) prepared from deoxynupharidine and by determination of the absolute configuration of a-methyladipic acid also obtained by degradation of the alkaloid.

C. SYNTHESIS The synthesis of deoxynupharidine has received attention from many chemists and several procedures have been developed.

452

J. T . W R O B E L

The first synthesis of dl-deoxynupharidine was reported by Kotake et al. ( 3 0 ) .The starting material was 2,5-lutidine which was made to react with formaldehyde to give the diol XXVII; on dehydration, acetylation, and condensation with malonic ester XXVII afforded the diester XXVIII. On hydrogenation and acid hydrolysis XXVIII was decarboxylated to the valeric acid derivative XXIX. After esterification the acid was acylated with 3-furoyl chloride and distilled with soda lime to yield dehydrodeoxynupharidine (XXX),and this on hydrogenation gave dl-deoxynupharidine (11).

XXVII CH3 I

FH2

1. HeiPt 2. HCI

CH3’

/N

COzEt

1. EtOH/HCl

CH3

COzH

COz Et

I1 CH3

F0 xxx Since hydrogenation of tlie pyridiiie ring leads chiefly to the ’;-axial methyl group (31) and hydrogenation of XXX also proceeds stereospecifically with formation of 4-axial hydrogen (%), the mixture produced in the synthesis referred to is composed chiefly of two diastereoisomers. Kotake et al. ( 3 1 ) separated this mixture by chromatography and crystallization of the salt with 1-tartaric acid whereby they completed the total synthesis of nupharidine.

10. Xuphar

453

ALKALOIDS

The several modifications of dl-deoxynupharidine synthesis that follo.cr.edincluded an interesting step proposed by Arata et al. ( 3 2 )which involves condensation of 1,7-dimethylquinolizidone-4 (XXXI)with the ester of furan-3-carboxylic acid according to the following scheme :

XXXI

1. NaRH4

Me

c=o

2. SOCl 3. SazCO,

A

I1

This sequence was similar to the work of Jezo et al. (33). In the deoxynupharidine synthesis published by Bohlmann et al. (23) the crucial step was the reaction of 1,7-dimethylquinolizidone-4 (XXXI) with 3-furoyl chloride.

X synthesis starting from acetylene compounds and 2-acetyl-5methyl pyridiiie has been developed by Wrhbel and Dabrowski ( 3 4 ): The resulting deoxynupharidine was a mixture of two diastereoisomers differing in their configuration at (2-1.

454

J . T. W R ~ B E L

1 . Ha/Pt

HC=C.COnEt

3. HzjPd

I

Hrjl'd

I1

111. Nupharamine Another alkaloid isolated from N . japonicum (35) is nupharamine (XXXII)which has a sesquiterpenoid structure with furan and piperidine rings.

A. STRUCTURE I n elucidating the structure of nupharamine d r a t a and Ohaslii (35) resorted to systematic degradation, of which the more important steps are shown in Chart 11.Their analytic data have shown the alkaloid to be a secondary amine incorporating one hydroxy and two methyl groups ; IR-spectra indicate the presence of a furan ring ( 3 5 ) .

10. A’uphar

455

ALKALOIDS

Chart 11

XXXII

/

I

O ;XL I

0

XSX”III XVII

1. Presence of the Trisubstituted Piperidine Ring When dehydrogenated with palladium nupharamine (XXXII) is converted to the pyridine derivative (XXXIII) and this can be oxidized with permanganate to pyridine-2,3,6-tricarboxylic acid (XXXIV)which indicates the location of the substituents (35).

2 . Anhyclronupharanediol from Nupharamine (35) Nupharamine (XXXII) can be hydrogenated t o the tetrahydro derivative (XXXV)which is converted by Hofmann’s degradation and hydrogenation to the compound XXXVI. Hofmann’s degradation of the product. also followed by hydrogenation, affords the alcohol XXXVII; upon treatment with thionyl chloride XXXVII g‘ives a

456

J . T. W R ~ B E L

mixture of two isomeric unsaturated compounds, and these can be hydrogenated to the anhydronupharanediol (XVII) obtainable also by degradation of deoxynupharidine (16). Since the last fact could not fail to suggest the possibility of some structural relationship between nupharamine and deoxynupharidine, it became the purpose of further research to explore this possibility.

3. Relation between Nupharamine and Deoxynupharidine The relationship between nupharamine and deoxynupharidine was demonstrated in a threefold way (see Chart 111): ( a ) Either alkaloid can be degraded stepwise to 9-(3-tetrahydrofury1)6-methylnonane-2-one (XXXVIII) which indicates the same carbon skeleton for both (14,22, 35). (6) With slight modifications stepwise degradation of either alkaloid leads to the same product, 1-(3-tetrahydrofuryl)-pentane-4-one (XL) ( 1 4 , 22, 35) which again indicates that the two share a single carbon skeleton.

10.

Nuphar

.

457

ALKALOIDS

Chart I11

XXXII

/

XXXIX 1 . HzlPd

2. Hofmann 3 . HiiPd 4. Hofniann 5.

XXXVIII

1. HziPd

\

2. Hofmann 1. IHofmann 3. rPd

j2\

0 3

XLI

XL 4. Hofmann

2x 5.

0 3

2. KOKlKeOEi

I

1. H d P d 2. Hofmann 3. Ha/Pd

CH3

/

J

I

I1

( c ) Nupharamine ( X X X I I ) is convertible to anhydronupharamine

(XXXIX)and this, via an organic boron compound, can be changed into isonupharamine (XI& which upon cyclization affords deoxynupharidine ( 3 6 ) .Consequently nupharamine has structure XXXII.

458

J. T. W R ~ B E L

B. ABSOLUTE COXFIGURATION Nupharamine ( X X X I I ) has three asymmetrical carbon atoms. I n determining the absolute configuration Kawasaki et al. (36)made use of chemical, IR-, and KMR-methods. Taking advantage of the findings of Leonard and Ryder that cis and trans isomers of dialkylpiperidines can be distinguished by their IR-spectra (36) and of Katritzky (28) and of Kotake ( 2 1 ) that axial and equatorial groups give maxima a t different positions in NMR-spectra, they observed a correlation between the configuration of nupharamine and the known one of deoxynupharidine. Isonupharamine (XLI) was converted to deoxynupharidine which was a mixture of diastereoisomers-( XLII) and (XLII1)-differing in configuration at C-7. After chromatographic separation on alumina the form XLII was shown to be identical with natural deoxynupharidine, i .e., 1e,7aa-dimethyl-4e-[ 3-furyl]-quinolizidine. XLI 1. SOCla

2. KOH/MeOH

XLII

XLIII

Furthermore, signals were observed for the equatorial methyl groups in the range of 0.68-0.89 ppm and for the axial in that of 1.10-1.19 ppm ; this evidence was additionally used to establish the conformation of C-2, C-3, and C-6. These results made it possible t o conclude that configurations at C-2, C-3, and C-6 in nupharamine are identical with those a t C-10, C-1, and C-4 in I-deoxynupharidine ; hence the absolute configuration a t the asymmetrical carbon atoms in H nupharamine is found to be C-2 (R), C-3(X), and C-6 (R) (36).

C. SYNTHESIS Whereas nupharamine has not yet been synthesized dl-deoxynupharamine (XLIV) was synthesized by Arata et al. ( 4 0 ) .

10. Suphar

459

ALKALOIDS

XLIV

The starting product was the keto acid XLV obtained in the following way : Ac Me Me’

C‘HsCOCHzCOzht >

\CHCH~CH~COC~

RCO-CHC02Et I

H

+ KaoEt

= isoamyl

XeI

--COzEt

Me

I

HrCHpCHzCOzEt

+R-COCHCOZEt

I I

JIeC--CHz

RCO

HCI +

1

CH2-CO2Et

/CHz\ Me-CH CHz

-

I

I

RCO COzEt XLV

The compound XLV gave-via the oxime, methylation, hydrogenation, and thermal cyclization-the 5-methyl-6-isoamyl-piperidone-2 (XLVI) which was converted into the aminoester XLVII which upon condensation with 3-furoyl chloride and cyclization with the aid of soda lime gave the compound XLIX. Hydrogenation of XLIX gave deoxynupharamine (XLIV) whose IR-spectrum was identical with that of the

scoo 1 . NHpOH 2. C H 2 S z F

Me

Me

1. HCl

2. EtOH/RCl

3. I ’ t O Z

4.

XLT’

A

H

XLVIL

XLVI

R = isoamyl

H 0

XLIX

XLVIII

460

J. T. W R ~ B E L

deoxynupharamine obtained from natural ( - )-nupharamine in the following way :

IV. Dehydrodeoxynupharidine

L

Dehydrodeoxynupharidine (L), a minor unstable Nuphar alkaloid, was isolated and investigated by Arata (37).

STRUCTURE The empirical formula is C15H210N and the IR- and NMR-spectra supplied evidence of a furan ring, a trans-quinolizidine system, and a double bond conjugated with furan. On reduction with sodium borohydride dehydrodeoxynupharidine gave the dihydro derivative, CI~H~~O which N , was identical with ( - )-deoxynupharidine; hence the problem of its structure was reduced to that of the position of the double bond. Since the IR-spectrum indicated conjugation between the double bond and furan the structure of the alkaloid could be either LI' or LI". Me

Me

I

Me

LI'

LI''

10. Nuphar

ALKALOIDS

46 1

The position of the double bond was proved by the following synthesis :

LIII

LII

1,7-Dimethyl-3-furoyl-4-quinolizidone (LII) (32) was converted into the dehydro derivative (LIII), the perchlorate of which proved to be in every respect identical with that of natural dehydrodeoxynupharidine. Since L I I I is reduced by NaBH4 t o (-)-deoxynupharidine, the absolute configuration of the latter-1 S; 7 R ; 10 R-is also that of dehydrodeoxynupharidine.

V. Nuphamine Isolated by Arata and Ohashi (38)from the rootstock of N . japonicum and found to have the empirical formula C~,H2302N,nuphamine proved to be an alkaloid incorporating piperidine and furan rings and to have structure LIV.

LIV

STRUCTURE Chemical analyses and IR-spectra indicate the group OH (3620cm-1) and a furan ring (3150 and 1500 cm-1) and show the alkaloid to be a secondary amine (it gives an X-methyl methiodide). The NMR-spectrum demonstrated the group CH3-CH < (9.09 doublet), CH3-&==C (8.36 singlet), a methylene group (6.20 singlet) and the vinyl proton (4.74broad). Treatment of nuphamine with thionyl chloride followed by catalytic reduction of the chloroderivative leads to ( - )-deoxynupharamine and hydrogenation to the dihydro derivative C15Hz502N.

462

J. T. W R ~ B E L

The NMR-spectrum demonstrates in the dihydro derivative two secondary methyl groups (9.10 doublet) and a methylene group (6.70 doublet) next to the hydroxyl. Taken together these data are sufficient evidence for structure LIV.

VI. Neothiobinupharidine This compound, isolated by Achmatowicz and Wrbbel ( l l )is , one of the sulfur alkaloids of N . luteum. It has been found to have the diterpenoid structure LV which incorporates the quinolizidine, furan, and tetrahydrothiophene systems (11,24, 39).

L \7

STRUCTURE The marked stability of the alkaloid has thwarted attempts to establish the structure by chemical methods (11)and has necessitated a physicochemical and physical approach. Achmatowicz and Wrbbel sought to settle the question by IR- and NMR-studies. The former revealed the trans-quinolizidine system, monosubstituted furan ring, methyl groups, and the system -CH2-S-C unconjugated with furan. The peaks in the NMR-spectrum plainly indicate furan and asymmetry of the molecule. Further NMR-data are misleading, indicating six instead of eight protons about the nitrogen, and four methyl groups, two of them tertiary. The mass spectrogram with an intensive peak for the molecular ion also demonstrated fragments with the masses of 359, 230, 178, 136, and 94, of which the last two are evidently shared with deoxynupharidine ; two of the remaining peaks are interpreted in the formulas LVI and LVII whereas the third, 359, corresponds to M-135, much like 98 in deoxynupharidine (98 = 233 - 135).

10. Nuphar

463

ALKALOIDS

Me I

Me

LVI ( 1 7 8 )

LVII (230)

I

This body of evidence, in which much emphasis was placed on the NMR-spectrum, led to the partly correct structure LVIII in which the Me

P

LVIII

two deoxynupharidine skeletons are wrongly combined. This was corrected to LV with the aid of X-ray analysis (39).

VII. Thiobinupharidine This is the second crystalline sulfur alkaloid of N. Zuteum (10, 11, 24). Its similarity to neothiobinupharidine is suggested by analytical data (empirical formula C ~ O H ~ ~ Oand ~ Ntwo ~ Smethyl , groups), and by UV-, IR-, NMR-, and mass spectra. However, the spectral data for this alkaloid (11) are more unequivocal and indicate in addition to a psubstituted furan and the trans-quinolizidine system : ( a ) symmetry of the molecule, as well as ( b ) two CH3-CH groups, and ( c ) the grouping -CHz-S-.

VIII. Castoramine (LIX) The scent glands of the North American beaver, Castor canadensis, contain the alkaloid castoramine which has been shown to be a hydroxy derivative of desoxynupharidine and is convertible into the latter (41). The hydroxyl is hydrogen-bonded to the nitrogen and this gave the first

464

J. T. W R ~ B E L

clue to its structure which was confirmed by a synthesis ( 4 2 ) . Ethyl a-methyl-, a-acetylsuccinate was decarboxylated to LX which was converted to a Mannich base and quaternized (LXI). The potential vinyl group in the latter added ethyl cyanoacetate a,nd the product (LXII) catalytically reduced to the quinolizidone LXIII. The ester group of the latter was partially reduced and the resulting hydroxyl protected through ether formation with dihydropyran (LXIV). The last stages involved treating with 3-lithium furan a t -7O", hydrolysis of the ether, and catalytic reduction of the enamine.

Xj,,, - /-n- flCO ,N,

LX

I

0

COzR

LXI

LXIII

ROzC

CN

LXII

LXIV

LIX

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

G. Dragendorff, Phurm. 2. Russland 18, 514 (1879).

W. Griining, Arch. Pharm. 20, 589 (1882). J. Arima and T. Takahashi, Bull. Chem. Soc. J a p a n 52, 815 (1931). E. Bures and M. Hoffmann, Casopis Ceskoslov. Lekarnictva 14, 129 (1934). 0. Achmatowicz and M. Mollbwna, Roczniki Chem. 19,493 (1939). Y. Arata and T. Ohashi, J . Pharm. SOC. Japan 77, 792 (1957). Y. Arata, Chem. & Phurm. Bull. (Tokyo) 12, 1394 (1964). Y . Arata and T. Ohashi, Chem. & Phurm. Bull. (Tokyo) 13, 392 (1965). M. Kotake, J. Kawasaki, S. Matsutani, S. Kusumoto, and T. Kaneko, BUZZ.Chem.

SOC. Japan 84, 160 (1963). 10. 0. Achmatowicz and 2. Bellen, Roczniki Chem. 36, 1815 (1962); Tetrahedron Letters p. 112 (1962). 11. 0. Achmatowicz and J. T. Wrbbel, Tetrahedron Letters p. 129 (1964). 12. M. Kotake, K. Kawanaga, T. Kubota, and A. Hagitani, Proc. I m p . Acad. (Tokyo) 19, 490 (1943). 13. Y. Arata, J . Phurm. SOC. Japan 66, 138 (1946). 14. Y. Arata,J. Pharm. SOC. J a p a n 76, 1447 (1956). 15. M. Kotake, S. Kusumoto, and T. Ohara, Ann. Chem. 606, 148 (1957).

10. Nuphar 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

ALKALOIDS

465

Y. Arata, hi. Koseki, and K. Sakai, J . Phurm. SOC. Japan 77, 232 (1957). Y. Arata and T. Ohashi, J . Pharm. SOC. Japan 77, 236 (1957). Y. Arata, J . Pharm. SOC. J a p a n 69, 319 (1949). Y. Arata, J. Pharm. SOC. J a p a n 77, 321 (1957). Y. Arata and T. Ohashi, J . Pharm. SOC. J a p a n 68, 77 (1948). M. Kotake, I. Kawasaki, T. Okamoto, S. Matsutani, S. Kusumoto, and T. Kaneko, Bull. Chem. SOC. Japan. 35, No. 8 (1962). Y. Arata and T. Ohashi, J . Pharm. SOC.J a p a n 77, 229 (1957). F. Bohlmann, E. Winterfeldt, P. Studt, H. Laurent, and K. M. Kleine, Chem. Ber. 94, 3151 (1961). 0. Achmatowicz, H. Banaszek, G. Spiteller, and J. T. Wrbbel, Tetrahedron Letters p. 927 (1964). N. Neuner-Jehle, H. Sesvadba, and G . Spiteller, Monatsh. Ckem. 95, 687 (1964). I. Murakoshi, J.Pharm. SOC. Japun 78, 594 (1958). M. Kotake, I. Kawasaki, T. Okamoto, S. Matsutani, S. Kusumoto, and T. Kaneko, Bull. Chem. SOC. J a p a n 35, No. 8 (1962). T. M. Moynehan, K. Schofield, R. A. Y . Jones, and A. R. Katritzky, J . Chem. SOC. p. 2637 (1962). Y . Arata, N. Hazama, and Y . Kojima, J . Pharm. SOC. J a p a n 82, 326 (1962). M. Kotake, I. Kawasaki, T. Okamoto, S. Kusumoto, and T. Kaneko, Ann. Chem. 636, 158 (1960); Bull. Chem. Soc.Japan 32, 892 (1959); T. Kaneko, I. Kawasaki, and T. Okamoto, Chem. & Ind. (London)p. 1191 (1959). M. Kotake, I. Kawasaki, S. Matsutani, S. Kusumoto, and T. Kaneko, BUZZ.Chem. SOC. J a p a n 35, 1494 (1962). Y. Arata and T. Nakanishi, J . Pharm. SOC. J a p a n 80, 855 (1960); Y. Arata, T. Nakanishi, and Y . Asaoka, Chem. & Pharm. Bull. (Tokyo) 10, 675 (1962). I. Jezo, M. Karwas, and K. Tihlarik, Chem. Zvesti 15, 283 (1961). J. T. Wr6bel and Z. Dabrowski, Roezniki Chem. 39, 1239 (1965). Y. Arata and T. Ohashi, J . Pharm. SOC.J a p a n 79, 127, 729, and 734 (1959); 77, 792 (1957). I. Kawasaki, S.Matsutani, and T. Kaneko, Bull. Chem. SOC. J a p a n 36, 1474 (1963). Y. Arata, Chem. & Pharm. Bull. (Tokyo) 13, 907 (1965). Y. Arata and T. Ohashi, Chem. & Pharm. Bull. ( T o k y o ) 13, 392 (1965). G. I. Birnbaum, Tetrahedron Letters p. 4149 (1965). Y. Arata, T. Ohashi, Z. Okumura, Y . Wada, and 11.Ishikawa, J . Pharna. Soc. J a p a n 82, 5 (1962); 83, 79 (1963). Z. Valenta and A. Khaleque, Tetrahedron Letters 12, 1 (1959). F. Bohlmann, E. Winterfeldt, H. Laurent, and W. Ude, Tetrah.edron 19, 195 (1963).

This Page Intentionaiiy Laft Blank

--CHAPTER

1 1-

THE MESEMBRINE ALKALOIDS* A. POPELAK A N D G. LETTENBAUER Research Department, C.F. Boehringer & Soehne GmbH, Mannheim, Germany

.................................................. 11. Occurrence and General History.

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

111. Chemistry of the Alkaloids.. .......................................... A. Isolation of the Bases. . . . . . . . . . . . . . ............... B. Mesembrine . . . . . . . . . . . . . . . ................................... C. Mesembrenine .......................................... D. Mesembrinol. .................................................... E. Channaine and Other Alkaloids with Undetermined Structures. . . . . . . . . . Table 111: Physical Constants of Derivatives and Degradation Products References

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

467 467

....

469 469 470 476 477 478 479

481

I. Introduction The mesembrine alkaloids, a group of alkaloids named after the most important representative, mesembrine, have been studied in detail only recently. The basic skeleton of these alkaloids is formed by mesembrane (I),an N-methyl-3a-(3’,4’-dimethoxyphenyl)-~~~-octahydroindole. The mesembrine alkaloids are closely related to the 5,1Ob-ethanophenanthridine group of the Amaryllidaceae alkaloids which are derived from crinane (11).

11. Occurrence and General History The mesembrine alkaloids were discovered in a drug preparation that was named Channa or Koegoed by the bushman of Namaqualand (1-3).

* Supplementary to Volume VII, page 514. 467

468

A. POPELAK A N D G. LETTENBAUER

The drug is obtained by fermentation from Sceletium species (Ficoidaceae) growing in the southwest Cape province. Channa is considered a favorite stimulant of the natives of South-west Africa. When chewed, the drug is said to have a narcotic and in some respects a cocaine-like effect ( 4 ) . The genus Mesembryanthemum Dill has not survived the scrutiny of taxonomists, and many plants originally referred thereto have recently been transferred to the genus Sceletium N. E. Brown (Ficoidaceae or Aizoaceae). Hence, the plant names in the older literature concerned with the alkaloids are based upon Mesembryanthemum as are the names of the alkaloids. The following plant names are presently accepted in lieu of those used originally: Scetetium expansum (L.) L. Bolus ( 3 ) ,X. tortuosum (L.) L. Bolus ( 3 ,5, 6),S. anatomicum (Haw.) L. Bolus ( 5 ) ,and 8. namaquense L. Bolus ( 7 ) .Meiring ( 8 )detected alkaloids in Channa in IS96 and Hartwich and Zwicky ( 3 ) in 1914 gave the name mesembrine to an amorphous base. Rimington and Roets (5) assigned to mesembrine the formula C I ~ H ~ ~based N O on ~ analyses of the picrate and the chloroplatinate. A crystalline hydrochloride of mesembrine was described by Bodendorf and Krieger (6) and the structure of the alkaloid was elucidated by Popelak and co-workers (7). Meanwhile a number of new alkaloids have been isolated from Sceletium species (Table I).

TABLE I

PHYSICAL CONSTANTS OF ALKALOIDS ISOLATED FROM CHANNA

Compound

Formula,

Melting or boiling point ("C)

[a]?

(solvent)

Reference

3, 5 , 6

Mesembrine

C17H23xO3

hlesembrenirte Mesernbrinol

C17H211\103

Oil, 186-190/0.1 m m 88-80

C17H25NO3

143-146

Kormesembrine Chaniiaine Alkaloid Sceletium A4

C16H21h'O3

159-180 Ci6HisX03 C Z O H Z ~ X Z O Z 155-156

+ 130"

11

Alkaloid Sceletium B3

C16HisNO3

( CHsOH) 0"

11

-

168

6, 8 9, 10

* 0" *

9

6

11.

THE M E S E M B R I N E ALKALOIDS

469

111. Chemistry of the Alkaloids

A. ISOLATION OF THE BASES The content of alkaloids in the Channa drug ranges from 1.0 t o 1.50/,. The hydrochlorides of mesembrine and mesembrenine were isolated in yields of 0.7 and 0.2 y;, respectively, from the drug. The other alkaloids occur only in very small quantities. Mesembrine, mesembrenine, and chanaine could be isolated by the following method : The ground drug was extracted with ethanol. Distillatioil of the alcohol afforded a residue which was dissolved in diluted sulfuric acid. After separation of undissolved materials by filtration and extraction of nonbasic products with ligroin the solution was made alkaline. First the solution was extracted exhaustively with ether and then with ethyl acetate. An oily residue was obtained from the ether solution and a solid one from the ethyl acetate solution. The ether-soluble oily fraction, dissolved in 2-propanol, yielded mesembrine hydrochloride upon acidification with ethereal hydrochloric acid. Fractional crystallization of the concentrated mother liquors gave, besides some mesembrine hydrochloride, the hydrochloride of mesembrenine. Crystallization of the solid ethyl acetate residue from a mixture of ethyl acetate and 2-propanol afforded channaine. The mesembrine alkaloids can be separated chromatographically by the ascending method on paper (Schleicher and Schuell 2042 b mgl), impregnated with a solution of formamide in acetone ( 1 :a), with the solvent systems A (methyl ethyl ketone :heptane = 2 : 3) and B (methyl ethyl ketone:xylene = 1 : l ) , in an atmosphere saturated with ammonia (11).After spraying with Dragendorff reagent an extract from S. namaquense showed a t least nine alkaloids. The R, values of the mesembrine alkaloids are given in Table 11. TABLE I1

R, VALUES OF MESEMBRINE ALKALOIDS System A

System B

Compound

Bt

Rl

Sceletium As Seeletium A0 illesembrine Mesembrenine Mesenibririol Sceletium B3 Sceletium Bs Channaine

0.73 0.38 0.45 0.30 0.18

0.90 0.85 0.61 0.38 0.20 0.13

470

A . POPELAK AND G. LETTENBAUER

B. MESEMBRINE 1. Chemical Properties

Mesembrine (III), N-methyl-3a-(3’,4’-dimethoxyphenyl)-6-oxo-~i~octahydroindole, is the most important alkaloid of the mesembrine group. It was isolated as the hydrochloride because the base is an uncrystallizable oil. Mesembrine gives a number of color reactions ( 3 ) . It was found to contain two methoxyls in a veratryl group, one N-methyl, and one ketocarbonyl. Naturally occurring mesembrine is optically active (7). ( k )-Mesembrine can be obtained by catalytic hydrogenation of mesembrenine. OCH3 I

(333

111

Upon treatment with hydroxylamine mesembrine gave an oxime, isolated as a crystalline hydrochloride (6). This ketoxime was reduced with lithium aluminum hydride to a primary amine ( 9 ) . By catalytic hydrogenation mesembrine yields an optically active alcohol, mesembrinol (6, 7). Condensation with benzaldehyde formed a dibenzylidene derivative of mesembrine (9). Crystallization of mesembrine hydrochloride from ethanol unexpectedly produced the hydrochloride of the enol ether I V (10).

I\’

The crystalline base of that enol ether, not formed direct.ly by refluxing mesembrine base and ethanol, was stable toward catalytic hydrogenation

11 .

471

THE MESEMBRINE ALKALOIDS

and resisted reduction with sodium borohydride. With 0.1 N hydrochloric acid, however, the enol ether was reconverted rapidly and quantitatively to mesembrine hydrochloride. Crystallization of mesembrine hydrochloride from 2-propanol always yielded unchanged material (11). Wolff-Kishner or Clemmenserl reductions of mesembrine afforded mesembraiie (I),the parent compound of the mesembrine alkaloids

( 7 , 12). 2. Structure

Mesembrine was subjected to a number of degradation reactions but in most cases no promising degradation products could be isolated.

CH3

V

VI

1. CH8.J

VIII

IX

VII

472

A . P O P E L A K X N D G . LETTENBACER

Hofmann degradation of the crystalline mesembrine methiodide afforded a definite desmethylmesembrine but further degradation failed (11). Alkali fusion, degradation by ozone, and selenium dehydrogenation ( 6 ) were also without success. Oxidation with potassium permanganate produced 3,4-dimethoxyphenylglyoxylic acid and 3,4-dimethoxybenzoic acid ( 7 ) . Evidence for the basic skeleton of mesembrine was furnished by the following sequence of reactions ( 7 ): Rlesembrine (V) was catalytically hydrogenated to mesembrinol (VI). Dehydration of mesembrinol with phosphorus pentoxide in boiling xylene afforded a mixture of two isomeric mesembrenes (VII). Methylation of the mixture and Hofmann degradation of the methiodides gave a homogeneous des-A-methylmesembrene (VIII). Further methylation with methyl iodide and Hofmann degradation of the methiodide produced 3,4-dimethoxydiphenyl (IX), ethylene, and trimethylamine by a surprising fragmentation reaction. In support of the structure which was derived from the results of the degradation, mesembrane (I), the basic skeleton of mesembrine was synthesized (8). The synthesis was performed in analogy with the synthesis of ( & )-crinane (11)by Wildman (13)as follows: OCH3 I

OCH3 I

OCH3

I

XI11

2-( 3',4'-DimethoxyphenyI)cyclohexanone (X) afforded by Michael reaction with acrylonitrile a 2-cyanoethyl derivative ( X I ; R = CN).

11.

THE MESENBRINE ALKALOIDS

473

Methanolysis gave the corresponding methyl ester ( X I ; R = COOCH3). Subsequent reaction with hydrazine hydrate yielded a hydrazone hydrazide which was decomposed with nitrous acid to produce the hexahydroindole XII. Catalytic hydrogenation of XI1 afforded normesembrane ( X I I I ; R = H), and a following methylation produced ( k )-mesembrane ( X I I I ; R = CH3), identical with ( & )-mesembrane obtained from ( k )mesembrine. ( k )-Mesembrane was resolved into its antipodes by fractional crystallization of the salts with cc-bromo-d-camphor-nsulfonic acid, and ( - )-mesembrane, identical with ( - )-mesembrane derived from mesembrine, was obtained ( 7 , 12). Cis fusion of the rings of the octahydroindole is anticipated when a hexahydroindole derivative is catalytically hydrogenated to an octahydroindole (14).For the rings C/D of crinane (XIV), synthetized in an analogous way, c i s fusion resulted ( l 4 a ) .

Besides ( & )-mesembrane the isomeric ( k )-isomesembrane (XV; R = CH3) with trans fusion of the octahydroindole system was obtained, when the methiodide, derived from the hexahydroindole XII, was catalytically hydrogenated. Reduction of the hexahydroindole XI1 with complex hydrides yielded almost equal quantities of ( k )-normesembrane and ( i )-norisomesembrane (XV ; R = H) (12). The synthesis of mesembrane, the parent skeleton of mesembrine, did not solve the position of the keto group for which there remained two

474

A . POPELAK A N D G . LETTENBAUER

possible positions. Evidence for its position was derived from the following series of reactions (7):

mesrmhrine

p +p p'. +

/

CH3

/

CH3

XVII

SVI

d

H3C

CH3

H*C=CH2 XVIII

+ N(CH3)3

XIX

By reaction with phenyl lithium, mesembrine produced phenylmesembrinol (XVI) which was dehydrated with thionyl chloride to a mixture of two isomeric phenylmesembrenes (XVII). Methylation and Hofmann degradation of the mixture of methiodides afforded a uniform des-A-methylphenylmesembrene (XVIII). Methylation of XVIII and Hofmann degradation of the resulting methiodide yielded, besides (XIX). The ethylene and trimethylamine, 3,i-dimethoxy-p-terphenyl isolation of 3,4-dimethoxy-p-terphenyl served to locate the position of the keto group. There are two possible conformations of mesembrine (XXa and XXb). The most probable is XXa, since it has only one axial substituent on the cyclohexane ring (10). CH3

I

OCH3 SXb

11.

475

THE 3ZESEMBRINE A L K h L O I D S

The remaining problem of the structure of mesembrine, the absolute configuration, was solved by an application of the octant rule (10).The enantiomer XXa should exhibit a negative Cotton effect and mesembrine, dissolved in dioxane did show such a negative effect.

3. The Synthesis of Mesernbrine The total synthesis of ( )-mesembrine was performed by Shamma by the following route (15):

&- @ 3 steps

0 3 stcps

&COO.

3 strps,

0-Ac

X

0-AC

XXII

XXI Ar

a

K

-

C

H

H SXIII

3

3 steps

3 stells

F I ; : H s

Br XXIV

H CHO

ss\-I1

Monoalkylation with sodium hydride and ally1 bromide of 2 - ( 3',4'dimethoxypheny1)cyclohexanone (X), the starting material of the

mescmbrane synthesis, gave a 2-ally1derivative which ivas reduced with lithium aluminum hydride to yield I allyl-2-(3’.1’-dimethoxyphen[vl)cyclohexanol. Xcetylation of the hydroxyl group afforded an acetate ( X X I ) which was oxidatively cleaved by osmium tetroxide and sodium periodate to an aldehyde acetate. This aldehyde was oxidized with alkaline silver oxide to the acid XXII. By treatment with oxalyl chloride the acid formed an acid chloride which gave a metliylamide when it wa5 reacted with methylamine. The methylamide was reduced with lithium aluminum hydride to give 2-(2”-methylaminoethyl)-2-(3’,4’-dimethoxyphenyl)cyclohexanol ( X X I I I ) . Reaction with ethyl formate afforded a formamide derivative, the secondary hydroxyl of which was oxidized with chromic acid to a keto group. Subsequent bromination produced the bromoketone XXIV which mas debrominated to an unsaturated ketoamide. Epoxidation of the unsaturated ketoamide yielded the epoxiketone XXV which was reduced with chromium-11-acetate to the P-hydroxy ketone XXVI. Reduction with sodium borohydride afforded a 1.3-diol. The less hindered hydroxyl of this diol was preferentially oxidized with air over platinum to give the Kformyl keto alcohol XXVII, which was dehydrated and hydrolyzed with ethanolic hydrochloric acid. Ring closure of the intermediary unsaturated ketone generated ( i. )-mehembrine.

4 . The Biogenesis of Mesembrine Some preliminary results regarding the biosynthesis of mesembrine were obtained by Jeffs by feeding Sceletiurn plants with radioactive unit of precursors (16). It was possible to show that the Cs-C2-N mesembrine is derived from tyrosine and that the six carbons of the aromatic ring are derived from phenylalanine.

C. MESEMBRENINE Jlesembrenine (XXVIII) was isolated from the mesembrine mother liquors as its hydrochloride ( 6 ) .It contains, in addition to the functional groups of mesembrine, a carbon-carbon double bond. M’hen mesembrenine was catalytically hydrogenated over palladium on charcoal ( & )-mesembrine was isolated from which ( f )-mesembrane could be produced by Wolff-Kishner reduction ( 8 ); consequently only structure XXVIII is possible for mesembrenine. The absence of optical activity in mesembrenine can be rationalized by assuming a P elimination to the symmetric intermediary product X X I X , and because of the two identical ,8 positions, a succeeding re-

1 1 . THE

MESEMBRINE ALKALOIDS

OCHZ

OCH3

XXVIII

XSIS

I

477

I

cyclization of the intermediary product XXIX must give racemic mesembrenine (10).Reduction of mesembrenine with lithium aluminum hydride yielded 6%yo of mesembreninol, an unsaturated alcohol which gave ( & )-mesembrinol on catalytic hydrogenation (6).

D. MESEMBRINOL Mesembrinol (XXX) was isolated by column chromatography from the mixture of bases which was extracted from Channa drug (9, 10).

CH3

Jlesembrinol is a dihydromesembriiie and was obtained by the catalytic hydrogenation of mesembrine ( 6 ) . Catalytic hydrogenation of mesembrenine or mesembreninol afforded ( )-mesembrinol (6). Reduction of mesembrine with sodium borohydride, however, produced a mixture of almost equal quantities of mesembrinol and epimesembrinol, differing only in the configuration of the hydroxyl (11).The crystalline base, mesembrinol, could be separated from the oily base. epimesembrinol, by crystallization or column chromatography.

478

A . POPELAK A S D G . L E T T E N B A U E R

Attempts to elucidate the structure of mesembrinol by degradationbefore the structure of mesembrine had been established-proved to be unsuccessful (11):

xXX1

XXXI

+

H3CO & N

H,C"CH,

Y

XXXII

I

1. AgtO 2. heat

+

+

X X X I X X X I I I S(CH3)3 + nonbasic materials

XXXIII

Mesembrinol gave a good yield of a methiodide which produced des-Nmethylmesembrinol ( X X X I ) by Hofmann degradation. Methylation of X X X I with methyl iodide afforded a noncrystalline methiodide ( X X X I I ; X =I).This methiodide, when heated with potassium hydroxide, produced, besides starting material X X X I , only the unsaturated ether XXXIII. After thermal decomposition of the methohydroxide X X X I I (X=OH-) which was obtained by treatment of the methiodide with pure silver oxide, a third of the theoretical amount of trimethylamine could be isolated. The corresponding amount of nonbasic materials was also produced but the main products were X X X I and XXXIII.

E.

CHANNAINE AND O T H E R ALKALOIDS

WITH

UNDETERMINED STRUCTURES

I . Channaine Channaine was first isolated by Bodendorf and Krieger from the ethyl acetate fraction of the Channa alkaloids. Analytical data provided the empirical formula C16H19N03 ( 6 )but there were some indications that channaine is represented by a dimeric formula (11).Channaine formed crystals from methanol or ethyl acetate and was found to be optically inactive (11).Spectral and analytical properties showed that channaine contains two methoxyls, probably in a veratryl group. NMR- as well as IR-spectra indicated that the alkaloid has no N-methyl nor carbonyl functions. From Zerewitinoff determinations and KMR-spectra values

TABLE I11 THEPHYSICAL CONSTANTS O F DERIVATIVES AND DEGRADATION PRODUCTS

Formula

Melting or boiling point ("C)

[a]: (solvent)

Reference ~~

205-205

- 10.4" (CH30H)

6,7 , 10

+4.S0 (HzO)

Perchlorate Methiodide Oxime hydrochloride Dibenzylidene ( 2 )-Mesembrine Hydrochloride Mesernbrine enol ethyl ether (IT') Hydrochloride Methiodide Des- N-methylmrsembrine Normesembrine hydrochloride Mesembrenine (XXVIII) Hydrochloride Mesembreninol Mesembrinol ( X X X ) Methiodide Yes-n'-methylmesembrinol ( X X X I )

Dihydro-des-N-methylmesembrinol 0-Methyl-des-A-methylmesembrinol hydrochloride ( X X X I I I ) Des-des-mesembrinol

11

196 169 235-236 171-1 72 183-185 88.5-87 250 201-202 (bp) 184/0.3mni 196-196 192-193 112 193 104 115 213

6 6 9

*

0" -t 102.4" (CzHsOH) t 9 1 . 6 " (CzH50H) 54' (CzHsOH) -56.8' (CH3OH)

+

8 10 10 10 11

9 0"

6, 8, 10

6

-9.9" (CzH50H)

I1 11 11 11

A . P V P E L A K ; I N D U. LETTENUAUER

Mesembrine (111) Hydrochloride

+F. 02 C

TABLE 111-cvntinued

Coinpound -

-

Melting or boiling point ( " C )

Formula ~

~

~~

101 141-142 ( b p ) 16SjO.l mm 159 (bp) 138/0.05 mrn 193 168

198 (bp) 144/0.1 mm 188 (bp) 130/0.4 mni 244-246 211-213 (bp) 145/0.2 m m 202-203 (bp) 146/0.1 m m 184-186 (bp) 135/0.1 m m 235-236 196-197

Rcfcrcncc.

+ 8 . 3 " (CH3011)

7 9

-3.2" (CH30H) (CzlI50H)

11

-4.1"

11

- 13.3"

11

- 16.3'

7, I 2 7, 12

(CHsOH) (CH3OH) - 6.3" (CH3OH) +48.4" (CH3OH)

*

0" -46.5' (CHsOH)

1%

x, I1 11 11

n +59.6" (CH30H) 58.9" (CH30H) -5.7" (CHsOH)

+

9 12

7 7

n 11

+ 62.8" (CH30H) + 8.6" (CH30H)

7

7

I2

THE 3IESEMBRINE ALKALOIDS

Maleinate Mesernhrane (I) H ydrochlorido Bromo-&camphor sulforiate ( & )-Menernbraiie Hydrochlorido Des-N-methylmosembrane Hydrochloride Des-dcs-mosembrane Aminornesembrtme Dihydrochloride Dimet'hiodide R'lesombrene VI1 Hydrochloride Des-N-methylmesembreiie ( V I I I ) Methiodide Tetrahydro-des-N-methylmesembrene Pbenylmesembrene ( X V I I ) Hydrochloride Des-A~-met~liylplienylmesembrene (XVIII) H ydrochlorido

(solvent)

~

11.

Phenylmesernbrinol ( X V I ) ( )-Mesemhrinol Epinieserrihrinol

~

~

11.

THE MESEMBRINE ALKALOIDS

481

between two and three active hydrogens were determined (11). A t present the structure of channaine can not be delineated.

2. Alkaloid Sceletium B3 This alkaloid was isolated by Popelak and co-workers by means of column chromatography and was obtained crystalline from methanol (11).The elementary analysis was in agreement with the empirical formula C16H19N03, isomeric with channaine. It was shown to contain two methoxyls, very probably in a veratryl group. The IR- spectrum showed no significant absorption in the carbonyl region and from NMRspectra the absence of AT-methyl could be concluded. The presence of one active hydrogen was indicated by a Zerewitinoff determination. No acceptable proposal can be given for the structure of this alkaloid. 3. Alkaloid Sceletium A 4 Chromatography of the mother liquors afforded this crystalline base from ethyl acetate (11).It possesses the molecular formula C 2 0 H 2 4 N 2 0 2 and contains two methoxyls, probably in a veratryl group, and one N methyl. It is not affected by catalytic hydrogenation with platinum in acetic acid. The presence of a second nitrogen in the molecule must allocate this alkaloid t o a separate structural group in the mesembrine alkaloids. 4 . Normesembrine Normesembrine was isolated by Bodendorf and Kloss (9).Aside from the melting point of the hydrochloride and the empirical formula, no additional data were given and consequently there can be no certainty as to its structure.

REFERENCES 1. E. RI. Holmes, Pharrn. J . cmd Tran. 810 (1574). 2. J. Meiring, Trans. S. African Phil. Soc., (1596). 3. G. Hartwich and E. Zwicky, Deut. Apotheker-Ztg. 925, 937, 949, and 960 (1914). E. Zuicky, Ph.D. Dissertation, Zurich (1914). 4. J. Watt and &I. Breyer-Brandwijk, “The Medicinal and Poisonous Plants of Southern Africa.” Edinburgh, 1932. 5. C. Rimington and G . C. S. Roets, Onderstepoort J . Vet. Sci. Animal Ind. 9, 187-191 (1937). 6. K. Bodendorf and W. Krieger, Arch. Pharm. 290, 441 (1957); W. Krieger, Ph.D. Dissertation, Karlsruhe (1956). I . A. Popelak, E. Haack, G. Lettenbauer, and H. Spingler, n’aturwissenschaften 47, 156 (1960); see Chem. Abstr. 54, 19742 (1960). r

482

A. POPELAK A N D G . LETTENSAUER

8. A. Popelak, G. Lettenbauer, E. Hasck, and H. Spingler, ~ a t u r ~ , i s s e n s c h a f t 47, e n 231 (1960). 9. K. Bodendorf and P. Kloss, Arch. Pharm. 294, 654-661 (1961). 10. E. Smith, N. Hosansky, H. Shamma, and J. B. Moss, Chem. I n d . ( L o n d o n ) pp. 402403 (1961). 11. A. Popelak and G. Lettenbauer, unpublished results (1960-61). 12. A. Popelak and G. Lettenbauer, U.S. Patent 3,028,394. 13. W. C . Wildman, J . Am. Chem. Soe. 80, 2567 (1958). 14. H. W. Whitlock and G. L. Smith, Tetrahedron Letters p. 1385 (1965). 14a. W. C. Wildman, Alkaloids 6, 367-368 (1960). 15. M. Shamma and H. R. Rodriguez, Tetrahedron Letters p. 4847 (1965). 16. P. W. Jeffs, private communication (1966).

-CHAPTER

12-

THE ERYTHRINA ALKALOIDS RICHARD K. HILL Princeton University, Princeton, New Jersey

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

...................... Structures of Erysodine, Erysovine, and Erythratine . . . . . . . . . . . . . . . . . . 11. Synthesis of Degradation and Rearrangement Products. . . . . . . . . . . . . . . . . . . A. Synthesis of the Apo Rearrangement Products ....................... B. Synthesis of Hofmann Degradation Products of a-Erythroidine . . . . . . . . . I. Introduction

483

C. Synthesis of 15,16-Dimethoxyeryt D. Synthesis of 15,16-Dimethoxyerythrinano1-3 ......................... E. Synthesis of 14,15,16,17-Tetrahydro-16-oxaerythrinane

485 486 486 487 490 493 494

111. Stereochemistry . . . . ........... A. Erythroidines.. . B. Aromatic Group ................................................. C. Stereochemistry of Erythrinanes ...................................

497 497 499 501

..................................................... ....................... ...... VI. Pharmacology ...................................................... VII. Addendum ................................... .................. References .........................................................

505

IV. Total Synthesis

512 513 514 514

I. Introduction I n 1957, at the time of writing the previous review of the Erythrina alkaloids in this series ( I ) , the structures of the mejor alkaloids had only recently been elucidated. Preliminary reports had appeared of syntheses of the parent skeleton which confirmed the unusual spiroamine framework of these alkaloids. Little chemical evidence was available concerning the stereochemistry, though an X-ray study had confirmed the structure and shown the relative configuration of erythraline, one of the aromatic subgroup. The eight years which have elapsed since t,hen have seen complete confirmation of the structures proposed, both by syntheses of most of the rearrangement and degradation products and by X-ray analysis of members of both major classes. Chemical and spectroscopic evidence for 483

484

RICHARD K . HILL

the relative and absolute configurations has been presented and again confirmed by the crystallographic studies. The initial syntheses of the spiroamiiie skeleton have been extended to derivatives containing double bonds and functional groups, and the extensive efforts of Jlondon and his collaborators at Kiel have culminated in a total synthesis of erysotrine. Ingenious biospthetic proposals involving oxidative coupling of tyrosine units have been put forward to account for the formation of the Erythrina group, and an exciting laboratory analogy for such a scheme has been realized. Tracer feeding experiments have confirmed the origin from tyrosine. This chapter reviews the literature on Erythrina alkaloids from 1958 through October of 1966. The structures of the major alkaloid?* are shown in formulas 1-111.

H--

\

OK:!

0

V0

Ia; I31 = R z = H. Erysopine I b ; Ri=CHz, & = H , Erysociinc~ Ic; H l = H , H z = C H 3 , Erysovinc I d ; R I , Rz=-CH:!-, Erythraline I e ; R l = K.r = CH3, Erysotrinc If; Erysoninr = Erysodine with -OH instoad of -0CH3

I g ; R = O H , Erythratine Ih; R = O

at C - 3

I1

111

IV

a-Erythroiclinr

,&Erythroitlinr

Erythriiiaric

* Erysotrine (Ie) does not occur naturally but is a comnion transformation product of the other aromatic alkaloids. In addition to the members shown, two dihydroderivatives occur in nat'ure : dihydroerythraline (erythramine)and dihydroerysodine.

12.

THE

Erythrina ALKALOIDS

485

They contain a tetracyclic skeleton with the three rings A, B, and C common to all the alkaloids and differ only in the nature of ring D. I n the aromatic subgroup, this ring is benzenoid, with oxygenated substituents at (3-15 and C-16, while in the two erythroidines ring D is an unsaturated &lactone. The close similarity in structure, which extends to stereochemical identity, is a strong indication that the two groups share a common origin. For simplicity in naming synthetic products, the saturated parent skeleton ( I V ) of the aromatic group has been given the trivial name erythrinane.

STRUCTURES OF ERYSODINE, ERYSOVINE, AND ERYTHRATINE The final constitutional ambiguities have been removed by the recent elucidation of structure of these three bases ( l a ) . Erysodine and erysovine are isomeric monophenolic ethers, both of which can be methylated to erysotrine (Ie), and which consequently differ only in the relative positions of the methoxyl and hydroxyl groups in ring D. Of the two singlets representing aromatic protons in the NMR spectrum of erysodine, that at 3.35 T could be assigned to the C-17 proton because of long-range coupling with the C-11 benzylic protons. This signal at 3.35 T disappears when erysodine is heated with D20, and the C-17 proton must therefore occupy a n exchangeable position ortho to the phenolic hydroxyl. This evidence fixes the structure of erysodine as Ib, and erysovine must be Ic. Independent evidence for the structure of erysodine, provided by a total synthesis of its dihydro derivative, is presented in section V. The structure of erythratine (Ig), known from earlier studies to be a hydroxylated dihydroerythraline, was elucidated largely from NMR studies, which revealed the part structure R~C--CHZ--CH(OCH~)CHOH--CH=CRz. The allylic nature of the hydroxyl was confirmed by oxidation to the u,P-unsaturated ketone (Ih). Borohydride reduction of Ih gave erpthratine and its C-2 epimer. The I R spectrum of epierythratine in dilute CC14 solution showed a band at 3556 em-1 due to intramolecular hydrogen bonding between the hydroxyl and methoxpl groups; these groups must be cis in epierythratirie and trans in erythratine. Dehydration of erythratine with methanesulfonyl chloride in pyridine afforded erythraline, showing the structural and stereochemical relationship to the other alkaloids. The ketone ( I h ) was recently isolated from Erythrina crystagalli ( l a ) .

486

RICHARD K . H I L L

11. Synthesis of Degradation and Rearrangement Products

A. SYNTHESIS OF

THE

XPO REARRANGEMENT PRODUCTS

A key reaction in the structure elucidation was the rearrangement leading to apo derivatives, which occurs when the &lkaloids are heated with strong acid. The reaction was formulated as shown in Fig. 1. The

1

-J

HO

OH

VI

YII

Apoerysopine

Apo-1-erythroidine

FIG.1. The apo rearrangement.

structures of the apo compounds were assigned by degradation and by a synthesis of apoerysotrine involving Ullmann coupling to form the biphenyl moiety ( I ) .A new synthesis of apoerysopine has been achieved and also a synthesis of apo-fl-erythroidine which confirm the structures of the rearrangement products in both series. 1. Apoerysopine

During the course of attempts to synthesize unsaturated derivatives of erythrinane Mondon and Menz (2) found an unexpected ring closure of VIII to form a seven-membered ring. The product ( I X ) could readily be converted to apoerysopine as shown in Fig. 2 . Several of the intermediates in the conversion of VIII to I X could be isolated using milder conditions.

12.

THE

Erythrina

487

ALKALOIDS

Hi d

q$

I'djC

+ A

v

J

IX 1. LiAlH4 2. HBr

VI FIG.2. Synthesis of apoerysopine.

2. Apo-p-erythroidine

The structure of the apo derivative in the p-erythroidine series (VII) has also been secured through a total synthesis by Rapoport et al. ( 3 ) ,as shown in Fig. 3. The fused indole X was prepared by a Fischer indole synthesis. The strain in this fused tricyclic system makes it susceptible to hydrolytic ring opening to XI. The seven-membered ring was constructed by Dieckmann cyclization and the ketone XI1 condensed with tert-butyl glyoxalate. Treatment of XI11 with the dimethylsulfoxide anion gave directly the doubly unsaturated lactone (XIV),apparently by an unusual intramolecular displacement on the intermediate epoxide. Hydrogenation then gave a mixture of apo-p-erpthroidine (VII) and its double bond isomer.

B. SYNTHESIS OF HOFMANN DEGRADATION PRODUCTS OF E-ERYTHROIDINE The primary evidence for the structure of u-erythroidine had come from Hofmann degradation of the reduction product XV. With one

488

RICHARD K. HILL

+ ROzC-CH2-CO-CsH5

SI

1. K O h 2. H30’

f--j ‘COzBu

Bu-0

/”=”

XI11

Isoapo-8erythroidine

FIG.3. Synthesis of apo-b-erythroidine.

12.

THE

Erythrina ALKALOIDS

489

double bond reduced, Hofmann elimination is accompanied by loss of methanol to generate an aromatic ring. Further Hofmann degradation gave the optically active tetrahydrofuran derivatives XVI and XVII. These two degradation products have subsequently been synthesized by Boekelheide and Morrison ( 4 ) by the route shown in Fig. 4. Although

I1

Hof.

q3 1. Hof.

Ti?

2 . Li.41Hs

3. Hof.

CHzOH CHzOH

CHzOH

xv

‘CH2OH

XVII

XVI

-

I

XVIII 1. AcOH, AciO 2. E O H

xrx

(_+)-XVI

FIG.4. Hofmann degradation of a-erythroidine.

ketone XVII would not add acetylene, it reacted readily with vinyl magnesium bromide. Allylic rearrangement of XVIII to the more stable conjugated isomer gave ( )-XVI. These syntheses of Hofmann degradation products established the structure of XV but left two possibilities for a-erythroidine itself, 11 or XIX. The correctness of I1 was demonstrated by showing that a- and /3-erythroidines could be interconverted by warming in aqueous alkali.

490

RICHARD K. HILL

The equilibrium favors p-erythroidine (111),in which the double bond is unconjugated but more highly substituted, consistent with earlier studies on unsaturated acids ( 5 ) .

c. SYNTHESIS OF 15,16-DIMETHOXYERYTHRINANE( X x ) Although the syntheses described above proved the structures of several of the important rearrangement and degradation products, it was still highly desirable to synthesize compounds containing the intact tetracyclic spiroamine system. The most suitable goal was hexahydrodesmethoxyerysotrine (15,1&dimethoxyerythrinane) (XX) which can be

Ie

V

3H

I_ Pt

xx prepared from erysotrine (Ie) by elimination of methanol through mild acid treatment, then catalytic hydrogenation, Synthesis of this key compound has been achieved by three independent methods. All three syntheses of X X create the spiro carbon by the use of variations of the Pictet-Spengler reaction. This long-known and valuable method of constructing tetrahydroisoquinolines ( 6 ) consists in the acid-

catalyzed condensation of an electron-rich arylethylamine with a carbonyl component (Eq. 1).The carbonyl compound is usually an aldehyde, and ketones are known to react poorly (7,8).Nevertheless, with the help of two modifications it is possible to raise the yields in ketone condensations to acceptable and even high levels. The first of these is the use of amides of p-phenylethylamines instead of the free amines ; the in-

12.

THE

Erythrina

49 1

ALKALOIDS

creased polarization of the C=N double bond in the intermediates X X I and X X I I makes the cyclization more facile, to the point where even

R XXI

XXII

unactivated benzene rings may be used successfully (9-11). Secondly, incorporation of all the components into a single molecule not only raises the yields but permits an elegant method of assembling the entire framework in essentially a single step. 1. Cyclixation of Amides of 3,4-DimethoxyphenylaceticAcid

The first synthesis of X X was achieved by Belleau (9).The necessary precursor for cyclization was prepared by acylation, in aqueous base, of hexahydroindole XXIII with 3,4-dimethoxyphenylacetyl chloride.

(-g XXIII XXIV

p,,

J

xxv Heating XXIV in polyphosphoric acid gave the tetracyclic lactam XXV in 71 yo yield. Reduction of the lactam with lithium aluminum hydride gave racemic XX. The racemic base was resolved with dibenzoyltartaric acid and the ( - )-enantiomorph was shown to be identical with X X from natural sources.

492

RICHARD K. HILL

2 . Cyclizution of Amides of 3,4-Dimethoxyphenylethylamine

An even more facile synthesis of X X u7as achieved by Mondon (10) using the amide derived from 3,4-dimethoxyphenylethylamine(XXVI) and 2-ketocyclohexaneacetic acid (XXVII). The amide XXVIII is prepared simply by heating the ethylene ketal of XXVII with XXVI ; it cyclizes on warming in phosphoric acid to a lactam (XXIX) isomeric with Belleau’s. Lithium aluminum hydride reduction gives the same racemic base (XX). The intermediate lactam X X X can be prepared in

I

H3P01

XXVI

0

docozH &J+

XXVI

A

__f

XXVII

xxx

c

XXIX

90% yield by heating XXVII and XXVI in xylene and then cyclized by acid ( 1 2 ) .Since both starting materials are readily available, the keto acid XXVII via enamine alkylation of cyclohexanone, this method represents the best large-scale synthetic route to XX. 3. Pictet-Spengler Condensation with Cyclohexan-1,Z-dione

A third synthesis of XX, by Xugasawa and Yoshikawa (13),begins with a normal Pictet-Spengler condensation using cyclohexane- 1,2-

12. THE Erythrina ALKALOIDS

493

dione as the carbonyl component. Cyclization of the N-acetyl derivative of X S X I ( R = H ) , or even better, the N-malonyl derivative (XXXI, R = CO-CHz-COzCzH5) completes the five-membered ring. Hydrogenation of the decarboxylated product (XXXII) gives the same lactam ( X X I X ) obtained by Mondon, from which X X is obtained by hydride reduction. The main drawback of this route is the low yield (less than 10%) in the first step.

I<=malonyl ____f

NaOEt

+ XXVI XXXI

XXIX

u XXXII

D. SYNTHESIS O F 15,16-DIMETHOXYERYTHRINANOL-3(XXXVII) A completely different route devised by Prelog and co-workers (14) not only afforded a new synthesis of the erythrinane skeleton but also achieved a method of introducing an oxygen function at C-3, the site of the aliphatic methoxyl in the alkaloids. The synthesis is outlined in Fig. 5. The dihydroisoquinolinium salt XXXIV was prepared by BischlerNapieralski ring closure of the lactam XXXIII. Hydrolysis of the vinyl chloride of XXXIV gave the methyl ketone XXXV. When this salt was made alkaline, addition of the carbanion from the acidic methyl to the C=N double bond created the spiro link. Sodium borohydride reduction of XXXVI gave a mixture of epimeric alcohols. One of them had an IR-spectrum identical with that of a, transformation product (XXXVII) of erysonine (If)and on resolution with tartaric acid its ( - )-enantiomer proved to be identical with XXXVII.

494

RICHARD K. HILL CHpOH

-

c1

c1

XXXIII

0

u XXXVI

CH3

-

J

XXXV

XXXIV

I

NaHH4

XXXVlI

+ 3-epimer FIG.5. Synthesis of 15,16-dimethoxyerythrinanol-3.

E.

SYNTHESIS OF 14,15,16,17-TETRAHYDR0-16-0XAERYTHRINANE (XLI)

The above syntheses of the parent spiroamine system establish the skeleton of the aromatic alkaloids. A synthesis of a derivative of /3erythroidine (111)with the intact spiro skeleton, achieved in Boekelheide’s laboratory (15), provides similar confirmation for the lactonic alkaloids. The necessary amine (XXXIX) was prepared from the acid dimerization product (XXXVIII) of acrolein. Condensation with XXVIIa using Mondon’s erythrinane synthesis led to the lactam XL and thence to the amine XLI, which was resolved with dibenzoyltartaric acid. A compound of the same structure was prepared from /3-erythroidine via

12.

THE

Erythrina ALKALOIDS

495

the hexahydrodesmethoxy derivative XLII, but though its IR-spectrum was similar to that of XLI it was distinctly different.

aCHO+ % /

XXXIX

XXXVIII

y-

I,iAIH4

a-XLI

111

H30’

+

LIAIHI, methylal

,--AlHi

v

4 Ha

Pt

9 0

XLII

P-XLI

496

RICHARD K. HILL

Since the most likely explanation for the difference appeared to be stereochemical, an alternate way of preparing XLI from ,L-erythroidine was sought which would yield the diastereoisomer epimeric a t C-6. It was found that lithium aluminum hydride reduction of 111,when carried out in refluxing methylal, not only reduced the lactone ring but also removed the methoxyl group with concomitant migration of the double bonds to give XLIII. A possible explanation is an S,2' attack of hydride as shown. Birch reduction of XLIII, followed by cyclic ether formation and hydrogenation, gave material identical with synthetic XLI. The prefixes cc and /3 were assigned t o the two diastereomeric series of degradation products ; it was suggested that the cc series had a cis A/B ring fusion and the /3 series a trans fusion. It is possible that these assignments should be reversed since catalytic hydrogenation of Erythrina derivatives has since been found to lead almost invariably to A/B cis compounds (see Section IIIC). An earlier attempt by Belleau (16)to prepare XLI by an alternate route failed in the last step. The tricyclic ketone XLV was synthesized from hexahydroindole (XXIII) using a Reissert-type synthesis to prepare

XXIII

CN-

d : O C &

CaHsCOCl

1. II('1

3. I%r-(CH2)3

I

('OOX

XLIV

&2 I

COOR

1. NaOEt

2 . H('1

XLVI

XLV

XLI

XLVII

12.

THE

Erythrina ALKALOIDS

497

XLIV, then building ring C by Dieckmann cyclization. Though the carbonyl group in XLV is too hindered to react with most reagents, the addition of ethoxyacetylenemagnesium bromide was successful, and acid-catalyzed rearrangement of the adduct gave the unsaturated acid XLVI. I n a model for the final step cyclohexenylacetic acid was found to undergo Prins’s reaction with formaldehyde leading to an unsaturated lactone of the type present in p-erythroidine ( 1 7 ) .This reaction failed with XLVI, giving instead a substance regarded as XLVII.

111. Stereochemistry All of the aromatic alkaloids (except for erythratine) and p-erythroidine possess two asymmetric carbon atoms-the spiro carbon (C-5) and the carbon substituted by methoxyl (C-3). a-Erythroidine has an additional center of asymmetry at C-12. Chemical, spectroscopic, and crystallographic methods have been used to assign relative and absolute configurations a t the asymmetric centers. A. ERYTHROIDINES An X-ray crystallographic study of dihydro-8-erythroidine hydrobromide carried out by Hanson (18) not only confirmed the structures

XLVIII

of the two lactonic alkaloids but also revealed the details of stereochemistry shown in XLVIII. Rings A and B are roughly planar and lie almost perpendicular to the rough plane formed by rings C and D. The C-0 bond at C-3 is c i s to the C--N bond a t C-5. Since tc- and 13-erythroidines are interconvertible by alkali, they must have identical configurations at the two common asymmetric centers. The X-ray study was extended to a determination of absolute configuration. The problem of the phase angle was solved by the Bijvoet method taking advantage of the anomalous dispersion of copper radiation

498

RICHARD K . HILL

by the bromine atom. The configuration is shown correctly in XLVIII; the erythroidines have the 3 R , 5 S configuration. X chemical determination of the absolute configuration a t C-3 by Boekelheide and Wenzinger corroborated this conclusion ( 1 9 ) . The dihydropyran derivative (L) derived from tetrahydro-p-erythroidine

%n

I11

n

+ H 1'Zt CH3O

0 XLIX

L

m

1. Hz ___f

2 . Hof.

1 . Hr A

2. Hof.

CHjO

FIG.6. Absolute configuration at C-3 of ,,!-erythroidine.

(XLIX)was degraded by Hofmariii elimiriations (Fig. 6) to a mixture of dienes which was oxidized to X( - )-3-methoxyadipic acid. The absolute configuration of this acid was known from earlier work in which it had been a key intermediate in establishing the absolute configuration of sterols (20)arid led to the 3 R coiifiguration for P-erythroidine. The configuration a t the remaining asymmetric center in a-erythroidine, C-12, was determined by Hill aiid Schearer (21) who took advantage of the Hofmanii degradation sequence carried out earlier (Fig. 4) which had yielded the dextrorotatory ketone XVII ; ( + )-XVII was synthesized by reaction of the organocadmium reagent from o-bromoethylbeiizeiie with the acid chloride from ( + )-tetrahydrofuran-3-carboxylic acid (LI). The configuration of L I was then established by conversion t o ( + )-3-methyltetrahydrofuraii which was also prepared from R(+ )-

12.

THE

Erythrina

499

ALKALOIDS

CHzCH3

Id1

(+)

~

XYII

(+)

1. LiAlH, 2 . SOCI* 3. J.iAIHI

0) <

CHzOH

(*H3---

I.iAIH~

CH3---

CH2OH

(+)

(+)

COOH

CH3--COOH R. ( + )

methylsuccinic acid. C-12 of a-erythroidine consequently has the S configuration and the complete configuration is that shown in 11.

B. AROMATIC GROUP Evidence for the relative configuration at C-3 and C-5 in a t least one alkaloid, erysonine, was provided during the investigation of the synthesis of 15,16-dimethoxyerythrinanol-3 (XXXVII ; see Sect'ion 11, D).

OCH3

XXXVII

I n contrast to the C-3 epimer, the infrared spectrum of XXXVII in dilute carbon tetrachloride solution exhibits an absorption band at 3277 cm-1, whose intensity is unchanged on dilution and which therefore can be ascribed to an intramolecular hydrogen bond between the hydroxyl group and the nitrogen atom ( 1 4 ) . Of the four possible racemates of structure XXXVII only one is capable of such internal hydrogen bonding-that in which the A/B ring junction is cis and the hydroxyl group axial, c i s to the C-15 to K bond. This evidence defines the relation of the two asymmetric centers in erysonine (If).Unfortunately this coilcIusion cannot be extended to the other aromatic alkaloids. Although

500

RICHARD K. HILL

erysonine can be prepared by treating erysodine (Ib) with dilute acid, this ether cleava,geundoubtedly proceeds by way of an allylic carbonium ion, so that the configuration of the allylic methoxyl in erysodine is not necessarily that of the hydroxyl in erysonine. Unambiguous proof that the rest of the aromatic group do indeed have the same relative configuration came from the X-ray analysis of erythraline hydrobromide (Id) (88).This study showed that the methoxyl is cis

to the C-15 to N bond and since erythraline has been interrelated with the rest of the aromatic group they must all have this arrangement. The cyclohexeiie ring A was shown to have the half-chair conformation with the methoxyl group occupying a pseudoequatorial position. The bond lengths are normal with the exception of the C-7 to C-8 bond in the fivemembered ring which is considerably shorter (1.42 A) than the usual sp2-sp3 bond. No determination of absolute configuration of any of the aromatic alkaloids by X-ray methods or direct chemical correlations has been made. One way in which this might be accomplished would be to interrelate one of them with the erythroidines, but attempts ( 2 3 ) to convert both groups to a common degradation product have not been successful. A strong case can be made by comparison of optical rotations and ORD-curves t o show that the two families of alkaloids have identical configurations : (a)The trienes (V) produced from both series of alkaloids by loss of methanol all have high negative rotations, and the differences in molecular rotations between the trienes and their hexahydro derivatives are large negative values in all cases ( 2 3 ) . (6) Both tetrahydro-P-erythroidine (XLIX) and 18,16-dimethoxyerythrinane ( X X ) give plain negative ORD-curves ( 2 3 ) . (c) The ORD-curves of P-erythroidine (111)and three of the aromatic alkaloids (Ia, b, d) all show strong positive Cotton effects ( 2 4 ) . This close correspondence in optical properties makes it almost certain that the two series have the same absolute configurations. Models show that the conjugated diene moiety in the alkaloids and the

12.

THE

Erythrina ALKALOIDS

501

triene system in V are nonplanar and the inherently dissymmetric chromophores resulting from the skewness are responsible for the high rotations and Cotton effects. Csiiig a rule derived from theoretical principles to relate the chirality of a skewed diene with the sign of its Cotton effect, M7eiss and Ziffer (24) attempted to deduce the absolute configuration of the Erythrina alkaloids from their positive Cotton effects, but the configuration predicted was the opposite of that determined by chemical and crystallographic methods. It is not clear just why the rule relating Cotton effect and skewed diene chirality, which holds in a number of other cases, fails for the Erythrina alkaloids; it may be that the presence of the hetero atom or a second “homoconjugated” chromophore (the aromatic ring or 12,13-double bond) vitiates the rule. The central assumption that the skewed conjugated diene is the chromophore primarily responsible for the Cotton effect is probably a t fault since the ORD-curves of the dihydroalkaloids are very similar to those of the alkaloids themselves. It is interesting to note that although the rule fails for the alkaloids, it gives the correct configuration when applied (19)to the trienes (V). Further, the relation between Cotton effects and chirality of “homoconjugated” dienes ( 2 5 )holds valid in the case of the dihydroalkaloids, which also exhibit positive Cotton effects. C. STEREOCHEMISTRY OF ERYTHRINANES When the alkaloids or any of their derivatives containing a double bond at C-6 are hydrogenated a new asymmetric center is created a t C-6. From a consideration of models and the fact that catalytic hydrogenation generally adds hydrogen from the less hindered face of a double bond, most early investigators had argued that the hydrogen at C-6 should enter trans to the C-5 to C-13 bond, thus creating a trans A/B ring junction (Fig. 7 ) ( I , 9, 15, 26). This reasonable assumption has proved, surprisingly, to be incorrect. It has already been shown (Section 111,B) that hydrogenation of erysonine leads to an A/B cis ring junction. The chain of evidence which leads unambiguously to a cis A/B fusion in 15,lBdimethoxyerythrinane (XX) is depicted in Fig. 8. Using the method developed in their laboratory for the construction of the erythrinane skeleton, RIondon and Hansen (27) prepared lactam L I I I beginning with the oxalyl derivative (LII) of 4-methoxycyclohexanone. Hydrogenation of L I I I followed by treatment with concentrated sulfuric acid afforded the bridged ether (LIV). This highly fused structure can exist only if rings d and B are fused cis. This compound of rigidly defined stereochemistry was then converted to 15,IB-dimethoxyerythrinane (XX).Acid-catalyzed ether cleavage gave a mixture of t w o

502

RICHARD K . HILT,

H2

RO

OR

I

RO

Ro R OA j B cOR is

OR A/B trcrns

FIG.7. Stereochemistry of hydrogenation.

olefins, LV and LVI, which after saponification were hydrogenated to the same lactam (LVII). Removal of the liydroxyl group was accomplished by conversion to the iodide and reduction. The resulting lactam was identical with the intermediate (XXIX) in Mondon’s dimethoxyerythrinane synthesis and was converted to XX by hydride reduction. The other possible isomer of XX, that with rings X and B fused trans, has not yet been prepared; all reported syntheses lead only to the cis isomer. Models suggest that in the erytlirinane syntheses in which the AjB ring junction is generated by Pictet-Spengler ring closure the cis geometry is more favorable. I n addition, the cis isomer is presumably more stable, so that if the formation of either asymmetric center is reversible (as in the Prelog synthesis of XXXVII) the cis product would predominate. Only in two cases has an erythriiiane derivative of trrciz,s geometry been reported : ( a ) Synthesis of 14,15,16,17-tetrahydroerythriiiane(LYlII) by Belleau’s method (Fig. 9), which has been achieved by two independent groups (16.28),gives a product nowregarded as the trans isomer (LT’IIIa). It is distinct froin the product prepared by Mondoii’s method. The latter is undoubtedly the cis isomer (LTIIIb) since it ran be prepared also by reduction of erythrinaiie (IP)with lithium in et,hylamiiie (25); I V , pre-

12.

THE

Erythrina

503

ALKALOIDS

LII

-

a O LIV

AcO

& -

A

AcO

1. O H -

+

2. Hz

-

J

LVI

LV

-

LVII

-

1. TsCl

T.i.llH 4

2. I3. Ha

(k) xx

J

XSIS

FIG.8. Stereochemistry of 1,5,16-din~ethos~er;\-thrinane (XX)

pared in the same way as its dimethoxy analog ( X S ) is assumed to have the same c i s configuration. ( b )It was noted in Section 11,E that two stereoisomers of 14,15,16,17tetrahydro- 16-oxaerythrinane (XLI) have been prepared by degradation

504

q+J-%

RICHARD K . HILL

“1-co XXIII

+

+ OH-

1 . HaPO4

2 . LiAlH,

-

LVIIIa

Li

> CtHsNHz

IV

LVIIIb

FIG.9. Synthesis of 14,15,16,17-tetrahydroerythrinane.

of ,k-erythroidine. The A/B ring junction of the 3, isomer is generated by catalytic hydrogenation and consequently is probably cis. The stereochemistry of the cc isomer is fixed during Birch reduction of XLIII, and it seems reasonable to expect that this should lead to the trans r

XLIII

1

LIX Cz

LXI

12.

THE

Erythrina ALKALOIDS

505

isomer for the same reason that Birch reduction of 3-keto-4-octalins leads to trans-/i-decalones (29) (i.e., in the intermediate carbanion (LIX) overlap of the unshared electron pair with the r-orbitals of the double bond is most favorable in a trans conformation). On the other hand the u isomer is also produced by a Mondon-type synthesis which affords cis isomers in all other cases reported, so these assignments of stereochemistry to CL and /i LXI cannot be considered unequivocal.

IV. Total Synthesis With several practical methods available for assembling the erythrinane skeleton (Sections 11, C and D) attention turned to the problem of introducing the double bonds and methoxyl group at C-3 necessary to complete the total synthesis of one of the alkaloids. With the exception

SSVI

? G O LX o H

LXI

LXII

I

-

J

LXIII

LXIV

1

1

LiAlHr

1.iAlH~

606

RICHARD K . HILL

of the synthesis of the 3-hydroxy derivative XXXVII nearly all of the subsequent synthetic work has been contributed by Mondon and his co-workers a t Kiel. Preliminary attempts to introduce unsaturation into the readily available lactam XIX were unsuccessful. Kitrosation, bromination, selenium dioxide oxidation, and condensation with benzaldehyde all failed to yield useful products ( 3 0 ) .Consequently efforts were directed toward systematically modifying the structure of 2-ketocyclohexane-

P RX

LXIII

HzSOr

L

---A

"'

LXVI

LXV OH

H+

LXII

+

_ _ f

L

v

i

i

LXIV

LXVII

12.

THE

Erythrina ALKALOIDS

507

acetic acid (XXYII), the starting material in the original Mondon condensation. ( a )One series began with the hydroxy derivative L X prepared by a Reformatsky reaction on the monoisobutyl enol ether of cyclohexane- 1,2dione (31).Condensation of L X with amine XXVI gave the hydroxylactam L X I in high yield; it was dehydrated to the dime L X I I with acetic anhydride and potassium bisulfate. Both lactams could be cyclized by acid, L X I I requiring more vigorous treatment. L X I led to the hydroxylactam LXIII and the corresponding unsaturated derivative LXIV as the major products, while L X I I gave LXIV. Lithium aluminum hydride reduction of LXIII and LXIV gave the corresponding tetracyclic bases (32). Two minor by-products formed in the phosphoric acid catalyzed cyclization of LXI have different carbon skeletons than the main products. One is the hydroxylactam LXV, shown t o arise by acid-catalyzed rearrangement of LXIII. I n acid solution it exists as the colored imonium ion LXVI (33).The second by-product is LXVII. Its formation is explained by the generation of two different cations from L X I I in acid, one leading to the erythrinane skeleton (LXIV),the other to the isomeric apo skeleton of LXVII. Bromination of LXI with N-bromosuccinimide afforded the bromo derivative VIII, whose cyclization led almost exclusively to the apo skeleton and a synthesis of apoerysopine (see Fig. %). Use of the related unsaturated ketoacid LXVIII in the initial condensation gave the tetracyclic lactam L X I X in which the double bond has shifted from its original position. An attempt to introduce additional

LXVIII

LXX

LXIX

LXXI

508

RICII.%RD K. IIILL

unsaturatioii in these intermediates with the brominated scetoxylactoiie LXX led only to the aromatized product LXXI,showing a limitation to the degree of substitution permissible in the ketoacid component ( 3 2 ) . ( h ) X second approach used the readily prepared oxalyl derivative (LXXII) of cyclohexanone. Heating this with two equivalents of XXT'I gave the enamine-amide LXXIII, which was simultaneously cyclized

1,SXII

1,sS I V

LSXIII

LXSV

and hydrolyzed by heating with dilute phosphoric acid. The ketolactam product exists largely in the enol form LXXIV. Hydrogenation gave a single alcohol LXXV, which was dehydrated to LXIV by heating the tosylate in collidine. By this route LXIV can be prepared in 36-39% overall yield from cyclohexanone (30). To introduce another double bond, LXXIV was brominated, affording the bromo derivative LXXVI in nearly quantitative yield ( 3 4 ) .Elimination of HBr from LXXVI proved surprisingly difficult. Heating with collidine regenerated LXXIV, while hot KOH gave the diol LXXVII. An attempt to effect dehydrobromination by heating with lithium chloride in dimethylformamide yielded LXXIV, the hydrolysis product LXXVIII, and two chlorine-containing products of more far-reaching reactions, LXXIX and LXXX. The vinyl chloride LXXIX could be converted to the ketolactam LXXXI, while the structure of LXXX was proved by conversion to LXXXII, a compound obtained earlier by von Braun degradation of erysotrine ( 3 5 ) .

12.

-

L x x v III

THE

Erythrina ALKALOIDS

509

c

LXXIX

n c LXXXI

When these approaches proved uiisuccessful, a total synthesis of erysotrine was finally achieved beginning with the oxalyl derivative (LII)of 4-methoxycyclohexanone. The synthetic scheme has so far been reported only in preliminary communications (27, 36).The condensation with ~-(3,4-dimethoxyphenyl)-ethylamine leading to the tetracyclic erythrinane skeleton and the further conversion to LV have been discussed in Section 111, C (Fig. 8 ) ; the remainder of the synthesis is outlined in Fig. 10. Epoxidation of LV gave the epoxide L X X X I I I which was treated with dimethylamine t o afford the amiiioalcohol LXXXIV. Cope

510

RICHARD K . HILL

elimination of the N-oxide led to the allylic alcohol LXXXV. Treatment with methanolic HCI gave a mixture of epimeric methyl ethers (LXXXV1)-products of a fortunate allylic rearrangement. The two

LXXXVI

LXXXV

Ie FIG.10. Synthesis of erysotrine.

epimers were separated and one was carried through the rest of the steps. Reduction of the lactam grouping with lithium aluminum hydride gave amine LXXXVII. The final dehydration was accomplished by elimination of the methanesulfonate. The product was shown from its IR-spectrum to be dl-erysotrine (Ie) and resolution with dibenzoyltartaric acid gave a dextrorotatory enantiomer identical with erysotrine from natural sources.

12.

THE

Erythrina ALKALOIDS

51 1

Hod ,COOH

2

HO

LXXXVIII

+ I

+ HO

n

0-

0

LXXXIX

RaO

XCII

I

CH3O

XCIII FIG.11. Suggested biosynthetic routes.

512

RICHARD K . HILL

V. Biosynthesis The presence in the Erythrina alkaloids of two oxygenated six-membered rings joined by a single bond is a clue to a biogenetic origin involving oxidative coupling of phenols. Such coupling of the phenolic rings of tyrosine-derived units is now known to be a common process in the biological construction of the Amaryllidaceae and many isoquinoline alkaloids. The most attractive dctailed hypotheses (Fig. 11) suggest the formation of the erythrinane skeleton by oxidation of LXXXVIII, a symmetrical intermediate derived from two molecules of tyrosine or dihydroxyphenylalanine. The two additional bonds necessary might be formed in either order. I n one hypothesis ( I , 37) oxidation of one aromatic ring to the o-quinone (LXXXIX) is followed by nucleophilic addition of the amino group and further oxidation to XC (or the related o-quinone). This sequence is exactly analogous to the in vitro oxidation of dihydroxyphenylalanine itself to the quinone dopachrome ( 3 8 ) . Nucleophilic or radical addition of the second phenolic ring to the quinoid system would complete the spiro skeleton of XCI. I n a different hypothesis (39),oxidative coupling a t the positions para to the hydroxyl groups in LXXXVIII, followed by further oxidation leads to the diphenoquinone XCII. This is capable of an internal Michael addition also yielding XCI. I n both schemes reduction of XCI to XCIII followed by dehydration would give the correct oxidation state and unsaturation pattern of the aromatic alkaloids. It is supposed that cleavage of the C-15 to C-16 bond could initiate further changes leading to the lactonic ring D of the erythroidines. The heart of these biosynthetic proposals is the oxidation of LXXXVIII to XCI, and the plausibility of this conversion has received dramatic support in two laboratories. I n vitro oxidation of LXXXVIII (R1 = Rz = CH3) with alkaline ferricyanide was found by both Scott and coworkers (40) and by Mondon and Ehrhardt (40a)to afford XCI (R1 = RZ = CH3) in 35 yG yield. Mondon and Ehrhardt were then able to convert XCI to ( i )-dihydroerysodine, using the reactions shown in Pig. 12. This synthesis incidentally confirms the substitution pattern in ring D of erysodine. The facile formation of the erythrinane skeleton in this manner supports the basic biogenetic scheme, and the results of incorporation experiments with isotopically labelled LXXXVIII and XCI will be awaited with great interest. The first tracer feeding experiments in this series have recently been reported by Leete and Ahmad ( g o b ) , who found that dl-tyrosine-2-14C was incorporated into ,8-erythroidine in E . berteroana. Degradation

12.

THE

Erythrina ALKALOIDS

CH30

513

OH

( & )-Dihydroerysodine

FIG. 12. Synthesis of Dihydroerysodine.

of the labelled erythroidine showed that essentially all the activity of the alkaloid was located at C-8 and C-10 and was equally divided between these two positions. Labelled phenylalanine was not incorporated. These results place the bjosynthetic scheme of Fig. 11 on a firm experimental basis, and provide the first evidence that the fission of aromatic rings is a valid principle in the biosynthesis of alkaloids.

VI. Pharmacology The remarkable curariform activity of the Erythrina alkaloids has been discussed in earlier volumes of this series and a review has been published ( 4 1 ) .More recent comparison of the activity of dihydro-p-erythroidine with standard curare agents such as d-tubocurarine shows that the former is faster acting although less potent (42, 43).

514

RICHARD K . HILL

Other pharmacological studies of dihydro-f-erythroidine in recent years include its effect on cholinergic transmission in the brain ( 4 4 , 4 5 ) and spinal cord ( 4 6 )and on Renshaw nerve cells (47-49). It is worth pointing out that the readily accessible synthetic base, dl15,16-dihydroxyerythrinane,shows strong curariform activity (10).

VII.

Addendum

Cocculolidine, an alkaloid with striking insecticidal properties isolated from the leaves of Cocculus trilobus D C , has recently been isolated and assigned the structure (XCIV) of a lower homolog of 13-erythroidine (50).The degradation reactions reported closely parallel those of f-erythroidine. This makes the second report of Erythrina alkaloids in Cocculus species, dihydroerysodine having been isolated earlier from C. laurifolius (51).

XCIV

REFERENCES 1. V. Boekelheide, A l k a l o i d s 7, 201 (1960). l a . D. H. R. Barton, R. James, G. W. Kirby, D. W. Turner, and D. A. Widdowson, Chem. Commun. p. 294 (1966). 2. A. Mondon and H. U. Menz, Tetrahedron 20, 1529 (1961). 3. J. Blake, J. R. Tretter, andII. Rapoport, J . Am. Chem. Soc. 87, 1395 (1965);J. Blake, J. R. Tretter, G. J. Juhasz, W.Bonthrone, and H. Rapoport, ibid. 88, 4061 (1966). 4. V. Boekelheide and G. C . Morrison, J . Am. Chem. SOC.80, 3905 (1958). 5. J. W. Baker, "Hyperconjugation," p. 65. Oxford Univ. Press (Clarendon), London and New York, 1952. 6. W. &I. Whaley and T. R. Govindachari, Ory. Reactions 6 , 151 (1951). 5. J. Gardent, Ann. Chim. (Paris) [12] 10, 420 (1955). 8. J. Knabe, J. Kubit'z, and H. Roloff, Arch. Phnrm. 298, 401 (1963). 9. B. Belleau, Cati. J . Chem. 35, 651 (1955). 10. A. hlondon, C h e m Ber. 92, 1461 (1959). 11. E. Crundwell, J . Chem. Soc. p. 3831 (1962). 12. A. Mondon, C"hem. Ber. 92, 1472 (1959). 13. S. Sugasawa and H. Yoshikawa, Chem. &* Phann. Bull. ( T o k y o )8, 290 (1960). 14. V. Prelog, a.La.ngemann, 0 . Rodig, and 11.Ternbah, H e k . C'him. 3 ctrc 42, 1301 (1939). 15. XI. Muller, T. T. Grossnickle, a n d V . Boekelheide,J. *4?n. Chew!.S o r . 81, 3959 (1959). 16. B. Belleau, Can. J. Chem. 35, 663 (1955).

12.

THE

Erythrina

ALKALOIDS

515

17. B. Belleau, Can. J . Chem. 35, 673 (1957). 18. A. W. Hanson, -4cta Cryst. 16, 939 (1963); Proc. Chem. SOC.p. 52 (1963). 19. V. Boekelheide and G. R. Wenzinger, J . Org. C‘hena. 29, 1307 (1964); Proc. Chem. SOC. p. 53 (1963). 20. 11. Viscontini and P. Miglioretto, Helc. Chim. Acta 38, 930 (19551; K. Brenneisen, C. Tamm, and T. Reichstein, ibid. 39, 1233 (1956). 21. R.K. Hill and W. R. Schearer, J . Org. Chem. 27, 921 (1962). 22. 1%’. Nowacki and G . F. Bonsma, 2. Krist. 110, 89 (1958). 23. V. Boekelheide and M. Y . Chang, J . Org. Chem. 29, 1303 (1964). 24. U. Weiss and H. Ziffer, Ezperientia 19, 108 and 660 (1963). 25. L. S. Forster, A. Moscowitz, J. G. Berger, and K. Rlislow, J . Am. Chem. Soc. 84, 4353 (1962); K. Rlislow, A n 7 ~K . Y . Acud. Sci. 93, 457 (1962). 26. V. Prelog, Angew. Chem. 69, 33 (1957). 27. A. Mondon and K. F. Hansen, Tetrahedron Letters 14, 5 (1960). 28. V. Boekelheide, M. Muller, J. Jack, T. T. Grossnickle, and M. Chang, J . Am. Chern. S O C . 81, 3955 (1959). 29. G. Stork and S. D. Darling, J . L4rn. Chem. Soc. 86, I761 (1964). 30. A. Mondon, A n n . Chem. 628, 123 (1959). 31. A. Mondon, H. U. Menz, and J . Zander, Chem. Ber. 96, 826 (1963). 32. A. Mondon, J. Zander, and H. U. Menz, A n n . Chem. 667, 126 (1963). 33. A. Mondon, Tetrahedron 19, 91 1 ( 1 963). 34. A. Mondon, H. J. Nestler, H. G. Vilhuber, andM. Ehrhardt, Chem. Ber. 98,46 (1965); Angew. Chem. 76, 596 (1964). 35. V. Prelog, B. C. McKusick, J. R. Merchant, S. Julia, and M. U‘ilhelm, Helv. Chim. Acta 39, 498 (1956). 36. A. Mondon and H. J. Nestler, Angew. Chem. 76, 651 (1964). 37. V. Prelog, Festschr. Arthur Stoll p. 739 (1967). 38. J. D. Bu’Lock and J. Harley-Mason, J . Chem. SOC.p. 2248 (1951). 39. D. H. R. Barton and T. Cohen, Festschr. Arthur Stoll p. 117 (1957). 40. J. E. Gervay, F. McCapra, T. Money, G. M. Sharma, and A. I. Scott, Chern. Commun. p. 142 (1966). 40a. A. Mondon and M. Ehrhardt., Tetrahedron Letters, p. 2557 (1966). 40b. E. Leete and A . Ahmad, J . Am. Chem. Soc., 88, 4722 (1966). 41. V. Deulofeu, i n “Curare and Curarelike Agents” (D. Bovet, F. Bovet-Nitti, and G. B. IIarini-Bettolo, eds.), p. 163. Elsevier, Amsterdam, 1959. 42. C. Hanna, W. H. McBlillan, and P. B. McHugo, Arch. Intern. P h a r m c o d y n . 124, 445 (1960). 43. R. L. Irwin and E. G. Trams, J . Phurmucol. Exptl. Therup. 137, 242 (1962). 44. J . P. David, S. Bfurayama, X. Illachne, and K. R. Unna, Intern. J. Neuropharmcol. 2, 113 (1964). 45. I. McCance and J. fV. Phillis, Ezperientia 20, 217 (1964). 46. J. K. Kiraly and J. W. Phillis, Brit. J . Phnrmacol. 17, 224 (1961); J. M. Mitchell and J. 1%’. Phillis, ibid. 19, 531 (1962). 47. V. G. Longo, W. R. Martin, and K. R. Unna, J . Pharmacol. Exptl. Therap. 129, 61 (1960). 48. H. D. Henatsch, D. Langrehr, F. J,Schulte, and H. J. Kaese, Arch. Ges. Physiol. 274, 511 (1962)). 49. R. IT. Ryall, S. E. St,one,D. R. Curtis, and J. C. Watkins, A‘ature 201, 1034 (1964). 50. K. Wada, S. Marunlo, and K. hlunakata, Tetrcth.edrou Letters, p. 5179 (1966). 51. XI. Tomita and H. Ya.maguchi, Pfutrm. B?clE.4, 225 (1965).

This Page Intentionaiiy Laft Blank

-CHAPTER

13--

TYLOPHORA ALKALOIDS T. R. GOVINDACHARI C I B A Research Centre, Goregaon, Bombay, India

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

517

11. The Alkaloids of Tylophora asthrnatica .................................. A. Isolation ........................................................ B. Tylophorine ..................................................... C. Tylophorinine ...................................................

518 518 518 522

I. Introduction..

111. The Alkaloids of Tylophora crebrijora .................................. A. Isolation.. ...................................................... B. Tylocrebrine. ....................................................

................................ ........................................................ Biological Activity of Tylophora Alkaloids .............................. References .........................................................

IV. The Alkaloids of Vincetoxicum oficinale. V. Biogenesis.. VI.

525 525 525

526 527 527 528

I. Introduction The family Asclepiadaceae is a large one comprising over 320 genera and 1700 species. While many plants belonging to this family have been investigated, alkaloids have been encountered only in a few. Nicotine was isolated ( I ) from Asclepias syriaca. Cryptolepine was isolated from Cryptolepis triangularis ( 2 ) and Cryptolepis sanguinolentu ( 3 ) .The alkaloids isolated from plants belonging to the genus Tylophora form the subject matter of this chapter. Two of these alkaloids, tylophorine and tylocrebrine, have also been isolated from Ficus septica, a plant belonging to the Moraceae ( 4 ) . An alkaloid isolated from Vincetoxicum oficinale ( 5 ) and probably identical with antofine isolated earlier from Antitoxicum funebre ( 6 ) has been shown t o have the same phenanthroindolizidine skeleton as present in the Tylophora alkaloids. It is of interest that the closely similar phenanthroquinolizidine system is present in cryptopleurine ( 7 )isolated from a plant belonging to the Lauraceae, a family far removed botanically from Asclepiadaceae. 517

518

T. R. GOVINDACHARI

11. The Alkaloids of Tylophora asthrnatica

A. ISOLATION Tylophoru asthmatica Wight et Arn. (syn.Tylophoru indica) is a perennial branching climber, belonging to the family Asclepiadaceae and growing wild in the plains forests in eastern and southern India. Hooper (8)showed the presence of a crystalline alkaloid but the amount isolated was inadequate for a proper characterization. Ratnagiriswaran and Venkatachalam (9) isolated from the plant two alkaloids, tylophorine and tylophorinine, for which they assigned the molecular formula C24H2704N and C23H2704N, respectively. The separation was achieved by taking advantage of the insolubility of tylophorine in chloroformether (1: 4) while tylophorinine remained in solution. Chopra et al. (10) could obtain only tylophorine from T . asthrnatica, but not tylophorinine, although they obtained a second amorphous base (mp 125"-130") which was not further characterized. Govindachari et al. (11)were able to isolate both tylophorine and tylophorinine from T.asthrnatica and the alkaloids were separated by chromatography on alumina. After crystallization from chloroform, tylophorine melted a t 286"-287" (dec.) and had [.ID - 11.6' ( C 1.07, CHC13). Tylophorinine was purified (12)by rechromatography over alumina and converted to a hydrochloride which was subjected to repeated crystallization from ethanol. The base regenerated from the pure hydrochloride melted at 248"-249" after recrystallization from chloroform and had [a],, - 14.2" (c 1.76, CHC13). Careful analysis of the base and its salts resulted in the revision of the molecular formula of tylophorinine to C23H25O4N.

B. TYLOPHORINE 1. Determination of Structure (13,14)

Tylophorine, C24H2704N (IV), is a tertiary base having four methoxyl groups but no N-methyl group and no easily reducible unsaturation. I t s UV-spectrum has maxima at 255, 290, 340, and 352 mp (loge 4.74, 4.49, 3.30, 2.83) indicating the presence of a phenanthrene chromophore. On submitting tylophorine to the Hofmann degradation, tylophorinemethine, C25H2904N (mp 190"),is obtained, which on a second Hofmann degradation yields de-N-methyltylophorinemethine,C26H3104N (mp 167"),and a nitrogen-free product, C24H2405, formed by the replacement of a dimethylamino group in the former by a hydroxyl group. Since the

13. Tylophora ALKALOIDS

519

second-stage Hofmann product is still basic it follows that the nitrogen atom in tylophorine is common to two rings. Tylophorine methiodide is converted by boiling with alkali into the racemic isomethiodide. Tylophorinemethine does not undergo reduction under catalytic hydrogenation conditions, but is transformed to the isomethohydroxide, identified by conversion to the isomethiodide. Reversion of a methine to one of the racemic forms of the quaternary salt from which i t is derived has been observed in the case of quinolizidine alkaloids of the canadine type (15)-a transannular reaction characteristic of eight-, nine-, or ten-membered rings incorporating a nitrogen atom. Treatment of tylophorine with cyanogen bromide yields a crystalline bromocyanamide, which on treatment with sodium borohydride yields a hydroxycyanamide. The latter on hydrolysis with sulfuric acid yields tylophorine, indicating the presence of a 1 : 4 or 1 : 5 amino-alcohol system in the compound. On submitting tylophorine methochloride or isomethochloride to the Emde degradation, isodihydrohomotylophorine, C Z ~ H ~ ~isOobtained. ~N, This can be dehydrogenated with PdjC to detetrahydroisodihydrohomotylophorine, a nonbasic compound showing a positive Ehrlich test indicating the presence of a pyrrole ring. On catalytic reduction the original isodihydrohomotylophorine is obtained, proving that no change in ring size has occurred during the dehydrogenation. The presence of a five-membered, nitrogen-containing ring is thus established. Oxidation of the Hofmann degradation product from isodihydrohomotylophorine yields a mixture of acidic products. These can be converted to the corresponding methyl esters and then separated by chromatography into a mono ester, C21H2206 (mp 185'-186"), and a

Meo&

Meo$

/

fiIeo

' OMe

I

cO\

co

/

CH3

Me0

\ OMe

I1

diester, C22HzzOg (mp 246"-247"). The monoester on hydrolysis and decarboxylation yields 2,3,6,7-tetramethoxy-9-methylphenanthrene (I), identical with an authentic synthetic specimen. The diester is hydrolyzed

520

T. It. GOVIND-*CHAKI

to a dicarboxylic acid which is also obtained by the oxidation of tylophorine isomethohydroxide with permanganate along with a small amount of an imide, C~oH1706N.The latter was shown to be 2 , 3 , 6 , 7 tetramethoxyphenanthrene-9,lObdicarboxylimide(11) by comparison with a specimen obtained by oxidation of the dihydroisoquinoline (111) synthesized for the purpose from 2,3,6,'i-tetramethoxyphenanthrene-!laldehyde by standard procedures (14).

Meo&

MeO@NJ

/

/

/N Me

MeO. \

MrO

\

OMe

OMe

IV

111

Vigorous oxidation of tylophorine methiodide with permanganate yields m-hemipinic acid as the only isolable product. Oxidation of tylophorinemethine with permanganate in pyridine yields a neutral nitrogeneous substance, C25H2705N (mp 241"-244"), formed by the oxidation of a methylene group adjacent to the nitrogen atom to a carbonyl group

(13). On the basis of these degradation studies tylophorine is formulated as 9,11,12,13,13a,14-hexahydro-2,3,6,7-tetramethoxy-dibenzo[~,h]pyrrolo[ 1,2-b]isoquinoline (IV).* The structures of tylophorinemethine, de-Nmethyltylophorinemethine, isodihydrohomotylophorine, and detetra-

Me0g7.+ \

Me CHzSMez

Me Me0

/

Me0

OMe

/ OMc,

V

* The numbering of the parent ring system is shown opposite.

VI

13. Tylophora' ALKALOIDS

52 1

hydroisodihydrohomotylophorine can then he depicted as V, VI, VII, and V I I I , respectively.

Me

Me

Me0

Me0

OMe

OMe

VIII

\'I1

The Emde degradation of tylophorine methiodide yields a product identical with that obtained from tylophorineisomethiodide. When tylophorinemethine is submitted to the Emde degradation, a compound, C26H3304N (mp 158"-156"). is obtained which may be formulated as IX. M e O P H XPO@

/

Me0

I

\

/Me (CHZ)3x Me 'Me

/

Me0

I

\

/

\

' OMe

OMe

IS

x

A different product (mp 148"),is obtained by submitting isodihydrohomotylophorine (VII) to the Hofmann degradation. Both the compounds yield the same isotetrahydrohomotylophorinemethine on reduction. Since the compound (mp 148'), has a strong band a t 10.93 p

522

T. 11. G O V I N D A C H A R I

characteristic of a trans-disubstituted ethylenic linkage. it is formulated as the trans isomer corresponding to IX. The double bond in tylophorinemethine forms part of a nine-membered ring and is likely t o have the less strained cis-configuration (16). I n isodihydrohomotylopliorine, on the other hand. no such restriction is present and it gives rise t o the more stable t r a m isomer. Application of the Hofmann degradation t o le-S-methyltyloi)lioriiiemethine (VI)yields a compound, C 2 4 H 2 4 0 4 ( m p 181"-188"), which may be formulated as X or a derived transformation product. This could be formed by attack of base at the doubly allylic position of VT.

2. Synthesis (17) Treatment of

2,3,B,S-tetramethoxy-~-cliloromethylpheriaiithrene with pyrryl magnesium bromide yielded 2-(2,3,6,7-tetramethoxy-9phenanthrylmethy1)pyrrole (XI) which was reduced t o the corresponding pyrrolidine. The X-formyl derivative of the latter underwent smooth cyclization with phosphorus oxychloride t o the quaternary salt (XII)reduced in good yield t o ( )-tylophorine by sodium borohydride. The synthetic compound was resolved through ( + )-camphorsulfonic acid into ( - )-tylophorine (mp 292"; [.ID - 11.5'), and ( + )-tylophorine (mp 282"; [.In + 12.15'). The ( - )-tylophorine was identical with natural tylophorine.

Meop Meox&J c1-

Me0

/

Me0

OM?

OMF:

XI

XI1

C. TYLOPHOEININE I . Determination of Structure (12) Tylophorinine. C23H2504N (XVb), is a tertiary base with three methoxyl groups but no X-methyl group. I t s UV-spectrum with maxima a t 258, 287, and 340 m p (loge 4.61, 4.34, 2.91) is very similar t o t h a t of cryptopleurine, a 2,3,6-trimethoxyphenanthrenederivative ( 7 ) .

13. Tylophora

523

ALKALOII)~

The fourth oxygen atom is present as an alcoholic hydroxyl group, the IR-spectrum showing a band (in liquid petrolatum) at 3.1 p. It forms an acetate with IR-bands (CHC13) a t 5 . 8 and 8.0 p. Since the UV-spectrum of the alkaloid is not changed by addition of alkali, the hydroxyl group is not phenolic. Alpplicationof the Hofniann and Emde reactions to tylophorinine did not lead to any useful result. Vigorous oxidation of tylophorinine gave m-hemipinic acid as the only isolable product. Mild oxidation of the methiodide yielded an imide. C1gH1505K (mp 297"), and an acid readily converted to an anhydride and yielding with diazomethane a crystalline diester, C21H2007 (mp 160"-16d"). The identity of the imide as 2,3,6trimethoxyphenanthrene-9,1O-dicarboxylimide( X I I I ) was established by comparison with a synthetic specimen obtained by oxidation of the dihydroisoyuinoline (XIV)synthesized by the standard route from 2,3,6trimethoxyphenanthrene-%aldehyde. Further, the diester was shown

to be identical with dimethyl 2,3,6-trimethoxyphenanthrene-9,lO-dicarboxylate obtained by oxidation of cryptopleurine followed by esterification. OMe

xv a: K = H

b; R = O H

XVI

524

T. R. GOVINDACHARI

Catalytic hydrogenation of tylophorinine in acetic acid-perchloric acid in the presence of PdjC yields deoxytylophorinine, C23H2503N (mp 252"-254"),by hydrogenolysis of the hydroxyl group. On the assumption that tylophorinine has the same structural framework as tylophorine, this compound can be formulated either as XVa or XVI. Both the compounds were synthesized (12, 18) 6, the same route as employed for tylophorine, and deoxytylophorinine was found to correspond to 9, 11, 12, 13, 13a, 14-hexahydro-3,6,7-trimethoxydibenzo[f,h]pyrrolo[ 1,2-b]isoquinoline (XVa). Since tylophorinine does not behave like a carbinolamine and since it suffers hydrogenolysis in acetic acid-perchloric acid, the hydroxyl group is benzylic and can be located uniquely, as shown in XVb. Tylophorinine can therefore be formulated as 9,11,12,13,13a,14-hexahydro14 - hydroxy - 3,6,7-trimethoxydibenzo - [f,h]pyrrolo[ 1,2 - blisoquinoline

(XVb).

2. Synthesis (19) Condensation of 9-chloromethyl-3,6,7-trimethoxyphenanthrene with methyl L-prolinate yielded methyl 3,6,7-trimethoxy-N-(g-phenanthrylmethyl)pyrrolidine-2-carboxylate(XVII). The corresponding acid obtained by hydrolysis was cyclized by polyphosphoric acid to 9,11,12,13, 13a, 14-hexahydro-3,6,7-trimethoxy-l4-oxodibenzo[f,h]pyrrolo[l,2-b]isoquinoline (XVIII).

Reduction with sodium borohydride yielded a mixture from which one compound (mp 246"), was isolated in a state of purity. Its IRspectrum (KBr, CHC13) was identical with that of natural ( - ) tylophorinine.

13. Tylophora ALKALOIDS

525

111. The Alkaloids of Tylophora crebrijlora

A.

ISOLATION

(20)

Tylophora crebriJlora S . T. Blake (T.Jloribunda Benth.) occurs in North Queensland. Extraction of the plant material with hot methanol afforded the crude mixture of alkaloids which was purified by chromatography on cellulose powder using propanol-2 N acetic acid as the eluent. Further purification by repeated chromatography yielded tylophorine (R,0.5 in 0 . 2 in the same solvent butan-1-01-acetic acid 97 : 3) and tylocrebrine (Rf system) (mp 218"-220"; [a]%-45" f 2" (c 0.1, CHC13). (+)-Tylocrebrine isolated from Ficus septica Forst. f. was found ( 4 ) to have mp 220"-222" and [a]'$? + 20.5"& 2" ( c 0.8, CHC13). Besides tylophorine and tylocrebrine, four additional alkaloids of the same group have been reported to be present in the plant ( 2 1 ) .These possess either alcoholic or phenolic hydroxyl groups but details of the structural work are not available. B. TYLOCREBRINE

1. Determination of Xtructure (20) Tylocrebrine, C24H2704N (mp 218'-220°), is a tertiary base having four methoxyl groups, no N-methyl group, and no easily reducible unsaturation. Its UV-spectrum with absorption maxima a t 263, 342, and 360 mp (log€ 4.81, 3.25, 3.09) is practically superposable on that of 3,4,6,7-tetramethoxy-9-methylphenanthrene. The IR-spectrum confirms the absence of OH, NH, or carbonyl functions. Since the alkaloid is isomeric and occurs jointly with tylophorine, it may be assumed to have the same phenanthroindolizidine system; on the basis of the UV-spectrum two structures (XIX or XX) may be proposed. A choice between the two structures was made by synthesis as described in the next section. OMe

OMe

XIX

xx

526

T. R. GOVINDACHARI

2 . Xynthesis (20) The syntheses of 9,11,12,13,13a,l4-hexahydro-2,3,5,6-tetramethoxydibenzo[f,h]pyrrolo[1,2-b]isoquinoline (XIX) and the 3,4,6,7-tetramethoxy isomer (XX) were accomplished by the same sequence of reactions as employed for tylophorine, starting from methyl-3,4,6,7tetramethoxyphenanthrene-9-carboxylate and methyl-2,3,5,6-tetramethoxyphenanthrene-9-carboxylate,respectively. Natural tylocrebrine was found to correspond to structure XIX.

IV. The Alkaloids of Vincetoxicum oflcinale Platonova et aE. ( 6 ) have reported the isolation from Antitoxicum funebre Boiss. and Kotschy of the alkaloid antofine, C23H2503N (mp 213"-215"), containing three methoxy groups. Pailer and Streicher ( 5 ) have suggested that their alkaloid A from Vincetoxicum oficinale Moench could be identical with antofine. Both A and tylophorine were isolated from this plant. Alkaloid A has the molecular formula C23H2503N and three methoxyl groups. Its UV-spectrum is very similar to that of tylophorine. The IRspectrum shows the absence of NH or OH. The mass spectrum of A shows a molecular ion peak a t m/e 363 and a base peak a t m/e 294 (M-69), a behavior parallel to that of tylophorine which shows a molecular ion peak a t m/e 393 and a base peak a t m/e 324, probably by the fragmentation depicted below :

3 OMe

363

294

The presence of a phenanthroindolizidine ring system can be assumed on the basis of the UV- and mass-spectra. Oxidation of the alkaloid with alkaline hydrogen peroxide yielded m-hemipinic acid as the only isolable product. On the basis of its IR-spectrum and biogenetic considerations, the methoxyl groups can be assigned to the 2,3,6- or 3,6,7-positionson the phenanthroindolizidine system leading to the alternate structures XVa and XVI. It is of interest that racemic forms of both the possible structures have already been synthesized (12, 18).

13. Tylophora ALKALOIDS

527

V. Biogeneeis (13,5,22) The phenanthroindolizine alkaloids can be visualized as arising by the condensation of two molecules of dihydroxyphenylalanine or one molecule of dihydroxyphenylalanine and one of tyrosine (or their equivalents, the corresponding benzoyl acetic and phenyl pyruvic acids) with ornithine (or its equivalent, y-aminobutyraldehyde). 0H

3

The joint occurrence of tylophorine and tylocrebrine with the secophenanthroindolizidine alkaloid septicine (XXI) in Ficus septica ( 4 ) lends support to the biogenetic scheme outlined above. It is also of interest that septicine is transformed to a mixture of tylophorine and tylocrebrine on UV-irradiation. It is quite possible that the amorphous base (mp 125"-130"), of Chopra et al. (10)is in fact septicine. OMe

I

OMe

XXI

VI. Biological Activity of

Tylophora Alkaloids

The pharmacology of tylophorine was studied by Chopra et al. (10). Tylophorine is toxic to Paramecium caudatum in a dilution of 1 :50,000.

528

T. R . G O V I N D A C H A R I

It is lethal to frogs at a dose of 0.4 mg/kg but toxicity to mice and guinea pigs is very small. It has a paralyzing action on the heart muscles but a stimulating action on the muscles of the blood vessels. The initial drop in blood pressure and subsequent rise to a level above normal on administration of tylophorine is thus explained. Tylocrebrine shows high activity against lymphoid leukemia L12 10 in mice, the best results being obtained at a dose level of 10 mg/kg. ( 2 3 ) . The powerful vesicant action of these alkaloids has heen commented upon by all the investigators ( 9 , 12, 20). REFERENCES 1. L. Marion, Can. J . Res. B17, 21 (1939). 2. E. Clinquart, BUZZ. Acad. Roy. Med. Belg. [5] 9, 627 (1929); see Chem. Abstr. 24, 1139 (1940). 3. E. Gellert, Raymond-Hamet, and E. Schlittler, Helv. Chim. Acta 34, 642 (1951). 4. J. H. Russel, Il’atur7uissenscha.ften50, 443 (1963). 5. M. Pailer and W. Streicher, Monatsh. Chem. 96, 1094 (1965). 6. T. F. Platonova, A. D. Kuzovkov, a n d P . S. Massagetow, Zh. Obshch. Khim. 28, 3131 (1958); see Chem. Abstr. 53, 7506d (1959). 7. E. Gellert and N. 1‘. Riggs, Australian J . Chern. 7, 113 (1954); J. Fridrichsons and A. Mathieson, Nature 173, 732 (1954). 8. D. Hooper, Pharm. J . [1] 21, 617 (1891). 9. A. N. Ratnagiriswaran and K. Venkatachalam, India%J . Med. Res. 22, 433 (1935); see Chem. Abstr. 29, 8229 (1935). 10. R. N. Chopra, N. N. Ghosh, J. B. Bose, and S. Ghosh, Arch. Phurm. 275, 236 (1937). 11. T. R. Govindachari, B. R. Pai, and K. Nagarajan, J . Chem. Soc. p. 2801 (1954). 12. T. R. Govindachari, B. R. Pai, I. S. Ragade, S. Rajappa, and N. Viswanathan, Tetrahedron 14, 288 (1961). 13. T. R. Govindachari, M. V. Lakshmikantham, K. Nagarajan, and B. R. Pai, Tetrahedron 4, 311 (1958). 14. T. R. Govindachari, M. V. Lakshmikantham, B. R. Pai, and S. Rajappa, Tetrahedron 9, 53 (1960). 15. F. L. Py-man, J . Chem. Soc. 103, 817 (1913); A. Voss and J. Gadamer, Arch. Pharm. 248, 43 (1910). 16. A. T. Blomquist., L. A. Liu, and J. C . Bohren,J. Am. Chesn. Soc. 74, 3643 (1952). 17. T. R . Govindachari, M. V. Lakshmikantham, and S. Rajadurai, Tetrahedroit 14, 284 (1961). 18. T. R. Govindachari, I. S. Ragade, and N. Viswanathan, J . Chem. Soc. p. 1366 (1962). 19. T. R. Govindachari, B. R. Pai, S. Prabhakar, and T. S. Savitri, Tetrahedron 21, 2573 (1965). 20. E. Gellert, T. R . Govindachari, M. V. Lakshmikantham, I. S. Ragade, R. Rudzats, and N. Viswanathan, J . Chem. Soc. p. 1008 (1962). 21. K. V. Rao, “Advancing Frontiers in the Chemistry of Katural Products,” p. 20. Hindustan Publ., India, 1965. 22. E. Wenkert, Ezperientia 15, 165 (1959). 23. E. Gellert and R. Rudzats, J . Med. Chem. 7, 361 (1964).

_ _ CHAPTER 14-

THE GALBULIMIMA ALKALOIDS* E. RITCHIEA N D W. C. TAYLOR Department of Orgnriic Cheiriistry, l'iiirersity of Sydney, Sydriey, Australia

I. The Family Himantandraceae. . . . . . . . . . . . . . . . .

. . . . . . . . . . 529

11. The Alkaloids .................................................. A. Classification . . . . . . . . . . . . . . . . . . ........... B. Variability in Yield. . . . . . . . . . . . . ........................ C. Isolation . . . . . . . . . . . . . . . . .

ITI. The Himbacine Group

530 530 530

........

A. The Structure of Himba.cine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. The Absolute Stereochemist.ry of Himbacine . ...... C. The Structures of Himbeline D. The Structure of Himgravine . . . . . . . . . . . . . . E. Derivatives of Himbacine . .

533 540

IV. The Structure of Himbosine . . . . . . . . . . . . . . . . . . References . . . ..........................

I. The Family Himantandraceae The Iimantandraceae of the order Magnoliales is a sma I relic family consisting of only one genus. The naming of the genus and the number of species in it have been the subject of some discussion (1-3). Originally four species were accepted : Galbulimiina baccata F. 31. Bail. from North Queensland and G. belgraveana (F.Rluell.) Sprague, G. nitidu (Bak. f. and Norman) Sprague, and G. parvifolia (Bak. f. and Norman) Sprague from New Guinea. I n a taxonomic revision of the genus in 1942, A. C. Smith considered that the name Himantundra for the genus was more consistent ; although accepting the Queensland species as valid he recognized only one species from New Guinea, namely, Hiinantundra belgraveana (F.Muell.) Diels, and reduced the other two from this area to synonyms of this species. His conclusions were criticized by L. S.Smith in 1960 on the grounds that by the rules of the International Code of Botanic Komenclature (1956) the correct name of the genus was Galbulirniina F. M.

* Supplementary t o Volume Y I I ,

page 512. 529

530

E. RITCHIE AND W . C. TAYLOR

Bail, arid that a sufficient number of plant specimens had not been examined to enable a conclusion concerning the number of species involved to be reached. I n a more recent examination of the question in 1962 van ltoyan ( 4 )accepted Galbulirnima as the correct name of the genus. He also concluded that because of the extreme morphological variation throughout the habitat of the genus, which extends through all parts of New Guinea (except the southern areas), the Moluccas, and the rain forest areas of North Queensland, only one species, G. belgruveana (F. Muell.) Sprague, should be recognized. Until general agreement has been reached in this somewhat confused situation it seems best when discussing the alkaloids to denote the plant material from which they were isolated by its source. The plants themselves are large trees which may reach a height of 130 feet.

11. The Alkaloids A. CLASSIFICATION The leaves and the wood contain only minor amounts of basic material which has not been examined but twenty-eight alkaloids have so far been isolated from the bark ( 3 ) .They are listed in Table I in which is given also t h e sources of the plant material, the molecular formulas, and the physical constants. At the time of the first isolation of the alkaloids ( 5 )it was thought that Hiwmntandra was the correct name of the genus and consequently the trivial names bestowed on them began with the syllable “him.” These names have been retained but since the total number of alkaloids is now relatively large and powers of etymological invention have waned the newer alkaloids are denoted by a code number, e.g., “G.B. 1,” fortunately taxonomically noncommittal. Each alkaloid has also been characterized by its UV-, IR-, and NMRspectrum. This information together with some degradative work permits the recognition of the three classes of alkaloids listed in Table I : ( I ) tetracyclic lactones, ( 2 ) highly oxygenated hexacyclic esters, and (3) one hexacyclic and two pentacyclic bases of low oxygen content. Several alkaloids, as yet unclassifiable, are collected in the inevitable miscellaneous group. IN YIELD B. VARIABILITY

Whether the genus consists of one, two, t>hree,or four species the variability of alkaloid content with respect both to total amount and t o

14. THE Galbulirnima ALKALOIDS

53 1

TABLE I Grilbztlimimtt ALKALOIDS

Xelting point Alkaloid

Source"

Formula

("(3

[al~(CHC13) -

Class I Himbacine Himbeline Himandravine Himgravine

132 100 119 I20

+ 63" + 19"

+ 28"

+ 23'

+ 47"

Class 2 Himbosine Himandridine Himandrine

S Q , KG NQ, KG NQ, NG

262 205 186

G.B. 1 G.B. 2 G.B. 3 G.B. 4 G.B. 5 G.B. ti G.B. i G.B. 8 G.B. 9 G.B. 10 G.B. 11 G.B. 12

KQ, NG S Q , KG KG NQ, S G NQ, S G XQ NQ KG NG NG NG NG

242 238

237 238 234 1i 0 183 188 168

162 239 "22

- '"'0 - 38"

+ 8"

. $38" +SS"

+ 63" + 60" - 12" + 35" + 63" + 23" + 19"

+ 64" + 23"

Class 3 Himgalirie Himbadine G.B. 13 Miscellaneous Himgririe G.B. 11

G.B. G.B. G.B. G.B.

a

15 lfi li

18

KQ = S o r t h Queetisland ; KG = S e w Guinea.

* Hemihydrate. c d

Blethiodide. Monohydrate.

r .O

226 1146

- I0

185

- 84"

2°C

lotid

230 203 ll5d 120

- 60"

-

+ 58"

+ 5.50" -210

+ 37"

531

E . RITCHIE AND W . C. TAYLOR

individual alkaloids is striking and possibly unique. Of the eleven bark samples from Korth Queensland and the seven from New Guinea that have been worked up for alkaloids no two have been alike. Even samples collected in the same area and at approximately the same season have been quite dissimilar. The variability thus revealed by actual isolation of the alkaloids has been confirmed by a paper-chromatographic survey of the alkaloids of an extensive series of samples ( 6 ) . The yield of total alkaloid varied from a trace to about 0.5%. The major and commonest alkaloids in bark from both sources were himbacine and himandridine. Himbadine and himgaline, which are structurally related, were also major alkaloids in bark from North Queensland but were not found in material from New Guinea, except in one instance when a trace of himgaline was isolated. Himbosine was usually present in small amounts in all samples but all of the other alkaloids occurred irregularly and should be regarded as minor. Some of them have been isolated only once. Ligiians are also present in the barks and available information (1, 3, 7 ) suggests that their occurrence too is irregular. Galbulin, galbacin, and galcatin appear to be restricted to the North Queensland trees and galbelgin and galgravin to the New Guinea trees. Although the chemical results are incomplete and inconclusive they do tend to support the hypothesis that the genus consists of a t least two species.

C. ISOLATION Because of the variability it was not possible to devise a generally applicable detailed scheme of isolation. Himgaline being the strongest base was readily separated; likewise the isolation of himbosine, a very weak base, was usually easily achieved. The separation of the main bulk of the alkaloids into two major fractions was accomplished by taking advantage of the fact that one fraction formed chloroform-soluble hydrochlorides while the other did not. Each major fraction was then separated by a combination of column chromatography on alumina and countercurrent distribution between ethyl acetate and phosphate-citrate buffers of pH 4-7. These processes were rather tedious and it was unlikely that all alkaloids present were always isolated. I n the most extended effort made sixteen alkaloids were separated from one New Guinea sample. It is possible that some of the alkaloids at least are artifacts produced from true alkaloids by the isolation procedures. However, it appears from the subsequently ascertained reactivities of the fuiictional groups present that the relatively mild methods of isolation would not have

14.

THE

Galbulincima ALKALOIDS

533

effected chemical changes, and it is believed that the bases in Table I are genuine natural products.

111. The Himbacine Group

A. THESTRUCTURE OF HIXBACINE Himbacine was shown to have structure I by degradation ( 2 ) .Analytical methods revealed the presence of one methylimino and two terminal methyl groups (but no terminal ethyl group) and the formation of a methiodide established that the nitrogen was tertiary. The UV-spectrum had oiily rising end absorption but the IR-spectrum indicated the presence of a trans-disubstituted double bond and a y-lactone ring (vIIIaX980, 1778 cm-1). Catalytic hydrogenation under pressure yielded dihydrohimbacine, the IR-spectrum of which lacked the former band. Since treatment of himbacine with hot aqueous alcoholic potassium hydroxide gave a crystalline potassium salt which reverted to the alkaloid on treatment with water or ethanol, it was concluded that the lactone ring was cis-fused. Additional evidence for the presence of a y-lactone ring was afforded by reduction with lithium aluminum hydride which gave the diol (11) converted by hot dilute acid to the anhydrodiol (111). Hydrogenation of this substance gave the dihydroanhydrodiol (IV)

CH-CHs \

OH

CHpOH

II

0

I1

I Himbacinr

111

Iv

534

E . RITCHIE AND

W.

C . TAYLOR

hich was also accessible by- successive treatment of dihydrohimbacine itli lithium aluminum hydride and hot dilute acid. Dehylrogeiiation of himbacine 1% ith palladium-charcoal a t 260" furnished dehydrohimbacine (Y). That the transformation involved the saturation of the double bond and the conversion of an S-methylpiperidine sj-stcm into a pyridine derivative was apparent from the elemental analysis of the product, its UV-spectrum (A,,,,, 265 mp, log6 3.fi5), and the marked change in pli, from 9 . 3 to 5.1 (50% ethanol). Compound Y 11as also obtained from dihydrohimbacine under the same conditions.

\i

i 0

Under more vigorous conditions with selenium at about 350" there were produced methylamine, 2,6-dimethylpyridine, 2-ethyl-6-methylpyridine, and two hydrocarbon fractions which were isolated as their 1,3.5-trinitrobenzene adducts. The first of these was identified as %ethyl3-methylnaphthalene. The other. obtained in only minute yield, was identified as a pyrene derivative by its UV-spectrum. It was evidently formed by a double cyclization onto a naphthalene nucleus of the alkyl chain arising from the elimination of methylamine. Subsequent attempts at its synthesis (8)showed, however, that in spite of its apparent homogeneity, it was almost certainly a mixture which arose by partial elimination of alkyl residues. I n an attempt to gain information on the position of the carbonyl group in himhacine the diol was a130 dehydrogenated. The same products were obtained in approximately the same yields and it was then erroneously concluded that the carbonyl group v as attached to a tertiary carbon atom. This error and also theincorrect assumption that the ethyl groups of the pyridine and naphthalene derivatives were derived from the same portion of the structure caused some confusion but Tvere eventually rectified. As it transpired, during the dehydrogenation complete elimination of the a-substituent of the decalin

14. THE Galbulimima ALKALOIDS

535

had occurred and the carbonyl group had been fully reduced; both processes had precedents (9, 10). Himbacine methiodide was stable to a boiling solution of potassium hydroxide in ethylene glycol but the methiodide of the dihydroanhydrodiol was degraded smoothly to the methine-I ( V I ) . The presence of a vinyl group in this compound was established by its IR-spectrum, by the production of formaldehyde on ozonolysis, and by hydrogenation to dihydromethine-I (VII). Further degradation of the methiodide of the latter yielded trimethylamine and dihydromethine-11, a gummy mixture of two isomeric olefins. Hydroxylation of the mixture with osmium tetroxide followed by cleavage with periodate gave approximately equal amounts of pentanal and hexanal in a volatile fraction together with a nonvolatile fraction. Further oxidation of the latter with silver oxide yielded the C-16 acid (VIII) and the C-15 acid (IX). These were interrelated by a Barbier-Wieland degradation and a further degradation of I X furnished the C-14 acid (X). The series of reactions admitted of only the interpretation depicted.

vI

-CH2--CH=CH

536

E. R I T C H I E AND W. C. TAYLOR

Next, the methiodide of the arihydrodiol was degraded. Three gummy products, each characterized by its crystalline methiodide, were isolated. The first was isomeric with the anhydrodiol and was presumably formed by isomerization involving an allylic hydrogen. The second product, methine-I, had only end absorption in its UV-spectrum, but the third,

I

xv

XVI

I

14.

THE

Galbulimima

ALKALOIDS

537

isomethine-I, was a conjugated diene (A,,,,, 234 mp, loge 4.42). I n view of the results of the previous Hofmann degradation the present methine-I had structure X I and the isomethine-I had structure XI1 or XIII. To distinguish between the two possibilities the substance was oxidized with permanganate. The product was the (3-14 acid (X) and hence isomethine-I was X I I . A minor product of the oxidation was a c - 1 3 ketone (XIV). The isolation of XI1 did not necessarily establish the position of the double bond in himbacine since under the vigorous conditions of the degradation it could have shifted into conjugation with the newly formed double bond. On catalytic hydrogenation of methine-I only one double bond was reduced and dihydromethine-I (XV) was formed in which was retained the original trans-ethylenic linkage (ulllaS 980 cm-1). Hofmann degradation of its methiodide led to a nitrogen-free gum which was a mixture 236 mp, loge 4 . 3 0 ; A,,, 242 mp, loge 4.28). of conjugated dienes (A,, , Ozonolysis of the gum again yielded pentanal and hexanal together with a nonvolatile fraction which on oxidation with permanganate furnished the c - 1 4 acid (X)and the c - 1 3 ketone (XIV).It followed that himbacine contained a 6-(1,2-dimethylpiperidy1)-vinyl residue. Also on this basis the formation of the dihydromethine-I1 of structure XVI was explicable by the vinylogous elimination process illustrated. Himbacine was not readily attacked by ozone or by osmium tetroxide nor did a useful result follow treatment of the anhydrodiol (111)with the latter reagent or with performic acid. With perphthalic acid the anhydrodiol gave only the N-oxide. Under strictly defined conditions oxidation of the anhydrodiol with permanganate yielded the C-14 acid (X),thus confirming the position of the double bond, together with the C-13 ketone (XIV) in low yield. Similarly oxidation of himbacine furnished a C- 14 lactone acid (XVII) (v,,, 1770 cm-1) and alow yieldof a C-13 ketolactone (XVIII) (vmax 1783, 1710 cm-1). A better yield of the latter substance was obtained by oxidation of himbacine with chromic anhydride in war= acetic acid, but none of the lactone acid could be isolated. With this oxidizing agent, the anhydrodiol gave an unexpected but useful result :himbacine was formed, thus showing that its conversion into the anhydrodiol had not been attended by any unusual changes. A small yield of the ketolactone (XVIII) was also isolated. Both C-13 ketones were presumably formed by further oxidation of the corresponding C-14 acids but attempts to convert the acid (X)to the ketone (XIV) by permanganate oxidation were unsuccessful ; the product of the reaction was the acid XVII. However, a conversion of acid XVII into ketone XVIII was effected by a more circuitous route:

538

E. RITCHIE AND W . C. TAYLOR

Anhydrodiol

Himbacine

I11

I

I

XVIII

reduction of the acid chloride by sodium borohydride gave a primary alcohol, the mesylate of which on heating with collidine yielded an olefin ; hydroxylation of this substance with osmium tetroxide followed by cleavage with periodate then gave XVIII. COOH

I

CH

/ \

d

COCl

l

+ I

CHzOH CH

T ,

/\

XVII

CHz

II

C

/\

CHzOH

+ I

C-OH /\

CHzOSOZCH3

d

l

+

CH /\

-

0

II

C

/ \

XVIII

Dehydrogenation of the lactone acid (XVII)with palladium-charcoal yielded 2-ethylnaphthalene and under the same conditions the acid X afforded 2-ethyl-3-methylnaphthalene. The formation of these two hydrocarbons disproved the earlier hypotheses that the carbonyl group of himbacine was attached to a tertiary carbon atom and that the ethyl groups of 2-ethyl-6-methylpyridine and 2-ethyl-3-methylnaphthalene, isolated from the selenium dehydrogenation of himbacine, were derived from the same structure in the alkaloid. Moreover, since the results of the Hofmann degradation and the oxidation experiments had shown that the 6 4 112-dimethylpiperidyl)-vinyl group was attached to a decalin residue by reason of the formation of the C-13 ketones, it only remained t o establish the point of attachment. For this purpose the carboxyl group

14.

THE

Galbulimima ALKALOIDS

539

of C-14 acid ( X ) was reduced via its methyl ester to a hydroxymethyl group and thence to a methyl group. However, attempts to dehydrogenate t,he two latter substances with palladium-charcoal at 330" gave an inseparable mixture of C-13 and C-14 naphthalene derivatives by partial elimination of a methyl group while aromatization failed to occur with sulfur at 230". Some support for the 1,2,3-arrangement of substituents in the decalin nucleus was found in the behavior of the C-13 ketone (XIV)which gave a negative Zimmermann test and failed to yield a piperonylidene derivative ; it therefore did not contain an unhindered active methylene group. Also since the ketolactone XVIII gave a negative ferric test it was not a 8-ketoester; i.e., it had structure XVIII rather than XIX.

O XVIII

XIX

Conclusive evidence for structure LVIII was obtained from a study of the action of alkali on it. While its UV-spectrum in ethanol had the absorption due to a saturated aliphatic ketone,,A,( 220, 292 mp, loge 1.98, 1.33), in alkaline ethanol the absorption was typical of an a$unsaturated ketone, ,A,( 245,318 mp, loge 3.45,1.91). Thelatter function had clearly been generated by the /3 elimination process illustrated. The a$-unsaturated ketone, isolated as a gum by acidification, on ozonolysis afforded acetaldehyde and an acidic gum. Mild pyrolysis of the latter gave carbon dioxide and a crystalline acid which was identified as ( + )$(trans-2-carboxycyclohexyl)-propionic acid (XX) by direct comparison with the synthetic racemic modification. CH-CHs

*

__f

c

COOH

I/

O

XVIII POOH CH3CHO

COOH

+ 'CHzCH (COOH)2

(CHz)&'OOH

xx

540

E . R I T C I I I E AND W .C. TAYLOR

The degradation reactions had established in himbacine the presence of a decalin residue, the nature of the substituents attached to it, and the substitution pattern but it should be noted that there was no proof that the decalin residue was trrins, since if it had been c i s , isomerization could have occurred when XYIII was treated with alkali and the same trans acid (XX) would have resulted.

B. THEABSOLUTESTEREOCHEMISTRY OF HIMBACINE The degradation of himbacine had revealed its gross structure, but much of the stereochemistry remained undefined. These deficiencies were remedied by the X-ray crystallographic examination of himbacine hydrobromide monohydrate carried oct by Fridrichsons and Mathieson ( I I ) , who in addition established the absolute stereochemistry represented by XXI.

?XI Himbacinc

C. THESTRUCTURES OF HIMBELINE AND HIMANDRAVINE Hinibeline was readily identified as X-demethylhimbacine since methylation with formaldehyde-formic acid gave himbacine ( 2 ) . The alkaloid was further characterized by its acetyl and methane sulfonyl derivatives ;rather surprisingly these derivatives could not be hydrolyzed under the usual conditions. In contrast to this unreactivity the double bond of himbeline was easily hydrogenated, readily suffered oxidation by permanganate to yield the lactone acid XVII, and was attacked by performic acid to give the epoxide and glycol. No explanations of these abnormal reactivities have been advanced.

14.

THE

Galbulimima ALKALOIDS

541

Like himbeline, himandravine contained an imino group, a transdisubstituted double bond, and a y-lactone group (v,,,,, 3320, 1765, 976 cm-1). Methylation gave an N-methyl derivative and catalytic hydrogenation readily furnished a dihydro derivative. The latter substance was readily methylated but hydrogenation of N-methylhimandravine under the usual conditions did not occur. The difference in reactivity between himandravine and its N-methyl derivative recalled the parallel behavior of himbeline and himbacine and was further illustrated by the ready oxidation of himandravine to the lactone acid XVII. Dehydrogenation of himandravine by palladium-charcoal gave dehydrohimbacine (V) in good yield. The structure of the alkaloid therefore differed from that of himbeline merely by having a different configuration a t one or both of the asymmetric carbon atoms of the piperidine ring ( 2 ) .

D. THE STRUCTURE OF HIMGRAVINE The spectral properties of himgravine (A,,,,, 218 mp, log< 4.0; v,,, 1754, 1684 cm-1) revealed the presence of an m,P-unsaturated y-lactone ring. Catalytic hydrogenation afforded himbacine in good yield and therefore the structure of the alkaloid was X X I I or X X I I I ( 2 ) .A clear decision in favor of the former was readily reached from a study of the NMR-spectrum ( 1 2 ) .

dx5-cH3 CI1 0

CmH3 C 0 II

XXIII

XXII Himgravine

R = CqH16N

E. DERIVATIVES OF HIMBACINE Since himbacine showed antispasmodic activity with low toxicity and few side effects (13)a number of derivatives were prepared for pharmacological testing ( 1 4 ) . Few proved to he as effective as himbacine and none was better ( 1 3 ) . By the action of phenyl lithium on himbacine, the diol (XXIV) was obtained and converted by treatment with acid into the tetrahydrofuran

542

E . RITCHIE A N D Wr.C. TAYLOR

derivative (XXV). The corresponding derivatives of dihydrohimbacine were also prepared.

Attempts to demethylate himbacine with a variety of reagents under several conditions were unsuccessful but dihydrohimbacine was readily converted by cyanogen bromide into the cyanamide (XXVI).Th'is was stable to acid and only slowly hydrolyzed by alkali but catalytic hydrogenation afforded dihydrohimbeline in good yield. By standard methods the following N-substituted derivatives were prepared : ethyl, /3hydroxyethyl (p-nitrobenzoate and trimethylgallate), allyl, n-butyl, ethoxycarbonylmethyl, cyclohexyl, benzyl, /3-phenylethyl, y-phenylpropyl, and phenylcarbamido.

(I

IV. The Structure of Himbosine Sirice himbosine u a s available in only relatively small amount and since its structure appeared likely to provide the key to the large ester group an X-ray crystallographic examination of the hydrobromide was undertaken by Love11 (15).The structure determined by him is represented by XXVII, in which relative stereochemistry only is implied.

14. THE Galbulimima ALKALOIDS

543

Concurrent, chemical studies on other members of the ester group have shown t h a t they also possess the same hexacyclic cage structure (16). OCOCHQ

REFERENCES 1. G. K. Hughes and E. Ritchie, Australian J . Chem. 7 , 104 (1954). 2. J. T. Pinhey, E. Ritchie, and W. C. Taylor, AustraZianJ. Chem. 14, 106 (1961). 3. S.V. Binns, P.J. Dunstan, G. B. Guise, G. M. Holder, A. F. Hollis, R. S. McCredie, J. T. Pinhey, R. H. Prager, M. Rasmussen, E. Ritchie, and W. C. Taylor, Australian J . Chenz. 18, 569 (1965). 4. P. van Royan, Nova Guinea 8-10, 127 (1962). 5. R. F. C. Brown, R. Drummond, A. C. Fogerty, G. K. Hughes, J. T. Pinhey, E. Ritchie, and W. C. Taylor, Australian J . Chem. 9, 283 (1956). fi. E. Ritchie and W. C. Taylor, unpublished results (1965). 7. A. J. Birch, B. Milligan, E. Smith, and R. N. Speake, J. Chem. SOC.p. 4471 (1958). 8. M. Moyle and E. Ritchie, AustraZianJ. Chem. 11, 211 (1958). 9. W. Cocker, B. E. Cross, and J. McCormick, J . Chem. SOC.p. 72 ( 1 952). 10. L. Ruzicka, HeZw. Chim. Acta 19, 419 (1936). 11. J. Fridrichsons and A. McL. Mathieson, Acta Cryst. 15, 119 (1962). 12. R. J. Abraham and H. J. Bernstein, Australian J. Chem. 14, 64 (1961). 13. R. F. Raffauf, private communication (1964). 14. M. N. Galbraith, J. J. Hobbs, and R. A. Massy-Westrop, AustvflinnJ . Chem. 16, 112 (1963). 15. F. M. Lovell, Proc. Chem. SOC.p. 58 (1984). 18. L. N. Mander, E. Ritchie, and W. C. Taylor, unpublished results (1964).

This Page Intentionaiiy Laft Blank

-CHAPTER

15-

THE STEMONA ALKALOIDS 0. E. EDWARDS National Research Council, Ottawa, Canada

I. Introduction.. ......................................................

545

11. Tuberostemonine. ...................................................

545

................................................. Tuberostemonine-A. ................................................. References .........................................................

111. Isotuberostemonine.

550

IV.

550 550

I. Introduction The Stemona alkaloids were reviewed over a decade ago (Volume V, p. 323) at which time there was both confusion as to the number of alkaloids and contradictory evidence bearing on their structure. Two apparently new alkaloids have since been described and the structure of tuberostemonine has been elucidated.

11. Tuberosternonine

Kaneko extended the early work of Schild on tuberosternonine, demonstrating the presence of a C-ethyl group and two lactone rings ( 1 ) . Edwards et al. ( 2 )used spectroscopic methods to elaborate this picture. Bisdehydrotuberostemonine*, the product of silver nxide oxidation ( 3 , 4 ) , was shown to contain a pyrrole ring substituted as in I. The NMR-spectrum of this compound confirmed the presence of the C-ethyl group. I n addition it was deduced that the second lactone ring was substituted as in 11, with a possible further carbon-carbon bond at position 3. It was concluded that tuberosternonine contained the corresponding pyrrolidine dilactone system and that it was saturated and pentacyclic. The simultaneous and more extensive work of Gotz and colleagues ( 5 ) enabled them to suggest a complete structure. They deduced the same

* The Japanese workers call this compound dehydrotuberostemonine. 545

546

0. E. EDWARDS

I

I1

substitution of the pyrrolidine ring. I n addition, using fission by cyanogen bromide, they were able to prove that the third group attached to nitrogen was part of a tetramethylene chain. The bromocyano compound (partial structure 111)was reduced by lithium aluminum hydride to a base (partial structure IV), which gave butyric and valeric acids on modified Kuhn-Roth oxidation.

\

IV

I11

That a cyclohexane ring was fused to the pyrrolidine ring was shown by conversion of tuberostemonine, using phenyl magnesium bromide, to a triphenyl derivative V which could be simultaneously dehydrated and acetylated to VI.

f

V

c

VI

15.

THE

Stemona

ALKALOIDS

547

Oxidation of V I with chromium trioxide in acetic acid gave a methy] keto ester V I I from which benzoic acid was eliminated under mild conditions to give an +unsaturated methyl ketone. When air was bubbled into an alkaline solution of the cr,/!-unsaturated ketone it was

OH

1

If., d. VII I

dehydrogenated to a compound with the spectral characteristics of an 0-or m-aminoacetophenone. A new aromatic hydrogen was evident from its NMR-spectrum, with a chemical shift corresponding to an 0- or p-relation to the acetyl group. The unusually high-field signal given by this hydrogen in the corresponding methyl carbinol showed it to be ortho or para to the amino group. The mild aromatization conditions seem to preclude rearrangement, hence the benzene ring had to be fused to the pyrrolidine ring forming a dihydroindole. I n view of the few carbons not precisely accounted for, the third group attached to the nitrogen had to be coupled to the ortho position on the aromatic ring. It followed that the aromatized product was VIII and that tuberostemonine was IX or X.

0 7

IX

X

Uyeo and co-workers provided independent confirmation of these two structural possibilities ( 6 ) . They found that tuberostemonane, an important product from the dehydrogenation (Pd, charcoal) of tuberostemonine, had a UV-absorption spectrum similar to that of indole. When oxidized with chromic acid it gave a product having an isatin-like absorption spectrum.

548

0.E. EDWARDS

I R - and NMR-spectroscopic evidence showed that tuberostemonane had only one unsubstituted position on the benzenoid ring and that the P-position of the indole ring was free. Thus the substitution pattern was as shown in XI, XII, or XIII.

XI

XI1

XI11

Oxidation of tuberostemonane with ozone followed by permanganate in acetone gave an amido acid. This could be hydrolyzed by vigorous acid treatment, giving valeric acid. The expected amino acid was decarboxylated during the hydrolysis so that the nitrogen-containing fragment was obtained as a base. This had UV-, NMR-, and IR-spectra consistent with it being 6,8-diethyl-2,3,4,5-tetrahydro1H - 1-benzazepine (XIV). The structure of XIV was confirmed by synthesis. It was also converted by reaction with chloral and hydroxylamine followed by acid-catalyzed cyclization into the isatin derivative mentioned above. It followed that tuberostemonane had structure XV.

Dehydrogenation of tuberostemonine, using palladium on asbestos in the presence of sodium carbonate, had given a variety of dehydrogenation products retaining more of the original functions. A study of their spectra now led ( 7 ) to assignment of structure XVI or XVII to the most important one. From this structures I X and X again follow for tuberostemonine. Edwards and Feniak were able to distinguish between the two possibilities by study of the NMR-spectrum of bisdehydrotuberostemonine (8). I n the two alternative structures XVIII and XIX the starred hydrogen should give rise to an NMR-signal near 7.0 T. For XVIII this should be a triplet or pair of doublets while for X I X it should be more

15.

549

THE 8temOna ALKALOIDS

complex (sextet or quartet with ratio 1 : 3 : 3 : 1). I n fact, a triplet was observed a t 6.9 T , which collapsed to a doublet when decoupled from the hydrogen on the adjacent carbon carrying the ethereal oxygen of the lactone (triplet a t 5.45 T ) . Thus XVIII is the structure of the bisdehydro compound and IX is the structure of tuberostemonine.

XVIII

SIX

This assignment was confirmed by the work of Kaneko (9). Tuberostemonine was converted to the lactam XX which was transformed by reduction with lithium aluminum hydride followed by cleavage with cyanogen bromide into XXI. Debromination by hydrogen over palladium followed by reductive removal of the cyano group gave XXII. The

XX

XXI

XXII

corresponding methohydroxide was oxidized by alkaline permanganate to one diastereoisomer of 1-ethyl-2-butylsuccinic acid. Clearly, of the

550

0. E. EDWARDS

two alternative structures for tuberosternonine, only I X could give rise to this fragment. Aside from the fact that the methyl group in the lactone attached to the pyrrolidine ring has the same configuration as that in I-methylsuccinic acid, the stereochemistry of tuberostemonine is unknown. A stereoisomer was produced when tuberostemonine was exposed to hydrogen in the presence of platinum ( 2 , 10). The structure of one interesting product, oxotuberostemonine, formed on air (11)or mercuric acetate ( 2 )oxidation of tuberostemonine, is still uncertain. Many possibilities were eliminated by the work of Edwards et al. (2). The most likely one seems to be X X I I I on the basis of known hydroxy enamine formation by mercuric acetate (12).

XXIII

111. Isotuberostemonine This base, C22H3304N (mp 125"; [a]= -86"; perchlorate, mp 213"), was isolated from Stemona tuberosa Lour. by Kondo et al. (13).

IV. Tuberosternonine-A This isomer of tuberostemonine (mp 120"; [.ID -65" (in ethanol); hydrochloride, mp 141") was isolated in moderate yield from#. sessilifolia Franch. et Sav. ( 2 ) . It gave bisdehydrotuberostemonine (XVIII) on silver oxide oxidation and the same lactam as tuberostemonine (XX) on oxidation with alkaline permanganate. Hence it only differs from tuberosternonine in the sterochemistry a t C-2. REFERENCES 1. T. Kaneko, Ann. Rept. Itsuu Lab. 11, 45 (1960). 2. 0. E. Edwards, G. Feniak, and K. L. Handa, Can. J. Chem. 40, 455 (1962). 3. H. Schild, Chern. Ber. 69, 74 (1936).

15.

THE

Stemona

ALKALOIDS

55 1

H. Kondo, K. Suzuki, and M. Satomi, J . Pharm. SOC. J a p a n 59, 177 (1939). M. Gotz, T. Bogri, and A. H. Gray, Tetrahedron Letters p. 707 (1961). S. Uyeo and T. Shingu, J . Pharm. SOC.J a p a n 84, 555 (1964). S. Uyeo, T. Shingu, and Y. Tsuda, J . Pharm. SOC. J a p a n 84, 663 (1964). 0 . E. Edwards and G. Feniak, Can. J . Chem. 40, 2416 (1962). T. Kaneko, Ann. Rept. Ztsuu Lab. 14, 49 (1965). 13. Kondo, M. Satomi, and T. Kaneko, Ann. Rept. Ztsuu Lab. 8, 51 (1957). 11. H. Kondo, M. Satomi, and T. Odera, Ann. Rept. Itsuu Lab. 5 , 99 (1954). 12. N. J. Leonard, L. A. Miller, and P. 0. Thomas, J . Am. Chern. SOC. 78, 3463 (1956). 13. H. Kondo, M. Satomi, and T. Kaneko, Ann. Rept. Ztsuu .Cab. 7,64 (1956). 4. 5. 6. 7. 8. 9. 10.

This Page Intentionaiiy Laft Blank

AUTHOR INDEX Kumbers in parentheses are reference numbers and are included t o assist in locating references where the author’s name is not mentioned in the text. Pu’umbers in italics refer t o the page of the chapter on which the reference is listed.

A

Arigoni, D., 311(21), 315(45), 358(21), 315(45), 367(45), 388, 389(204), 390 (204), 418(21), 420, 425 Arima, J., 441, 442(3), 464 Arndt, C., 175(6), 194(6), 208(103), 209 (105), 218,220 Arndt,R. R., 15(23,24,25), 17(23),25(24), 27 (62),28(24),29(25), 37, 39,257 (151), 267 Arthur, H. R., 3(2), 28(2), 37, 224(18, 19), 263 Asada, S., 37(67), 39 Asada, T., 49(53a), 112 Asahi, Y., 120(56), 124 Asahina, H., 121(95, 96, 102), 125, 126 Asahina, Y . , 227(44), 264 Asaoka, Y., 453(32), 461(32), 465 Asbun, W. L., 379(220), 404, 425 Ashford, W. R., 103(143), 114 Aslanov, H., 181(14), 218 Aslanov, K. A., 199(75), 200(76), 213(115, 117), 219, 220, 221 Attenburrow, J., 413(230), 425 Aurousseau, M., 123(286), 131 Awe, W., 120(21, 33), 123, 124 Ayer, W. A., 23(54), 24(54), 38 Ayers, R. H., 57, 112

Aaron, H. S., 275(22a, 22b), 301 Abraham, H.J . , 541 ( 2 ) , 543 Abreu, B. E., 123(281),131 Abushanab, E., 379(214), 380(214), 400, 401 (214),404,405(22la).425 Achmatowicz, O., 442(5), 443(10), 444, 449(24), 462(11, 24), 463(10, 11, 24), 464, 465 Adrasfalvy-Vicenty, M., 121 (113), 126 Aguilar-Santos, G., 152(61,66), 172 Ahmad, A., 512, 515 Aisic, C., 121(233, 234, 237), 130 Akramov, S. T., 17(40), 18(44), 38, 45(18), 103(18),111 Aksanowski, R., 122(252), 130 Albonieo, S. M., 19(46),38 Alburn, H. E., 312(27), 420 Alexander, W. M., 123(281), 131 Alumbaugh, R. L., 151 (57), 172 Anand Rao, D., 121(152), 127 Anderson, D. M. W., 121 (135), 127 Ando, M., 407(228), 408(228), 412(228), 414(228), 425 Andres, W. W., 338(86), 354(86), 422 Andrew, H., 69, 113 Aneja, R., 260, 267 Anet, F. A. L., 228(61, 230(61), 264 Anjaneyulu, B., 162(97, 98), 173 B Antonaccio, L., 12(17), 37 Raarschers, W. H., 12(lS), 15(23, 24, 2 5 ) , Aoki, T., 142(24), 171, 228(66), 229(66), 17(23), 25(24), 27(62), 28(24), 29(18 232(66), 264. 360(144, 145), 363(144, 2 5 ) , 37,39 145), 423 Bacre, V. J., 121(66), 125 Aoyagi, Y., 135(5), 141(17),170 Bachli, E., 120(37), 124 Appelt, J., 17(33a),36(33a), 38 Bagreeva, M. R., 121 (139), 127 Apreotesei, C., 121(11<5),122(115),126 Rainova, M. S., 275(21), 301 Arata, Y., 442(6, 7, 8, 13), 445(13), 446, Baker, J. W., 490(5), 514 447(13, 14, 19, 22)) 448(16), 451, 4.53, Balatre, P., 121(62, 110), 124, 126 434, 455(35), 456(14, 16, 22, 3 5 ) , 458, Banaszek, H., 449 (24), 462 (24), 463(24), 460, 461, 464, 465 465 Archer, S., 291 ( 7 3 ) , 302 553

554

AUTHOR INDEX

Bandelin, F. J., 44(8), 110 Ranerjee, A., 47(3R, 39), 57(39), 102(39), 105(39), I l l Banfi, D., 295(76), 302 Ran'kovskii, A. I., 50(69), 112, 229(74), 223(74), 235(74), 265 Baran, J. S., 197(71), 219 Baranowski, P., 194(61, 62), 196(62), 219 Barman, B. K., 227(39), 229(39), 264 Barnes, C. S., 386(196), 425 Baron, W., 335(116, 117), 423 Barragan, V., 44(3),110 Barrowcliff, M., 280(41), 301 Barton, D . H . R., 19, 30(63), 38, 39, 94, 95 (128), 113, 114, 136, 137, 170, 359(140, l 4 l ) , 360, 418(140), 423, 485(1a), 512 (39), 514,515 Bartos,M.L., 122(241),130 Bartz, J., 19F(68), 206(92), 208(102), 219, 220 Barua, A. K., 47(35), 111 Basu, N. K., 347(134), 423 Batterham, T. J., 224(9), 263 Battersby, A. R., 19(49, 50), 21(51, 51a), 38, 84, 88, 94, 98(129, 130), 103(116), 113, 114, l l S ( 7 , 14), 120(7, 14, 26, 27), 123, 135(6), 169(125), 170, 174 Bauer, V. J., 343(94), 355(94), 358(94), 360 (94) 422 BauerovB, O., 121 (200), 129, 318(52), 376 (52), 379(52, 2 2 2 ) , 380(52), 381 (52), 383(52),384(52), 389(52), 400(52), 406 (222),421,425 Bayer, I., 121(124), 126 Bazilevskaya, G. I., 275(21), 301 Beak, P., 396(210), 425 Beal, J. L., 49(60, 65), 112, 122 (245), 130 Beard, C., 322(61), 421 Becconsall, J. K., 288(66), 289(66), 302 Becker, B., 284(52), 302 Begiey, R. W., 123(281), I 3 1 Beke, D., 43(75), 51 ( 7 5 ) , 112 Belcher, R., I21 (130), 126 Bell, M. R., 291 ( 7 5 ) ,302 Belleau, B., 365(151), 424, 491, 496, 497 (17), .501(9), 502(16), 514, 515 Rellen, Z . , 443 (lo), 444, 463(10), 464 Benn, W . R., 322(60), 323(62), 421

Bennet, R. D., 417(233), 418(237, ZB), 426 Bentley, K . W., 60, 106(89), l O i ( X 9 ) . 108 (89), 212, 120(22), 121(22), 123 Berezhinskaya, V. V., 233, 266 Berger, ,J. G., 501 ( 2 5 ) , 515 Bernasconi, R., 176(l), 204(90, 91), 228, 220 Rcrnath, G., 287(61), 302 Bernauer, K., 17(37),38 Bernoulli, F., 70(95), 104(95), 113 Bernstein, H. I., 277(34), 278(34), 301 Bernstein, H . J., 541 (12), 543 Bersch, H. W., 78(104, l06), 79, 113 Bertho, A., 332(107), 333(107, 110), 343 (107), 345(127), 347(131, 132), 358 (107), 422,423 Bertin, D., 404(221), 425 Ressanova, I. A., 254(147), 225(149), 267 Bessho, K., 17(33b), 38(33b), 30(33b), 32 (33b), 33(33b), 35(33b), 38, 159(86, 88), 161(86, 93), 168(113, 114, 116, 117, 118, 119), 173, 174 Beton, J . L., 393(207), 394(207), 395(207), 425 Bettschart, A., 121 (174), 122(174), 128 Beugelmans, R., 366(154), 369(154, 155), 374(178),424 Beyerman, H. C., 224(22), 236(122), 237 (122, 124), 238(122), 239(124), 243, 246, 247(122), 263, 266 Beyl, H., 238(129), 244, 266 Bhattacharayya, J., 224(3), 227(40), 229 (40, 95). 263, 264, 265 Rhattacharyya, P . K . , 336(120), 371(184), 374(164, 177), 423, 424 Bhatty, M . K., 121 (130), 126 Bick, I. R. C., 134, 135(6), 148, 152,(65), 155, 156(79), 157(4, SO), 159(87), 170, 171, 172, 173 Bickerman, H. A., 122(264),131 Biglino, G., 121(231), 130 Biniecki, S., 121(92), 122(92), 125 Binns, SylviaV., 227(37), 2 2 8 ( 3 7 ) , 229(37), 230(37), 263, 529(3), 530(3), 5 3 2 ( 3 ) , 543 Birch, A. J., 5 3 2 ( 7 ) ,543 Birnbaum, G. I., 462{39), 463(39), 465 Bishop, R. J., 288(64), 302

AUTHOR INDEX

Bisset, N.G., 307(3), 308(3),313 (3), 317 (3), 348(3),352(3),381(201, 205), 382(201, 205), 383(201,205), 388(201, 205), 389 (POI), 391 (2Ol), 392(205), 396 (201), 397 (205),399 (205),400 (TOO:?),417 (205), 419(205), 419, 425 Rlaha, K., 118(15), 119(15), I20(l5), 122 (15),123 Blake, J.,487(3), 514 Manpin, 0.. 313(28, 29, 30, 31, 3 2 ) , 420 Blaschke, G., 19(45, 47), 38, 136, 168(12, 13, 120, 121), 170, 174 Blazsek, A., 121 (log), 122(109), 126 Blodorn, H. K., 430(6), 439 Blomquist, A. T., 522 (16), 528 Blossey, E., 271 (Sa), 291 (Sa), 301 Bobbitt, J. M . , 160(41), 124, 167(111), 168 (111, 122 123) 173 174 Bodendorf K., 468, 470(6, 9), 472(6), 476 (6), 477(6,9), 478(6), 479(6, 9), 480(9), 481,481, 482 Boegemann, W. H., 121(93), 125 Bagri, T., 545(5), 551 Bohm, F., 230,265 Boekelheide, V., 483(1), 489, 494, 498, 500 (23), 501(1, 15, 19), 502(28), 512(1), 514, 515 Bognitr, R., 287 (62),302 Bohlmann, F., 177(3, 4,5, 6 ) , 181(12), 183 (31), 154(35, 36), 186(44), 187(45, 46), 188(31), 189(35, 5 2 ) , 190(36, 56), 192 (36, 58), 193(59), 194(6), 195(64), 196 (5, 31, 35, 70), 198(52, 72, 73),200(80), 201(84, 85, 86), 202(86), 204(84, 85, 86), 205(73), 206(35, 7 2 ) , 207(35, 56), 208(l03), 209(5, 105, 106), 211(106), 218, 219, 220, 449(23). 450, 453(23), 464(42), 465 Bohren, J. C., 522 ( l 6 ) , 528 Boit, H.G., 44(7), 45(13), 110, 120(34),124 Honamico, El., 388(198),425 Boner, H., I22 (270), 131 Bonsma, G. F., 500(22), 515 Bonthrone, W . ,487 (3),514 Boorsma, W. G., 237(126), 238(126), 266 Borgwardt, G., 121 (76,175), 122(175), 125, 128 Boroschewski, G., 192(58), 193(59), 21.9 Bose, J. R., 518(10), 527(1O), 528 Bose, S., 228(71), 264

555

Bose, P. K., 228(56, 73), 264 Hosson, J. A , , 234(119), 266 Bothner-By, A. A., 295(81), 296(81), 302 Bottini, A. T., 288(69), 302 Boulanger, P., 117(1), 122(1), 123 Bowman, It. M., 249(135), 256, 257(135), 266, 267 Brackel, H., 198(72), 206(72), 219 Brackett, J . W., 121 (60),124 Bradford, L. W., 121(60), 124 Bradsher, C. K., 68, 69, 71(93, 96), 72, 87 (93), 108(92),113 Bratek,M.D., 183(32),188(32,50),189(32, 51), 196(51),207(50, 51, 98), 209(51), 218, 219, 220 Bratek-Wiewiorowski, M. D., 207 (97), 220 Braun, W., 427(2), 429(2), 439 Brauninger, H., 121(175), 122(175), 128 Breen, G . J . W., 229(84), 265 Brenneisen, K., 498(20), 515 Brewer, H. W., 167(112), 168(112),173 Breyer-Brandwijk, M., 468 (4),481 Briggs, L. H., 121(64), 122(64),1 2 4 ,2 2 4 ( 5 ) , 227(42), 228(42), 229(42),263, 264 Brochmann-Hanssen, E., 121(117, 154), 126, 127 Brown, D. W., 89,113 Brown, H. C., 247(134), 266 Brown, K . S., 375, 376(187, 189), 378(184, 187), 380(184, 185, 187, 191, 206), 381 (184), 383(186), 384(184, 185, 187, 191),385(191),389(186), 392(187,189, 206), 395(206), 401(191), 405(188), 424, 425 Brown, R. F. C., 228(62), 234(62), 264,530 (51, 543 Brown, R. T., 21 (51), 38 Brown, T . H., 19(50), 21 (51a), 38 Bruchausen, F., 152(66),I 7 2 Bruns,D., 103(144,147),104(145,147),105 (145), 115 Buchschacher, P., 311(21), 358(21), 418 (21), 420 Buck, J. S., 105(159), l06(159), 108(159), 114 Budesinsky, B., 121(132, 148), 127 Budzikiewicz, H., 6 2 , 64(90), 65(90), 113, 271(8a, 8b), 291(8a, Yb), 301, 308(12, 13). 309(12, 141, 310(13), 322(61), 420, 421

556

AUTHOR I N D E X

Buchi, G., 291 (74), 302 Buchi, J., 121(99, 111, 159, 230), 122(111), 126, 127, 130 Bu’lock, J. D., 512(38), 515 Bunns, V. sf., 122(264), 131 Bures, E., 441, 442(4), 464 Burger, G., 107(170), 108(170), 114 Burgin, A., 121(162), 122(162), 127 Burgstahler, A. W., 313(38), 348(38), 421 Buric, I., 120(52),124 Burkhalter, J. H., 345(128), 423 Buzas, A., 48(45a), 111 Buzetti, F., 371, 424 Byerrum, R. U., 183,228

C Cab0 Torres, J., 121(101), 122(101), 126 Cahn, R. S., 278, 301 Cainelli, G., 315(45), 367(45), 421 Calame, J. P., 388, 389(204), 390(204), 425 Calderwood, J. M., 17(28a), 38 Calvert, B. J., 275(25), 301 Cambie, R. C., 227(42,43), 228(42,43), 229 (42,43), 264 Camps,R., 331,442 Cannon, J. R., 85, 113, 229(83), 230(83), 265 Casinovi, C. G., 388 (198), 425 Castedo, J. L., 204(87), 220 Castells, J., 332,423 Cava, M. P., 17(33b), 28(33b), 30(33b), 32 (33b), 33(33b), 38, 49(60, 63, 65), 67 (63), 112, 122(245), 130, 155(75), 156 (75), 172 CavB, A., 318(53), 320(54, 55, 56), 336(55), 349(53, 54, 56), 350(53, 54, 56), 366 (157,158),369 (157),370(158),417 (56), 421, 424 Ceglowski, M. J., 317(47), 349(47), 421 Celap, M. B., 121(119, 123), 126 Gem$, V., 308 ( l o ) ,309 ( l o ) ,3 10 ( 10,20), 313 ( 2 0 ) ,315(20),317 (46), 323(64), 325(71, 72), 428(73), 331(102), 333(77), 334 (97), 335(72,97), 336(77), 337(77), 342 (97), 343(97),345, 350(64, 71), 352(73, 77), 355(95, 97, 98), 357(95), 358(95), 371(98), 372(97, 166, 167, 168, 170), 374(176), 410(64), 420,421, 422, 424 Chakraborty, D. P., 227 (39), 229(39), 264

Chakravarti, K. K., 144(30), 145(30), 171 Chakravarty, K. K., 2 2 7 ( 5 2 ) , 264 Chan, It. P. K., 30(64), 39 Chang Cheng-chieh, 118(17), 12.3 Chang, C. H., 153(70), 172 Chang, ill. Y., 500(23),502(28), ,525 Chao, C., 146(36), 171 Chao, Y. C., 146(36), 171 Chatterjee, A., 5 ( 5 ) , 2 8 ( 3 ) , 29(3), 37, 224 (20), 227(30, 48), 228(20, 71, 72), 229 (20,95),230, 263, 264, 265, 313(33, 36, 37), 325(70),348(35),408(50), 409(70), 412(70), 420 421 Chatterjee, R., 47(35, 39), 57(39, 87), 102 (39, 134), 104(87, 134), 105(39, 134), 111, 1 1 2 , 1 1 4 Chaudhry, G. It., 163(67), 172 Chaudhury, B., 227(48), 228(72), 264 Chen, K. K., 237(125), 238(125), 244, 266 Chen, W., 147(39, 40),171 Chernova, I. I., 138(15), 170 Cheung, H. T., 224(18), 263 Chichiro, V. E., 121(193), 128 Chopra, R. N., 518, 5 2 7 , 528 Chou, Y . , 146(36), 147(38),171 Chung-Tungshun, 369(153), 424 Cieleszky, V., 121 (204), 122(204), 129 Cihakova, M., 121 (134), 127 Claeys, C., 121 (62), 124 Clarke, C., 167(112), 168(112),173 Clarke, E. A., 224(14), 247, 257(14), 261, 263,266 Clarke,E.G.C., 121(70),122(70,248),125, I30 Clarke, R. T., 214(123), 221 Clements, J. H., 19(50), 21(51), 38 Clezy,P.S., 14(22),15(22,22a),37,148(46), 152(fi5), 159(87), 171, 172, 173 Clinquart, E., 517(2), 528 Closs,G.L.,257(63),302 Clugston, D. M., 224 ( l o ) ,263 Coch-Frugoni, J. A., 121(183, 186), 122 (153, 186, 244), 128, I 3 0 Cocker, W., 535(9), 543 Cohen, B. M., 122(264), 131 Cohen, T., 19, 38, 136, 137, 170, 512(39), 515 Colebrook, L. D., 121 (64), 122(64),124,224 (5), 263 Comin, J., 17(31), 38, 208(100), 220

AUTHOR INDEX

Conreur, C., 318(50), 333(111), 349(50), 421, 423 Constantinescu, A., 121 (112, 240), 122 (112), 126, 130 Cooke, R. G., 2 2 7 ( 3 5 ) , 228(35), 263 Corey, E. J., 358,418(139),423 Corral, R. A., 227(31), 228(31), 230(31), 238(31),263 Corrodi, H., 69, 7 2 , 105(94), 113 Cox, J. S . G., 386(192), 424 CrabbB, P., 355(136), 423 Craig, J. C., '73, i 4 , 113 Cram, D. J . , 289(71), 302 Cross, B. E., 535(9), 543 Crow, W. D., 152(65), 172, 208(99), 220 Crundwell, E., 491(11), 514 Csepreghy, Gy., 277(33), 281 (43), 301, 302 Curtis, D. R., 514(49),515 Cymerman Craig, J., 30(64), 39 Czollner, F., 123(285), 131

D Dabrowski, Z., 453,465 Dadlez, J . , 121 (69), 122(69),125 Dalton, D. R., 49(63), 67(63), 112, 155(75), 156(75),172 Dane'ants, V. A., 121 (166), 128 Danilovic, M., 121 (184), 122(184),128 Dankova, T. F., 284(54), 302 Darling, S. D., 362(148), 424, 505(29), 515 Das, B., 313(35, 36, 37), 3 2 5 ( 5 0 ) ,348(35), 408(70), 409(70), 412(i0), 420, 421 Das, K. C., 2 2 8 ( 5 6 ) ,264 Das, K . G., 313(33,34), 420 Das Gupta, A. K., 47(35), 111 Dasgupta, B., 17(42), 38 Dauben, W. G., 365(150), 372(169, 169a), 424 David, J. P., 514(44), 515 Damson, R.F., 295(81), 29G(Sl), 302 Deb, A., 224(20),227(48), 2 2 8 ( 2 0 ) ,229(20), 263, 264 Debska, W., 121(188), 122(188), 128 de Carmago Fonseca Moreas, E., 122(243), 130 de Flines, J., 343(126), 338(126), 423

557

DeJongh, D. C., 49(63), 67(G3), 112, 155 (75), l56(75),172 Deki, M., 121 ( 8 8 ) , 125 cle Langhe, J . , 227(53), 229(53), 264 Delcambre, J. P., 121(G2, 110), 124, 126 Demay, D., 121(127), 127 Deno, N. C., 27(60), 39 D e Oliveira, M . M., G(9), 28(9), 29(9), 37 Derkosch, J., 196(65), 219 Deslongchamps, P., 214(121), 215(127), 216(127),221 Deulofeu, \'., 17(31), 19(46), 38, 135(8), 170, 208(100), 220, 227(53), 229(53), 264,513(41), 515 Devissaguet, P., 332 (108), 339 (85), 344 (85), 354(85), 419(240), 422, 423, 426 Dewey, V.C., 122(264),131 Dhar, M. L., 153 ( G T ) , 172 Dickel, D. F., 317(47), 349(47), 421 Dieterle, H., 238(129), 244, 266 Diller, H., 121(74), 125 Diskina, B. S., 214(122), 221 Djerassi, C., 62(90),64(90),65(90), 113, 120 (36), 124, 167(111, 112), 168(111, 112, 123), 173, 174, 270, 291(8a, Sb), 301 308 (12),309 ( 1 2,14), 322 ( G l ) , 362 ( 147) 364 (147), 420,421,423 Dobbie, J. J., 103(146), 114 Dob6, P., 281 (44),302 Dobrowsky, A., 103(145a), 114 Doda, & 300(95), I., 303 Doclson, R. M., 322 (60), 421 Dopke, W., 48(45), 111, 121(158), 127, 384 (222a), 425 DolejB, L., 279(213), 280(213), 308(10), 309 ( l o ) , 310(10, lG), 3 3 3 ( 7 5 ) , 336(77), 337(77), 352(77),355(95),357(95),358 (95), 389(16), 400(21.3), 401 (213), 420, 422, 425 Dominguez, X. A , 44(3), 110 Douglas, B., 17(33b), 27(62), 28(33b), 30 (33b), 32(33b), 33(33b), 35(33b), 35, 39 Douglas, G K., 15G(79), 172 Dowden, B. F., 288(G9), 302 Dragendorff, G., 441, 464 Drisko, R. W., 151 (57), 172 Drummond, R., 530(6), 543 Dryon, L., 121 (196), 129 Dubravkova, J., 120(20), 123

558

AUTHOR I N D E X

Dudock, B. S., 17(43), 28(43, 66), 34(43), 38, 39,49(61, 62, 63), 66(61, 62), 67,68 (62), 108(61,62), 109(61),1 1 2 , 1 5 5 ( 7 5 ) , 156(75),172 Duffield, A. M., 226 ( 2 8 ) ,228 (28,68,69,70), 229, (69, 70), 263, 264 Duncan, J. L., 121(135), 127 Dunstan, P. J., 529(3), 530(3), 531(3), 543 Duran, A., 201 (83), 220 Durham, L., 167(112), 168(112), 173 Dutschewska, H. B., 144(31), 145(31, 35), 146(31), 171 Dutta, C. P., 325(70), 408(70), 412(70), 421 Dutta, N. L., 68(92,93), 71 (93), 87(93), 108 (92),113 Dyke,S.F.,89,113 Dzhalilov, D. R., 47(37), 111 Dziemian, R. L., 317(47), 349(47), 421 Dzyuba, N. P., 121 (225), 129

E Eastham, J. F., 365(150), 424 Ebermann, R., 168(122), 174 Eckert, J. M., 288(70), 302 Edwards,O. E., 122(247),130,274(18), 301 409(224), 425, 545, 548, 550, 550, 551 Egels, W., 46(30), 111 Egorov, N. V., 121 (go), 125 Ehmke, H., 45 (13), 110, 120(34), 124 Ehrhardt, M., 508(34), 512,515 Eisner, U., 214(124), 221 Ellert, H., 122(256), 130 Elliot, D. F., 413(230), 425 EIRidi, M. S., 121 (239), 122(242), 130 Emmermann, S. L., 291 (74), 302 Endo, N., 122(271), 131 Engelbrecht, H. J., 121 (72), 125 Erdtman, H., 136, 170 Eskairov, M., 229(85, 86), 253(85, 86, 141), 254(86, 146), 265, 266, 267 Esser, W., 438(22), 439 Evans, W. C., 276 (27,28), 280 (27), 299 (go), 301, 303 Ewell, T., 419(239), 426

F Fales, H. M., 121 (64,197), 122(64),124,129

Fakhrutdionova, I. RI., 227 (55), 229 (%), 231 ( 5 5 ) , 233(53, 142), 255(142), 264, 266 Farmilo, C. G., 120(57), 121(63, 66, 125, 153, 185), 124, 12,5, 126, 127, 128 FaurP;, &375(179), I., 376(180), 424 Faust, E. S., 438, 439 Favre, H., 311(23), 317(23), 318(23), 331, 420, 422 Fazekas, E., 121 (71), 125 Feist,K., 102(137), 105(137, 156), 106(137, 156), 108(137), 114 Feniak, G., 545(2), 548, 550(2), 550, 551 Ferrari, C., 135(8), 170 Figdor, S. K., 167(111), 1 6 8 ( l l l ) , 173 Findlay, St. P., 274, 301 Fischer, P., 121(162), 122(162), 127 Fischer, R., 121 (loo), 126 Fiset, L., 121(185), 128 Fish, F., 17(28a), 38 Flagler, M. B., 308(6), 420 Flataker, L., 123(287), 131 Fleischer, K., 53(77), 78, I 1 2 Flentje, H., 44(7), 110 Floss, H. G., 262, 267 Fluck, H., 121(174), 122(174), 128 Fodor, G., 269(2), 271(8a, l l ) , 273(12, 13, 14, 15), 274(13, 15, 17, 18, 19), 277(30, 31, 33), 278(37, 39a), 280(39b), 281 (43, 44), 254(31, 50, 51, 53, 55, 56), 285(2, 58, 59), 286(59, 58, 60), 287(2, 60), 288(58, 59, 64), 291(76, 78), 300 (2, 58, 59), 300, 301, 302 Fogerty, A. C., 5 3 0 ( 5 ) ,543 Foley, G. E., 122(264), 131 Foltz, R. L., 185(42), 191 (57), 218, 219 Fonzes, L., 204(88), 220 Forster, L. S., 501 (25), 515 Fouli, A. M., 121 (81), 125 Fraga, F., 201 (83), 220 Francis, R . J., 94(124), 98(129), 114 Franck, B., 19(45, 47), 38, 136, 168(12, 13, 120, 121), 170,174 Franek, R. W., 343(94), 355(94), 358(94), 360(94), 422 Franke, A. K., 121(189), 122(189), 128 Franke, H., 121 (72), 125 Freeman, W. J., 209(107), 210(107, l l l ) , 220

AUTHOR INDEX

Frerichs, G., 107(171), 115 Freudenberg, K., 2i7, 301 Freund, If.,53(77), 78, 103(149), 112, 114 Frey, H., 386(193, 194), 424, 425 Fridrichsons, J., Sly(?), 522(7), 528, 540, 543 Friebel, H., 122(259, 26Y), 130, 131 Friedrich, W., 375, 376(180), 380(180), 382 (l80,183),383(lS3),384(180, 182), 388 (180,182,183), 389(183),400(182),424 Friese, U., 184(36), 192(36), 209(106), 211 (106), 218,220 Fritsch, N., 310(19), 420 Frolova, V. I., 50(69), 112, 227(49), 228 (49),229(49,74),230(49),233(74,117), 235(74), 264, 265, 266 F u , S. C., 17 (3O), 38 Fujie, M., 13(19), 37 Fujita, E., 17(42), 38, 149(48, 51), 158(81, 82,84), 171,172 Fujita, M., 121(133, 160), 122(133), 127 Fujitani, K., 135(5), 141(17, 21), 153(69), 170, 172 Fukagawa, K., 24(56), 25(56), 26(56), 38, 50(71),112 Fukuda, H., 122(262,275),131 Fukumoto, K., 141, 170 Furukawa, H., 135(5), 144(32), 145(32), 146(32, 37), 147(41, 42, 43), 148(37, 43), 165(105, 106, 108), 170, 171, 173 Furuya, T., 121(117), 126 Fuse, M., 49(55), 85(55), 103(55), 104(55), 106(55),107(55),112

G Gadamer, J., 43, 53(78, 79), 54(79), 102 (133), 103(147), 104(135, 147, 153, 154), 106(154, 167), 107(167),112,114, 519(15),528 Gaenshirt, H., 121(86), 125 Galbraith, M . N., 229(82), 2 3 0 ( 8 2 ) , 265, 541 (14), 543 Galinovsky, F., 196(65), 219 Galivan, I., 201 (83), 220 Gallagher, T . F., 365(151), 424 Ganguli, N. G., 121 (180), 128 Garcia, A., 204(87), 220 Gardent, J., 490(7), 514

559

Garratt, S., 88(116), 103(116), 113 Gatica, J., 362(147), 364(147), 423 Gatscheff, B., 186(44), 201 (86), 202(86), 204(86), 218, 220 Gautier, J. A., 121(127), 127 Gear, 5. R., 92(123), 113, 120(29, 30, 31) 123, 124 Geissman, T. A., 9(14), 28(14), 37, 325(69), 407(69),410(69), 421 Gell, R. J., 228(59), 264 Gellert, E., 14(22), 15(22, 22a), 37, 517(3, 7), 522(7), 525(20), 5 2 6 ( 2 0 ) , 528(23), 528 Genest, K., 121 (63), 124 Georgievs’kii, V . P., 121 (225), 129 German, E., 122(264), 131 Gerrans, G. C., 206 (93, 94), 220 Gertig, H., 229(77), 265 Gervay, J. E., 512(40), 515 Gessner, O., 438, 439 Gheorgiu, A., 45(19), 111, 121(240), 130 Ghosal, S., 261,267 Ghosh, N . N., 518(10), 527(10), 528 Ghosh Majumdar, S., 121 (180), 128 Ghosh, S., 518(10), 527(10), 528 Gibson, M. S., 16(26),37 Gilbert, B., 6(9),28(9), 29(9), 37 Gilbert, M . E . A., 6(9), 28(9), 29(9), 37 Gilham,P.T., 228(61, 62), 230(61,62), 234 (62), 264 Gill, S., 176(1),218 Gluzman, M. Kh., 121 (77), 125 Godse, D. D., 371(164), 374(164, 177),.424 Goeber, R., 121(220), 129 Goerner, H., 121 (73), 125 Gottlicher, S., 435(15), 439 Gotz, M., 332 (107), 333 (107), 343 (107), 358 (107), 422, 545, 551 Golankiewicz, K., 195(63), 219 Gonzalez, A. G., 212(114), 220 Gonzales Gomez, G., 121 (IOI), 122(101), 126 Goodeve, A. M., 300(94), 303 Goodman, J. J., 419(239), 426 Goodwin, S., 224(7, 12), 229(12), 230(12), 236, 237(12, 123, 127), 238(12, 130), 239, 240(130), 241(7, 130), 242(12), 243(7, 12), 250(12), 257(130), 263, 266 Goosen, A., 206(96), 220 Gopinath, K . W., 162(97,98), 173

560

AUTHOR INDEX

Gorbacheva, I. N., 138(15), 142(25), 170, 171 Gorecki, P., 120(23, 24), 121(198), 123, 129 Gorman, M., 120(36), 124 Goryaev, M. I., 4 7 ( 3 i ) , 111 Got, R., 46(24), 111 Goto, K., 105(175), 115 Goto, R., 229(97), 265 Goutarel, R., 307(3), 308, 309(11, 15), 310 (11, 15, 1 7 , IS), 3 1 1 ( l i , 18), 312(5, 24, 25, 26), 313(3, 18, 35a), 314(35a, 39, 40), 315(18, 42, 44), 317(3, 35a), 318 (39, 50, 5 3 ) , 320(54, 55, 56, 58), 322 ( 5 8 , 59), 323(58, 59, 63), 324(35a, 63, 68), 330, 332(108), 333(111), 334(76, 115), 336(55), 337(44), 338(96), 339 ( 8 2 , 8 5 ) , 342(91, 93), 343(84, 93), 344 (83, 84, 8 5 ) , 345(74a, 78, 83, I N ) , 347 (74a, 79,80, 130), 348(3, 17, 18, 22,24, 35a, 39), 349(17, 18, 22, 24, 26, 39, 42, 50, 5 3 , 54, 55, 5 8 ) , 350(39, 53, 54, 56, 63, 74a), 351 (35a, 39, 58, 59, 63), 352 (3, 18, 42, 44),353(74a, 76, 78, $9, 80, 82), 354(82, 83, 84, 8 5 ) , 355(91, 96), 356(39, 40), 357(74a), 373(173, 174, 175), 379(15), 381 (201, 205), 282(15, 201, 205), 383(201, 205), 388(15, 201), 389(15, 201), 391 ( 2 0 l ) , 392(205), 396 (15, 201), 395(15, 2 0 5 ) , 399(205), 400 (205), 402(15, 218), 404(218), 405(68), 412(35a), 417(56, 205), 218($8), 219, 419, 420, 421, 422, 423, 424, 425 Govindachari, T. R., 16(28), 38, 42(1), 82 (log), 105(IG0), 106(160), 110, 113, 114, 115, 162(97, 98), 173, 2%(67), 229(67), 230(67), 231(105), 2 3 2 ( 1 I l , 113), 264, 265, 266, 490(6), 514, 518, 520(13, 14), 5 2 2 (12, 17), 524(12, 18, 19), 525(20), 526 (12, 18, 20), 527(13), 528(12), 528 Gow, P., 228(6l), 230(61), 264 Grabarczyk, H., 2 2 9 ( 7 i ) , 265 Gray, A. H., 545(5), 551 Green, A. F., 122(260), 130 Greenberg, hf. A., 49(61), 66(61), 108(61), 109(61), I 1 2 Greenspan, G., 312(27), 420 Gresham, J. T., 209(107), 210(107, I l l ) , 220

Griffin, W. J., 276(27), 280(27), 299(90), 3 0 1,3 0 3 Grossnickle, T . T., 494(15), 5 0 l ( l S ) , 502 (28), 514, 515 Griining, W., 441,464 Grundon, %I. F., 134, 151(54, 55, 56), 170, 172, 214(123), 222, 224(14), 231(108), 247, 249(135), 256, 257(14, I%), 2 6 1 , 263, 265, 266, 267 Gudju, I., 121(112), 122(112), 126 Guirard, B. &I., 122(264), 131 Guise, G. B., 5 2 9 ( 3 ) ,530(3), 531(3), 543 Gupta, R. N . , 94, 114, 120(32), 124 Gupta, . ' 1 N., 229(96), 265 Gyorgy, L., 300(95), 303

H Haaf, G., 429(.51),434(13), 436(1B, 17), 439 Haack, E., 468(7, 8 ) , 4 7 0 ( 7 ) , 4 7 l ( 7 ) , 472 ( 7 , 8 ) , 473(7), 474(7), 476(8), 4 7 9 ( i , 8 ) , 480(7, 8),481, 482 Haars, O., 104(151), 105(l63), 114 Habermehl, G., 427(3), 429(3, 5), 4 3 2 ( 8 , lo), 4 3 3 ( l l ) , 434(3, 12, 13), 435(15), 4 3 6 ( 1 6 , 1 7 ) ,439 Hacaperkova, J., 121 (178), I 2 2 ( l 7 8 ) , 128 Haede, W., 310(19), 420 Haginiwa, J., 208(104), 220 Hagitani, A., 442 (12), 443 ( I I ) ,446 (12), 464 Haining, C. G., 300(96), 303 Halmos, M., 273(13), 274(13), 301 Halpern, B., 227(37), 2 2 8 ( 3 7 ) , 229(37), 230 (W), 263 Halsall, T. G., 393(207), 394(20i), 393(2005), 425 Hammarlund, E. R., 120(40), 124 Handa, K . L., 122(247),130,409(224), 4 2 5 , 5 4 5 ( 2 ) ,550(2), 550 Hanna, C., 513(42), 515 Hanscn, IT. F., S o l , 509(27), 51; Hanson, A. W., 497,515 Hantzsch, A., 43, 112 Hanui, V., 308(10), 309(10), 310(10, I G ) , 379(213), 380(213), 389(16), 400(213), 401 (213), 420, 425 Hara, S., 122(267), 131 Harada, K., 227(47), 228(47), 229(47), 264 Hardegger, E., 69, 7 2 , l03(94), 113

AUTHOR INDEX

Harley-Mason, J., 134(4), 155(4), 1 5 5 ( 4 , 80), 170,172,206(93,94),220,512(38), 515 Harris, W. M., 9 ( 1 4 ) , 28(14), 37 Harrison, I. T., 362(148), 424 Hartman, R. E., 338(86), 354(86),422 Hartwick, G., 467(3), 468, 470(3), 481 Hasegawa, M., 379(200), 381 (ZOO), 382 ( 2 0 0 ) , 388, 400, 401 (200), 402(200), 425 Hassall, C. H., 214(119, 120), 216(128), 221 Hausermann, H., 122(249), 130 Haussermann, Z., 121(176), 128 Haworth, R. D., 102(139), 104(139), 105 (157, 158), 106(158), 108(139),114,261 (l58), 267, 306(2), 311 (23), 315(43), 317(23), 318(23), 3 2 0 ( 5 7 ) ,330(99), 332 (99), 333(2), 336(81), 339(2), 353(81), 387(43), 396(43), 419, 420, 421, 422 Hayes, L. J., 30(63), 39 Haynes, H. F., 227(35), 228(35), 263 Hazama, N., 451 (29), 465 Hearst, P. J., 151(57), 172 Heftmann, E., 417(233), 418(237, 238), 426 Heimaster, J. W., 290(73), 302 Henatsch, H. D., 614(48), 515 Hensle, B. L., 317(47), 349(47), 422 Herbert, R. B., 169(125), 174 Herlem-Gaulier, D., 309(15), 310(15), 379 ( l 5 ) , 282(15), 388(15), 389(15), 396 (15), 397(15), 402(15, 218), 404(218), 420, 425 Hernalsteen, L., l22(265), 131 Hernandez, B. R., 212((114),220 Herran, J., 155, 172 Hertler, W. R., 358, 418(139), 423 Hess, K., 213(118), 214(118), 221 Hesse, R. H., 94(l26), 95(128), 114 Heusler, K., 375, 376(180), 378(181), 380 (180, 181), 381(181), 382(180), 384 (180), 388(180, 181), 424 Heusner, A., 281(46), 282(47, 4S), 284(53), 302 Heydenreich, K., 121(212, 215, 216, 217, 218,221), 129 Highet, P. F., 121 (197), 129 Highet, It. J., 215(126), 221 Hill, R. K., 498, 515 Hindorf, H., 181(20, 21, 22, 24, 25), 218

561

Hirasawa,RI., 122(251),1 3 1 Hirschmann, F. R., 388(197), 425 Hirschmann, H., 388(197), 425 Hirst, hl., 94(124), 114, 120(26), 123 Hobhs, J. J., 541 (14), 543 Hobson, J. D., 275(25), 301 Hochstein, F. A., 121 (93), 125 Hoffrnann, M., 441, 442(4), 464 Hogg, R., 49(60), 11 2 Holden, K. G., 224(13), 228(13), 230(13), 236, 237(13), 238(13), 244, 246(13), 247,263, 266 Holder, G. M., 529(3), 530(3), 531 (3), 543 Hollis, A. F., 227(38), 2 2 8 ( 3 8 ) ,229(38), 230 (38), 264,529(3), 630(3), 531 ( 3 ) ,543 Hollstoin, U., 6(9), 28(9), 29(9), 37 Holmes, E. hl., 467(1), 481 Holter, H., l05(16l), 114 Holubek, J., 121(177, 203, 205, 206, 226, 2 2 7 ) , 122(203, 205), 128, 129 Honda, J., 229(94), 265 Hooper, D., 518, 528 Hora, J., 325(72), 334(97), 335(72, 97), 342 (97), 343(97), 355(97). 372(97, 168, 170), 421,422,424 Horak, V., 284(56,57),302 Hori, T., 168(115), 274 Homing, E. C., 184(38, 39), 189(38), 206 ( 3 8 ) , 218, 224(12), 229(12), 230(12), 236(12), 237(12, 123, 127), 238(12, 130), 239, 240(130), 241 (130), 242(12, I”), 243(12), 250(12), 257(130), 263, 266 Hosansky, N., 468(10), 474(10), 475(10), 477(10),479(10),482 House, H. O., 275(24), 301 Housley, J. R., 261 (157), 267 Howell, F. H., 363(149);424 Hrhek, J., 118(15), 119(15), 120(15), 122 (15), 123, 169(124),274 Hsieh, Y., 147(39, 40), 172 Hsing, C.Y., 153(70),172 Hsu, H. -Y.,229(89), 265 Huang-Minlon, 102(140), 114, 369(153), 424 Huher, R., 121(111, 159), 1 2 2 ( 1 l l ) , 126, 127 Hubner, G., 181 (20), 218 Hiinig, S., 335(116, l l i ) , 423 Huffinan, J. W., 89, 113

562

AUTHOR I N D E X

Hughes, G . K., 83(112), 113, 2 2 7 ( 3 7 ) , 228 (37, 59, 00, 62), 229(35, 83, 8 8 ) , 230 (60, 61, 62, 83) , 234(62), 233(120), 236 (120), 263, 264, 26i, 266, 529(1), 530 (3),332(1),543 Hui, I T . H . , 3(2), ax(’), 37 H u n g - Y u a n Hsu, % ( T O ) , 112 Hussein, F. T., 4 9 ( 6 5 ) , I 1 2 Husson,H.P., 369(153, 136),374(158),419 (244),424,426 Hutley, B. G., 288(67), 289(Ki), 290(67), 302 Hwang Wen-kuei, 118(17), 123

I Ibuka, T., 26(58), 38, 4 9 ( 5 5 ) , 85(65), 103 ( 5 3 ) , 104(55), 106(55), 107(55), 112, 135(5), 154(71, 7 3 ) , 1 7 0 , 1 7 2 Ikram, ill., 121 (168). 128 Il‘inskaya, T. A,, 122(257, 258), 130 Il’inskaya, T . N., 49(54), 112 Imaseki, I., 44(10, l l ) , 45(20), 71, 74, 7 5 (99), 102(10, 99), 103(20), 104(20, 99), 111,113 Inglis, A. S.,121 (131), 126 Ingold, C. K . , 278, 301 Inuhuse, M.,227 (U), 264 Inubushi, Y., 117(4), 123, 164(102, 103), 165(102, 1 0 i ) , 168(114, l l 5 ) , 173, 174 Jonescu-Matiu, E., 45(19), 111 Iriarte, J., 225(23), 22i(23), 2 3 8 ( 2 3 ) ,263 Irwin, R. L., 513(43), 51.5 Ishbaev, A. I., 199(73),200(S(i, i 8 ) , 219 Ishii, H., 227(45, 46, 47), 268(47), 229(45, 47, 98), 264, 265 Ishikawa, ill.,458(40), 465 Islam, M.,121(168),128 Ismailov, Z. F., 143(27, 28), 144(29), 135 (T(i), 271, 172 Isseliutz, B., sen., 269 (5), 301 Itkin, S . E., 122(264), 131 Ito, K., 49(50), 111, 142(23, 24), 145(43), 171 Iverach, G. G., 21 (51), 38 Iwasa. .J., 110, I 1 5 Iyer, K.T., 313(38), 348(38), 421 Izmailo\-, N . A., I21 (166. 189), 122(189), 128

J Jack, J., 502(28), 5f.5 Jackson, A . H., 13(20), 22(20, 3 2 ) , 23(20), 37, 38 James,K.,485(1a), 514 Jangic, T. J., 121 (123), 126 Janiak, B., 190(56),207(56), 219 J a n o t , M . -&I.,310(17, 18), 311(15, 18), 312 (24, 25, 26), 313(18), 314(40), 315(18, 42, 44),318(.50, 5 3 ) , 320(54, 58), 322 ( 3 8 , 59), 323(58, 59), 330, 337(44), 338 (961, 339(85), 342(91), 343(84), 344 (84,85), 345(74a, 7 8 , 130), 347(74a, 13O), 348(17, 18, 22, 24, 35a), 349(17, 18, 22, 24, 42, 50, 53, 54, 58), 350(53, 54, 74a), 351 (58, 59), 352(18, 42, 44), 353(74a, 78), 354(84, 85), 355(91, 93, %), 356(40), 357(74a), 373(173, 174, l i S ) , 410(18), 418, 419(74a, 78, 96, 240), 420, 421, 422, 426 Janzs6, G., 2 7 7 ( 3 0 ) , 295(76), 298(87), 301, 302, 303 Jarreau, F . X., 332(108), 333, 334(76, 115), 345, 347(74a, 130), 350(74a), 352(75), 353(74a, 75, TF), 357(74a), 419(240), 422, 423, 426 Jasinski, T., 122(256)! 130 Jefferies, P. R., 226 ( 2 8 ) .228 (28,68,69, i O ) , 229(69, 7 0 ) , 263, 264 J e f f s , P. W., 78(106), 79, 80(105), 82((105), 113,476,482 Jeger, O., 305, 311(21), 315(45), 345, 356 ( l ) , 358(21), 367(45), 371(165), 418 (21), 419, 420, 421, 424 Jon-Hung Chu, 45(12), 49(53), 50(72), 110, 112 Jennings, J . P., 135(6), 170 Jevtic, V. D., 121 (123), 126 Jewers, K., 330,422 Jezo, I., 120(20), 123, 453(33), 465 Jo h n s, S. R., 9(13a), 28(13a), 3S(13a), 37 Johnson, L. F., 224(7), 241(T), 243(7), 263 Johnson, W. S., 343(94), 335(94), 358(94), 360(94, 143), 362,422, 423 Johnston, R . G., 300(96),303 Johnstone, It., 225(24), 238(24), 26.3 Jones, D . N . , 336(118), 423 Jones, E. R. H., 393(207), 391(207), 393 (207), 425

AUTHOR I S D E X

Jones, <J. H., SX(92), 108(92), 113 Jones, R. A. Y., 2888(66), 289(66), 902,431 (28), 4.%(28), 466 Jones, K.R., 123(281), 131 %Jordaan, A., 2 5 7 ( l 5 l ) , 267 Josephi, W.. l 0 3 ( l 4 9 ) , ill Jowett, H. A. D., 83, I O i ( l l l ) , 113 Joyrit, V. P., 257(151), 267 Jucker, E., 1i8(3N), 282(38, 49), 2 8 4 ( 3 1 ) ,

301,302 Juhasz, G. J., 487 (31, 514 Jui-Ch'un Ch'en, 49(53), 112 Julia, S., 508(35),515 Jullan, P. L., 107(173), 115, 31i(48), 338 (4S), 421

563

Karle, I.L.. 214(123),215(125), 221 Karle, J., 214(115), 21.5(125),221 Karrata, Z., 121 (66), 1%; Karrer. P., 120(37), 124 Karnas, M.,433(33), 465 Kasal, A., 317(46), 328(i3), 330, 331 (102), 345(102), 352(73), 372(166), 373(46), 374(1ifj), 421, 422, 424 Kashida, Y., 208(104), 220 Kashirna,T., 1 2 l ( l 2 I ) , l L 6 Kassner, E., 295(77), 302 Kataoka, H., 1i8(8, 9), 218 Kato, .4., 135(5),I70 Katritzky, A. R., 288(64), 302, 451(28),

458,465

Jurzysta, M., 122(252),130

Kamanaga, K., 442(12), 445(12), 446(12),

464

K Kaczkowski, J . , 296(83), 302 Kaese, H. J . , 514(48), 515 Kakac, B., 121(178),122(178), 128 Kalb, BT.,431 (73), 112 Kallquist, L., 122(261), 131 Kalvoda, J., 311(21), 358(21), 371(165), 418(21), 420,424 .Kalvoda, P., 121(209), 129 Karnata, H., 208(104), 212(113), 213(116),

220 Kamber, B., 313(45), 367(45), 421 Kamernitzky, A. V., 3 2 8 ( $ 3 ) , 352(i3),422 Kametani, T., 141, 143, 170,171 Kamilov, I. K., 254(145) 267 Karnimura, BI., 1 5 ( 5 7 ) , 38 Kamp, W., 121(118, 167), 122(118, 16i),

126, 128 Kan, C., 366(154), 369(154),417(234),424,

426 Kaneko, T., 4 4 2 ( 9 ) , 444(9), 449(21), 451 ( 2 i ) , 45?(30. 31). 457(36), 458(21, 36), 464,465,543(1),549, 550(10, 13), 550, ;;I Kano, K., 121(121), 12G Kano, Y., 49(64), 112,149(48, 49, SO), 158,

171, 172 Kantharnani, S., 336 (120), 423 Kanzaki, P., 120(51), 124 Kao, I., 147(38), 171 Kao, Y., 147(39, 40). 171 Kapczynska, >I., 121(69), 122(69), 125

Kawasaki, I., 449 (21),451 (27), 432(30, 31), 457 (36), 458, 465 Kawasaki, <J., 442 (9), 464 Kawanishi, M.,42(2), 110 Kav azoe, Y., 232 (140), 266 Kelentai, R., 123(285), 13f Keller, K., 194(60), 218 Khaloque, A., 463(41),465 Khalifa, K., 121(239), 122(241),130 Khuong-Huu-Lain& F., 307(3), 308, 309 (11, IS), 310(11, 13), 313(3), 317(3), 338(96), 348(3), 3 3 2 ( 3 ) , 355(96), 379 ( I L > ) , 381(201, 20.5), 382(15, 101, 205), 383(101, 205), 388(15, P o l ) , 389(13, 201), 391 (20l),392(2003),396(15, 201), 3'37(13, 205), 3 9 9 ( 1 0 5 ) , 400(205), 402 (13, 218), 404(218), 417(205), 419(96, 2003), 419,420,422,425 Khuong-Huu, Q., 308 ( l l ) ,309(1l ) , 310(11, 17, IS), 311(17, 18), 31%(24,25, 26), 313(1X,&?a),314(33a, 39,40), 315(18), 317(33a), 318(39), 323(63), 324(35a, 63), 330(39, 40), 332(108), 3 3 2 ( 5 6 , l l 5 ) , 339(82, 83), 341(91, 93), 343(84, 93), 341(83, 84, 8 5 ) , 343(74a, 7 8 , 83, 130),347(74a, 79,80, 130), 3 4 8 ( 1 i , 18, 2 2 , 24, %a, 39), 349(17, 18, 22, 24, 26, 39). 350(39, 63, 74a), 331 (33a,39, 63), ) ( l 8 ) , 353(74a, i t i , 78, '79, 80, 8 2 ) , 3.54(82, 83, 84, 8 3 ) , 335(91, 93), 356 (39, 4 0 ) , 357(74a), 410(18), 412(35a), 418(78), 419(74a, 78, 240), 420, 421,

422,421,426

564

AUTHOR I N D E X

Kibal’chich, P. N., 22i(49), 228 (49), 229 (49). 230(49),264 Kidder, G. TV., 122(264),131 Kidu-ai, A. R., 406(223), 407(223)), 408 ( 2 2 3 ) ,409(21’3), 426 Kielczexvski, >I., 309(14), 420 Kikkama, I., 30(65),39 Kikuchi, T., 47(43), 49(52), 111, 135(5), 159(86, 88, 89,90,91), 161 (86,93), 168 (114), 170, 173, 174, 315(41), 348(41), 407, (41. 225, 226, 228, 229), 408(41, 228, 2331, 2 3 2 ) , 411(225, He)),412(41, 228, 229), 413(229), 414(228), 415(41, 229),417(231,232),419(241), 421, 42.5, 426 Kincl, F. A , , 2 2 4 ( 2 1 ) , 2 2 5 ( 2 3 ) , 2 2 7 ( 2 3 ) , 238 ( 2 3 ) ,263 King, F . E., 261(157), 267, 386(192), 424 King, RI. L., 17(42), 38 King, T. J., 261(157), 267, 386(192), 424 Kinze, W., 121(155, 192, 194), 127, 128 Kiraly, J . K., 514(46), 515 Kirby, G. W., 30 (63), 39, 94 (126), 95 ( 128), 114, 485 ( l a ) ,514 Kishimoto, T., 153(69),172 Kiss, S., 281 (45), 284 ( 5 3 ) , 302 Kitamura,T., 7(10), 24(10, 55), 37, 38 Kitamura, Y., 149(51), 171 Kitano, M., 135(5), 170 Kitasato, Z., T i , 108(103), 109(103), 113 K j u H i Shin, 204(88), 220 Klee, W . , 53(79),54(79), 112 Klein, D., 430(6, 7), 439 Kleine, K. N., 449(23), 450(23), 453(23), 465 Kleiner, E. &I., 138(15), 170 Kleinschmidt, G., 120(25), 121 ( l s l ) , 1 2 2 (151),123, I27 Kloetzel, BI. C., 345 (129), 423 Kloss, P., 468(9), 470(9), 475(9), 479(Y), 480(9), 481, 482 Klyne, W., 133(6), 170 Knaack, W.F., 325(69), 4Oi(ii9), 410(69), 421 Knabe, J.,490(8), 514 Kniers, K., l 8 6 ( 4 3 ) , 218 Knittel, V., 417 (236), 426 Koch, K., 429(4), 432(9), 439

Kocjan, R., 313(35a), 314(35a), 324(35a), 348(35a), 351 (35a),412(35a), 420 Koczka, K., 287(61), 302 Koczor, I., 277(30), 298(8’i), 301, 303 Kodaira, S., 82((108),83(108),84(108), 106 (log), 106(108), 113, 118(11, 12, 13), 120(13), 123 Koepfli, J. B., 105(157),114 Koezuka, Y., 37 (67), 39 Kogan, 0. >I., 121 (go),125 Kohli, J . BI., 406(223), 405(223), 408(223), 409 ( 2 2 3 ) ,425 Kojima, Y., 451 (29),46.5 Kolankiewicz, J., 121 (187), 728 Kondo,H., 102(138),105(138),1 1 4 ,5 4 5 ( 4 ) , 550,550,551 Kondo, K., 55(85),112 Kondo,Y., 6 4 , 55(85),80, 106(85), 112 Konita, T., 117(4), 123 Konowalova, R. A., 214(122), 222 Korbl, J., 121 (132), 127 Kori, S., 121 (133, l60), 127 Koseki, M., 446(16), 447(16), 448(16), 456 (lB), 465 Kotake, M., 442(9, 12), 444(9), 445(12), 446, 447(15), 449(16, 21), 451, 452, 458,464, 465 Kovacs, J., 121(87), 125 Kovjcs, 273(13, 14, 15), 301 Kovacz, K., 121 (204), 122(204),129 Kovalenko, 1’. N., 233 (116), 266 Kovar, J., 118(15), 119(15), 120(15), 122 ( l 5 ) , 123 Kozuka, nf., 3 ( 3 ) , 8(1?), 1713, 12, 32), 28 (3, 12),37, 110(180),115 Kracmar, J., 121 (122), 126 Kraczkowsak, J., 122(252), 130 Krausz, I., 121 ( 8 i ) , 1.25 Kress,W., 121 ( 2 3 5 ) , 130 Krieger, W., 468, 470(ii), 4?2(ii), 476(6), 477(6), 478(6), 479(6), 481 Krogerus, 1’. E., 121 (98), 122(98),126 Kruglykhina, G. K., 47(37), 111 Kubitz, J . , 490 (S), 514 Kubota, S., 338(87), 354(87), 422 Kubota, T., 442(12), 445(12), 446(12), 464 Kuck, A. M.,17(31), 19(4G), 28(6lb), 34 (Glb), 38,39 Kudrnac, S., 121 (177,206), 128,129

o.,

AUTHOR INDEX

Kugo, T., 47(34), 48(44), I l l , 138(14), 139 140(14), 148(44, 46), l 5 4 ( 4 4 , i2), 170, 171, 172 Kuhn, L., l i ( 4 1 ) , 38 Kulka, &I., 134(1, 2 ) , 141(2), 148(1, 2 ) , I50 (1, 2 ) , 159(2),l(il(1, 2 ) , 170 Kulkami, B. D., 336(120), 423 K u m - T a t t Lee, 121 ((is, 59, 125, 153), 124, 125,126, 127 Ihnitorno, %J., 17(38), 25(5i), 38, 4 9 ( 6 6 ) , 5O(B7, (X), 85, 8(i(113), 87(114, l l 5 ) , 89, 91(120), 103(115), 112, 113, 136, 138(9), 140, 141 (9), l42(9), 148(9), 149 (9), 150(9), 151(9, 53), 153(9), l59(9, 92), I 6 1 (9), l 6 5 ( 1 0 4 ) , 170, 172, 173 Kupchan, S . l l . , 17(42)),38, 144(30, 32, 33, 34), 145(30, 32), 153(68), 1 7 1 , 172, 338 (85), 354(87), 375, 376(185, 189), 378 (184, 187),379(220),380(184,185, 187, 191, 206, 2 l 4 ) , 381 (184), 382(203), 383 (186, 203, 204a), 384(184, 186, 187, 191), 387(191), 389(186, 203), 391 (204a), 392(187, 189, 206), 395(206), 400,401(191,214),404,406(l88,“%la), ,422, 425 Kuriyama, K., 118(11, 12), 123 Kurosawa, E., 382(203), 383(203), 389 (203), 425 Kushmuradov, Yu, K., 213(115, 117), 220, 22 I Kusomoto, S.. 442(9), 444(9), 446(15), 445 (15), 449(15, 21), 451(25), 4 5 2 ( 3 0 ,3 1 ) , 458(21), 464, 465 Kuwayama, Y., 232 (log), 265 Kuzovkov, A. D., 49(54), 112, 225(49), 228(49), 229 (49), 230(49), 233( l l i ) , 264, 266, 517(6), 526(6), 528 Kzelovskaya, G. G., 121 (139), 127

L L a Barre, J., 122 (2i3, 274), 131 Labenskij, A. S., 121 (21 I ) , 129 Labler, L., 310(20), 313(20), 315(20), 3 2 3 ( M )3,2 3 ( 6 7 , 71, T 2 ) , 428(73, i 4 ) , 334 ( 6 7 ) , 335(73),338(6i),347(79, 8 0 ) , 330 (64, 51), 351(67), 362(73), 353(65, 79, SO), 368(137), 371,410(64),419(79, 80, 159, 160, 243), 420, 421, 422, 423, 424, 426

565

Labriola, R., 227(53), 229(53), 264 Lainh, F., 310(18), 311(1X), 313(18), 315 (18, 42, 44), 337(44),348(18), 349(18, 42), 35?(15, 42, &), 410(18), 420, 421 Lakshniikantharn, 31. V., 518(13, 14), 520 (13, 14), 522(17),525(2O),32((i(20),528, 527(13),5 2 8 ( 2 0 ) , 528 Lalaurie, M., -%(;(?A), 111 Lambrrton, J . A , Y(l3a), 28(13a), 35(13a), :17, 224(9), 22X(58), 230(58), 263, 264 Lan, P. K., 15(30a), 38 Langejan, hl., 121 (146), 122(146),127 I,angerriann, A,, 493(14), 499( 14), 514 Langrrhr, D., 514(48), 515 Laos, J., 342( I is),423 Lau, D. 1’.I<., I5(22a), 37 Laucler, A., 103 (146), 114 Laug, P., 372(lti9, 169a), 424 Laurent,H., 190(50),205(56),219,449(23), 450(23), 453(23), 464(42), 465 Leboouf, M . , 320(65, 56), 3 3 6 ( 5 5 ) , 349(55), 350(56), 417, 421 LeCount, D.J., 88(116), 103(116), 113 Lee, K. H., 17(35), 38 Lecte, E., 120(28), 123,295(79,YO), 296(80, 8 2 ) , 299(92,93),300(93), 302, 303, 512, 515 LeFBvre, It. ,J. W., 2 8 8 ( 7 0 ) ,302 Lcgler, G., 5(11), 13(11, 21), 14(11),P8(11), “ ( ? I ) , 37 Legocki, A. 13., 196(69), 8/11 Logrand, fir., 404(221), 425 Lehfeldt, ,J., 181(18, 19, 23, 26), 218 Leifels, W., 121 (163, 182), 122(163, 182), 127,128 Leit.he, W., 105(169), I 1 4 Le Men, J., 366(152, 154, 157, 158), 367 (IS? ), 369(154, 1-55, 156, 157), 370 (158), 374(162, 178), . 417(234), 419 (244), 4 2 4 , 4 2 6 Leonard, N . J . , l i 6 , 218, 550(12), 551 Lerner, &I. I., 142(25), 170 Lettenbauer, G., 468 (7, 8, 1 l ) , 469 (1l ) , 470 ( 7 , 11, 12),451(7, 11, 12),472(7,8, I I ) , 473(7, 12),474(7), 4 5 6 ( 8 ) , 478(11),459 (i, 8, l l ) , 4Y0(7, 8 , 11, 12). 481(11), 481, 482 Levi, L., 1 2 0 ( 5 7 ) , 121 (G), 124 Lewejohann, B., l ( % ( l 2 0 ) , 174 Liberalli, C. H., 121 (233, 234, 237), 130

566

AUTHOR I N D E X

Liehisch, H. W., 297 (86), 303 Lin Geng-shou, 118(17), I 2 3 Lin-Hsing Ho, 45(12j, 110 Lin, F. >I., 17(30a),38 Lin, T . J . , l 4 T ( 4 l , 42), 171 Lin, Y . >I., I i ( 3 0 ) , 38 Lindc, H., TO(9.i). 104(95), 1 1 3 Lindemann, A., 2 6 9 ( l ) , 2 7 8 ( 3 8 ) , 2 8 2 ( 3 8 , 49), 300, 301,302 Linnavuori,H., 120(39),124 Liu,L.A.,622"(6),528 Lloyd, H . A., 121(19i), 129, 183(33), 184 (38, 39, 40), 188(33), 189(33, 3 8 ) , 206 (33, 38), 215(40), 216(40), 218 Loh, L. Y. S., 224(19), 263 Longo, P.G., 514(17), 515 Loo, s. N., 3 ( 2 ) , 2 8 ( 2 ) , 37 Lompa-Krzymien, L., 195 (63), 219 Longevialle, P., 250(8), 295(8), 301, 308 ( l l ) , 310(11), 320(58), 322(58, 59), 323 (5S,59), 349(58), 351 (58,59),406(222), 420, 421, 425 Louden, M. L., 299(93), 300(93), 303 Lovell, F. &I.,542, 543 Lu,S.T., 5(13), 17(30, 30a), 28(13), 30(13), 37, 38, 144(32), 145(32), 146(32), 152 (63, 64), 171,172 Lucas, R. A., 317(47), 349(47), 421 Lucich, P. H., 228(69), 229(69), 264 Luckner, M.,260(152), 267 Ludwiecki, H., 121 (198), 129 Ludy-Tenger, F., 121 (75,78), 125 Lukasiewiez, M.,121 (200), 129 Lusinchi, X . , 312(25,26), 349(26), 373(173, 174, l 7 5 ) , 420, 424 Lux, R., 121(120), 122(120), 126 Lyle,G.G.,53(97), 113,118(10),1 2 3

M McCaldin, D. J., 120(27), 123 McCance, I., 514(45), 515 A'IcCapra, F., 512(40), 515 bIcCarthy, R. E., 122(264), 131 Rfachata, G., 121 (157), 127 McClosekey, J. A., 2i0(8),295(8), 301 hlccorkindale, N. J., 224(6), 231 (108), 263, 265 McCormick, J., 533(9), 543

Macek, K., 121(178), 122(1T8),128 IIcCredie, R . S.,5 2 9 ( 3 ) , 530(3), 531 ( 3 ) , 543 BIcEwen, TV. E., 313(38), 348(38), 422 McGarvey, J . E . R., 151 ( 3 5 , 56), I 7 2 JIacGillavry, C. H., 2 7 5 ( 2 3 ) , 286(60), 287 ( G O ) , 301, 302 Xachne, S., 514(44), 51.5 JIcHugo, P. R., 5 1 3 ( 4 2 ) , 515 McKusick, B. C., 508(35), 515 Maclean, D. B., 224(10), 26.3 hlchlillan, W. H . , 513(42), 515 McKenna, J., 288(65, 66, 67, 68), 289(65, 66, 67, 68), 290(6i, 68), 302, 311 (23), 3 I5 (43), 31T (23), 3 IS (23), 320 (57), 330 332(99), 3 3 6 ( 8 l ) , 353(81), 3 8 i ( 4 3 ) , 396 (43), 420, 421, 422 McKenna, J. Ill., 288(65),2S9(65), 302 McKennis, H., 151(.57), 172 McKenzie, A , , 301 McKonzie, A. W., 228(63), 229(63), 264 XacPhillamy, H. B., 317 (4i), 349(47), 421 Rlaffii, G., 122(266), 131 Blagdeleine, M. J., 381 (201), 382(201), 383 (201), 385(201), 389(201), 391 (201), 396 (201), 425 Magrupova, 31.A., 254 (145),267 Maiti, P. C., 57(87), 104(87), 112 Majumdar,P.L.,5(5), 28(5), 29(5), 37 nlaekh, S.K., 1 5 5 ( T 6 ) ,156(77, i 8 ) , 172 Makisumi, S., 120(38), 121 (140, 150), 124, 127 Malesh, W., 441 ( 8 ) , 110 Rlamlock, L., 2 8 0 ( 4 0 ) , 301 Rlamoon, &I., 121 (239), 122(242)),130 Rlancera, O., 3 6 2 ( 1 4 T ) , 364(145), 423 Mandell, L., 209(105), 210(107, 110, l l l ) , 220 &lander, L. N., 543 (16), 543 Manske, R. H. F., 12(15), 17(29), 37, 38, 45(15, 19), 75, 81(105), 102(132, 135, 136, 141), 103(142, 143, 144, 148), 106 (135, 141, 144, 164, 165, 166), lOi(164, 166, 172, l i 4 ) , 108(107, 135, I M ) , 109 (107, lTS), 111, 113, 114, 115, 118(18), 123, 141 (21), 170 Manuchian, N.,45(19), 111 Marcinkowska, K., 122(256), 130 Blariani, A., 122(250), 130 Mariani-3Iarelli, O., 122(250), 130

AUTHOR I S D E X

hlarini-Bettblo, G. B., 121(183, 186), 122 183, 186, 244), 128, 1.30, 388(198), 425 Narinier, B., 331, 422 Marion, L., 1 2 ( 1 i ) , 37, 183(32)),188(32), 189(32), 201(82)), 204(88), 218, 220, 274(18), 295(79), 301, 302, 517(1), 528 Markey, S., 17(33b), 28(33b), 30(33b), 31' (33b), 33(33b), 35(33b),38 Markley, F . S . , 167(111), 168(111),173 Marshall, F. L., 118(6),123 Marshall, J . A., 360(143), 362, 423 Martin-Sans, E., 376(190), 424 Martin, F., 271 (9), 301 hlartin, J . A . , 13(20),22(20, 6 2 ) , 2 3 ( 2 0 ) 37, , 38 Martin, W. R., 514(47), 515 Martini, C. RI., 274(20), 301 MartucciPalma, E. T . , 122(243),130 Marumo, S., 514(50), 515 Mary, N . Y., 121 (154), 127 Marx,A. F., 343(1 2 6 ) ,358(126), 423 Marx, M., 419(239), 426 Masaki, Y., 141 (17), 170 Maslen, E. N., 228(68), 264 Illassagetow, P. S., 51T(G),526(6), 528 Massicot, J . , 121(104, 105), 126 Massy-Westrop, R. A,, A41 (14), 543 Mathieson, A. McL., 517(7), 5 2 2 ( 5 ) , 528 540,435 Matsuda, Y., 232(109), 265 Matsui, M., 49(fi4),112 Illatsumoto, ill., 121 (202), 122(202), 129 Matsumoto, S., 117(4),123 Matsutani, S., 442(9), 444(9), 449(21), 451 ( 2 7 ) , 457(36), 468(21), 464, 465 Mayda, K., 123(2882),131 &layer-&fader,It., l86(44), 218 Meakins, G. D., 332,423 Meindl, P., 196(65), 219 Ileinwald, J., 291 (i-t), 302 Meiring, J., 465 ( 2 ) , 468, 481 Meise, W., 341 (YO), 354(9O), 422 Meisels, A., 2-1.?(23, 25), 2 2 7 ( 2 3 ) , 238(23), 263 Rleissner, W., 196(66, 65, 68), 279 Melander, B., 122(2G1), 131 Blendelsohn, H . , 419(239),426 Rlenz,H.U., 486, 507(31, 3 2 ) , 508(32), 514, 51 5 Merchant, J. R., 508(35),515

567

Mercier, E., 123(280), 131 llercier, J., 123(280), 131 Xlerck, F., 213(118), 214(118), 221 Merlis, V. hZ., 121 (139), 127 lieyer, E . W., 317(48), 358(48), 421 Meyer, K., 50(95), 104(95),113 Mcystre, C., 386, 424, 425 Rliana, G. A , , 121 (168), 128 Michael, AI., 3 0 6 ( 2 ) , 3 3 3 ( 2 ) ,339(2), 419 Illicheel, F., 121(163, I @ ) , 122(1(33, 182), 127,128 Michels-Nyomarkay, K., 121 (113), 126 Rliescher, K., 386, 424, 425 illiglioretto, P., 498(20), 515 Miller, E. G., 89, 113 Miller, L. A,, AAO(l2),,551 Miller,M.R., l06(165),114 Millict, A., 381 (POA), 382(205), 383(205), 388(201, 205), 392(205), 397(205), 399 (205), 400(205), 417(205), 419(205), 425 Milligan, B., 532(7), 543 Minato, H., 212(112), 220 Miram,R., 121(103,107,213,2I4,215), 122 (103), 126, 729 lfiranda, P., 121 (106), 126 Mirosnichenko, L. D., 275(21), 301 Mishima, H., 209 (109),220 Mishinskaya, S. Kh., 121 (201), 129 Rlislow, K., 501 (?A), 515 Mitchell, J . & 514(46), I., 515 Mitchell, W. F., 271 (9, lo), 301 Mitsumori, Y., 3 ( 3 ) , 17(3),2 8 ( 3 ) , 37 Xiyawaki, IlI., lAi(103), 173 Miyazaki, T., 2 2 5 ( 3 2 ) , 2 2 8 ( ( 3 5 ) ,229(65, 7 5 ) , 263, 264,265 Mnat'sakanyan, V. A,, A(8),l i (40),37,38 Mollenhoff, F . , 438(21!,.439 Jlorncr, L., 417(235), 426 Rloir, R.Y., 118(1G),119(16),123 hlokranjac, ill., 121 (91), 125 Moll, N.,N I ( 9 2 ) , 122(92), 125 hIoll,K., i ( 1 1 ) , 1 3 ( l l ) , 14(11), 28(11), 37 3lollov, N. hI., 144(31), 145(31, 35), 146 (31), 171 Mollbrvna, JI., 442 (5),444,464 IIolnar, L., 121 (207, 2 0 8 ) , 122(207, 208), 129 Rlolnarova, K., 121 (207, 208), 122(207, 208), 129

568

AUTHOR INDEX

3Iondon, A., 486, 491(10), 492, 501, 500 (30), 505(31, 32, 3 3 ) , dOS(30, 32, 34). 509(27, 36), 512, 514(10), 514, 515 Money, T., 512(40), ,515 MtlonkoviC, I., 49(58), fid, 93(58), 100, 112, 261, 267 Illonneret, C., 314(40), 330(40), :j34(115), 339(82), 344(83), 345(83), 353(82)),354 ( 8 2 , 83), 356(40), 421, 422, 423 Monscur, X., 313(3da), 314(35a, 39, 40), 318(39, SO), 324(35a), 330(39, 40). 348 (35a, 39), 349(39, 50), 350(39), 351 (35a, 39), 356(39), 412(35a), 420, 421 Mookerjce, A,, 1 2 8 ( 7 3 ) ,264 Morgan, L. R., 359(140, 141), 418(140), 423 Mori, Y., 228(66), 229(66), 231 (106, 105), 232(6Ci, 107), 233(114), 264, 265 Morozumi, S., 82(108), 83(108), 84(108), 105(108), 106(108), 113, 118(9, 11, 12, 13, 19), 119(9, 19), 120(13, 19), 123 Morrison, G. C., 489, 514 Moscowitz, A., 501 (25), 515 Mosettig, E., lOfi(167), 10T(I f i T ) , 108(176, 177), 114,115 Moss, J. B., 468(10), 474(10), 475(10), 477 (10),179(10),482 Mothes, K., 120(25),121(161),123,127, 181 (17,20), 2 1 8 , 2 9 6 ( 8 3 ) ,287(85), 302, 303 Mothes, U., 262, 267 hloyle, M., 534(8), 543 Moynehan, T . M., 451 ( 2 8 ) ,458(28), 465 Moyse-Mignon, H., 229(80, 81), 265 Rliiller, B., 384(222a), 425 Miiller, H . C., %76(24),301 Miiller, M., 494(15), 501 ( I S ) , d02(28), 514,

515 Miiller, 0. W., 435(14),439 Mukherjee, K . S., 325(70), 408(70), 409 (70), 41%(TO),421 Rlukherjer, H.,5(5), 28(5), 29(5), 37 Mukerjec, S . K., 260(156), 267 Jlunakata, K., 514(50), 515 Murai, I<., 1 2 1 (93), 125 I\.lurakoshi,1.,208(104),212(113), 220,451, 452(26),465 Alurayama, S.,514(44), 515 Murray, A. W . , 60, 106(89), 107(89), 108 (89), 112, 120(22), 121 ( 2 2 ) , 123 Rlurrill, S. J. B., 120(28), 123 Mushinskaya, S. Kh., 121(166), 1 2 8

N Nachod, F.,254(20), 301 Nadeau, G., 121 (185), 128 Nridor, I<., 274(19), 300(95), 3 0 1 , 30.3 Naegeli, P., 184(40), 215(40, 126), 216(40), 218, 221 Naegeli, It., 215(126),221 Nagarajan, K., 518(11, 13), 520(13), 527 (13), 528 Nagata, W., 360(144, 145), 363, 423 Nagy, J . , 123(282), 131 Nakagawa, E., 3 ( 3 ) , 17(3), 28(3), 37 Nakanishi, T., 453(32), 461 ( 3 2 ) ,465 Nakano, T., 17(35),38, 168(123), 174, 379 (200),380(209), 381 (200,208, 209,211, "2), 382(200, " 8 , 209), 383(209), 388, 393,396(209,211),397(209), 398(109), 399(212), 400, 401 (ZOO), 402(200), 419 (242), 425, 426 Nakasato, T., 37(fi7), 39 Narahashi, K., 227(51), 229(91), 230(91), 250(5i), 251(138, 1391, 264, 265, 266 Narayanan, C. R., 336(120), 423 Nartlet, J. C., 121 (ti6), 125 Naruto, S., 110, 115 Navarro, J., 123(286), 131 Neher, R., 386( l93), 424 Neill, K . G., 228(60), 23O((iO), 235(120), 236(120), 264, 266 Noogi, N. C., 347(134), 423 Nestler, H. J., 508(34), 515 Nesvadba, H., 177(7), 196(65), 218, 219, 449(25), 465 Neubauer, D., 121 (l61,219),127,129 Neurnann, D., 297 (84),302 Neuner-Jehle, N., 177(7),218,449(25), 465 Nichol, A. W . , 14(22), l5(22, 22a), 37 Nijland, M . M., 17(34, 36), 38, 49(57), 65, 102 (91),112,113 Nikolia, K., 120(51),124 Nikonov, G. I<., 122(251),130 Nikoronow, M., 121(187), 128 Nishinaga, T., 335(41), 348(41), 40i(41, 226), 408(41), 411 ( 2 2 6 ) , 412(41), 41.5 (41), 419(241), 421, 425, 426 Noda, C., 228 (66),229 (66,88),232 (66),264, 265 Nogueira Prista, L., 121(106), 126

AUTHOR INDEX

569

Nomura, K., 164(102, 103), 165(102, 107), 173 Norri, R., 120(39),124 Novak, JZ., 121 (177, 206), 128, 129 Nowaeki,E., 181(13), 183,218 Nowacki, W., 500(22), 515 Nuriddinov, R. N., 200(77, 81). 219, 220 Nussbaum, A. L., 120(36), 124, 3 2 3 ( 6 2 ) , 421

Ota, Y., 122(271),131 Otsuki, T., 17(38), 38 Ottaviano, G., 204(90), 220 Otterbcck, N., 121 (loo), 126 Otto,P., 3 2 5 ( 6 6 ) ,334(66), 336(66), 341(66), 350(66), 3.51 (M), 353(66), 354(66), 355 (M), 421 Overwion, H . , 189(52), 198(52), 201 (85), 204(85), 219, 220

0

P

Obata, T., 229(90),265 Ockenfels, H . , 338(88 ) ,347(88, 89), 354(88, 89), 357(89), 418(89), 419(89), 422 Odegaard, N. K., 117(2), 123 Odera, T., 550(11), 5 5 1 Oestreicher, P. & 1I 2 0.(, 5 7 ) ,124 Otvos, L., 295(76), 302 Ohara, T., 446(15),447(15), 449(15), 464 Ohashi, If., 62(90), 64(90), 65(90), 113, 271 (sa), 291 ($a),301, 309(14), 420 Ohashi, T., 442(6, 8), 446(17, 2 2 ) , 454, 455 ( 3 5 ) ,456(22,35), 458(40), 461,464,465 Ohta, G., 383(204a), 391 (204a), 425 Ohta, M., 82(108), 83(108), 84, 105(108), 106 (108), 113, 118 (9, 11, 12, 13, 19), 119(9, 19), 120(13, 19), 123 Ohta, T., 2 2 7 ( 3 2 , 44), 228(65, 66), 229(65, 66, 5 5 , 89, 91, 93), 230(91), 231(106, 107), 232(66, 107), 233, 251(138), 263, 264, 265, 266 Okamoto, T., 449(21), 451 ( 2 7 ) , 452(30), 458 ( 2 1 ) ,465 Okamoto, Y., 141(20, 21, 2 2 ) , 170, 172 Okuda, S., 178(8, 9), 208(104), 212(113), 213(116), 218, 220 Okumura, Z., 458(40), 465 Onaka, T., 117(5), 123 Onderberg, W. J . M., 121(167), 122(1GS), 128 O m , M., 121(95, 98, lo?), 125, 126 Openshaw, H . T., 2 2 3 ( 1 ) ,263 Orazi, 0. O., 227(31), 228(31), 230(31), 238 (31), 263 Orgler, K. H., l96(65), 219 Osata., R. L., 412(227), 425 Ososwiecki, M., 48(48a),111 Ota,H., l20(38, 140, 160), 124,127

Pachler, K.G.R., 12(18),1.5(25),27(62), 29 ( 1 8 ) ,37,3D Pachter, I. J., 227(41),229(41), 264 Padilla, J., 155,172 Pagel, H., 189(52), 1 9 8 ( 5 2 ) ,219 Pai,B. R., l6(28), 28(6la), 34(61a), 38, 39, 4 2 ( l ) , 110, 162(97, 98), 173, 230(101), 23%(111,112),265,266,518(11, 12, 13, 14), 520(13, 14), 522(12), 524(12. 19), 526(12), 627(13), 528(12), 528 Pailer, M., 517(5), 526, 5 2 7 ( 5 ) , 528 Pais, M . , 332(108),419(240), 423, 426 Pakanaev, Y . A , , 209(108), 220 Pakovic-Filipovic, Z., 121 (91), 125 Pakrashi, S. C., 224(3), 227(40), 229(40), 263,264 Paliatseas, P. G., 103(146), 114 Palmer, K. H., 229(79), 265 Palumbo, M., 121 (141), 127 Pan, P., 147(38,40), 171 Pappo, R.,334(92), 342(92, 125), 343(92), 355(92), 372, 422, 423, 424 Paquette, L. A., 290(73), 302 Parello, J., 270(8), 295(8), 301, 333(111), 423 Paris, R. It., 229(79, 80, 81), 230(100), 265 Parrak, V., 122(246), l30 Pastukhova, V. I., 224 (17). 226 ( 2 6 , 2 7 ) ,254 (147), 263, 267 Patterson, E. L., 3 3 8 ( 8 6 ) ,354(86), 422 Paulik, V., 3 1 8 ( 5 2 ) , 3 5 6 ( 5 2 ) , 379(52), 381 ( 5 2 ) , 383(52), 384(52), 389(52), 400 (52), 421 Pavlov, V. P., 284(54), 302 Pechmann, E., 121 (199), I29 Pelah, Z., 309(14), 420

570

AUTHOR I N D E X

Pellcrin, F., 121 (127), 127 Penafiel Sagues, C., 122(268),131 Penny, G. F . , 413(230j. 42.5 Prrkin,W. H.,.Jr., i02(139), 104(139, 155), 105(155, 137, 158. 159), 106(158, 159), 108(139. 155, 139), 1 1 4 Petcu, P., 4i(36,41,42),111 Pfeifer, S., l i ( 4 1 ) , 38, 121 (94, 103, 107, 108, 116, 126, 149, 191, 210, 212, 213, 214. 215 "16 '317, 218, 220, 221, 222, 223, (94. 103, 116, 126, I S ] ) , 125, 126,127,128,129,130 Pfeiffer,H., 121 ( i 4 ) ,22.5 Philips, P. C., 393 (207), 394(205),395(207), 425 Phillis, J. W., 514(45, 46), 515 Pike, J. E . , 362 (146), 423 Pillay,P.D.,336(119),423 Pillay, P. P., 313(33, 34), 420 Pincus, J . L., 345(129), 423 Pinder,A.R., l l 7 ( 3 ) , 123,269(5), 301 Ping-Lu Chien, 313(38), 348(38), 421 Pinhey, J. T., A29(2, 3), 530(3, 5), 5 3 2 ( 3 ) , 5 3 3 ( 2 ) , 540(2), 541(2), 543 Pinyazhko, R . M., 120(59), 121(59), 122 (59), 124 P i t t , C. G., 275(24), 301 Pjevska, L . , 118(1<5),119(15), 120(15), 122 (15), 123 Platonova, T. F., 5 1 i ( 6 ) , 626, 528 Plisnier, H., 122(265, 273, 274), 131 Pozdnyakova, V.T., 120(42),121 ( 2 3 8 ) ,122 (42, 238), 124, 130 Poe, C. F.,123(288),131 Poethke, W., 121 (i52, 155, 19-3, 194, 199), 127, 128, 129 Poetsch, E . , 209( 106), 211 (106),220 Poldkovh, A , 3 2 8 ( 7 3 ) , 3 5 2 ( 5 3 ) , 422 Polievtsev, N. P., 254(145, 148), 267 Polonovski, hlax, 120(53),1 2 4 Polonovski, Michel, 120(53j, 124 Popela.k,A.,468,469(11),4i0(i), 171 (7, 1 I , 12), 4 i 2 ( 7 , 8, 11), 473(7, 12), 4 i 4 ( 5 ) , 476(8), 478(11), 479(7, 8, l l ) , 480(7, 8,11,12),481(11),487,482 Potier, P., 366(157, 158), 369(155, 156, 157), 350(158),417, 419(244), 424, 426 Powell, R . G., 311 ( 2 3 ) . 315(43), 317(23), 318(2:3),330('39), 332(99), 387(43,j 396 (43), 420, 421, 4 2 2 9

-

3 -

Prabhakar, S., 2330(101), 231 (105j, 232 (111, 112, 113), 265, 266, 524(19), 528 Prager, R . H., 2 2 7 ( 3 8 ) , 2 2 8 ( 3 8 ) , 2 2 9 ( 3 8 ) , 2 3 0 ( 3 8 ) , 231(104), 234(104), 2:36(121), 264, 26.5, 266, 529(3), 530(3), 531(3). 5 4 .? Prelog, V.,2 7 8 , 301, 303, 345, 35ti(l), 419, 493, 499(11j, ROl(26), 508(35), d l 2 ( 3 7 ) ,5 1 4 , 51.5 Preobrazhenskii, N. A., 138(15), 142(25), 161(94), 170, 271, 173, 275(21), 284 (54), 301, 302 Price, J . R., 224, 225(24), 228(58, 6 3 ) , 229 (63, 83), 230(58, 8 8 ) , 238(24, 131), 240 ( 1 31 ) ,2 4 1 ,2 6 0 ( 1 5 2 ) ,2 6 3 ,2 6 4 ,2 6 5266, , 267 Prins, D.A., 318(49), 421 Printy, H. C., 317(48), 358(48), 421 Privat, G., 4 6 ( 2 4 ) , 111 Prinznar, M., ? i 4 ( 2 0 ) , 301 Progressov, N.N., 152(58), 158(59), 172 Przyszlakowslti, S., 121 (128), 122(128),126 Pucket,t, R. T., 405(221a), 425 Pyman, F. L., 54, 85, 107(111, 168), 112, 113, 114, 118(6), 1 2 3 , 339(122), 423, 519 (15), 528

Q Quevauviller, A., 313(28, 29, 30), 420

R Raamstad, E., 300(94), 303 Rabinovich, Ill. S., 214(122)),221 Rader, C. P., 275(22aa,I % ) , 301 Rae, A . I. JI., 228(68), 264 Raffauf, R . F., 17(33b), 28(33b), 30(33b), 32(33bj, 33(33bj, 3 5 ( 3 3 b ) , 38, 227(41), 22!3(4l), 264, 308(6), 335(93), 357(93), 358(95). 420, 422,541 (13),543 Rapacle, I. S., 51 8 (12), 522 (12),524( 12, 18), 325(20), 526(12, 18, 20), 528(1?, 20), 528 Kahim, A. JI., 3 3 8 ( 8 7 ) ,354(87), 422 Rahman, A. A. A.. 12i(68, 81, 1 8 1 ) , 123, 128 Rahtz, D., 2 0 8 ( 103), 209(105), 220

57 1

-4UTHOR INDEX

Rajadurai, S., 42((1),82((109),105(160), 106 (l60), 110, 1 1 3 , 114, 522(1i), 628 Rajappa, S.,518(l2, l i ) , 520(14), 322(12), 524 ( 1 2 ) , 526 (12). 528 ( 1 a), 528 Rakhmatkaricv, A. U., 143(28), 144(29), 171

Rlikhczi, J., 281 ( i 3 , 4 5 ) , 30% Ram, ll., 371 (l64), 374(lti4, l i i ) , 424 Ramadas, C., 4 2 ( l ) ,110 Rankin, J., 105(158), 106(158),I14 Rao, K. V.,4 9 ( 6 3 ) , 6 7 ( 6 3 ) , 112, 155(75), 156(i5),161(95,96), 162(99, 1 0 0 ) , 1 7 2 , 173, 5 2 5 ( 2 1 ) , 528 Kapoport, H., A(9), 2 8 ( 9 ) , 29(Y), 37, 224 (13), 227(50), 228(13), 230(13), 236, 237(13), 238(13), 244, 246(13), 247, 26.3, 264, 266, 487,514 Rashid, &I. H., 214(121), 221 Rasmussen, N.,234(119), 266, 5 2 9 ( 3 ) , 530 ( 3 ) ,531 ( 3 ) ,543 Ratnagiriswaran, A. N., 518, 528(9), 528 Rausch, J., 123(282),1 3 1 Raymond-Hamet,617(3),528 Rees, R., 312(25),420 Regnier, G., 48(4Xa),111 Reichle, C., 122(259),130 Reichstein, T., 498(20), 515 R,eifer, I., 121(12i),126, 183(34), 2 0 7 ( 9 i ) , 218,220 Reiss, R., 121(136), 1 2 7 R'emar, %J.F . , 2 7 ( 6 0 ) , 38 R,enner, U., 318(49),421 Renner, W., 227(34), 229(34, 76), 263, 265 Resplandy, A., 49(51),111 Reusche, W., 181(12), 198(73), 205(73), 218,219 Reuther, F. W., 121(97, 159), 122(95),125, 128 Reynoso, J., 120(36),124 Ribas, I., 199(i4), 201 (83), 204(85), 219, 220 Ribeiro, O., 6(9), 28(9), 29(9), 37, 227(41), 229 (41),264 Richards, A. B., 123(281), 131 Riggs,N.V., 12(17),37,517(7),522(7),528 Rimington, C., 468, 481 Rink, M.,121(120, 142), 122(120),126, 127 Ristic, N., 121 (184), 122(18i), 128 Ritchie, E., 8 5 ( l l 2 ) , 113, 2 2 7 ( 3 6 , 37, 38), 2 2 8 ( 3 5 , 38, 59, 61, 62), 229(37, 38, 82,

83, 84),230(36, 3 7 , 38, 61, 6 2 , 82, 83, 99), 231(104), 234(62, 104, 118, 119). 235(1?0), ?36(120, 121), 263, 264, 265, 2G6, 529 (1, 2, 3), 530 (3, 5 ) )53?( 1, 3, 61, 5 3 3 ( 2 ) )5, 3 4 ( 8 ) ,.540(2),541(2),543(16), 543 Robert'son, A. V., 2 2 4 ( 8 ) , 234(119), 236 (l21),263,266 Robinson, R., 9 2 , 100, 107(131), 113, 114, 118(6),12.3, "50, 267 R,ockerbie, R. A., 121(ED), 124 Rodger, 31. N., 231 (108),265 R'odig, A., 493(14), 499(14), ,514 R'odriguez,H.R.,475(15),482 Roe, T . , 151( 5 i ) , 172 Roemisch, H., 121 (138), 127 Roets, G. C . S., 468, 481 R'oloff, H., 490(8), 514 Komeike, A., 269(3), 277(29, 31), 284(31), 295(58), 297(86), 2 9 8 ( 8 i , 88, 89), 300, 301,302,303 Romo, J., 224(121), 263 Rooda, R . TV.,224(22), 236(122), 237(122, 124), 238(122),239(124), 243, 246, 247 (122), 263,266 Rosenkranz, G., 22%4(21), 225(23), 2 2 7 ( 2 3 ) , 238 ( 2 3 ) , 263, 362 (147), 364 (14T),423 Rosenthaler, L., 121 ( i s , i s ) , 125 Roux, A., 121(229), 130 Row, L. R., 161(95, 96), 162(99, loo), 173 Roy, A. C., 334(114), 345, 347(114), 423 R,oy, S. K., 30(64), 39, 73, 74, 113, 2 2 7 ( 3 0 ) , 263 Rubtsov, J. A., 284(54), 302 Rubtsova, V. P., 121 ( S T ) , 125 Rudzats, R., 525(20), 526(20), 528(20, 1 3 ) , 528 Rucgger, 9., 2 3 i (128),243, 266 Runge, F . , 121( T Z ) , 126 Ruschig, H., 310(19),420 Russel, J. H., 5 l i ( 4 ) , 525(4), 527(4), 528 Ruveda, E . A , , 98(129),114 Ruzicka, L., 535(10), 543 Ryall, K . IT.,514(49), 515

S Sacca, S., 121(141), 127 Saclykov,A. S., 199(55), 2 0 0 ( i 6 , 7 7 , i8,81), 209(108), 213(115, 117), 21.9, 220, 221

572

AUTHOR I N D E X

Saeki, Y . , 419(242)), 426 Safe, S., 118(16), 11 9 ( 1 6 ) ,123 Sagae, T . , 148(4(i),271 Saha, S.K., 3(4), 5(5),28(5), 29(5), 37 Sakai, %I., 446(16), 445(16), 448(16), 456 ( l 6 ) , 465 Sakurai, H., lZl(82, 83, 84, 85, l69), 125, 128 Sallay,I.,57, I12 Samek, Z., 419(243),426 Sanchez, E., 17 (31),38 Sandberg, F., 204(89), 220 Sandke, G., 181(18),218 Sandstede, G., l05(156), lOti(l56), 114 Sangster, A. W . , 120(58),1 2 2 ( 5 8 ) ,124, 224 (1l ) , 263 Santav$,F., 118(15), 119(15), 120(15), 122 ( l s ) , 123, 169(124, 125), 174 Santhanam, P. S., 230(101), 232(111, 112), 265, 266 Sargazakov, D., 143(27),171 Sarkany, S.,121(113), 126 Sarsunova, M., 121 (196), 129 Sasaki, Y., 121(66), 125 Sato, M., 122(275),131 Satomi, &f., 545(4), 550(10, 11, 13), 551 Savitri, T. S., 524(19), 528 Schtifer,C., 181(13,14,15),218,152(66), 172 Schearer, W. R., 498, 515 Scheclrer, H . J . , 122(249), 130 Scheuer, P. J., 226(29), 227(29), 228(29), 230 (29), 256(29), 257(29), 263 Schild, H., 545 (3), 550 Schillcrova, V., 121 (129), 126 Schiuchi,Y., 121(121),126 Schlingloff, G., 19(45, 47), 38, 136(13), 170 Schlittler, E., 375, 376(180), 378, 380(180, 181), 381(181), 382(180, 183), 383 (183),384(180,182),388(180,181, 182, 183), 389(183),400, 424, 517(3), 528 Schniall, M., 121 (172), 128 Schmid, H., 120(37), 124 Schmidt, H. L., 295(77), 302 Schmidt-ThomQ,J., 310(19), 420 Schmidt, O., 187(45, 46), 198(73),205(73), 218, 219 Schmutz, J., 48(49), 69(49), 104(49), 105 (a), 1 11 Schneider, G., 2 2 8 ( 5 5 ) , 229(92), 233, 264, 265

Schneidewind, U., 45(14), 111 Schonberger, W., 347( 131), 423 Schopf, C., 5ti, 112, 194(60), 219, 260, 267, 4-37,429(2, 4). 430(6, 7 ) , 132(8,9),435 ( i 4 ) , 4.39 Schofield, K., 451 ( 2 8 ) ,458(28), 465 Schreiber, H . , 104(152),114 Schroeter, H.-B., 297(84), 302 Schubert, JI., 168(122), 174 Schiitte, H . K . , 181(10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20,21,22,23,24,25, 2 0 ) , 218, 296(83), 2 9 7 ( 8 5 ) ,302, 303 Schuette, J., 121 (114), 126 Schulenbcrg, J. W., 291 ( 7 5 ) , 302 Schulte, F . J.,514(48),515 Schultz, 0 . E., 121(73), 125 Schulz, H., 1 7 7 ( 4 ) , 185(41),218 Schumacher, H., 121(99, 111, 230), I22 (11l ) , 126,130 Schumann, D., 177(4, 5, 6), 184(35), 189 (35), 190(35, 56), 194(6), 195(64), 196 (5, 35), 200(80), 201(84, 85, 8 6 ) , 202 (86), 204(84, 85, 86), 206(35), 207(35, 56), 209(5, 106), 211(106), 218, 219, 220 Schutz, R. S., 296(81), 296(81), 302 Schwarz, V., 121 (196), 129 Schmeickert, &I., 56, 112 Scopes, P. hl., 135(6),170 Scott, A. I., 512, 515 Seetha, M., 230(101), 232(112), 265, 266 Sefcovic, P., 120(20),123 Seidler, R., 277 (32), 301 Seitz, G., 48(48), 111, 430(6), 439 Sekcra, A., 276(26), 301 Seshadri, T. R., 229(96), 260(15B), 265, 267 Shafer, E . G. E., 121 (172),128 Shakirov, T. T., 229(87), 252(87, 143, 144), 253(87), 254(144), 26.5, 266, 267 Shamma, H . , 468(10), 474(10), 475(10, 15), 477(10),479(10),482 Shamma, JI., 2(1), 12(16), 17(43), 22(53), 27(1, 60, 6 l ) , 28(43, 66), 29(1, l G ) , 30(6l, 6 4 ) , 3 4 ( 1 6 , 4 3 ) , 3 7 ,38,39,49(61, 62, 63), 62(90), 64(90), 65(90), 66(61, 62), 67, 68(62), 108(61, 62), 109(61), 112, 113, 155(75), 156(75),172 Shankar, J., 347(134), 423 Shanmugasundaram, G., 16 ( 2 8 ) , 38 Sharma, G. &I., 512(40),515

AUTHOR INDEX

Shchelchkova, I. I., 49(54), 112 Shemyakin, F. fir., 121 (go), 125 Sheng-Teh Lu, 4 i (38, 40), 1 1 1 Sheng-Ting Shen, 49(53), 112 Sheppard, N., 134(4),155(4), l 5 i ( 4 ) ,170 Shin, K. H . , 17(P9),38 Shine, R. J., 28(66), 39 Shingu, T., 5 4 7 ( 6 ) , 648(7), 551 Shoolery, J . N . , 224(7), 337(125), 2 4 l ( i ) , 242(127), 243(7), 263, 266 Short, J. H., 345(129), 423 Shostenko, Yu. V., 121(201), 129 Shrader, S.R.,49(63), 67(63), 112, 155(75), 156(75), 172 Shun,T.,44(4),110 Siddiqui, S., 332(105, loci), 334(112, 113), 336 (119), 422, 423 Sidyakin, G. P., 224(15, 16, l i ) , 22e(26, PT), 227(16, 54, 55), 229(16, 61, 55), 230 ( 1 0 3 ) , "I(%), 236(103), 252, 253 (15,16,54,55,85,86,87, 103, 141, 142), 254(86, 144, 146, 147), 255(142, 149), 263,264,265,266, 267 Sih, C. J., 338(87), 354(87), 422 Silvestrini, R., 122(266), 131 Sim, G. A., 405(221a),425 Simon, I. S., 121 (189), 123(189), 128 Singh,K. P., 209(107), 210(107, 110, l l l ) , 220 Skinner, B., 51(76), 112 Slavik, J., 5 ( 0 , T), lT(33, 33% 39), 28(15), 36 (33a), 37, 38, 44(4, 5 , 6, 9), 45(21, 22, 23), 46(25, 26, 27, 28, 29, 31, 3 2 ) , 47 (33), 110, 110, 111, 115 Slavikova, L., 6 ( 6 ) , 17(33, 33a), 2 8 ( 6 ) , 36 (33a),37, 38, 44(4, 5 , (i), 45(22, 2 3 ) , 46(35, 26, 2 7 ) , 110, 110, 111, 115 Slivic, S., l 2 0 ( 5 l , 5 2 ) , 124 Sloane, E., 201 (83), 220 Slusarchyk, W. A., 2 ( 1 ) , 12(16), 23(53), 27 ( l ) , 2 9 ( 1 ,1 6 ) , 3 4 ( 1 6 ) , 3 7 , 3 8 , 6 2 ( 9 0 ) , 6 4 (go),65(90), 113 Smirnov, D. &I., 121 (164), 127 Smith, A. F., 314 (12), 229 (12), 230 (12). 236 (12), 237(12, 123), 238(12), 239(12), 242(12), 243(12), 250(12), 263, 266 Smith, E., 468(10), 4 i 4 ( 1 0 ) , 475(10), 474 ( l o ) , 481(10), 482, 5 3 2 ( i ) , 543 Smith, G. L., 4i3(14), 482 Smith, L . L., 312(27), 419(239), 420, 426

573

Smolikovii, J., 419(243), 426 Snatzke, G., 341 (go), sa.r(go), 417(235, 236), 422, 426 Snell, E. F., 122(264),131 Soholewski, G., 121 (185). 128 Solt, 31. L., 295(81),2 9 6 ( 8 1 ) , 302 Sondheimer, F., 224(21), 225(23, 2 5 ) , 227 ( 2 3 ) , 238(23), 263 Sorgenfrey, C1. H., 121(61), 122(61),124 Sorrn, F., 214(1P4), 221, 308(10), 309(10), 310(10, 20), 313(20), 315(20), 323(64), 325(67), 428(i4), 331(102), 333(77), 334 (Gi),336 ( 7 i ) ,337 (77j, 338 (67), 345, 347(i9),350(64),351 (ei), 3 5 2 ( 5 7 ) , 313 (67, 79), 356(95, 98), 357(95), 358(93), 3i1, 3i2(166, 167, 168, l70), 374(176), 410(64), 419(159, 160, 243), 420, 421, 422, 424, 426 %ti, P.,278(39a), 280(39b), 284(55), 288 (64), 301, 302, 355(95), 357(95), 358 (95),422 Soucek, M., 181 ( I G ) , 218 Spiith, E., 103(146a), 105(161), l06(l67), 107(167, 169, 170, 173), 108(l70, 176, 1 7 7 ) , 114,115 Spaldonova, R., 121 (ZOO), 129 Speake, R. N., 5 3 2 ( 7 ) , 543 Spencer, H., 84, 113, 118(7, 14), 120(7, 14), 123 Spenser, I. D., 49(58, <59),65, 92, 93(68), 100, 101(59),112, 113, 114, 120(29, 30, 31, 3 2 ) , 123, 124, 262,267, 295(79),302 Spingler, H., 468(7, 8 ) , 470(7), 471(7), 472 ( 7 , 8), 473(7), 474(7), 476(8), 479(7, 8 ) , 480(7, 8 ) , 482, 482 Spiteller, G., 177(7), 218, 449(24, 25), 462 (24), 463(24), 465 Stambouli, P. S., 230(i00), 265 Stanek, J . , 118(18), 120(35),123, 124 Stanislas,E.,309(16), 310(15), 379(15), 382 (15), 388(15), 389(15), 39(i(l5). 397 (15)402(15),420 Starrat, A. N., 360,423 Stauffacher, D., 237(128), 243, 266, 376 (188), 379(188), 384(188), 404, 406 (188), 424 Staunton, J., 94(124), 98(129), 114 Steinegger, E., l i ( i ( l ) , 187(4'7, 48), 204(90, 91), 218,219,220

574

AUTHOR INDEX

Steldt, F. A., 237(125), 238(123), 244, 266 Stellfeld, C., 121 (236), 130 Stenszly, E., 123(285),131 Stippler,H., 103(130),105(150),114 Stoepel, P., 107(151),115 Stoll, E., 2 7 8 ( 3 8 ) , 282(38,49),284(32)),301, 302 Stoll, W. G., 318(49), 421 Stone, N. E., 514(49),515 Stork, G., 362(148), 4 2 4 , 5 0 5 ( 2 9 ) ,515 Strathern, R . C., 301 Street, J. P., 123(288),131 Street,N.V., 121(190), 122(190), 126 Strehlke, P., 196(70),219 Streicher, W., 517(5), 526, 5 2 7 ( 5 ) , 528 Strzelecka, J., 121 (92), 122(92),125 Stuart, K. L., 30(63), 39, 120(58), l22(58), 124, 224(11), 263 Studt, P., 449(23), 450(23), 453(23), 465 Sudasarnam, V., 230(101), 232(111, l l 2 ) , 265, 266 Sudzuki, H., 107(175),I 1 5 Sugamoto, itf., 48(46), 111 Sugasawa, S., 42(2), 110, 492, 514 Sun, T., 147(38), 171 Sun, Y . T., 121 (171), 128 Sundarajan, V. N., 228(67), 229(67), 230 ( G T ) , 264 Susplugas, J., 46(24), 111 Suszko, J., 196(66),206(92), 219, 220 Sutton, L. E., 288(64), 302 Suzuki, K., 545(4), 551 Swinbourne, F. J., 288(64), 302 Szab6, S . , 287(62), 302 Szasz, G . , 121 (71), 125 Szegi, J., 123(282), 131

T Tagahara, K., 76(102), SO(l02). 113 Taguchi, H., 44(10, l l ) , 4 5 ( 2 0 ) , 71, 74, 75 (99), 102(10, 99), 103(20), 104(20, 99), 110,111,113 Takagi, K., 122(262,275), 131 Takahashi, T., 441, 442(3), 464 Takami, Y., 121 (133), 1%2(133),127 Takano, Y . , 27 (59), 39

Takao, N., 45(15, 16), 49(56), 75(15, l6), 76(99a, 100, 102), 77(100), 80(102), 103(1+5, 16), 104(100), 107(16), 111, 112,113 Takao, S., 76(100, 102), 77(100), 80(102), 104(100),113 Takeda,K.,212(112),220 Takemoto, T., 5 4 , 5 5 ( 8 5 ) ,106(85),112 Talapatra, S. K., 5 ( 5 ) ,%8(5),29(5), 37 T a m , C., 498(20), 5 1 5 Tan, L., 320(55),3 3 6 ( 5 5 ) ,349(55), 350(56), 421 Tanaka, Ch., 123(283,284),131 Tanaka, M., 148(46), 171 Tanaki, Y., 121 (160), 127 Tani, C., 45(15, 16), 49(56), 75(15, IG), 76 (100, 102), 75(100), 80(102), 103(15, IG), 104(100), 107(16), 111, 112, I 1 3 Tani, H., 82(108), 83(108), 84(108), I05 (108), 106(108), 113, 118(9, 11, 12, 13, 19), 119(9, 19), 120(13, 19), 123 Taraoka, A., 1G6(109), 173 Taylor, D. A. H., 363(149), 424 Taylor, W. C., 85(112), 113, 227(36, 38), 228(38), 229(38, 82, 84), 230(36, 38, 82, 99), 2331(104), 234(104, 119), 236 (121), 263, 2 6 4 , 2 6 5 , 2 6 6 , 529(2, 3), 530 (3, 5), 5 3 2 ( 3 , 6), 533(2), 540(2), 541 ( 2 ) , 5 4 3 ( 1 6 ) ,543 Taylor,W.I.,23(54),24(54),38 Telang, S. A., 71 (96), 72, 113 Telezhenetskaya, M. V., 152(59), 158(59), I72 Teodoziu, hf., 121(115), 122(115), 126 Terao, S., 380(209), 381 (208,209,211,212), 382(208, 209), 383(209), 393, 396(209, 211), 397(209), 398(209), 399(212), 419(242),425,426 Teresaka, hf., 227(5l), 228(64), 229(91), 230(64, 91), 230(51, 136, 137), 251 (137, 138), 252(140), 264, 265, 266 Teresawa, T., 360(144, 145), 363(144, 145), 423 Ternbah, )I., 493(14), 499(14), 514 Thayer, P. S . , 122(264), 131 Thierfelder, K., 260, 267 Thies, H., 121 (61,97, l i 9 ) , 122(61,97),124, 125, 128 Thomas, P. O., 550(12), 5 S l Thoms, H., 2 2 7 ( 3 3 ) , 263

575

AUTHOR I N D E X

Thrift, R. I., 88(116), 103(116), 113 Thyagarajan, B. S., 153(68), 172 Tiberi, R., 323(62), 421 Tihlarik, K., 453(33), 465 Tishler, BI., 269(6), 301 Tjan Gwan Hiem, H., 225 (50), 264 Toczko, K., 121 (127). 126 Todd,A.R., 225(24),238(24), 263 Todd, J., 277 (32), 301 Tolkachev, 0 . N., 161 (94), 173 Tomikawa, Y . , 227(51), 250(51), 264 Tomimatsu, T., 49(64), 112, 149(48, 49, 50, 51), 158, 171, 172 Tomita,M.,3(3),8(12,13),13(19),17(3, 12, 30, 30a, 32, 3 5 ) , 24(56), 25(56), 26(56, 58), 27(59), 28(3, 12, 13), 30(13), 37, 38, 39, 47(34, 43), 48(44, 46), 49(52, 53a, 55), 50(68, 71), 85, 86(113), 87 (114, 115), 89, 91(120), 102(138), 103 (55, 115), 104(55), 105(138), 106(55), 107(55), 109(180), 111, 112, 113, 114, 135, 138(9, 14), 139, 140, 141 (9,20, 21, 22), 142(9, 23), 144(32), 145(32), 146 (32), 147(41, 42), 148(9, 44), 149(9), 150(9), 151(9), 153(9, 69), 154(44, 71, 73), 159(9, 89, go), 161(9), 165(105, 106,108), 166(109,110),168(114, 115), 1 7 0 , 1 7 1 , 1 7 2 , 1 7 3 , 1 7 4 , 2 2 7 ( 4 5 , 4 6 )229 , (45), 264, 407(225, 229), 411(225), 412 (229), 413(229), 415(229), 425, 514 (51), 515 Tomko, J., 121(200), 129, 310(16), 318(51, 5 2 ) , 376(52), 379(52, 213, 215, 2 2 2 ) , 380(52),383(52), 384(52), 389(16, 5 2 ) , 400, 401 (213, 215, 216), 402(215, 217), 400,406(222), 419151), 4 2 0 , 4 2 1 , 4 2 5 Tompsett, S. L., 121 (156), 127 Tonescu-Matiu, E., 121 (240), 130 Toste, A. H., 212(114), 220 T6th, J., 273(12), 278(37), 284(51), 285 (59), 286(59), 288(59), 300(59), 301, 302 Trabert, H., 45(14), 111 Traisnel, M., 121 (62, IlO), 124, 126 Trams, E. G., 513(43),515 Trautner,E.RI.,271(10), 301 Tretter, J. R., 487(3), 514 Trier, G., 91 (120), 113 Trothandl, O., 108(177), 115

Truong-Ho, %I., 313(33a),314(35a, 39), 318 (391, 333 (63), 334(35a, 63), 330(39), 343(74a, 78,130), 347(74a, %,SO, 130), 330(39, 63, 74a), 351 (35a, 39, 63), 333 (74a, 78, 79, S O ) , 356(39), 357(74a), 412(35a), 418(78), 419(74a, 78), 420 421,422,423 Trutneva, E. A., 233,266 Tsang-Hsiung Yang, 47(38, 4 0 , 4 3 ) , 48(47), 111, 152(GO, 62), 172 Tschesche, R., 7(11), 13(11, 21), 14(11),28 ( l l ) , 29(21), 37, 308(8), 324(65, 66), 325, 3 2 8 ( 6 5 ) , 334(66, 114), 336(66), 338(88), 341(66, go), 345, 347(88, 89, 114), 350(66),351 (65,66), 3 5 2 ( 6 5 ) ,353 (GB), 354(66, 88, 89, go), 353(66), 357 (89), 417, 418, 419(89), 420, 421, 422, 423,426 Tsuchiya,l\l., 121(121),126 Tsuda, K., l78(8, 91, 208(104), 209(109), 212(113), 213(116), 218, 220 Tsuda, Y . , 117(4), 123, 201(82), 220, 548 (7), 551 Tsukamoto, H., 121 (88), 125 Tsuyama, K., 49(55), 85(55), 103(55), 104 (55), 106(55), 107(55),112 Tulecki, J., 120(23),123 Tulley, A., 288(65), 289(65), 302 Tuovinen, J., 121 (98), 122(98), 126 Tuppy, H., 230, 265 Turner, D. W., 485(la), 514 Tutm, F., 280(41), 301

U Ude, W., 464(42), 465 Ueda, S., 163(101), lGB(lO9, 110), 173 Uffelie, 0. F., 17(36), 38 Uffer, A., 339(123),423 Ugai, F., 120(44, 54, 143, 173), 124, 127, 128 Uji, A., 49 (64), 112 Ullyot, G. E., 227(41), 229(41), 264 Umeda, N.,121(84, 169), 125, 128, 233 (114), 266 Unna, K. R., 514 (44,47), 515 Unser, M. J., 291 ( 7 5 ) , 302 Urban, G., 438(23), 439 Usui, T., 121 (140), 127

576

AUTHOR I N D E X

Uyeo, S., llO(I80). 11.5, 313(41), 348(41), 4 0 i ( 4 1 , 2 2 3 , 226, 228, "9), 408(41, 228, 231, 2 3 2 ) , 411 ( 2 2 3 , 226), 4 1 2 ( 4 l , 228, 229), 41:3(229), 414(228), 415(41, 229), 41 7 (231, 2 3 2 ) , 4 19 (24 1), 421,425, 426, 347(ci), 3 4 8 ( 7 ) , 551

v Vaciago, A., 3 8 8 ( 198), 42,5 Vaisman, G. A., 121 ( S O ) , 125 Valenta, Z., 214(121), 215(127), 216(127), 221, 463(41), 465 Varnvacas, C., I20(37), 124 Van d e n Heuvel, J. A., 121 (191), 129 van der Sitlje, D., 343(126), 368(126), 42.3 van der Waard, W. F., 343 ( 1 2 6 ) , 358 (126), 423 Vandewoude, G., 339 (124a), 423 VanEtten, R. L., 288(69), 302 van Hove. L., 339(124, 124a), 423 van Moorselaar, R., 357( l 3 5 ) , 423 van Koyan, P., 630, 543 v a n Seters, W . A., 121(167), 122(167), 128 van Soeren, J . H . , 269(4),300 van Tamelcn, E . E., 185(42), l 9 l ( 5 7 ) , 197 (71), 218,219 Varnakova, L. P., 138(15), 142(25), 170, 171 Vasistha, S . K . , 332(106), 422 Vassov6, A , , 3 I 8 ( 5 2 ) , 376(52), 379(52), 380 (62), 381(52), 3 8 3 ( 5 2 ) ) , 384(52), 389 ( 5 2 ) , 400(52), 421 Vaughan, J . R., 412(227), 425 Vautin, S . T . K., 227(36), 230(36), 263 Vedsoe, S.,121(144, 145), 127 Velasevic, M. I<., 1 2 0 ( 5 l , 52), 124 \'elasqucz, A.A., 224(12),229(12),230(12), 236(12),237(12),238(1P),239(12), 242 (I?), 213(12), 250(12), 263 Venkatachaiam, K., 518, 528(9), 528 Vernengo, Rl. J . , 16(27), 37, 134(4), 135(6), l 4 8 ( 4 6 ) , 135(4), 157(4, SO), 170, 171, 172 Vetter, W., 270(8), 293(8), 301, 308(11), 309(11), 310(11), 420 Vidic,E., 121(114),126 \'ilhuber, H. G., 508(34), 515

Villareal, S., 152(61), 172 Vinczc, I., 2 7 3 ( 1 2 ) , 278(37), 284(51), 285 (59), 286(59), 288(59), 300(59), 301, 302 Viscontini, &I.,498(20), 515 Viswanathan, K., 82(109), 113, 518(12), 522(12), 324(12, 18), 5 2 6 ( l 2 , 18), 528 ( I ? ) , 528 Volke, .J., 121(203, 203, 226, 2 2 7 ) , 122(203, PO:?), 129 Yolkwein, G., 434 ( 1 3 ) ,439 X'olynskaya, M. H., 50(69), 112, 229(54), P33(74), 236(74),265 vonBruchhausen, F . , 7 6 , 1 0 3 ( 1 0 1 , 1 5 0 ) ,104 (154), 105(150), 106(154), 113, 114 von Schuckmann, G., 347(131), 423 Voronin, V. G., I61 (94), 173 T'oss,A.,519(15),528 Votick9, Z., 120(20), 123, 310(16), 318(51, 52), 376(52), 379(52, 213, 215, 2 2 2 ) , 3 8 0( 5 2 ) ,381(52), 383(52), 384(62), 389 (16, 5 2 ) , 400(213), 401(213, 215). 402 (215, 2 l 7 ) , 400(62), 406(222), 419(51), 420, 421, 425 Vredenburgh, W. A., 362( 146), 423

W Wachtmeister, C. A., 136, I70 Wada, K., 514(50), 515 Wadam, Y., 458(40), 465 Waksmundzki, A., l28(165), 128 Walter,R.,232(110),266 Walthew, J.M., 16(26),37 Wandrey, D., 201 (84), 204(84), 220 Wang, S.-J., 8(13), 28(13), 30(13), 37 W a r d , N . B., 122(260), 130 Warnecke, H . , 339(121), 423 Washburn, R. M . , 345(129), 423 Watanabe, Y., 49(53a, 5 3 ) , 103(55), 10.4 ( X I ) ,106(55), 107(55), 112, 150(52), 171 Watkins, J. C., 514(49), 513 Watt, J., 468(4), 481 N'awrzynowicz, T., 128(165), 128 Weaver, L . C., 123(281), 131 Woi-Yuan H u n g , 50(72), 112 IVeisbach, J. A., 17(33b), 25(62), 38(33b), 38, 39

577

AUTHOR INDEX

Weise, W., 209 (105) 220 Weiss, F., 121 ( 2 2 2 , 2 2 3 ) , 129 Weiss, C., 500(24), 501, 515 Weisz, I . , 273(14, la), 274(15, l i ) ,290(72), 301,302 U’eitz, G., 4 3 2 ( 8 ) ,439 Wellendorf, &2I i. 6 (, 2 8 ) , 301 Welzel, P., 7(11), 13(11, 21), 14(11), 28 ( l l ) , 29(21),37 Wenkert, E., 6 ( 9 ) , 28(9), 2 9 ( 9 ) , 37, 260 (154), 261,267,299(91),3 0 3 ,3 9 6 ( 2 1 0 ) , 425, 5 2 5 ( 2 2 ) , 528 Wenzinger, G. R., 498, 501 (19), 515 Werner, G., 295(77), 302 Wcrny, F., 226(29), 227(29), 228(29), 230 (29), 256 (as),2%(29), 263 West, T. S., 121 (130), 126 Wettstein, A., 386(193, 194, 195), 424, 425 Whaley, W. M., 490(6), 514 Wharton, P. S., 362(148), 424 White, E . P., 200(79), 207(95), 219, 220 White, J., 288(65, 67, 68), 289(65, 67, 68), 290 (67,68), 302 Whitfield, G. H., 311 ( 2 3 ) ,317(23), 318(23), 336(81), 353(81), 420, 422 Whitlock, H. W . , 473(14), 482 Whitmore, F. C., 277(34), 278(34), 301 Wickberg, B., 6(9), 28(9), 29(9), 37 Wickham, P. P., 275 (24), 301 Wicki, W., 371(165), 424 Wicky, K., 187(47, 48, 49), 219 Widdowson,D.A.,485(la), 514 Wiegrebe, W., 120(21),123 Wiensz, K., 324(65), 325(65), 328, 351 (65), 352(65), 421 Wierzowski, Z., 122(252), 130 Wiewiorowski, BI., 183(32, 34), 188(32, S O ) , 189(32, 51), 190(53, 54, 55), 194(61, GZ), 195(63), 196(51,62,66,67,68,69), 206(92), 207(50, 51, 9’7, 98), 208(101, 102). 209(51). 218, 219, 220 Wightman, R. H., 214(121), 221 Wildman, W. C., 121 (64,197), 122(64), 124, 129, 1 8 4 ( 4 0 ) , 216(40, I Z ) , 216(40), 218, 221, 472, 4i3(14a), 482 Wilhelm, M., 508(35), 515 Willcocks, D. V., 230(99), 265 Williams, D. H.,62(90),61(90),95(90), 113, 2 i l (Sb), 291 (Sb), 301, 308(12), 309 (12), 420

Williams, M.,121 (70), 122(70), 125 Willis, J. B., 224(4) 263 Wilson E. M.,184(37), 214(119, 120), 216 ( 3 7 ) , 218, 221 Wilson, J . M . , 62(90), 64(90), 65(90), 113, 309(14),322(61),420,421 Wilson, J. S., 214(121), 216(127), 216(127), 221 Winek, Ch. L., 122(245), 130 Winkler, W., 120(33), 124 Winter, C. A., 123(287),131 Winterfeld, K., 186(43),218 Winterfeldt, E., 183(31), 184(36), 186(44), 118(31), 189(52), 190(56), 19?(36,58), 193(59), 195(64), 196(31), 198(52, 72, 7 3 ) , 201(84, 86), 202(86), 204(84,86), 205(73), 206(72), 207(56), 218, 219, 220, 449(23), 450(23), 453(23), 464 (42), 465 Winterstein, E., 91 (120), 113 Witkop, B., 347, 423 Witte, A. H . , 122(255),130 Wolfel, E., 432(8), 439 Wojciak, Z., 121 (69), 122(69), 125 Wolinska-Mocydlarz, J., 190 ( 5 3 , 54, 55), 208(lOl), 219,220 Wolffenstein, R., 280(40), 301 Wollish, E . G., 121 (172), 128 Wolski, T., 128(165), 128 Woodward, P., 330(99), 332(99), 422 Wrbbel, J . T., 443(11), 444, 449(24), 453, 462,463(11, 24), 464, 465 Wysocka, W., 208 (l02), 220

Y Yagi, H., 143,171 Yakunina, T . G., 229(78), 265 Yamaguchi, H., 514(51), 515 Yamaguchi, S., lZ0(44), 124 Yamakawa, T., 229(75), 265 Yamamoto, A., 407(228), 408(228), 412 (228), 414(228), 425 Yamamoto, C., 17(38),38 Yamamoto, I<.,252(140), 266 Yanaura, S., 122(267, 272), 131 Yang, N . C., 291 (74), 302 Yang,P., 146(36),I 7 1

578

AUTHOR I N D E X

Yang, T., 152(63, 64), 172 Yang, T. H., 14i(41, 42), 171 Yano, I<., 122(262),131 Yassi, J., 339(82),342(93), 343(84, 93), 344 (83, 84), 353(82), 3S4(82, 83, 84), 355 (93),422 Yen Ch'en, 45(12), 110 Yokoyama, N., 144(30, 33, 34), 145(30), l53(68), 171, 172 Yoshikawa, H., 492,514 Yoshimura, M., 121 ( 8 8 ) , 125 You-HoChian, 50(72)),112 Yuh-Cheng, Chen, 50(72), 112 Yunusov,M.S., 18(44),35,45(18), 103(18), 111 Yunusov,S.Y.,5(8), 17(40), 18(44), 37, 38, 45(18), 103(18), 111, 143(27, 28), 144 (29), 152(58, 59), 155(76), 156(77, 78), 158(58, 59), 171, 172 Yunusov, S. Yu., 224(15, 16, 17), 226(26, 27), 227 (16, 54, 55), 229 (15, 54, 55, 85, 86), 230 (103), 231 ( 5 5 ) ,236 (103),252, 253 (15, 16,54, 55, 85, 86, 87, 103, 141,

l42), 254(8ti, 144, 146, 14i), 255(142, 149), 263, 264, 265, 266, 267

Z Zalesky, S., 427, 439 Zaman, A , , 406(223), 407(223), 408(223), 409(223), 425 Zander, J., 505(31,32)),508(32), 515 Zapesochnaya, G. G., 142(25), 171 Zamack, U., 201(84), 204(84), 220 Zarnack, Z., 121(116, 191), 122(116, 119), 127,128 Zeile, K., 281 (46), 282 (47, 48), 302 Zenitz, B. L., 274(20), 301 Ziffer, H., 500(24), 501, 515 Zimmer, H., 232 (1lo), 266 Zoller, P., 273 (15 ) , 274 ( l a ) , 301 Zuman, P., 284(56, 5 i ) , 302 Zweifel, G., 247(134), 266 Zwicky, E., 467(3), 468, 470(3), 481 Zyka, J., 121(122, 129, 134, 147), 122(147), 126, 127

SUBJECT INDEX A 8-Acetonyldihydroberberine, 54 AV-4cetylchonemorphine,3 13 0-Aeetylsamandarine, 428 Acronycidine, 230, 232 Acronidine, 234 dcronychia buueri, 228 Actinodaphnine, 17 Adlumidine, 119 Adlumine, 119 Aegle mnrmelos, 227 Alkaloid A, 379, 406, 407 Alkaloid B, 384, 406, 408 Alkaloid C, 384 Alkaloid D, 384, 407, 410 Alkaloid E, 407, 410 Alkaloid M, 384 Alkaloid N, 384 Aliocryptopine, 44, 45, 46, 61 Allomatrine, 192, 209, 213 Allomatridine, 192, 209 Allothiobinupharidine, 443 3 a -Aminoconan- 5 -ene, 333 Aminolupinane, 179 3-Aminopregnane, 308 20-Aminopregnane, 310 Anabnsis aphylla, 200 Anagyrine, 178, 179, 180, 19i Androcymbium melanthioides, 169 Angustifoline, 175, 205 Anhydronupharanediol, 448 Anolobine, 17 Anonaine, 17 Antitoxicum funebre, 517, 52G Aphyllidine, 175, 199 Aphylline, 175, 188, 199 Apo-P-erythroidine, 486 Apoerysopine, 486 Aporheine, 46 Argemone rreneri, 44 Argemone olbcz, 44 Argernoiie rnericano, 44 drgem.one. plntycerns, 44 Argeinonine, 44 Argyrolobine, 175, 201 Argyrolobiuin megnrhizum, 201

dristolochiri debilis, 50 Aromoline, 133, 148 Asclepias syriaca, 51 7 Asimilobine, 1, 7 , 28 -4simina triloba, 7, 17 Atherosperma moschtum, 152, 156 Atherospermidine, 11 Atherospermoline, 133 Atropine, 280, 295 Aurotensine, 45, 46

B Baleabuxidine, 379, 404 Baleabuxine, 379, 402 Balfourodendron eburneum, 244 Bulfourode7idron riedelinnum, 223, 227, 236, 237, 244 Balfourodine, 238, 244, 24s Balfourolone, 237, 244 Baptifoline, 197 Base 11, 74 Base XI, 407, 414 Bebeerine, 133, 161 Bebuxine, 379, 389 Beilschmeidirc elliptica, 14 Berbamine, 47, 133, 152 Berbamunine, 133, 138, 139 Berberastine, 41, 65, 102 Berberine, 41, 43, 44, 45, 46, 47, 48, 49, 50,102 Berberis amurensis, 47, 139 Berberis usintica, 47 Berberis hauniensis, 47 Berberis illieasis, 47 Berberis kawakamii, 47, I52 Berberis lnmbertii, 41, 47, 57 Berberis luurinrc, 121 Berberis mingetsensis, 47, 152 Berberis morrisoneiisis, 152 Berberis serratn, 47 Berberas silvatriroucana, 47 Berberis thunbergii, 47 Berberis tschonoskynnn, 48, 148, 154 Berberis vulgaris, 48 579

SUBJECT INDEX

Berberubine, 47 Berlambine, 47, 57 Bervulcine, 48 Bicuculline, 45, 75, 119, 122 Bisdehydrotuberostemonine, 545 Bisnorargemonine, 44 Boenninghausenia albiflora, 227 Boldine, 13 Boronia ternata, 226, 228 Bufotaline, 437 Bulbocapnine, 23, 27, 45, 46 Bulbocapnine methyl ether, 32 Burasia madagmcariensis, 49 Buxamine-E, 379, 405 Buxamine-G, 404 Buxaminol-E, 379,405 Buxazine, 384 Buxdeltine, 384 Buxenine-G, 404 Buxetine, 384 Buxidine, 384 Buxomegine, 318, 384 Buxpiine, 379, 381 Buxpsiine, 379, 406 Buxtauine, 379, 381, 400 BUXUS balearica, 384 B u x u x microphylla, 384 B u x u s rolfei, 384, 391 B u x u s sempervirens, 318, 375, 384

C Caaverine, 1, 7 Cadaverine, 18i Calpurnia lasiogyne, 207 Calpurnia subdecandra, 207 Calpurnine, 206 Canadine, 41, 57, 107 Candicine, 50 Calystegia hydracme, 50 Calystegine, 50 Capauridine, 102 Capaurimine, 102 Capaurine, 102 Cmirniroa edulis, 224, 227 Casimiroin, 225 Casimiroinol, 225 Cassyfiline, 1, 8, 28

Cassythafiliformis, 8, 35 Cassythidine, 1, 28, 35 Cassythine, 1 Castoramine, 441, 463 Castor ca m d en si s, 463 Catalpifoline, 1, 35 Cepharanthine, 133, 150 Channa, 467 Channaine, 467, 468, 469, 478 Cheilanthifoline, 102 Chelerythrine, 44, 45, 46 Chelidonine, 44, 46, 47 Chelidoniurn m a j u s, 44 Chelilutine, 45, 46 Chelirubine, 44, 46, 47 Chloroxylon swietenia, 228 Choisya ternata, 223, 229, 233, 235 Choisyine, 233 d-Chondrocurine, 133, 161 Choiidrodendron tomentosum, 159 Chonemorpha fragrans,313 Chonemorpha penangensis, 3 13 Chonemorphine, 313, 348 C in n a mon eamphora, 17 Citrus aurantiurn, 229 Citrus u nsh i u , 229 Cocculolidine, 514 Cocculus laurifolius, 5 14 Cocculus snrrnentosus, 165 Cocculus trilobus, 514 Columbamine, 47, 102 Conamine, 306, 310, 334,353 Conarrhimine, 353 Conessidine, 345 Conessimine, 336 Conessine, 330, 358, 359, 363 Conkurchine, 345, 347, 353 Conkuressine, 334, 353 Conopharyngia durissirna, 3 17 Conopharyngia pachysiphon, 31 7 Conopharyngine, 317, 348 Coptisine, 44, 45, 46, 47, 75, 101 Coptis japonica, 49 Coramine, 41, 71, 103 Coreximine, 88, 89, 102 Corlumine, 119, 122 Coromine, 45 Corybulbine, 44, 103 Corydaline, 41, 45, 46, 54, 103 Corydalis ambigua, 44, 45, 74

58 1

SUBJECT INDEX

C o r y d a ~ i ntigustifolia, s 45 Corydalis cuucr, 45 Corydalis d e c i p i e m , 45 C o r y d a l i s gortschnbouii, 1 Corydalis gouatriana, 122 Corydcrlis irlcisa, 41, 45, 75 Corydnlis pseudoadunca, 45, 71 Corydalis pumila, 45 Corydcrlis solida, 45 Corydnlis spp., 45 Corydalis tuberosa, 45 Corydalmine, 41, 45, 71, 103 Corydine, 17, 21, 27, 47 Corynoline, 75 Corypalmine, 45, 75, 108 Corysamine, 41, 45, 75, 103 Corytuberine, 17, 46 Croton cumingii, 1 7 Croton sparsriflorus, 3 Cryptolepine, 517 Cryptolepis sanguinolenta, 517 Cryptolepis triangularis, 51 7 Cryptopalmatine, 61 Cryptopine, 61 Cryptopleurine, 517, 522 Curine, 133, 161 Cusparia macrocnrpu, 227 Cyclanoline, 49, 50, 85, 103 Cyclea burmanni, 153 Cyclea insularis, 49, 159 Cyclen peltata, 153 Cycleanine, 49, 133, 159 . Cyclobaleabuxine, 380 Cyclobuxamine-H, 380, 392 Cyclobuxamines, 377 Cyclobuxoxazine-A, 381, 399 Cyclobuxoxazine-C, 381, 398 Cyclobuxoxazines, 377 Cyclobuxine, 375, 381, 400 Cyclobuxine-D, 379, 360, 395 Cyclobuxines, 377 Cyclomalayanine, 381, 391 Cyclomethoxazine-R, 38 1, 399 Cyclomicrobuxine, 381, 402 Cyclomicrobuxinine, 400 Cyclomicrophyllidine-A, 381, 398 Cyclomicrophylline-A, 381, 388, 393 Cyclomicrophylline-B, 382 Cyclomicrophylline-C, 382 Cyclomicrophyllines, 37 7

Cycloneosamandaridine, 428, 436 Cycloneosamandione, 428, 435 Cycloprotobuxine-A, 382, 389 Cgcloprotobuxine-C, 382, 388 Cycloprotobuxine-D, 389 Cycloprotobuxines, 377 Cyclorolfeinc, 391 Cyclorolfoxazine, 400 Cyclovirobuxeine-A, 391 Cyclovirobuxines, 377 Cyphomandra betacea, 297 Cytisine, 180, 183 Cytisus laburnum, 183

D Daphnandrine, 133 Daphnoline, 133, 148 Dasycarpine, 214 Datura cornigera, 276 Datura ferox, 277, 297 Dntura stramoniurn, 277 Dauricine, 133, 141 Daurinoline, 133, 141 Dehydroalbine, 175 Dehydrocorybulbine, 44, 104 Dehydrocorydaline, 44, 45, 104 Dehydrocorydalmine, 41, 45, 71, 104 Dehydrodeoxynupharidine, 441, 442, 460 Dehydrohimbacine, 534 Dehydroisocorybulbine, 104 Dehydrothalictricavine, 104 Dendrobiurn lohohense, 117 Deoxynupharidine, 352,441, 442,444, 446, 456 Descret'amine, 48, 69, 70, 104 Descretine, 69, 104 Descretinine, 48, 49, 69, 70, 104 Dicentm spectrahilis, 45 Dicentrine, 27, 46 Dicranostigrna franchetianurn, 45 Dieranostigmn lnctucoides, 45 Dictamnine, 226 Dictamnus albus, 227, 229 Dictamnus caucnsicus, 229 Dictyodiamine, 314, 348 Dictyolucidamine, 328, 356 Dictyolucidine, 328, 356 Dictyophleba lucida, 314, 328

582

SUBJECT INDEX

Dictyophlebine, 314, 348 Dihydroberberine, 47, 57, 104 Dihydrochelerythrine. 44 Dihydroconessine, 326 Dihydrocoptisine, 104 Dihydrocyclomicrophylline-C, 397 Dihydrocyclomicrophylline-F,397 Dihydroerysodine, 484, 512, 513, 514 Dihydroerythraline, 484 Dihydroholarrhimine, 37 1 Dihydroisoconessimine, 336, 353 Dihydropalmatine, 105 Dihydrosanguinarine, 44 Dihydropseudoberberine, 105 Dihydropseudoepiberberine, 105 l,l0-Dihydroxy-2-methoxyaporphine, 1, 6 6,7-Dimethoxydictamnine,228 6,8-Dimethoxydictamnine,228 7,8-Dimethoxydictamnine,228 15,16-Dimethoxyerythrinane, 483, 490 15-16-Dimethoxyerythrinanol-3, 483, 493 3a-Dimethylamino-5a-conanine, 338 Dimethylcorytuberine, 26 0,N-Dimethyllaurelliptine, 15 0,O-Dimethyllaurifoline iodide, 26 0,O-Dimethylmagnoflorineiodide, 26, 33 0,N-Dimethylnandigerine, 32 1,7-Dimethylquinolizine,449 I ,2-Dimethyl-4-quinolone, 226, 256 Diphylline, 47 Diplospartyrine, 175, 194 Domesticine, 17, 23, 46, 48 Dubamine, 224,252, 253 Dubinidine, 223, 255 Dubinine, 223, 252, 255 Dubirheine, 46

E Ecogonine, 295 Ecgoninols, 269, 273 Echinospartum lusitanicum, 187 Edulein, 225 Eduline, 224 E n u n t i a chlorantha, 48 E n a n t i a polycarpa, 48 11-Epiaphylline, 200 13-Epibaptifoline, 197 Epiberberine, 60, 105

Epihydroxylupanine, 206 Epilupinine, 175, 179, 184 13-Epirnethoxylupanine, 207 20-Epi-S-Rlethylparavallarine, 369 Epipachysamine A, 407, 408, 412 Epipachysamine-B, 407, 411 Epipachysamine-C, 407, 412 Epipachysamine-D, 407, 411 Epipachysamine-E, 407, 411 Epipachysamine-F, 407, 41 1 Epipachysandrine-A, 419 Epistephanine, 133, 150 Eriostemon brucei, 228 Eriostemon coecineus, 228, 229 Eriostemon difformis, 228 Eriostemon thryptomenoides, 228, 229 Eriostemon tomentellus, 228, 229 Erysocline, 483, 484, 485 Erythraline, 484 Erythramine, 484 Erythratine, 483, 484, 485 Erythrina berteroana, 5 12 Erythrina crystagalli, 485 Erythrinane, 484, 512 Erythrinanes, 501 a-Erythroidine, 484, 489 8-Erythroidine, 484 Erythroidines, 483, 497 Erysonine, 484, 499 Erysopine, 484 Erysotrine, 484, 510 Erysovine, 483, 484, 485 Eschscholtzia calqornica, 17 Euryale ferox, 441 Evodia littoralis, 227 Evodia tanthoxyloides, 228, 235 Evodine, 236 Evolitrine, 227, 250, 256 Evoxine, 225, 230, 235, 253

F Fagara angolensis, 229 Fagara chilopcrone, 17 Fagara COCO, 227 Fagara hyemalis, 17 Fagara nigrescens, 33 Fagara pterota, 17 Fngara rhoifolia, 17

583

SUBJECT I S D E X

Fagara tingunssoibn, 1, 12, 20 Fagnra viridis, 279 Fagnrtr zcinthosyloides. 229 y-Fagarine, 227 Fangchinoline, 133, 153 Fetidine, 133, 142 Fihramine, 49 Fihraminine, 49 Fibraurea tinctoria, 49 Ficus septica, 517, 525 Flindersia acunainata, 227 Flindersia bennettiana, 229 Flindersia bourgotiana, 229 Flindersia collina, 228 Flindersia dissosperma, 2 2 7 Flindersin iflaiana, 234 Flindsersia maculosa, 227 Flindersia laeuicarpa, 229 Flindersia pubescens, 22 7 Flindersia schottiana, 228 Flindersia xanthoxyla, 230 Flindersiamine, 230, 232 Foliosidine, 225, 252, 253 Foliosine, 253 F umar ia oficinalis, 46 Funtessine, 339, 353 Funtudiamine-A, 348 Funtudiamine-B, 348 Funtudiamine-A and -B, 317 Funtudienine, 344, 354 Funtuline, 343, 354 Funtumafrine-B, 348 Funtumafrine-B and -C, 311 Funtumafrine-C, 348 Funtumia aJricaiaa, 310, 311 Fuiatumin ZatiJolia, 311, 317, 324, 343 Funtumidine, 312, 348 Funtumine, 311, 313, 349 Funtuphyllamine-A, 318, 349 Funtuphyllamines-A, -B and -C, 310 Funtuphyllamine-B, 349 Funtyphyllamine-C, 349

G Galhacin, 532 Galhelgin, 532 Galbulimima baccata, 529 Galbulimima belgraveann, 529

Gulbulimima nitida, 529 Galbulimima parvifolia, 529 Galhulin, 532 Galcatin, 532 Galgravin, 532 Geitista lusitanica, 187 Gen.istn rhodorhizoides, 2 12 Gindarycine, 49 Glaucentrine, 1, 11 Glaucine, 2 2 , 26, 27 Glaucium corniculatum, 46 Glaucium oxyloburn, 17, 46 Glycosmis arboren, 227 Glycosrnis pentaphylla, 228 Graveoline, 224 Graveolinine, 224 Guatteria psilopus, 9 Guatterine, 1, 9

H Haplophyllidine, 223, 252, 253 Hnplophyllum bucharicum, 229, 253 Haplophyllum dubium, 224, 253 Haplophyllum foliosum, 225, 229, 253, 255 Haplophyllum pedicellatum, 227, 253 Haplophyllum perforatum, 229, 230, 236, 252,253 Haplophyllum robustum, 227, 253 Haplophyllum versicolor, 253 Haplopine, 230, 252, 253 Hernandaline, 35 Hernandezine, 49, 133, 137, 138, 155 Hernandia catalpiJolzn, 35 Heriaandin ovigera, 17, 30, 35, 144 Hernovine, 1 Himandravine, 529, 631, 540 Himandrine, 531 Himandridine, 531, 532 Himantandra belgraueana, 529 Himbacine, 529, 531, 533, 540, 541 Himbadine, 531, 532 Himheline, 529, 531, 540 Himhosine, 529, 531, 532, 542 Himgaline, 631, 532 Himgravine, 529, 531, 541 Himgrine, 531 Holadienine, 344, 354 Holadysamine, 323, 349

584

SVBJECT IXDEX

Holadysine, 322 Holafebrine, 317, 349 Holaline, 339, 3.54 Holamine, 313, 320, 349, 417 Holaphyllaminc, 313, 318, 349, 417 Holaphyllidine, 320, 350 Holaphylline, 318, 350, 417 Holaphyllinol, 350 Holarrheline, 339, 354 Holarrhena a.fricrtnn, 318, 320 Holarrheiin antidysentericn, 324 Holarrhenn jebrifugri, 3 18 Holarrhenine, 339 Holarrhidine, 325, 350 Holarrhimine, 350, 391 Holonamine, 347, 354 Homoaromoline, 131, 148 Homopiptanthine, 214 Hortia arboren, 227 Hunnemannin fumariccefolin, 110 Hydrastine, 49, 118, 121 Hydrastis canadensis,49, 65, 92, 120 a-Hydroxyconessine, 333 7~-Hydroxyconessine,338, 354 7/3-Hydroxyconessine, 338, 354 8-Hydroxydictamnine, 253 14-Hydroxyepiberberine,60 6P-Hydroxyhyoscyamine, 269, 277 Hydroxylunacridine, 237, 242 Hydroxylunacrine, 238, 242 Hydroxylunidine, 237 Hydroxylunine, 238 Hydroxylupanine, 175, 181, 204 Hydroxymultiflorine, 175, 208 18-Hydroxyprogesterone, 37 1 4-Hydroxyquinolone, 248 Hyoscinc, 269, 277, 282, 297 Hyoscyamine, 269, 277, 280, 295, 297 Hypoepistephanine, 133, 150

I Ifflaiamine, 234 Insulanoline, 133, 159 Insularine, 49, 133, 159 Irehamine, 350 Irehdiamine-A, 323, 350 Irehdiamine-R, 323, 351 Irehdiamine-C, 324, 351

Irehine, 307, 318, 351, 419 Irehline, 345, 347 Isobalfourodine, 238, 249 Isoboldine, 1, 13, 23 Isochondrodendrine, 49, 133, 159 Isoconessine, 332 Isocorybulbine, 105 Isocorydine, 17, 27, 45, 46 Isocorypalmine, 1 O i Isofugapavine, 1 Isoliensinine, 133, 138, 146 Isolupanine, 179 Isornacrorine, 257 Isoorixine, 250 Isosophoramine, 175, 212, 213 a-Isosoarteine, 179, 192, 199 P-Isosparteine, 179 Isotetrandrine, 47, 133, 152, 154 Isothebaine, 20 Isotrilobine, 133, 137, 163 Isotuberostemonine, 545

J Jamaicensine, 189 Jamaidine, 189, 206 Jamine, 214 Jatrorrhizine, 47, 48, 49, 50, 105

K 8-Ketosparteine, 191 Khaplofoline, 253, 255 KibatnIirz gilingensis, 366, 369 Kibataline, 366, 369 Koegoed, 4fi7 Kokusagininc, 228, 230, 232, 250, 266 Kurchaline, 322, 351 Kurchamine, 323, 331 Kurchessine, 325, 351 a-Kurehessine, 325, 351 Kurchiline, 320, 351 Kurchimine, 323 Kurchiphyllaminc, 322, 351 Kurchiphylline, 321, 351 Kurcholessine, 341, 354, 419

SUBJECT INDEX

L Lamhertine, 47, -57,104 Latifoline, 342, 355 Latifoliniue, 342, 355 Launobine, 1 Laurelliptine, 1, 14 Laureline, 1, 16 Laurifoline, 17 Laurolitsine, 17 Laurotetanine, 17 Lnurus nobilis, 3, 17 Leontine, 209 Liensinine, 133, 138, 146 Litseti cubebtc, 15 Lophoeereus schottii, I 68 Lophocerine, 137 Lunacridine, 237, 239, 247 Lunacrine, 238, 239, 247 Lunacrinol, 238 Lunamarine, 237 Lunasiu affkarfz,223, 224, 229, 236, 237 L u n a s i a yucrcifolia, 225 Lunasine, 238, 239, 241 Lunidine, 237, 243 Lunidonine, 237, 243 Lunine, 238, 243 Lnnulone, 237 Lupanine, 155, 179, 181 Lupinine, 175, 178, 181, 184 Lupinus nlbus, 188 L u p i n u s angustqolius, 182, 188, 207 L u p i n u s luteus, 181, 182 L u p i n u s polyphyllus, 188 Lusitanine, 175, 187 Lysine, 181

M hlacarpine, 46, 47 Xctcleriya microcnrpa, 46 Maerorine, 257 Macrorungicz longistrobus, 223, 257 Rlacrorungine, 257 Maculine, 230 Maculosidine, 228, 231 Maculosine, 225, 234 Magnocurarine, 136 Magnoflorine, 1 7 , 47, 48, 49, 50 Magnolamino, 133, 142

585

Mognolirc compressa, 148 Magnoline, 135, 138 Mrrhonia fortunei, 48 Mrihonin japonica, 48 Mahonin limarivolin, 48, 152 Mohonin morrisonensis, 48, 152 Nrihonia philippinensis, 152 Malarboreine, 355, 357 Malarborine, 355, 358 Mnlouetia bequaertinnn, 307, 31 3, 315 Malouetine, 315, 352 Malouphyllamine, 337, 355 Malouphylline, 315, 356 Malouphyllinine, 317, 352 Matrin, 175, 181, 208 Mecambrine, 5, 46 Illecarnbroline, 1, 5 Meconopsis cambrica, 5 Meconopsis pnniculnta, 46 Melanthioidine, 133, 138, 169 Melicope fareana, 229 Menisarine, 133, 137, 165 Illenisperine, 50 Menispermum dahuricum, 122 Menispermum dauricum, 141 Mesembrane, 480 Mesembrene, 480 Mesembreninol, 477, 479 Mesembrenine, 467, 468, 469, 476, 479 Mesembrine, 467, 468, 469, 470, 475, 4 79 Mesembrinol, 467, 468, 477, 479 Mesocorydaline, 105 hleteloidine, 269, 281 6-Methoxydictamnine, 227, 230, 256 8-Blethoxydietamnine, 227, 228 1-Methoxy-2-hydroxyaporphine, 8 8-Rlethoxy-6,7-methylenedk1xydictamnine, 230 4-Methoxy-2-(3',4',-methylenedioxyphenyl)quinoline, 237 7-Methoxy-1-methyl-2-phenyl-4quinolone, 237 4-Methoxy-2-phenylquinoline, 237 A'-Methylactinodaphnine, 1 A-Rlethylalbine, 175 O~-Methylbalfourodinium,238 0-Methylherbarnine, 133, 152 N - Meth ylcassyfil ine , 9 0-Methylcassyfiline, 9 A'-Methylcorydinium cation, 1

586

SUBJECT ITDEX

S-Methylcytisine, 18 1 0-Methyldauricine, 141 0 -Methyldomesticine, 48 6,7-Rlethylenedioxydictamnine,230 7,8-Jlethyleneclioxydictamnine,230 S-Methylhernovine, 33 3-S-Methylholarrhimine, 325, 352 20-S-Methylholarrhimine, 325, 352 17aa->fethyl-~-homoandrostane, 3 10 0-Methylisoboldine, 14 A’-Methylisocorydinium cation, 17 N-Methyllaurotetanine, 13, 15, 17, 27 N-Methylnandigerine, 1 N-Rfethylovigerine, 1, 32 0-Methyloxyacanthine, 133, 148 1-Illethyl-2-phenyl-4-quinolone, 237 0-Methylpreocoteine, 35 N-Methyltetrahydroberberine, 86 0-Methylthalicberine, 133, 138, 158 Michelia compressa, 49, 148 Micranthine, 137 Monspessulanine, 175, 200 Multiflorine, 175, 208 Muwaya omphalocarpu., 229

N Nandigerine, 1 N a n d i n a domestica, 13, 48 Nandinine, 107 Nantenine, 23 Narcotine, 118, 122 Narcotoline, 118 A’ectandra porphiria, 17 A’ectundra rodioei, 151 Neferine, 133, 138, 146 Xclumbo lutea, 17 Xelumbo nucijera, 17, 146 Neoconessine, 332, 419 Neolitsea ncuminrrtissima, 17 Neolitsen pulchelln, 2 Xeolitsea sericea, 37 Neolit.sine, 1, 2 A’elUWlbiUTn SpCCiGSuWC, 146, 441 Neooxyberberine, 110 Neothiobinupharidine, 441, 443, 462 Neprotine, 42 Nicotine, 517 Noradrenaline, 66:

Sorargemonine, 41 Korcoralydine, 49, 62, 72, 86, 88, 10; Norcycleanine, 133, 159 Norlatifoline, 343, 355, 360 S-Korlaudanosine, 7 2 Normacrorine, 257 Normenisarine, 137 h’ormcsembrine, 468, 481 Nornuciferine, 7, 17 Nororixine, 250 Nortenuipine. 133, 157 Nortropine, 276 Norushinsunine, 17 hTuciferine, 17, 23, 27 Nuphamine, 441, 442, 461 Nupharamine, 441, 442, 454, 456 Nupharidine, 441, 442, 444, 452 P-Nupharidine, 442 Nupharidinic acid, 449 Nupahrine, 442 Nuphar jttponicum, 44 1 Nuphar Euteum, 441 Symphaetr. tdbn, 44 1 Nympheine, 441, 442

0 Obaberine, 133, 148 Obamegine, 48, 133, 154 Ocotea gltrziouii, 6 Ocoteine, 1, 9, 16, 17, 25 Ocotine, 133, 151 Ophiocarpine, 41, 54, 82, 106, 118 Opium, 17 Orientaline, 21 Orientalinone, 22 Orixajaponica, 223, 227, 250 Orixidinine, 251 Orixine, 250 Ormojamine, 214 Orniojanine, 217 Ormosanine, 2 13 Ormosia dasycnrpu, 2 14 Ormosin jamuice,rsis, 184, 189 Orrnosicr.pnnameirsis, 189, 213 Ormosinine, 2 13 Ornithine, 295 Oroboidine, 206 Oscine, 269, 282, 286

587

SUBJECT I N D E X

Ovigerine, 1 Oxoaphyllidine, 1i 5 , 200 17-Oxolupanine, 1 i 5 17-Oxosparteine, 175, 195 Oxotuberostemonine, 5.50 Oxycanthine, 47, 49, 133, 148 Oxrberberine. 47, 57 Oxysanguinarine, 46

P Pnchysnndm termintrlis, 325, 408 Pachysamine-A, 407, 411 Pachysamine-B, 407 Pachysandrine-A, 407, 412 Pachysandrine-B, 407, 413 Pachysandrine-C, 408, 414 Pachysandrine-D, 408, 414 Pachysantermine-A, 408, 417 415 Pachystermine-A and -B, Pachystermine-B, 408 Palmatine, 44, 47, 49, 60, 106 Panamine, 213, 216 Papnuer cnucrisicum, 17 P a p m ? r co~,mzutcilum,17 Papnuer dubium, 1 7 , 46 Pap" uer fugnx, 17 Pnpaver orielitale, 21 Papnuer paeoniflorurn, 120 Pcrpuuer rhoeris, 46, 120 Papaver somniferum, 96 Pczrtrbaencc hirsutn, 49 Paravallaridine, 366, 367 Paravallarine, 366, 367, 374 Pnrciunllaris microphylla, 366, 367 Phollodondrine, 41, 50, 85, 89 Phellodemlron nmurense, 49, 50, 85 Ph.ellodendron lnucillei, 50 Phelloclenclro,i wilsonii, 50 I'hlebaliurrk m d u m , 227 Phoebe porpliirici, 17 Phylicn rogersii, 15, 17 Phyllalbine, 269, 270 PhyElnntus cliscoide8, 270 Piloceredine, 133, 168 Pilocereine, 133, 137 Pilokeanine, 2 2 3 , 256, 257 Piptamine, 214 Piptanthine, 214

r i p t n nthu.9 nfoius, 2 I4 Plat>-cerine,44 Z'lntyde.smn ccrmpanulcitn, 2 2 3 , 2 2 6 , 230, 256 Platydesmine, 223, 256 Plntysterno)~ccilifortiicus, 46 Poneirus trifolicitn, 229 .ia-Prsgnan-3P-,l8-diol-_"0-one, 351 Pregnane, 306, 310 Psoudothiobinupharidine, 443 Preocnteine, 1 2 - )L -Propyl-4-quinolone, 22 6 Protopine, 44, 45, 46, 47, 48, 75 Protosinomenine, 96 Pseudo berberine, 106 Pseudocorydine, 22 Pseudoepiberberine, 106 Pseudostrychnine, 60 Pseudotropine, 269, 274, 294 Pteleine, 230 Ptelen trifolinta, 230 Putrescine, 297 Pycnarrhena. manillensis, 152

Q %Quinolone, 252

R Rauwolfitr heterophylln, 120 Rewenm spectnbal~s,228 Repandine, 133, 150 Retrimct sphaerocarpu, 199 Ketamine, 1 7 5 , 200, 201 Retlculine, 23 Rhoeadine, 46 Hobustine, 232, 253 Rodlasine, 133, 151 Roemerine, 17, 46 Rogersin?, 1, 15 Kotundino, 42 Ruta graueolens, 224, 228

S Saracocine, 408, 409 Saracodine. 408, 409 Saracodinine, 3 2 5 , 407, 408, 409

588

SUBJECT INDEX

Sarcococca pruniformis, 325, 376, 406, 408 Samandaridine, 428, 432, 433 Samandarine, 428, 429 Samandarone, 428, 432 Samandenone, 428, 434 Samandinine, 428, 434 Samandiole, 430 Salumandra maculosa maculosa, 429 Salamandra maculosa taeniuta, 429 Samanine, 428 Sanguinarine, 44, 45, 46, 47, 75 Sarothamnus scoparius, 182 Sceletium A4,. 468, 481 Sceletium Bar 468, 481 S c e k t i u m a n a t m i c u m , 468 Sceletium expansum, 468 Sceletium namaquense, 468 Sceletium tortuosum, 468 Scopoline, 269, 282 Scoulerine, 45, 46, 106 Sepeerine, 133, 151 Septicine, 527 Shihunine, 117 S k i m m i a arisanensis, 229 S k i m m i a japonica, 229 Skimmia laureola, 229 Skimmia repens, 227 Skimmianine, 226, 228, 230, 250, 253 Sophocarpine, 175, 212 Sophora$avescens, 208 Sophora pachycarpa, 213 Sophora tetraptera, 182 Sophorctmine, 175, 2 12 Sophoranol, 208 Sparsiflorine, 1, 3 Sparteine, 175, 179, 181, 183, 191, 208 Spartyrine, 194 Stemona sessilijolia, 550 Stemonu tuberosa, 550 Stephania glabra, 49 Stephania hermndijolia, 166 Stephania japonica, 154 Stephania rotunda, 110 Stephanine, 49 Stepharotine, 110 Stepholine, 133, 154 Stephonine, 85, 106 Strychnos melinoniana, 120 Strychnine N-oxide, 60 Stylophorum diphyllum, 47

Stylopine, 44, 88 Symplocos celastrinea, 7, 13

T Takatonine, 49 Teclea sudunica, 230 Tenuipine, 133, 157 Terminaline, 408, 414 Tetrahydroberberastine, 49 Tetrahydroberberine, 41, 44, 45, 49, 57, 60, 107 Tetrahydroberberubine, 107 Tetrahydrocolumbamine, 47, 107 Tetrahydrocoptisine, 44, 45, 47, 88, 107 Tetrahydrocorysamine, 76, 107 Tetrahydroepiberberine, 107 14,15,16,17-Tetrahydroerythrinane, 504 Tetrahydrojatrorrhizine, 108 Tetrahydrorhombifoline, 175 Tetrahydropalmatine, 44, 45, 49, 60, 88 Tetrahydropalmatrubine, 88 Tetrahydropseudoepiberberine,108 Tetrahydrothalidastine, 108 Tetrahydrothalifendine, 108 14,15,16,17-Tetrahydro-l6-oxaerythrinane, 483, 494 Tetrahydroworenine, 108 2,3,6,7-Tetramethoxy-9 -methylphenanthrene, 519 N,N,N’,N’-Tetramethylholarrhimine, 328 Tetrandrine, 133, 153 Thalicarpine, 133, 138, 144 Thalicberine, 133, 138, 158 Thalictricavine, 65, 80, 109 Thalictrifoline, 80, 109 Thalictrum dasycarpum, 49, 137, 144 Thalictrumfendleri, 17, 34, 41, 49, 65, 66, 137 Thalictrumfoetidurn, 143 Thalictrum hermndezii, 155 Thalictrum isopyroides, 143 Thalictrum minus, 144, 152 Thalictrum rochebrunianum, 155 Thalictrum simplex, 155 Thalictrum thunbergii, 49, 149, 158 Thalidastine, 49, 65, 66, 108 Thalifendine, 49, 66, 109 Thalifendlerine, 49, 66, 137

589

SUBJECT INDEX

Thalmelatine, 133, 138, 144 Thalmine, 133, 152 Thaliporphine, 1 Thalisopine, 133, 143 Thalsimine, 133, 138, 155 Thermopsine, 179, 197 Thiobideoxynupharidine, 443 Thiobinupharidine, 441, 443, 463 6P-Tigloyloxy-3a-tropano1, 269, 276 Tiliaeora racemosa, 161 Tiliacorine, 133, 138, 161 Tiliarine, 133, 138, 161 Trilobine, 133, 137, 165 5,7,8-Trimethoxydictmnnine, 230 Trop-6-en-3-one,269, 284 Tropic acid, 295 Tropine, 294 Tryptophan, 300 Tuberostemonane, 547 Tuberostemonine, 545 Tuberostemonine-A, 545, 550 Tubocurarine, 133, 161 Tylocrebrine, 517 Tylophora asthmatica, 517 T y l o p h o r ~crebrijlora, 5 17, 525 Tylophora Joribunda, 525 Tylophora indica, 518 Tylophorine, 517, 518 Tylophorinine, 517, 518, 522

U Umbellatine, 42 Ushinsunine, 11

V Valeroidine, 269, 271, 278, 284 Vepris bilocularis, 228 Vincetoxicum offkinale, 5 17 Virgilia capensis, 206 Virigilia oroboides, 206 Virgiline, 206 Vulracine, 48

W Worenine, 109

X Xanthorhiza simplicissma, 49 Xylopia descreta, 41, 48, 69 Xylopine, 49, 69 Xylopinine, 49, 62, 69

Z Zanthoxylum ailanthoides, 227 Zanthoxylum alatum, 227 Zanthoxylurn rhetsa, 229 Zanthoxylum schinif olium, 2 29 Zanthoxylum venejicum, 85

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