THE ALKALOIDS Chemistry and Physiology
Volume XVIII
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THE ALKALOIDS Chemistry and Physiology Foutzding Editor
R. H. F. MANSKE Edited by
R. G. A . RODRIGO Wilfrid Laurier University Wrrrerloo, Ontario, Canudu
VOLUME XVIII
1981 ACADEMiC PRESS NEW YORK
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LONDON
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TORONTO
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A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT @ 1981, BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION I N WRITING F R OM T HE PUBLISHER.
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United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London N W l
IDX
L i b r a r y o f Congress Cataloging i n P u b l i c a t i o n Data Manske, Richard k l r m t h Fred, Date. The a l k a l o i d s ; chemistry and physioloqy. Vols. 8-16 e d i t e d by R. H. F. Manske. v o l s . 17e d i t e d by R . H. F. Manske, R . G . A. Rogrigo. Includes bibliographical references. 1. Alkaloids. 2 . Alkaloids--Physiological e f f e c t . I . tblmes, Henry Lavergne, j o i n t a u t h o r . 11. Title: Thru physiology. W421. M3 547.7'2 ISBN 0-12-469518-3 ( v . 18)
50-5522 AACRl
PRINTED IN THE UNITED STATES OF AMERICA 81 82 83 84
9 8 7 6 5 4 3 2 1
CONTENTS LISTOF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTENTS OF PREVIOUS VOLUMES. . . . . . . . . . . . . . . . . . . . .
vii ix xi
Chapter 1. Erythrina and Related Alkaloids S. F . DYKEA N D S. N . QUESSY I . Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . .
I1 . Erythrina Alkaloids
. . . . . . . . . . . . . . . . . . . . . . . .
111. Homoerythrina Alkaloids IV. Cephalotaxus Alkaloids V. Biosynthesis . . . . . VI . Synthesis . . . . . . . VII . Pharmacology . . . . . References . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . .
1
2 27 42 51 61 91 93
Chapter 2. The Chemistry of Cz,. Diterpenoid Alkaloids S. WILLIAM PELLETIER A N D NARESH V. MODY
I . Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . .
I1 . Veatchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . 111. Atisine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . IV. Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . V. Behavior and Formation of the Carbinolamine Ether Linkage in VI . VII . VIII . IX .
Diterpenoid Alkaloids: The Baldwin Cyclization Rules W-NMR Spectroscopy of CZrDiterpenoid Alkaloids Mass Spectral Analysis of Czo-Diterpenoid Alkaloids Synthetic Studies . . . . . . . . . . . . . . . . . A Catalog of CZo-DiterpenoidAlkaloids . . . . . . References . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . .
100
102 122 144 149 160 163 168 1% 211
Chapter 3 . The 'T-NMR Spectra of Isoquinoline Alkaloids D . W. HUGHESA N D D . B . MACLEAN I . Introduction
. . . . . . . . . . . . . . . . . . . . . . . . . . .
I1. 1,2,3,4 Tetrahydro and 3-4-Dihydroisoquinolines
111. Benzylisoquinoline Alkaloids
. IV. Bisbenzylisoquinoline Alkaloids V. Cularine . . . . . . . . . . VI . The Morphine Alkaloids . . .
. . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
217 219 223 226 227 228
vi
CONTENTS
VII . Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . VIII . Pavine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . IX . Aporphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . X . Reduced and Nonreduced Proaporphines . . . . . . . . . . . . . . XI . Tetrahydroprotoberberine Alkaloids . . . . . . . . . . . . . . . . XI1 . Protopine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . XIII . Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . XIV. Modified Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . XV. Benzo[c]phenanthridie Alkaloids . . . . . . . . . . . . . . . . . XVI . Spirobenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . XVII . Rhoeadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVIII . Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . XIX . Emetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XX . Miscellaneous Alkaloids . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .
.
. . . .
.
230 234 235 238 239 243 245 249 250 252 257 257 259 260 261
Chapter 4 . The Lythraceae Alkaloids W. MAREKGCKFBIEWSKI A N D JERZY T. WROBEL
I . Introduction . . . . . . . . . . . . . . . . . I1. Lactonic Biphenyl Alkaloids . . . . . . . . . . I l l . Lactonic Biphenyl Ether Alkaloids . . . . . . IV. Simple Quinolizidine Alkaloids . . . . . . . . V. Ester Alkaloids . . . . . . . . . . . . . . . . VI . Piperidine Metacyclophane Alkaloids . . . . . VII . Quinolizidine Metacyclophane Alkaloids . . . . VIII . Synthesis . . . . . . . . . . . . . . . . . . . IX . Biosynthesis . . . . . . . . . . . . . . . . . X . Physiological Activity . . . . . . . . . . . . . References .
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . .
263 266 281 284 286 288 294 303 313 319 3 20
Chapter 5 . Microbial and in Vitro Enzymic Transformations of Alkaloids H . L . HOLLAND
I . Introduction . . . . . . . . . . . . . . . . . I1 . Enzymes Involved in Alkaloid Transformations 111. Transformations of Indole Alkaloids . . . . . IV. Transformations of Isoquinoline Alkaloids . . . V. Transformations of Pyridine Alkaloids . . . . . VI . Transformations of Pyrrolizidine Alkaloids . . . VII . Transformations of Quinoline Alkaloids . . . . VIII . Transformations of Steroidal Alkaloids . . . . IX . Transformations of Tropane Alkaloids . . . . . References . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
324 325 328 348 376 376 381 383 391 395 401
LIST OF CONTRIBUTORS
Numbers in parentheses indicate the pages on which the authors' contributions begin.
S. F. DYKE"( l ) , School of Chemistry, The University of Bath, Bath BA2 7AY, England W. MAREKG O K ~ B I E W (263), S K I Department of Chemistry, University of Warsaw, Warsaw 02-093, Poland (3231, Department of Chemistry, Brock University, St. H. L. HOLLAND Catharines, Ontario L2S 3A 1, Canada D. W. HUGHES(217), Department of Chemistry, McMaster University, Hamilton, Ontario LSS 4M1, Canada (217), Department of Chemistry, McMaster University, D. B. MACLEAN Hamilton, Ontario L8S 4M1, Canada NARESHV. MODY(99), Institute for Natural Products Research, Department of Chemistry, University of Georgia, Athens, Georgia 30602 S. WILLIAMPELLETIER (99), Institute for Natural Products Research, Department of Chemistry, University of Georgia, Athens, Georgia 30602 S. N. Q U E S S Y(l), ~ School of Chemistry, The University of Bath, Bath BA2 7AY, England JERZYT. WROBEL(263), Department of Chemistry, University of Warsaw, Warsaw 02-093, Poland
* Present address: Department of Chemistry, Queensland Institute of Technology, Brisbane, Queensland, Australia. f Present address: Research and Development Department, Riker Laboratories, Thornleigh, New South Wales, Australia. vii
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PREFACE This volume of “The Alkaloids” presents timely reviews of three groups, the Erythrim, Lythraceae, and C,,-diterpenoid alkaloids. The chapters are organized in the traditional manner and cover all aspects of the recent chemistry of these groups. A useful catalogue of Czoditerpenoid alkaloids is also included. One chapter is devoted to a discussion of the I3Carbon spectra of benzylisoquinolines and the fifth chapter collects and reviews work on the microbial and it? cirro transformations of the alkaloids. Both subjects have attracted increasing attention in recent years. The editor wishes to thank the authors for their cooperation in making this volume possible. We hope that it will be as useful to researchers in alkaloid chemistry as the previous seventeen have been and we welcome advice or criticism from our readers.
R. G. A. RODRICO
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CONTENTS OF PREVIOUS VOLUMES Contents of Volume I CHAPTER 1 . Sources of Alkaloids and Their Isolation B Y R . H . F. MANSKE 2 . Alkaloids in the Plant B Y W . 0. JAMES . . . . . . . . . . . 3 . The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . 4 . Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . 5 . The Pyridine Alkaloids B Y LEOM A R I O N . . . . . . . . . . 6 . The Chemistry of the Tropane Alkaloids B Y H . L . HOLMES. . 7 . The Strychnos Alkaloids B Y H . L . HOLMES. . . . . . . . .
. . . . .
1
. . . . . . . . . .
15
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. . . .
. . . .
. . . .
. . . .
91 107 165 271 375
Contents of Volume II 8.1.
8.11. 9. 10. 1 1. 12. 13. 14. I5.
The Morphine Alkaloids I B Y H . L . HOLMES . . . . . . . . . . . . . 1 The Morphine Alkaloids B Y H . L . HOLMESA N D ( I N PART) GILBERTSTORK 161 Sinomenhe B Y H . L . HOLMES. . . . . . . . . . . . . . . . . . . . 219 Colchicine BY J . W . COOKA N D J . D . LOUDON. . . . . . . . . . . . 261 Alkaloids of the Amaryllidaceae B Y J . W. COOKA N D J . D . LOUDON. . . 33 1 Acridine Alkaloids B Y J . R . PRICE . . . . . . . . . . . . . . . . . . 353 The Indole Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . . 369 The Erythrina Alkaloids BY LEOMARION. . . . . . . . . . . . . . . 499 The Strychnos Alkaloids . Part I1 B Y H . L . HOLMES . . . . . . . . . . 513
Contents of Volume 111 16. The Chemistry of the Cinchona Alkaloids B Y RICHARD B. T U R N E R A N D R . B . WOODWARD . . . . . . . . . . . . . . . . . . . . . . 17 . Quinoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 18. The Quinazoline Alkaloids B Y H . T . OPENSHAW. . . . . . . . . . . . 19. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . . . 20 . The Imidazole Alkaloids B Y A . R . BATTERSBY A N D H . T. OPENSHAW. . 21 . The Chemistry of Solanum and Veratrum Alkaloids B Y V . FRELOG A N D .OJEGER . . . . . . . . . . . . . . . . . . . . . . . . . . 22 . P-Phenethylamines BY L . RETI . . . . . . . . . . . . . . . . . . . 23 . Ephreda Bases B Y L . RETI . . . . . . . . . . . . . . . . . . . . . 24 . The Ipecac Alkaloids B Y MAURICE-M.~RIE JANOT . . . . . . . . . . .
1
65 101 119 20 1 247 313 339 363
Contents of Volume IV 25 . The Biosynthesis of Isoquinolines B Y R . H . F. M.4NSKE . . . . . . 26. Simple Isoquinoline Alkaloids B Y L . RETI . . . . . . . . . . . .
xi
1
7
xii
C O N T E N T S OF P R E V I O U S V O L U M E S
CHAPTER 27 . Cactus Alkaloids B Y L . RETI . . . . . . . . . . . . . . . . . . 28 . The Benzylisoquinoline Alkaloids B Y ALFREDBURGER. . . . . . . 29. The Protoberberine Alkaloids B Y R . H . F . MANSKE A N D WAL .TER R . ASHFORD. . . . . . . . . . . . . . . . . . . . . . . . . . 30. The Aporphine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . 31 . The Protopine Alkaloids BY R . H . F. MANSKE . . . . . . . . . . 32. Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€KA N D R . H . F. MANSKE . . . . . . . . . . . . . . . . . . . . . . . . . . 33 . Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . 34. The Cularine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . 35 . a-Naphthaphenanthridine Alkaloids B Y R . H . F. MANSKE . . . . . 36. The Erythrophletcrn Alkaloids BY G . DALMA . . . . . . . . . . . 37 . The Aconitum and Delphinium Alkaloids B Y E . S. STERN . . . . .
. . . .
23 29
. .
77 119 147
. .
. . . . . .
. . . . . . . .
167 199 249 253 265 275
Contents of Volume V 38 . 39 . 40. 41 . 42. 43. 44. 45 . 46. 47 . 48 .
Narcotics and Analgesics B Y HUGOKRUEGER. . . . . . . . . . . . . Cardioactive Alkaloids BY E . L . MCCAWLEY. . . . . . . . . . . . . Respiratory Stimulants B Y MICHAEL J . DALLEMACNE. . . . . . . . . Antimalarials BY L . H . SCHMIDT . . . . . . . . . . . . . . . . . . Uterine Stimulants B Y A . K . REYNOLDS . . . . . . . . . . . . . . . Alkaloids as Local Anesthetics B Y THOMAS P. CARNEY . . . . . . . . Pressor Alkaloids BY K . K . CHEN . . . . . . . . . . . . . . . . . . Mydriatic Alkaloids BY H . R . ING . . . . . . . . . . . . . . . . . . Curare-like Effects B Y L . E . CRAIG . . . . . . . . . . . . . . . . . The Lycopodium Alkaloids B Y R . H . F . MANSKE . . . . . . . . . . . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE. . . . . .
1
79 109 141 163 211 229 243 259 265 301
Contents of Volume VI 1. 2. 3. 4. 5. 6. 7. 8. 9.
Alkaloids in the Plant B Y K . MOTHES . . . . . . . . . . . . . . . . The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . . . . . . Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . . . . . . The Pyridine Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . The Tropane Alkaloids BY G . FODOR . . . . . . . . . . . . . . . . . The Strychnos Alkaloids BY J . B . HENDRICKSON. . . . . . . . . . . The Morphine Alkaloids B Y GILBERTSTORK . . . . . . . . . . . . . Colchicine and Related Compounds BY W. C . WILDMAN. . . . . . . . Alkaloids of the Amaryllidaceae B Y W. C . WILDMAN . . . . . . . . .
1
31 35 123 145 179 219 247 289
Contents of Volume VII 10. The Indole Alkaloids BY J . E . SAXTON. . . . . . . . . . . . . . . . 11. The Eryrhrina Alkaloids BY V. BOEKELHEIDE . . . . . . . . . . . . . 12. winoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 13. The Quinazoline Alkaloids B Y H . T . OPENSHAW . . . . . . . . . . . . 14. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . .
1
201 229 247 253
C O N T E N T S OF P R E V I O U S V O L U M E S
CHAP^-ER 15. Steroid Alkaloids: The Holarrhena Group B Y 0 . JECERA N D V. PRELOG. 16. Steroid Alkaloids: The Solanum Group B Y V. PRELOGA N D 0. JEGER . . 17. Steroid Alkaloids: Verarrum Group B Y 0. JECERA N D V. PRELOC. . . . 18. The Ipecac Alkaloids B Y R . H . F. MANSKE. . . . . . . . . . . . . . 19. Isoquinoline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . . STANEK . . . . . . . . . 20. Phthalideisoquinoline Alkaloids B Y JAROSLAV 21. Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . . . 22. The Diterpenoid Alkaloids from Aconirum. Delphinium. and Garrya Species B Y E . S. STERN . . . . . . . . . . . . . . . . . . . . . . . . . 23 . The Lycopodium Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . 24 . Minor Alkaloids of Unknown Structure B Y R . H . F. MANSKE. . . . . .
...
Xlll
319 343 363 419 423 433 439 473 505
509
Contents of Volume VIII 1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11.
12. 13. 14. 15. 16. 17. 18. 19. 20 . 21 . 22 .
The Simple Bases BY J . E . SAXTON. . . . . . . . . . . . . . . . . Alkaloids of the Calabar Bean B Y E . COXWORTH . . . . . . . . . . . The Carboline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . The Quinazolinocarbolines B Y R . H . F. MANSKE . . . . . . . . . . . Alkaloids of Mirragyna and Ourouparia Species B Y J . E . SAXTON. . . . Alkaloids of Gelsemiurn Species B Y J . E . SAXTON. . . . . . . . . . . Alkaloids of Picralirna nitida B Y J . E . SAXTON . . . . . . . . . . . . Alkaloids of Alsronia Species B Y J . E . SAXTON . . . . . . . . . . . . The Iboga and Voacanga Alkaloids B Y W . I. TAYLOR . . . . . . . . . The Chemistry of the 2,2'-Indolylquinuclidine Alkaloids B Y W. I . TAYLOR The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids BY . . . . . . . . . . . . . . . . . . . . . . . . . . W . I . TAYLOR The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . Rauwolfia Alkaloids with Special Reference to the Chemistry of Reserpine B Y E . SCHLITTLER . . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Aspidosperma. Diplorrhyncus. Kopsia. Ochrosia. Pleiocarpa. and Related Genera BY B . GILBERT . . . . . . . . . . . . . Alkaloids of Calabash Curare and Strychnos Species B Y A . R . BATTERSBY A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Calycanthaceae BY R . H . F. MANSKE. . . . . . . . . Srrychnos Alkaloids B Y G . F. SMITH . . . . . . . . . . . . . . . . . Alkaloids of Haplophyton cimicidum B Y J . E . SAXTON. . . . . . . . . The Alkaloids of Geissospermum Species B Y R . H . F. MANSKE AND W . ASHLEYHARRISON. . . . . . . . . . . . . . . . . . . . . . Alkaloids ofPseudocinchona and Yohimbe B Y R . H . F. MANSKE . . . . The Ergot Alkaloids B Y S. STOLLA N D A . HOFMANN . . . . . . . . . The Ajmaline-Sarpagine Alkaloids B Y W . I . TAYLOR. . . . . . . . . .
1 27 47 55
59 93 119 159 203 238 250 272 287 336 515 581 592 673 679 694 726 789
Contents of Volume IX 1 . The Aporphine Alkaloids B Y MAURICE SHAMMA. . . . . . . . . . . 2 . The Proroberberine Alkaloids R Y P. W . JEFFS . . . . . . . . . . . . . 3 . Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€K. . . . . . . . .
1 41 117
xiv
CONTENTS OF PREVIOUS V O L U M E S
CHAP TER 4 . Bisbenzylisoquinoline and Related Alkaloids by M. CURCUMELLIRODOSTAMO A N D MARSHALL KULKA . . . . . . . . . . . . . . . 5 . Lupine Alkaloids BY FERDINAND BOHLMANN A N D DIETER SCHUMANN 6 . Quinoline Alkaloids Other than Those of Cinchona B Y H . T. OPENSH.AW 7 . The Tropane Alkaloids B Y G . FODOR. . . . . . . . . . . . . . . . . 8 . Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae B Y V. C E R NA ~N D F. SORM. . . . . . . . . . . . . . . . . . . . . . . 9 . The Steroid Alkaloids: The Salamandra Group B Y GERHARD HABERMEHL 10. Nuphur Alkaloids B Y J . T. WROBEL . . . . . . . . . . . . . . . . . 11. The Mesembrine Alkaloids B Y A . POPELAK A N D G . LETTENBAUER . . . 12. The Erythrina Alkaloids B Y RICHARD K . HILL . . . . . . . . . . . . 13 . Tylophora Alkaloids B Y T. R . GOVINDACHARI . . . . . . . . . . . . . 14. The Galbulimima Alkaloids B Y RITCHIEA N D W. C. TAYLOR. . . . . . IS. The Stemona Alkaloids B Y 0 . E . EDWARDS . . . . . . . . . . . . .
133 175 223 269 305 427 441 467 483 517 529 545
Contents of Volume X 1. Steroid Alkaloids: The Solanun Group BY KLAUSSCHRIEBER . . . . . . 2 . The Steroid Alkaloids: The Veratrum Group B Y S . MORRIS KUPCHAN A N D A R N O L D W . B.Y. . . . . . . . . . . . . . . . . . . . . . 3 . Erythrophleum Alkaloids BY ROBERT B. MORIN. . . . . . . . . . . . 4 . The Lycopodium Alkaloids BY D . B . MACLEAN. . . . . . . . . . . . 5 . Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . . . . . . 6. The Benzylisoquinoline Alkaloids B Y VENANCIO DEULOFEU, JORGE COMIN,A N D MARCELO J . VERNENGO. . . . . . . . . . . . . . . 7 . The Cularine Alkaloids B Y R . H . F . MANSKE. . . . . . . . . . . . . 8. Papaveraceae Alkaloids B Y R. H . F. MANSKE. . . . . . . . . . . . . 9 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . . . . 10. The Simple Indole Bases B Y J . E . SAXTON. . . . . . . . . . . . . . 11. Alkaloids of Picralima nitida B Y J . E . SAXTON . . . . . . . . . . . . 12. Alkaloids of Mitragyna and Ourouparia Species B Y J . E . SAXTON . . . . 13. Alkaloids Unclassified and of Unknown Structure B Y R . H . F . MANSKE . 14. The Tuxus Alkaloids B Y B. LYTHGOE . . . . . . . . . . . . . . . .
1
193 287 306 383 402 463 467 485 491 501 521 545 597
Contents of Volume XI 1. The Distribution of Indole Alkaloids in Plants
2. 3. 4. 5. 6. 7. 8. 9. 10.
B Y V. SNIECKUS . . . . . The Ajmaline-Sarpagine Alkaloids BY W. I. TAYLOR. . . . . . . . . . The 2.2‘-Indolylquinuclidine Alkaloids B Y W . I . TAYLOR. . . . . . . . The Zboga and Voacanga Alkaloids B Y W. I . TAYLOR. . . . . . . . . The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . The Eburnamine-Vincamine Alkaloids BY W. I . TAYLOR. . . . . . . . Yohimbine and Related Alkaloids B Y H . J . MONTEIRO. . . . . . . . . Alkaloids of Calabash Curare and Srrychnos Species B Y A . R . BATTERSBY A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Aspidosperma. Ochrosia. Pleiocarpa. Melodinus. and Related Genera B Y B . GILBERT . . . . . . . . . . . . . . . . . . The Amaryllidaceae Alkaloids B Y W. C . WILDMAN. . . . . . . . . .
1 41 73 79
99 125 145 189 205 307
C O N T E N T S O F PREVIOUS VOLUMES
CHAPTER 1 1 . Colchicine and Related Compounds B Y W. C . WILDMAN A N D B. A. RJRSEY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. The F'yridine Alkaloids B Y W. A . AVERA N D T. E . HABCOOD. . . . . .
xv
407 459
Contents of Volume XZZ The Diterpene Alkaloids: General Introduction B Y S . W. PELLETIER AND L . H . KEITH . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . Diterpene Alkaloids from Aconiturn. Delphinium. and Garrya Species: A N D L . H . KEITH . . The CIgDiterpene Alkaloids B Y S . W. PELLETIER 2. Diterpene Alkaloids from Aconitum. Delphinium. and Garrya Species: A N D L . H . KEITH . . The C2,,- Diterpene Alkaloids B Y S . W. PELLETIER 3 . Alkaloids of Alstonia Species B Y J . E . SAXTON . . . . . . . . . . . . 4 . Senecio Alkaloids B Y F R A N K L . WARREN. . . . . . . . . . . . . . . 5 . Papaveraceae Alkaloids B Y F . SANTAVY. . . . . . . . . . . . . . . 6 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE . 7 . The Forensic Chemistry of Alkaloids B Y E . G . C . CLARKE. . . . . . .
xv
2 136 207 246 333 455 514
Contents of Volume XZI1 1 . The Morphine Alkaloids BY K . W. BENTLEY . . . . . . . . . . . . . 2 . The Spirobenzylisoquinoline Alkaloids B Y MAURICE SHAMMA . . . . . . 3 . The Ipecac Alkaloids B Y A . BROSSI.S . TEITEL.A N D G . V. PARRY . . . 4 . Alkaloids of the Calabar Bean B Y B . ROBINSON. . . . . . . . . . . . 5 . TheGalbulimima Alkaloids B Y E . RITCHIEA N D W. C . TAYLOR. . . . . 6. The Carbazole Alkaloids B Y R . S . KAPIL . . . . . . . . . . . . . . . 7 . Bisbenzylisoquinoline and Related Alkaloids B Y M . CURCUMELLI. . . . . . . . . . . . . . . . . . . . . . . . . . . RODOSTAMO 8 . The Tropane Alkaloids B Y G . FODOR . . . . . . . . . . . . . . . . . 9 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE .
1 165 189 213 227 273
303 351 397
Contents of Volume XZV 1 . Steroid Alkaloids: The Veratrum and Buxus Groups B Y J . TOMKOA N D . VOTlCKf' . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Oxindole Alkaloids BY JASJITS. BINDRA . . . . . . . . . . . . . . . 3 . Alkaloids of Mitragyna and Related Genera BY J . E . SAXTON. . . . . . 4 . Alkaloids of Picralima and Alstonia Species B Y J . E . SAXTON . . . . . 5 . The Cinchona Alkaloids BY M . R . USKOKOVIC A N D G . GRETHE. . . . . 6 . The Oxaporphine Alkaloids B Y MAURICE S H A M MA A N D R. L . CASTENSON. . . . . . . . . . . . . . . . . . . . . . . . . . . 7 . Phenethylisoquinoline Alkaloids BY TETSUJIKAMETANI A N D MASUO KOIZUMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 . Elaeocarpus Alkaloids B Y S . R . JOHNSA N D J . A . LAMBERTON. . . . . 9 . The Lycopodium Alkaloids B Y D . B . MACLEAN. . . . . . . . . . . . 10. The Cancentrine Alkaloids B Y RUSSELL RODRIGO . . . . . . . . . . . 1 1 . The Securinega Alkaloids B Y V. SNIECKUS. . . . . . . . . . . . . . 12. Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE .
1 83 123 157 181
225 265 325 347 407 425
507
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CONTENTS OF P R E V I O U S VOLUMES
Contents of Volume XV CHAPTER 1. The Ergot Alkaloids B Y P. A. STADLER A N D P. STUTZ . . . . . , . . . 2. The Daphniphyllum Alkaloids B Y SHOSUKE YAMAMURA A N D YOSHIMASA HIRATA . . . . . . . . . . . . . . . . . . . . . . . . , . 3. The Amaryllidaceae Alkaloids B Y CLAUDIO FUCANTI . . , . . , . . . 4. The Cyclopeptide Alkaloids B Y R. TSCHESCHE A N D E. U. K A U B M A N. N. 5 . The Pharmacology and Toxicology of the Papaveraceae Alkaloids B Y V. FREININGER . . . . . . . . . . . . . . . . . . . . . . . , . . , 6. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE .
1 41 83 165
207 263
Contents of Volume XVI 1. 2. 3. 4. 5. 6.
7. 8. 9.
Plant Systematics and Alkaloids B Y DAVIDS. SIEGLER. . . . . . , . , The Tropane Alkaloids B Y ROBERTL. CLARKE . . . . . . . . . . . . Nuphar Alkaloids B Y JERZYT. WR6BEL . . . . . . . . . . . . . . . The Celestraceae Alkaloids B Y ROGERM. SMITH . . . . . . . . . . . The Bisbenzylisoquinoline Alkaloids-Occurrence, Structure, and Pharmacology BY M. P. CAVA,K. T. BUCK,A N D K. L. STUART. . . . . Synthesis of Bisbenzylisoquinoline Alkaloids B Y MAURICE SHAMMA A N D VASSILST. GEORGIEV, , . . . . . . . . . . . . , , . , , . The Hasubanan Alkaloids B Y YASUOINUBUSHI A N D TOSHIRO I B U K A. , The Monoterpene Alkaloids B Y GEOFFREY A. CORDELL . . . . . . . . Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE .
1
83 181 215 249 319 393 43 1 511
Contents of Volume XVZI 1.
2. 3. 4. 5.
The Structure and Synthesis of C,,Diterpenoid Alkaloids B Y S. WILLIAM PELLETIER A N D NARESH V. MODY . . . . . . . . , Quinoline Alkaloids Related to Anthranilic Acid BY M. F. GRUNDON , . The Aspidospmrna Alkaloids BY GEOFFREY A. CORDELL. . . . . . . , Papaveraceae Alkaloids, I1 B Y F. S A N T ~ V. ) . . . . . . . . . . . . . Monoterpene Alkaloid Glycosides B Y R. S. KAPILA N D R. T. BROWN . ,
1
105 199 385 545
-CHAPTER
1-
ER YTHRINA AND RELATED ALKALOIDS S. F. DYKE*AND S. N. QUESSY~ School o/Chei?iisfry.The Uniuersitj. of Bath. Bath, A t o i l , Encqland
I. Introduction . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . , , , . . . . . , 11. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................... B. Isolation and Detection . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . , . . . . . . . . . . , . . . . . . . . IV. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Structure Determination . . . . . . ...... . .. ... . .. V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . , , . . . . . . . . , . VI. ..... ...... ..... .. ..... . ..... .............................................. B. Homoerythrina Alkaloids . . . . _ . _ . . _ . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . .............. ............. V11. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1
2 2 6
1 21 21 30 31 42 42 45 51 51 58 59 61 61 12 16 91 93
1. Introduction The last review in this series (1)covered the literature to the end of October, 1966. At that time 10 Erythrina alkaloids were known, and the structures and stereochemistries of most of them had been established. The total synthesis of erysotrine had been described by Mondon’s group in a preliminary communication (2),but nothing was known about the biosynthesis of these alkaloids, although some speculations had been reported. * Present address: Department of Chemistry. Queensland Institute of Technology, Brisbane. Queensland, Australia. ’ CSIRO postdoctoral fellow, 1979. Present addrcss: Research and Dcvclopment Department. Riker Laboratories, Thornleigh, New South Wales, Australia. THE ALKALOIDS. VOL. X V l l l Copyright @ I Y 8 1 by Academic Press. Inc. All rights of reproduction an any rorin reserved.
ISBN 0-12-469SlR-3
2
S . F. DYKE AND S. N. QUESSY
Frc;. 1. The structures and accepted numbering system for A : 1,6-diene skeleton and B : A1(6)-alkene skeleton.
In the intervening 13 years the subject has expanded dramatically; over 60 compounds are now classified as Erythrina alkaloids, and the structures of most of these have been deduced from a combination of mass spectral fragmentation analysis, H-NMR spectral interpretations, and chemical correlations with alkaloids of known structures. Some ‘‘unusual’’ alkaloids have been obtained from certain Cocculus species and a new, as yet small, subgroup, the Homoerythrina alkaloids, has been recognized. The biosynthetic pathway from tyrosine through the aromatic bases to the erythroidines has been elucidated, and some significant advances have been made in methods of total synthesis. Reviews of the Erythrina alkaloids since 1966 have appeared (3-6). Because of the postulated biosynthetic derivation of the Cephalotaxus alkaloids from the Homoerythrina bases, the former, relatively new group is included in this chapter. Anticancer activity has been found in certain members of the Cephalotaxus group, so the subject has already been reviewed several times (7-9). Annual coverage is given to the Erythrina, Homoerythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports of the Chemical Society (20-ZZa). The Erythrina alkaloids are conveniently divided into two main structural groups: the 1,6-diene group and the A1(6)-alkene group (see Fig. 1). The biogenetically important alkaloid erysodienone cannot be classified in this way. The present chapter covers the literature from November 1966 to the end of May 1979. 11. Evythvitza Alkaloids
A. OCCURRENCE There are now over 60 Erythrina alkaloids of known structure 1-61 (see Figs. 2-4) and several more, the structures of which are yet to bz assigned (12). The alkaloids occur in species of Erythrina (Leguminosae), a genus of wide distribution in tropical parts of the world, and in species of Cocculus
R'
1
2 3 4 5 6 7 8 9 10
11 12 13 14 1s* 16 17*
Erysotrine Erysotramidine Erythravine Erythraline Erysovine Erysoline Erysodine Erysonine Erysopine Erysothiovine Glucoerysodine Eryso thiopine Erysophorine Coccuvinine Coccolinine Coccuvine Coccoline
CH30 CH,O CH30 -OCH2CH30 CH,O HO HO HO CH30 h U
CH30 H H H H
R2
R3
X
2H 0 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 0 0 0
FIG.2. Erj,llrrina alkaloids: 1,6-diene series. a : H0,CCH2S0,-,
R' 18 19 20 21 22 23 24 25 26 27 28 29 30 31
Erythrartine Erythristemine Erythrascine Erythrinine 1 I -Methoxyerythraline 1 I-Oxoerythraline I I-Hydroxyerysovine I I-Methoxyerysovine 1 I-Oxoerysovine 1 I-Hydroxyerysodine 1 I-Methoxyerysodine 1 I-Oxoerysodine I I-Methuxyerysopine 1 1-0xoerysopine
CH, CH, CH 3
R2
R3
CH3 CH 3 CH,
OH OCH OAc OH OCH -0 OH OCH, -0 OH OCH, -0
-CH,-~-CH, CH, ~~
CH, CH, CH, H H H H H
H H H CH.3 CH 3 CH, H H
,
0ch3 -0
b : I-/~-glucosyl,c: hypaphorine ester, d : alkaloid is possible artifact.
R1orJp
4
S. F. DYKE AND S. N. QUESSY
-
RZO
" ' oR
CH,O"
CH,O' R'
32" 33" 34* 35*
Erythrabine Crystamidine 10,ll-Dehydroerysovine 10,ll-Dehydroerysodine
R2
X
36 Isococculidine R
CH, CH, -CH2CH, H H CH,
0 0 2H 2H
37 Isococculine R = H
* means an alkaloid is a possible artifact.
X R' 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
Dihydroerysotrine Erythratidine Erythratidinone Erythramine Erythratine Erythratinone Dihydroerysovine Erysosalvine Erysosalvinone Dihydroerysodine Erysotine Eryso tinone Erysopitine Erysoflorinone Coccutrine Erythroculine Cocculidine
H H H H H H H H H H H H H H CH,O H H
R2
R3
CH,O CH,O CH,O CH,O CH,O CH,O -OCH,O-OCH20-OCH,OCH,O HO CH,O HO CH,O HO HO CH,O HO CH,O HO CH,O HO HO HO HO H OH CH,O CH,O,C H CH ,O
FIG.3 . Erythrinu alkaloids: Al(6) alkene series.
X H OH =O H OH =O H OH =O H OH =O OH =O H H H
= CH,
1.
E R Y T H R I N A AND RELATED ALKALOIDS
5
CH,O
CH 3
0
0
0
57 3-Demethoxyerythratidinone
59 r-Erythroidine
58 Erysodienone
60 [I-Erythroidine
61 Cocculolidine
FIG.4. Erythrina alkaloids: miscellaneous
(Menispermaceae), a genus of more limited distribution in tropical areas (13). A conspectus of the genus Erythrina was published by Krukoff who listed 108 species and 9 hybrids (14), and over half of these have been examined for their alkaloidal content. Attention must be drawn to the fact that Krukoff has reclassified several species. Notably, E. lithosperma has been subdivided such that E. lithosperma Blume is now a synonym for E. variegata L., wherer.5 E. lithosperma Miguel is a synonym for E. subumbrans Merril. In addition, E. orientalis, E. variegata uar. orientalis, and E. indica are synonyms for E. variegata L. (14).This reclassification has resulted in some misleading claims and doubtful identifications in the literature (15). Most studies have concentrated on examination of the seeds, which typically contain 0.1% alkaloids, although alkaloids have been isolated from the leaves, stalks, stems, bark, roots, pods, and flowers of Erythrina species. An extensive survey of Erythrina species has been made by two groups using combined GC-MS; Rinehart and co-workers at Illinois have examined American species (15, 16) and Jackson and co-workers at Cardiff examined old world species (12, 17). Other major investigations have been carried out by Barton and co-workers (18-21), by Ito and co-workers in Japan (22-32), and by Ghosal and co-workers (33-37), and Singh and Chawla in India (38-41). From the results of these studies it is apparent that individual species are often distinctive in their alkaloid profile, although the sections and subgenera are not clearly marked. Several patterns do emerge, however. Erysovine (5)and erysodine (7) are ubiquitous, although
6
S. F. DYKE AND S. N. QUESSY
they do not occur in all parts of each plant (12, 15-17); the sections Breviflora and Edules are low in alkaloid but high in amino acid content (13,42); the major alkaloids of E. folkersii are of the 1,6-diene type whereas those of E. salvizjlora are of the l(6)-alkene type ( 1 5 ) ; the American species do not contain 1 1-oxygenated alkaloids and presumably lack the capacity to hydroxylate ring C (12, 21). However, Ito has reported the isolation of erythrinine (21) from E. crysta galli L., an American species (30). The hybrid species E. x bidwillii elaborated two new alkaloids, erythrinine (21) (24, 25) and the dibenzo[e,f]azonine base erybidine (62), (23, 26) which had not been found in the parent species E. crysta galli and E. herbacea (13). Erythrinine has since been isolated from E. crysta galli (30) and erybidine has been isolated from several other Erythrina species (12, 27, 30,31). Although the alkaloidal profile of Erythrina species is often characteristic, there is considerable quantitative variation in different samples (17). Differences have been noted in the content of the bark, seed, and leaves of the plant (33, 35, 43, 4 4 , and some striking variations have been reported. In their GC-MS examination of E. folkersii, Rinehart’s group (15) failed to detect erythraline (4),which had been reported in an earlier study of this plant (45),although 4 could be detected in other species (16).Ghosal et al. reported erysotrine (1) to be the major component by far in the bark of E. variegata var. orientalis, with only minor amounts of 5 present (33), whereas Singh et al. (41) in a more recent investigation reported only 5 from the bark of the same species. Whereas some of the variation may result from the location of the plant or its age at harvest, there is some evidence for chemical variants within species. Barton et al. (21)reported a thorned variety of E. lithosperma Blume (E. variegata L.) that contained only erysotrine and a smooth variety that contained 1 along with erythratidinone (40), 3-demethoxyerythratidinone (57), and traces of erythraline (4).Letcher referred to two varieties of E. lysistemon harvested in Southern Rhodesia which contained either 1 or 1 1-methoxyerythraline (22) but not both. Although erythristemine (19) had been isolated from E. lystistemon from South Africa none was found in the varieties from Southern Rhodesia, and no change in the nonpolar alkaloids present in the leaves could be detected over a period of four months. It was therefore suggested that there are at least three chemical variants of E. lysistemon (46). B. ISOLATION AND DETECTION
The procedure of Folkers, where the ground plant material is extracted with hexane to remove fats, is widely used; but Rinehart and co-workers (16) pointed out that a significant quantity of alkaloid could be detected
1.
ERYTHRI.VA AND RELATED ALKALOIDS
7
by GC-MS analysis of the hexane fraction, so that earlier examinations where this fraction was discarded must be regarded as incomplete. Alcoholic extraction of the remaining marc gave the “free” alkaloids, whereas acid hydrolysis gave rise to the liberated alkaloids (usually the largest fraction). Ghosal(35) has described a detailed flow chart for the isolation of a variety of alkaloids from E. variegata. The greatest advance in the isolation and identification of Erythrina alkaloids has come from the powerful combination of GC-MS, which has provided a methodology for comprehensive taxonomic investigation of the whole genus. Its value derives from the facile identification of the alkaloids from their fragmentation patterns, the speed and accuracy of the method, the avoidance of large-scale extraction and chromatography, and the requirement of only milligram quantities of crude alkaloid extract. The power of the technique has been demonstrated by the number of new alkaloids detected and the number of species investigated using it (12, 15, 16). There are rarely more than eight alkaloids present in a species, and the possibility of the same GC retention time is not normally a problem. In cases where overlap has been observed it has proved possible to identify both components from the mass spectrum of the mixture. The crude alkaloid extracts are treated with trimethylsilyldiethylamine to form volatile TMS derivatives of the hydroxylated components. The presence of a free phenolic or hydroxyl group is then detected by an ion with mje 73 [(CH,),Si+]. Positional isomers [e.g., erysovine (5) and erysodine (7)] are resolved although u- and 8-erythroidine are not. The presence of perythroidine (60) can be estimated since it shows some enol content under the silylation conditions and gives rise to a monotrimisyl derivative with m/e 345 (15). As a supplement to electron impact MS, field ionization MS, which allows identification of the alkaloids by their molecular formula, has been introduced (47). The combination of HPLC-field desorption MS, which utilizes the greater resolving power of HPLC over GC, has been applied; and the presence of alkaloids not detected by GC-MS was revealed in one case (12). Various other alkaloids have been found concurrently with the Erythrina group. Hypaphorine is by far the most common, but choline, N-nororientaline, and erybidine (62) are not uncommon.
DETERMINATION C. STRUCTURE I . X-Ray Crystal Structures and Absolute Stereochemistry The absolute stereochemistry of the aromatic Erythrina alkaloids has been determined. An X-ray analysis of the 2-bromo-4,6-dinitrophenolate
8
S. F. DYKE AND S. N. QUESSY
salt of erythristemine confirmed the assumption that the 3R,5S configuration of the erythroidines exists in the aromatic group. This result also confirms the common biosynthetic origin of the two types. The configuration of the methoxyl group at C-11 was found to be S. The use of 2-bromo4,6-dinitrophenol for the preparation of a heavy-atom derivative was novel and may be applicable in other cases (20,48). The absolute stereochemistry of the A1(6)-alkene alkaloids cocculine (56) and coccutrine (52) has also been established by X-ray analysis. It was found that the cyclohexene ring A exists preferentially in an approximate half-chair conformation in the free base, but this was altered to an envelope conformation on protonation of the nitrogen atom (49). R I
CH,O'19 Erythristemine
56 R = H Cocculine 52 R = CH,O Coccutrine
The crystal structures of the alkaloids containing a hydroxyl group at C-2 have not been determined. The stereochemistry of erythratine (42) was established as 2R,3R,5S by Barton et al. (19) and that of erythratidine (39) as 2S,3R,5S by the same group (21)on the basis of optical rotation and N MR data for both pairs of C-2 epimers (see Section II,C,4b). The configuration at C-2 for erysosalvine (45), erysotine (48), and erysopitine (50) has not been defined. The absolute stereochemistry of other alkaloids rests on comparison of their CD and NMR characteristics with those of alkaloids of known stereochemistry as well as on chemical interconversions. 2. Spectral Characteristics a. Infrared and UV Spectra. The 1,6-diene alkaloids show IR absorbances a t 1610 cm-' and UV absorbances around 285 (dioxygenated aromatic ring) and 230-235 nm (diene). The 8-0~0-1,6-dienegroup exhibits a lactam absorbance at 1665 cm-' and an additional UV absorbance at 256 nm arising from the dienone chromophore (21). The Al(6)-alkene group absorb in the UV around 225 nm, whereas the enone group usually shows UV absorbance around 230 nm and IR absorbance in the region of 1675-1698 cm-'. Erysodienone (58) exhibits UV
1.
E R Y ? . H R / N A AND RELATED ALKALOIDS
9
absorbances at 240-242 and 285nm and IR bands at 1672, 1655, and 1614 cm-' (34). b. Circular Dichroism. The 1,6-diene alkaloids exhibit strong positive Cotton effects and previous attempts to relate this to the absolute configuration, using diene rules, have led to assignments of configuration opposite to that found by X-ray analysis. An explanation for the failure of the diene rules for Erythrina and other systems has been advanced. The allylic methoxyl system (at C-3) has helical chirality opposite to that of the diene chromophore, and it appears that the sign of the diene Cotton effect is determined by the former group (50). Members of the A1(6)-alkene group also show a positive Cotton effect, and this was used to assign the absolute configuration of cocculine (56) and cocculidine (54), later supported by X-ray analysis (51, 52). c. Mass Spectrometric Characteristics. Because of the heavy reliance on MS identification of Erythrina alkaloids, several studies of their fragmentation patterns have been made. A comprehensive analysis of the fragmentations of erythrinanes was described by Migron and Bergmann (53)but is not discussed here. The MS of a variety of Erythrina alkaloids were studied by Boar and Widdowson (54) who proposed fragmentation schemes based on the usual techniques of accurate mass measurement of major ions and on metastable analysis. Further elaboration was made through the use of deuterium-labeled samples. Only the general MS features will be discussed here, as several detailed schemes can be found in the literature (15, 21, 54). All the 1,6-diene structures show a simple fragmentation pattern, summarized in Scheme 1. The main pathway involves loss of the allylic substituent at C-3 which allows distinction between the isomeric groups. For example, erythravine (3) can be distinguished from erysovine (5) and erysodine (7) by the nature of RO. However, distinction between pairs isomeric in ring D, that is, between 5 and 7 or between 6 and 8, cannot be made by MS alone.
+ m 2m~ ~ .c trj CY l+.
IcJn71+. RO
SCHEME I . Mujor
RO
M S ~ f r a g i ~ ~ c ~ t ~ tpatterii u t i o r i fhr
1.h-drene srries (R = H,CH, or TMS)
The A1(6)-alkene alkaloids show a more complex fragmentation pattern in which loss of the allylic substituent is of only minor importance. A major
10
S. F. DYKE AND S. N. QUESSY
fragmentation pathway involves a retro-Diels-Alder reaction (path a in Scheme 2), and an alternative pathway involves loss of the C-2-C-3 unit (path b in Scheme 2). Each ion subsequently loses a hydrogen atom. The nature of the substituent at C-3 is readily established from path a and for all known Al(6)-alkene types is methoxyl. The substituent at C-2 is then defined by M + -C3H,0R, where R is usually H or OH (15, 16, 54). Distinction between A1(6)-alkene types and the isomeric A2( I)-alkene types [e.g., isococculine (37)] can be made by MS. For example, 37 exhibits a fragmentation pattern similar to the l ,6-diene types.
/ -C,I!,O
q7’+
\b -C,H ,OR\
//
HC SCHEME 2. Mujor M S Jkugmentutionpatiern for A1(6)-aNceneseries (R = H or OH)
The enone alkaloids, such as erythratidinone (40), do not undergo fragmentation by path b in Scheme 2, but exhibit loss of CO as shown in Scheme 3 (21, 54). Alkaloids containing 1 I-hydroxyl or 11-methoxyl groups show additional ions arising from loss of H,O or CH30H, respectively, from the
C * , O V
C
0
I1
0
CHO SCHEME
3. Frugmenmthn puirern .for enone f?‘pes
1.
ER YTHRIiVA A N D RELATED ALKALOIDS
11
parent ion (12, 20, 22, 46). The 1 1-oxoalkaloids show a characteristic fragmentation ion resulting from cleavage at ring C. For example, the TMS derivative of 11-oxoerysodine (29) exhibits a characteristic ion with m/e 222 (12)(see Scheme 4).
SCHEME 4
d. NMR Characteristics. Once the erythrinane skeleton is established, it is possible to deduce the complete structure from detailed NMR data with the aid of decoupling, NOE, and INDOR techniques. Assignments of stereochemistry at C-2, C-3, and C-11 have been made from the values of coupling constants by comparison with data from related alkaloids in the group, for which crystal structures have been determined (19-21,43,55-58). In a review of the NMR of the alkaloids (59) coverage is given to the Erythrina group. Protons attached to C-14 and C-17 in the aromatic ring can be readily distinguished. Irradiation in the benzylic region causes a sharpening in the signal due to H-17 (19),whereas irradiation of the axial C-3 proton produces about 15% NOE for the signal due to H-14 (57). The NOE effect arises because H-14 lies over ring A and spatially near the axial C-3 proton. The INDOR technique can also be used to locate H-14 (58). Combinations of these techniques have been used to determine the position of substituents in the aromatic ring (43,56-58). For example, dihydroerysovine (44)was found to contain methoxyl and hydroxyl groups at C-15 and C-16, and their relative positions were determined by NMR. The resonance for the proton at C-14 (6 6.99) was located by INDOR and confirmed by NOE. When the other aromatic proton (6 6.30) was monitored a NOE and decoupling effect was observed at the aromatic methoxyl signal (6 3.27), but this effect was not observed when the C-14 proton was monitored. This established that the methoxyl group was near C-17, i.e., at C-16 (57). The usefulness of the technique has also been demonstrated with cocculidine (54), which is of firmly established structure (60).The position of the aromatic methoxyl group could be established using INDOR by monitoring each aromatic proton in turn. It was found that the aromatic proton (6 6.93) with J value of 2.5 Hz was spatially near the C-3 axial proton,
12
S. F. DYKE AND S. N. QUESSY
hence the methoxyl group was at C- 15 (58).This was supported by synthesis of the alternative C-16 methoxyl isomer (63) and comparison of its NMR spectrum using INDOR and NOE techniques (58).
HO
44 Dihydroerysovine
54 R' 63 R'
= =
H , R Z = CH,O Cocculidine CH,O, RZ = H
The stereochemistry at C-3 in the 1,6-diene series can be determined from the value of J 2 , 3 . In all cases this value is small, about 2 Hz, suggesting that the proton at C-3 is quasi-axial and hence that the methoxyl group is equatorial. This assignment is supported by the observation of diaxial couplings (J3ax,4ax z 10 Hz) between protons at C-3 and C-4 (19-21,55, 56). The stereochemistries at C-2 and C-3 in erythratine (42) and erythratidine (39) were established partly by NMR (19, 21). With the aid of INDOR the value of J3,4was found to be 5.5 and 12 Hz for both alkaloids, suggesting that the C-3 proton was axial in both cases, This was supported by interconversion studies (see Section II,C,4b). In erythratine (42) the value of was found to be 7.5 Hz and in its C-2 epimer 3-4 Hz. This suggested stereochemistries A and B, respectively (as shown in Fig. 5), for erythratine and its C-2 epimer. The values off,,, (4.25 Hz) and 52,3(4.25 Hz) in erythratidine (39) suggested that the proton at C-2 is equatorial and that the stereochemistry is that of B in Fig. 5. Thus, 42 and 39 have opposite stereochemistry at C-2. The position of the extra methoxyl group in erythristemine (19) was established at C-11 when it was found that irradiation of the proton at C-17 caused slight narrowing of the methine signal at 6 3.94. The shift of this
OH A
B
FIG.5 . Stereochemistries in ring A
1.
ER YTH-HRINA A N D RELATED ALKALOIDS
13
methine suggested an attached methoxyl group, thus identifying the methoxyl group at C-l 1. This was confirmed by X-ray analysis, which also gave the absolute configuration. The value of J,,,, (4 Hz) was found with the aid of INDOR since the methoxyl signals partly obscured the methine signal. The stereochemistry at C-1 1 in the other 11-oxygenated alkaloids have been related to erythristemine by comparison of the value J,,,,,, which all lie around 4 Hz, suggesting the same configuration at C- 11 (43).
,
3. 1,6-Diene Series
a. Simple Types. Resolution of the final ambiguities in the structures of erysodine (7), erysovine (5), and erysonine (8) was discussed in the previous review (1)of this treatise on the basis of a preliminary communication (18). The complete details of this work have now been published (19). Erysotrine (l),long known only as a synthetic product, was isolated from E. suberosa Roxb. in 1969 (38,39) and has since been identified in a large number of Erythrina species (12, 16, 17, 31, 33, 44). An investigation of E. folkersii by Krukoff and Moldenke by GC-MS (15) revealed the existence of two new 1,6-diene alkaloids erythravine (C,,H,,NO,) and erysoline (C,,H,,NO,). Erythravine was identified as 3-desmethylerysotrine (3) from its MS fragmentation pattern. Erysoline appeared to bear a similar relationship to either 5 or 7. Demethylation of samples of both 5 and 7 resulted in the identification of erysoline with 3-desmethylerysovine (6) (see Scheme 5), from GC retention time and spectroscopic comparisons. R'O
R20
CH,O"
5 R' 7 R'
= CH,, = H,
R2 = H Erysovine
R Z = CH, Erysodine
HO' 6 R' 8 R'
= CH,, = H,
R2 = H Erysoline R 2 = CH, Erysonine
SCHEME 5
Erysophorine (13)was isolated from the water-soluble extract of the seeds of E. arborescens Roxb. (37). The molecular formula C,,H,8N,0,C1 was established by analysis. The mass spectrum of 13 gave no molecular ion but exhibited fragments consistent with a 1,6-diene Erythrina alkaloid and a carboxylated indole-3-alkylamine. Erysophorine appeared to be a combined alkaloid, and its UV spectrum was similar to that of an equimolar mixture
14
S. F. DYKE AND S. N. QUESSY
13 R = Hypaphorine
64 Hypaphorine
of 5 and hypaphorine (64). The presence of three quaternary N-methyl groups and two methoxyl groups was evident from the NMR spectrum. Hydrolysis of 13 in dilute hydrochloric acid proceeded readily affording 5 and 64, and erysophorine was deduced to be erysovine linked by esterification at C-15 to hypaphorine. This was the first example of a phenolic Erytkrinu alkaloid esterified to an acid other than sulfoacetic or hexuronic acids. Recently, another combined alkaloid has been isolated, this time from the seeds of E. oariegata L. (43).Hydrolysis of the alkaloid yielded 7 ; and since 64 was also positively identified in the extracts, it is possible that this alkaloid could be the complementary positional isomer of erysophorine. b. 8-0x0Types. Ito's group isolated two new alkaloids, erythrabine (C,,H,,NO,) (32)and erysotramidine (C,,HzlNO4) (2), from E. arborescens Roxb., which were both of higher oxidation level than the 1,6-diene types (27,28).The structures were assigned on the basis of spectroscopic and chemical investigations. Later, a similar alkaloid, crystamidine (C, *HI,NO,), was isolated from E. crysta galli L.; and MS data indicated an alkaloid of the 1,6-diene type. The NMR spectroscopic data established the presence of a methylenedioxy group, a methoxyl group, and two para-oriented aromatic protons. The UV and IR data suggested a heteroannular conjugated system, and the carbonyl group ( v ,,,1695 cm-I) was placed at C-8 after detailed examination of the NMR spectrum. The structure of crystamidine (33)was proved by correlation with erythraline (4), (see Scheme 6). Catalytic reduction of 33 gave a product (65) identical to that obtained by oxidation
33 Crqstdmidinr
65
SCHEME 6
4 Erjthralme
1.
E R Y T H R I N A A N D RELATED ALKALOIDS
15
of 4 with potassium permanganate, followed by catalytic reduction (32).This also established the stereochemistry at C-5 and C-3 in crystamidine. Two other 8-0x0 derivatives [coccoline (17) and coccolinine (15)] have been isolated from Cocculus species, and these are discussed separately later (see Section 11,C,5). It has been recognized that, since oxidation at C-8 is relatively facile, the 8-0x0 derivatives are probably artifacts produced in the drying process (55). Both 10,ll-dehydroerysovine (34) and 10,lldehydroerysodine (35), which have been detected in GC-MS studies, are thought to be artifacts produced by an elimination reaction from 11-methoxyor 11-hydroxyalkaloids (12).
c. C-11 Oxygenated Types. The first Erythrina alkaloid with oxygenation at C-11 was isolated from E. lysistemon Hutchinson and given the name erythristemine (20). The molecular formula C,oH25N04was established by analysis and confirmed by high resolution MS. The IR spectrum showed no hydroxyl nor carbonyl absorbances and the UV spectrum was almost identical to that of erythraline 4. The MS data were consistent with a 1,6-diene structure containing an additional methoxyl group in ring C or D. Careful examination of the NMR spectrum with the aid of INDOR (see Section II,C,2d) suggested that the methoxyl group was at C-11. Structure 19 was proposed and confirmed by X-ray analysis of the 2-bromo-4,6dinitrophenolate salt (20,48),which also established the complete stereochemistry shown in structure 19.
19 Erythristemine
A little later 11-methoxyerythraline (22), isolated as a pale yellow gum, was obtained from the same species (46).The spectroscopic properties of 22 were similar to those of erythristemine except that a methylenedioxy group was present instead of the two aromatic methoxyl groups in 19. The NMR spectrum of 22 could be interpreted completely without the necessity of INDOR, as the signals did not obscure one another. The coupling data were consistent with H-3 being quasi-axial, as in 19. At about the same time, Ito et al. (22) reported the isolation of an alkaloid C,,HIgNO4 from E. indica Lam. (now classified as E. variegata L.) to which
16
S. F. DYKE AND S. N. QUESSY
they gave the name erythrinine. The IR spectrum showed a hydroxyl function, which was further demonstrated by the preparation of an 0-acetate, and the UV and MS data suggested a 1,6-diene structure. Catalytic reduction of erythrinine followed by hydrogenolysis over Palladium black in aqueous hydrobromic acid gave tetrahydroerythraline (66) (see Scheme 7). This established the basic structure and the stereochemistry at C-5 and C-3. The hydroxyl group was placed at C-1 1 because of the ease of hydrogenolysis, and since oxidation gave a ketone in conjugation with the aromatic ring (vmaX1680 cm- I ) . Therefore, structure 21 was established for erythrinine although the configuration at C-1 1 was not determined. Erythrinine has since been isolated from E. x bidwillii (24, 25), E. crysta galli (30, 32), Eryrhrina species from Singapore (31),and old world species (12). OH (iJPtO,-H,
(ii) P d ~H , HBr ,
21 Erythrinine
66 Tetrahydroerythraline
SCHEME I
The name erythrinine had been assigned to an alkaloid isolated in 1969 from E. lithosperma (61). The formula for this alkaloid was found to be C30H,,N,0,, and little structural information was known except that it contained four methoxyl groups and one amide function and that all four nitrogen atoms were present in rings. No further elaboration of the structure has been reported. Erythrascine (C,,H,,NO,) was isolated from the seeds of E. arborescens Roxb. collected in India (36).The MS fragmentation pattern was typical of a 1,6-diene type, and the IR spectrum exhibited an absorbance at 1728 cmwith no hydroxyl absorption. The MS and NMR spectroscopic data were consistent with erythrascine being 11-acetoxyerysotrine (20). Soon afterwards the Japanese group reported the isolation of 1 I-hydroxyerysotrine (CI9Hz3NO,)from the seeds of the same species (27). Structure 18 was established from spectroscopic and chemical correlation studies. It is not clear whether both alkaloids 18 and 20 are natural products, since the possibility that erythrascine was an artifact was not discussed and since no other 11-acetoxyalkaloids have been reported. Further studies by Ito and co-workers (31) have resulted in the isolation of erythrinine (21) and 11hydroxyerysotrine (18) from other Erythrina species. Recently, examination
1.
E K Y T H R I . Y A A N D RELATED ALKALOIDS
17
CH,O’ 20 R 18 R
= CH,CO Erythrascine = H ll-Hyroxyerysotrine
(erythrartine)
of the flowers of E. uariegata L. collected in Egypt resulted in the isolation of an alkaloid (CI9H,,NO,) to which the name erythrartine was given. Erythrartine was deduced to be 1l-hydroxyerysotrine (18) on spectroscopic evidence (43).The authors were unable to compare their sample with that reported by the Japanese group. The statement that 18 is the first example of an ll-oxygenated Erythrina alkaloid from E. variegata (43) is incorrect since erythrinine (21) was isolated by Ito et al. in 1970 from E. indica Lam (22),a synonym for E. variegata L. (14). It has been suggested (43) that the absolute configurations of the 11oxyerythrina alkaloids 18, 20, 21, and 22 are the same as that of erythristemine (19), that is llj? (or 1lS), on the basis of correlation of optical rotations and since the value of J,,,,, is the same. Examination of old world Erytlzrina species by GC-MS has revealed the existence of a larger variety of 1 1-oxygenated alkaloids 23-31 (see Fig. 2), including examples with 1I-0x0 functions. The assignment of the structures of these compounds rests entirely on MS evidence (12)(see Section II,C,2c). 4. A1(6)-Alkene Series a. Without C-2 Oxygenation. Dihydroerysovine (44) and dihydroerysodine (47) have been isolated from Cocculus species (see Section II,C,5), although dihydroerysotrine (38) is still known only as a reduction product of erysotrine (1). Erythramine (47), previously known as a reduction product of erythraline (4) (62).was detected in E. crysta galli and in E. glauca Willd. (now classified as E. fusca Loureiro) (19). Since there was insufficient sample isolated, erythramine was prepared from erythraline and its structure established by NMR. In addition, erythramine was prepared by an alternative route from erythratine (42) (see Scheme 8) by chlorination and reduction. Since 42 could also be converted to erythraline (19),an alkaloid of known stereochemistry (631, the position of the double bond as well as the configurations a t C-3 and C-5 in erythramine were firmly established.
18
S. F. DYKE AND S. N. QUESSY
42 Erythratine
41 Erythramine SCHEME 8
Several other alkaloids like 41 but with abnormal substitution pattern in ring D, have been isolated from Cocculus species and are discussed in Section II,C,5. b. With C-2 Oxygenation. Erythratinone (43), which was synthesised by oxidation of 42 (19), has been isolated by Barton et al. (19) as a major alkaloid in E. crysta galli. Further work by the same group has resulted in the isolation of a similar alkaloid erythratidinone (C, 9H23N04)from E. lithosperma Blume (now classified as E. variegata L.) (21). This alkaloid exhibited spectroscopic data similar to those,of 43 and erythratidinone was established as a 1(6)-en-2-one structure. The NMR data established the presence of three methoxyl groups and the dpbstitution pattern of ring D. With the aid of INDOR it was concluded that the proton at C-3 was axial from coupling values of 5.5 Hz with H-4e, and 12.0 Hz with H-4a. Structure 40 was proposed for erythratidinone since borohydride reduction (see 273-) and its C-2 Scheme 9) gave the known erythratidine (39, [a],, 142"). Erythratidine had been isolated earlier from E.Jufcata epimer ([.ID Bentham (64),but its stereochemistry was unknown. By application of Mills' rule (65)39 was assigned the 2 s configuration (as 39), which was opposite to that established for erythratine (42)by the same group (19). Further evidence
+
+
0 40 Ervthratidinone
OH
39 Erqthratidine ( + C-2 epimer)
SCHEME 9
1 Erysotrine
1.
ERYTHRINA AND RELATED ALKALOIDS
19
for the configuration at C-2 in 39 came through the analysis of its NMR spectrum (see Section II,C,2d). The absolute configuration at C-5 in both 39 and 40 was established by dehydration of 39 to give erysotrine (1) (see Scheme 9) along with 2-chlorodihydroerysotrine. A second enone alkaloid (CI8H,,NO,) was isolated from E. lithospernza Blume in the same study and identified as 3-desmethoxyerythratidinone (57) by the similarity of its spectroscopic properties to those of erythratidinone (40). In the first GC-MS examination of Erythrina species, several new A1 (6)alkene-type alkaloids were discovered in E. salvi$ora Krukoff and Barneby (15). Erysotinone (49), previously known only as a synthetic racemate (66), was identified from its MS fragmentation pattern. The substitution pattern in ring D was established by conversion of the isolated alkaloid to dihydroerysodine (47)which was prepared from a sample of erysodine (7)(see Scheme 10). Another G C fraction which gave an identical MS to that of 49 was assigned the isomeric structure 46 and given the name erysosalvinone. A further fraction exhibiting a n enone fragmentation pattern similar to both 46 and 49 but with a molecular ion at 58 amu higher, due to an extra TMS (67) and one fewer CH, (15) group, was assigned structure 51 and named erysoflorinone. Fractions with MS fragmentation patterns similar to that of erythratidine were isolated and one identified with the reduction product of erysotinone (49). This product 48 was previously prepared from 49 by Barton et al. (68) and given the name erysotine, but neither erysotine (48) nor erysotinone (49) had been previously obtained from natural sources. Erysotine was found to have an N M R spectrum similar to that of erythratidine (39),and methylation of 48 using diazomethane gave a product that had identical melting point and G C retention time to that of 39 (see Scheme 11). In view of the fact that the structure given by Millington et al. (15) was that of 2-epierythratidine rather than 39, their stereochemistry for erysotine was also incorrect. This would seem to suggest that erysotine, like erythratidine, has the 2 s configuration; however the structures given by Millington et al. for both erysotine and erythratidine (Fig. 6 in ref. 1 5 ) were of the 2R configuration [as in erythratine (42)]. The alternative positional isomer [related to erysosalvinone (46)] was also identified in this study and named erysosalvine (45). Erysopitine (C,,H,,NO,) was isolated from E. uariegata L. and its structure (50) assigned from spectroscopic evidence (35).Conversion of 50 to erysotrine (1) (see Scheme 12) established the stereochemistry at C-3 and C-5, but the configuration at C-2 has not yet been defined. Of biogenetic interest (see Section V,A) was the isolation of erysodienone (58) along with N-norprotosinomenine (67) and protosinomenine (68) from E. lithosperma Blume (now E. variegata L.) (34,35).Erysodienone had been previously synthesised (54, 66, 6H), but this was the first report of its isolation
0 49 R’ 46 R’ 51 R’
= = =
H, RZ = CH, Erysotinone CH,, R Z = H Erysosalvinone R 2 = H Erysoflorinone
47 Dihydroerysodine
7 Erysodinc
SCHEME 10
49 Erysotinone
48 Erysotine
(
+ C-2 epimer) SCHEME 11
39 Erythratidine
1.
E R Y T H R I N A AND RELATED ALKALOIDS
21
CH,O
HO
OH 50 Erysopitine
1 Erysottine
SCHEME 12 HO
0
CH30 cH30?R OH
58 Erysodienone
67 R = H 68 R = C H 3
from plant material. Identification of 58 was made by comparison of its melting point and spectroscopic properties with the reported data and by reduction to the known transformation product erysodienol(35).
5. Abnormal Alkaloids from Cocculus Species Only 3 of the 12 species of Cocculus (Menispermaceae) have been examined for alkaloids and most studies have concerned C. laurifolius, which has yielded the greatest number of alkaloids (see Table I) (51, 55-58,60, 69-76). The Erythrina-type alkaloids obtained from Cocculus are abnormal in the sense that they contain no oxygen function at C-16, the only exceptions being dihydroerysovine (44), dihydroerysodine (47), and erythroculine (53). Erythroculine is, however, unusual in that it has a methoxycarbonyl group at C-16. The two alkaloids isococculidine (36) and isococculine (37) are of the A2( 1)-alkene type rather than the A1 (6)-alkene type. The insecticidal alkaloid cocculolidine (61), a lower homolog of B-erythroidine (60) (see Fig. 4), was mentioned in the previous review ( 1 ) where its isolation from C. trilobus DC was reported. It has now been isolated from C. carolinus DC, a species native to the Southeastern United States (69).
22
S. F. DYKE A N D S. N. QUESSY
TABLE I ERYTHRIXA ALKALOIDS FROM mP( C )
Alkaloid Cocculine
Isococculine Cocculidine Isococculidine Coccutrine Coccoline Coccolinine Coccuvine Coccuvinine Erythroculine Cocculitine Dihydroerysovine Dihydroerysodine Cocculolidine
217-218
COCCLLUS SPECIES
[.ID
Plant source‘
+271
~
86-87 (93-95) 95-96 263 -265 245-246 174- 175 137-1 38 103- 104 193-196b.C 142-1 43 h
208-209 144- 146
+ 260 + 124 + 232 + 233 ~
+ 194 + 93 + 233 + 224 + 273
Ref.
A B C A A A B
51,55
A
55
A A A A A B A B C
71 72
60 h9
70 51, 55, 58
55 60
56
73 74 57 75 76 69
“A. C. luurfolius DC (leaves); B, C. trilobus DC (leaves); C, C. carolinus DC (fruits). Oil. Styphnate.
Cocculine (C, , H 2 , N 0 2 ) and cocculidine (Cl8H2,NO,) were isolated from C. laurijolius in 1950 (77) but escaped mention in previous reviews of this treatise because only a partial structure, unrelated to the Erythrina alkaloids, had been advanced (78). On the basis of the spectroscopic properties of the alkaloids and their Hofmann degradation products, structures 56 and 54 (without stereochemistry) were proposed for cocculine and cocculidine, respectively (79); however, a different group (80) proposed structures 69 and 70, respectively, on the basis of similar evidence. The
CH,O’ 56 R = H Cocculine 54 R = CH, Cocculidine
69 R = H 70 R = C H ,
1.
E R ) TliRI,\ A A N D RELATED ALKALOIDS
23
AcO
56 Cocculine
71
SCHEME13
former group established the spiro structure of 56 by conversion to the 0 , N diacetate 71 (51) (see Scheme 13), and X-ray analysis of the hydrobromide salts of 56 and 54 established the structures originally proposed (51, 52). Although the absolute stereochemistry was stated to be 3 R 3 the structures were ambiguously represented as the mirror image of this configuration. A rigorous definition of the absolute configuration of cocculine was reported by McPhail and Onan in 1977 (49) whereby stereostructure 56 (i,e., 3R,5S9 was established for cocculine. It follows that cocculidine has stereostructure 54 since it has been demonstrated that methylation of cocculine using diazomethane gives cocculidine (77). Cocculine has also been isolated from C. trilobus (60)and C. carolinus (69).
52 Coccutrine
53 Erythroculine
A related alkaloid coccutrine (CI8H,,NO,) was isolated from C. trilobus (60)and structure 52 established spectroscopically, with the positions of the aromatic hydroxyl and methoxyl groups being defined by X-ray analysis. Coccutrine is the only example of an Erythrinu alkaloid containing an oxygen function at C- 17. An unusual alkaloid, erythroculine (C,,H,, NO,) was obtained from the leaves of C. luurifolius (67)and its structure (53) deduced from spectroscopic and degradative evidence (73). The MS data were consistent with a Al(6)alkene structure and the IR spectrum exhibited an absorbance at 1710 cm-'. The N M R spectrum established the presence of three methoxyl groups and two para-oriented aromatic protons. Reduction of 53 gave erythroculinol
53 Erythroculine
I
BC'I, CH,CI,
74
72 Erythroculinol
!
(I) AC,O ( i t ) yon Braun (iii) L A H (iv) CH,O,'NaBH,
&
NCH3
73
SCHEME 14
75
1.
25
E R Y T H R l N A A N D RELATED ALKALOIDS
(72) (see Scheme 14) which contained an IR absorption attributable to a hydroxyl group, but no carbonyl band was observed. Since one of the methoxyl groups in the NMR spectrum had disappeared, a methoxycarbonyl group was established. Demethylation of 53 gave a phenolic base 73 (Scheme 14)which showed a large bathochromic shift in the UV spectrum. This led to the assignment of the methoxyl function in 53 ortho to the methoxycarbonyl group, and the position of these groups was made on the basis of detailed NMR studies, including the observation of deuterium exchange ortho to the methoxyl group in erythroculinol. The environment of the nitrogen atom was established by Hofmann degradation of 72 (Scheme 14) and spectroscopic analysis of the degradation product 74. Erythroculinol was degraded by a combination of von Braun and Hofmann methods (see Scheme 14) to the biphenyl 75, whose structure was proved by an unambiguous synthesis. Finally, the stereochemistry at C-3 and C-5 was established by transformation of erythroculine (53) to tetrahydroerysotrine (76) as shown in Scheme 15. The presence of the methoxycarbonyl group in 53 is interesting from a biogenetic point of view.
i
53
performic acid
76 Tetrahydroerysotrine SCHEME 15
Continued examination of the pharmacologically interesting species C. laurifolius, particularly by Singh et al. (55,56,70-72, 74) has led to the isolation of more Erythrina alkaloids that have structures related to cocculine (56) and cocculidine (54). Coccuvine (C, 7H19N02) and coccuvinine (C,,H,,NO,) were found to be of the 1,6-diene type (56, 72) and the structures 16 and 14, respectively, were established on the basis of spectroscopic evidence and chemical interconversions. Methylation of coccuvine (16) (see
26
S. F. D Y K E AND S. N. QUESSY
Scheme 16) gave coccuvinine (141, which was reduced catalytically to give cocculidine, the structure and absolute stereochemistry of which was already established. The 8-0x0 counterparts of both coccuvine and coccuvinine were also isolated and given the names coccoline and coccolinine. Structures 17 and 15 (see Fig. 2) were assigned on the basis of spectroscopic studies including detailed examination of NMR spectra (55, 71). In addition methylation of 17 gave 15. The stereochemistry at C-3 was determined from coupling-constant data (see Section II,C,2d)and the configuration at C-5 was assumed. It was suggested, however, that 17 and 15 were artifacts produced during the drying process.
HO
9% CH,O p
&izHH1,
-
CH,O~’
’
16 Coccuvine
CH,O
-;I
-
CH,O-’
’
CH,O,’
14 Coccuvinine
54 Cocculidine
SCHEME16
Two further alkaloids, isococculine (C, ,H2 NO2) and isococculidine (C, sH2,N02),were isolated and found to be isomeric with cocculine 56 and cocculidine (54), but were discovered to have novel structures with respect to the position of the double bond (55, 70). Structures 37 and 36 for iso-
37 R = H Isococculine 36 R = CH, Isococculidine
55 Cocculitine
cocculine and isococculidine, respectively. followed from the analysis of the physical data. For example, the UV spectrum of 36 showed an isolated double bond, but the MS fragmentation pattern was similar to that of the 1,6-diene Erythrina structure rather than the A1(6)-alkene type. The A2(1)alkene structure was supported by the NMR spectrum which exhibited two olefinic protons at 6 6.06 and 5.85 ppm ( J , , 2 = 10.5 Hz). The absolute stereochemistry was not determined since a correlation between 36 and cocculidine (54) through their dihydro derivatives was not possible because
1. t R > THRl.tA
A N D RELATED ALKALOIDS
27
of the resistance of 54 to hydrogenation (55).However, the configurations at C-3 and C-6 were supported by coupling-constant data obtained from the NMR spectrum. A new alkaloid cocculitine (C,,H,,NO,) was isolated recently from C. laurijolius (74). The IR spectrum indicated the presence of a hydroxyl group (3460 cm- ’) which was further established by the formation of a mono-O-acetate (1715 cm-I). The NMR spectrum of cocculitine was very similar to that of erythratine (42),except in the aromatic region. The aromatic methoxyl group was located at C-15 on the basis of detailed decoupling experiments, and the stereochemistry at C-3 was determined from the coupling data, which suggested that the proton at C-3 was axial. A value of 8.5 Hz for J,,, suggested that the proton at C-2 was also axial and hence structure 55 was proposed for cocculitine. Only two “normal” Erythrina alkaloids have been isolated from Cocculus species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter recently from C. trilobus (57).Neither alkaloid has been found in Erythrina species. The structure 44 for dihydroerysovine was deduced from the spectroscopic evidence and by methylation using diazomethane to give the known dihydroerysotrine (38). The positions of the aromatic substituents were determined by detailed N M R experiments using NOE and INDOR techniques (see Section II,C,2d).
47 Dihydroerysodine
44 Dihydroerysovine
111. Homoerythrina Alkaloids
A. OCCURRENCE AND ISOLATION The C-Homoerythrina alkaloids are a relatively recently identified group, the first examples being isolated and identified from Schelharnnzera ~ ~ ~ u F. ~MueI1. c uin /I968 ~ (81). ~ ~Homoerythrina alkaloids have been isolated from all three species of Schelhanziwera (Liliaceae), in which they constitute a further addition to the various biosynthetically related alkaloids within the family Liliacea (82-85); from the leaves of species of Phelline (Ilicacea), where their presence raises some doubts about the taxonomic classification of the genus (86-88); and from the roots and stems of species
28
S . F. DYKE AND S . N. QUESSY
of Cephalotaxus (Cephalotaxaceae), particularly C. wilsoniana Hayata in which they are the major alkaloids (89-91) (see Table 11). Many members of the Homoerythrina group occur with their C-3 epimers, in contrast to the Erythrina group, and despite the fact that they appear in relatively few plant species, over 20 individual Homoerythrina alkaloids have been isolated, although the structures of two of them remain incomplete because of insufficient amounts of samples. Those alkaloids of known strucTABLE I1 PHYSICAL PROPERTIES OF HOMOERYTHRINA ALKALOIDS
Alkaloid
Formula
m P ( C)
88 89 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine Schelhammeridine 3-Epischelhammeridine 86 (Alkaloid 6) Schelhammericine 3-Epischelhammericine
186-1 88 133 170-171 151 -173 118 131-133 126 76-77 169-172' 170- 17I'
Ma (Alkaloid A)
188-1 89c 260d 173- 174 182-185 184-185 e 152-153 150-152 150-151 244 decd e e I43 -145' 100-1 01
~
84b (Alkaloid 1) Schelhammerine 3-Epischelhammerine 96 83 (Alkaloid B)
Wilsonine 3-Epiwilsonine 82a 82b 85 (Alkaloid 2) 97 (Alkaloid 5)
[.I; f 143
+ 140
+ 35
- 41
108 f24 f63 +I22 f 123 +98 I23 - 100 15 186 + I67 172 f76r +I11 +115 -51 58 +I18 + 122 72 +91
-
+ + + +
+ +
Plant sourceh (Ref.) E E A A A A D A A, B, C D F, G A D A A D F A, C F G D F F, G D D
Solvent: chloroform. A, S . peduncula/a F. Muell: B, S. niul/iflora R. Br.; C , S. Uiidulatu R. Br.. D. P. coniosa Labill: E. P. billardieri; F. C. harringroiria K. Koch var. hurr.iiiy/oiiiu: G, C. wilsoniuna Hay. Picrate. Hydrochloride. Noncrystalline. Doubtful value due to impure sample.
1.
29
ERYTHRINA AND RELATED ALKALOIDS
ture are shown in Figs. 6 and 7. Within the three genera, the alkaloid profile is fairly distinctive, with only 3-epischelhammericine (81b) occurring in all three. The alkaloids have been isolated either by alcohol extraction of the dried plant material (82,90) or by ether extraction of the basified plant material (87). The crude mixture is then fractionated by countercurrent distribution, followed by chromatographic purification and recrystallization. The Homoerythrina alkaloids have not been reviewed before, except briefly in conjunction with Cephalotaxus alkaloids, with which they occur in Cephalotaxus species (9). Y
R' 77a 77b 78 79
Schelhammeridine 3-Epischelhammeridine 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine
R2
-CH2-CH2-CH2-CH2-
R3
R4
X
Y
CH,O H CH,O CH,O
H CH,O H H
H, H2 0 H2
H2 H, H2 0
PIG. 6a. Homoerythrina alkaloids: 1,6 diene series
R2
80a 80b 81a
81b 82a 82b 83
Schelhammerine 3-Epischelhammerine Schelhammericine 3-Epischelhammericine 3-Epi-2,7-dihydrohomoerysotrine 2,7-Dihydrohomoerysotrine 2.7-Dihydrohomoerysovine
R2
CH2 -CH,-CH2-CH,CH, CH, CH, CH, CH, H ~~
R3
R4
X
CH,O H CH,O H CH3O H H
H CH,O H CH,O H CH,O CH,O
OH OH H H H H H
FIG.6b. Homoerythrina alkaloids: Al(6) alkene series.
30
S. F. DYKE AND S.
N. QUESSY
RZO
k4 R1 84a 84b 85
R2
3-Epi-6~,7-dihydrohomoerythraline -CH,6~,7-Dihydrohomoerythraline -CH CH, CH, 6a,7-Dihydrohomoerysotrine
R3
R4
CH30 H H
H CH,O CH,O
FIG.7a. Homoerythrina alkaloids: A2(1) alkene series
R4 R' 86 87a 87b
R2
3~-Methoxy-l5,16-methylenedioxy-6,7-epoxy- -CH2C-homoerythrinan-2(1)-em CH, CH, Wilsonine CH, CH, 3-Epiwilsonine
R3
R4
H
CH,O
CH,O H
H CH,O
FIG.7b. Homoerythrina alkaloids: epoxy- A2( 1) series
88 R = H 89 R = CH,
90 Phellibiline'
FIG.7c. Homoerythrina alkaloids : the homoerythroidines.
B. NOMENCLATURE Nomenclature for the Homoerythrina group is a problem because only a few of the alkaloids have been given trivial names. Since the structures of the Homoerythrina group parallel those of the Erytlzrina group we have
1.
EK > 7 H R I . V A A N D RELATED ALKALOIDS
31
decided to refer to the unnamed members as homo analogs of the corresponding Erythrina alkaloid. This has the advantage of illustrating the structural relationship between the two groups (as they are biogenetically related) and keeps the names relatively simple. When this is not possible the Chemical Abstracts system, which is based on the C-homoerythrinan ring 91, is used. We have used the Chemical Abstracts numbering system for the sake of consistency, even though it differs from that used in the literature (cf. 92).
11 6 % :s
14
7
3 2
91
2
92
C. STRUCTURE DETERMINATION 1. Spectroscopic Characteristics
In many ways the spectroscopic properties of the Homoerythrina group parallel those of the Erythrina series (cf. Section II,C,2). The UV and NMR characteristics are similar, particularly in rings A and B. The mass spectra of the 1,6-diene series show a simple fragmentation pattern, similar to that in the Erythrina 1,6-diene series, with the major fragmentation pathway involving loss of the allylic substituent (see Scheme 17). The A1(6)-alkene series shows a more complex fragmentation pattern, as do their A1(6)-alkene Erythrina counterparts. The same retro-Diels-Alder fragmentation occurs, but other important modes of fragmentation are initiated in ring C (see Scheme 18). As in the Erythrina group, the stereochemistry at C-3 may be assigned from coupling constant data; however, chemical shift data can also be used as an indicator of stereochemistry. For example, in the schelhammericine (81a) series (3S-methoxyl), the methoxyl resonance occurs at 6 2.74 ppm
32
S. F. DYKE AND S . N. QUESSY
Ic SCHEME
I
-CH,OH
18. Major fiagmentation pathway f o r A I ( 6 ) d k e n e - t y p eHomoerythrina alkaloids
with a quartet for the axial C-4 proton near 6 1.78 ppm. In the 3-epischelhammeridine (81b) series (3R-methoxyl), the methoxyl resonance occurs at 6 3.17 ppm, with an apparent triplet for the axial C-4 proton around 6 1.52 ppm. 2. Schelhammerine, Schelhammeridine, and Their C-3 Epimers The structural determination of the first Homoerythrina alkaloids, obtained from Schelhammera, was the subject of an elegant series of papers by the CSIRO group in Australia (81-85). Two major alkaloids from S. peduncufata F. Muell. were named Schelhammerine (C, ,H,,NO,) and ~ c h e l ~ a ~ ~ (CI9H2,NO3) e ~ ~ ~ i n e(82). The alkaloids had similar NMR characteristics in that both exhibited resonances attributable to a methylenedioxy group, a nonaromatic methoxyl group, and two para-aromatic protons ; but schelhammeridine contained two olefinic protons in its N M R spectrum and exhibited an isolated alkene absorption in the UV spectrum, whereas schelhammerine showed absorption arising from only one olefinic proton in the NMR spectrum, and the extra oxygen atom was found to be in a hydroxyl group. Furthermore, treatment of schelhammerine in pyridine with methanesulfonyl chloride gave schelhammeridine in 20% yield (see Scheme 19), revealing that the two alkaloids were structurally related. Since the nitrogen atom was tertiary, and evidence for N-methyl was not observed, a tetracyclic system was considered. The possibility that the fused heterocyclic rings were both six-membered was excluded through analysis
1.
E R Y 7 H R / , C A A N D RELATED ALKALOIDS
80a Schelhammerine
33
77a Schelhammeridine (20"f; yield based on recovered 80a)
SCHEME 19
of the signals for the C-7 and C-8 protons in the NMR spectrum of schelhammeridine, which clearly indicated a five-membered ring. The complete structure of schelhammerine (except for stereochemistry at C-2 and C-5) was deduced as 80a from a careful analysis of its 100-MHz NMR spectrum, with the aid of decoupling experiments. Values of 5.0 Hz for J3,4eq and 3.2 Hz for J3,4ax suggested that the proton at C-3 was equatorial; but a value of 3.0 Hz for J 2 , 3did not allow definitive assignment of the stereochemistry at C-2, although it suggested that the proton at C-2, was also equatorial. The absolute stereochemistry (as shown in 80a) was established by X-ray analysis of schelhammerine hydrobromide (92). The stereochemical assignments made from the NM R spectrum were further supported by the isolation of an alkaloid (alkaloid H) isomeric with schelhammerine, with similar UV and identical MS spectra. A value of 12 Hz indicated that the proton at C-3 was axial, but lack of large transfor J3,4ah diaxial couplings for J 2 , 3 suggested that the hydroxyl group at C-2 was axial, as in 80a. The alkaloid therefore had the structure 80b and is 3-epischelhammerine. The assignment of structure 77a for schelhammeridine followed from the NMR analysis and from the interconversion reaction (Scheme 19), which also established the absolute configuration at C-3 and C-5. In addition, a minor constituent (alkaloid G) was isolated, isomeric with 77a, having idenThe alkaloid tical UV and MS spectra but with a value of 11 Hz for J3,4ax. therefore appeared to be 3-epischelhammeridine (77b), demonstrated by a series of interconversions summarized in Scheme 20. Vigorous hydrolysis of 77a in acid gave a complex mixture of products, the major one being the alcohol 93, That epimerization at C-3 had occurred was evident from the values of 3.5 and 12 Hz for J3,4in the N M R spectrum. A minor product with values of 2.0 and 4.8 Hz for J3,4was found to be the alcohol, with retention of configuration at C-3. Methylation of 93 gave 77b, and conversely acid hydrolysis of 77b gave 93 thus establishing the configurations at C-3 and C-5 in 77b (83).
34
S. F. D Y K E AND S.
77a
N. QUESSY
93 (70“,) ( + C-3 epirner lo“,)
77b
SCHEME 20
The two isomeric alcohols 94a and 94b were isolated and identified among the minor products of the hydrolysis reaction. This finding revealed that
94a R’ = OH, R 2 = R 3 = H 94b R’ = R’ = H, R 2 = OH 94c R’ = OAc, R 2 = H, R3 = AC
the “apo rearrangement,” which occurs on acid hydrolysis of the Erythrina alkaloids, does not occur with the Homoerythrina group, where a bridged biphenyl system is formed. The ease of cleavage of the N-C-5 bond in schelhammeridine is also unparalleled in the Erythrina series. When schelhammeridine was heated at reflux in acetic anhydride a single stereoisomer 94c was obtained. It was then shown that the stereochemical outcome of the acid-hydrolysis reaction was temperature-dependent, because of limited rotational freedom of the biphenyl system. Hydrogenation of schelhammeridine (77a) in acetic acid gave rise to five products, and the structures of four of them were determined spectroscopically (83). The two major products were the 2,7-dihydro- and the tetrahydro derivatives 81a and 95, respectively (see Scheme 21). Hydrogenolysis and N-C-5 bond cleavage products were also observed. It was found that the yield of the dihydro derivative 80a was increased when ethanol was used as the solvent for the hydrogenation. The 6a-configuration in 95 was assigned on the assumption that hydrogenation would occur from the less hindered a-side of the molecule. In the Erythrina group, this assumption proved to be incorrect ( I ) , so the configuration at C-6 in 95 and in the A2( 1)dihydro series (Section 111,C,5) remains to be proved.
1.
E R Y T H R I V A A N D RELATED ALKALOIDS
77a
35
81a (30',,) (Schelhammencine)
SCHEME21
3. Oxoschelhammeridines Two alkaloids (C,,H,,NO,) were isolated from S. pedunculata, of which one was a base and the other was nonbasic (84). The base (alkaloid J) exhibited an IR absorbance at 1665 c m p l and UV absorbances at 232 (3,100), 277 (4,600) and 313 nm (5,000), suggesting an aryl ketone. Comparison of its NMR spectrum with that of schelhammeridine revealed a lack of C-1 1 methylene protons and a downfield shift of the C-17 proton. The ketone function was therefore located at C-lla. The stereochemistry at C-3 was assigned from the value of 4.0 Hz for J3,4ax and the configuration at C-5 was assumed. Structure 79 was proposed for the basic alkaloid, which is therefore 1 1a-oxoschelhammeridine.
The NMR spectrum of the nonbasic alkaloid (alkaloid K) showed the C-7 olefinic signal as a singlet, in contrast to the usual multiplet, and there were no signals attributable to the protons at C-8. A downfield shift observed for the protons at C-10 was consistent with the expected deshielding effect of a carbonyl group at C-8, which also accounted for the nonbasic nature of the alkaloid. An intense IR band at 1685 c m p l also supported the lactam structure 78. The value of 5.0 Hz for J3,4ax supported the stereochemical assignment at C-3, but rigorous proof of the structure 78 was obtained by oxidation of schelhammeridine using mangenese dioxide to give 8-oxoschelhammeridine (78) (see Scheme 22). This established the configuration at C-5 and proved the stereochemistry at C-3.
36
S. F. D Y K E A N D S. N. QUESSY
CH,O
CH,O
78
77a Schelhammeridine
SCHEME 22
4. Schelhammericine and the A l(6)-Alkene Series Schelhammericine ( C ,,H,,NO,) was recognized as a A1(6)-alkene structure from its MS fragmentation pattern (see Section III,C,l) and structure 81a was determined through analysis of its NM R spectrum. Values of 3.5 and 5.0 Hz for J3,4 suggested that the proton at C-3 was equatorial. Schelhammericine was identified as the dihydro product 81a obtained on catalytic hydrogenation of schelhammeridine (refer to Scheme 2 1) (84). An isomeric alkaloid (alkaloid E) was isolated from S. pedunculata and found to be the major alkaloid in 5’. rnultzj2ora R.Br. (85). Values of 4.0 and 11 Hz for J3,4suggested that it was the C-3 epimer 81b of schelhammericine. Structure 81b was proved by identification of 3-epischelhammericine with 2,7-dihydro-3-epischelhammeridine(see Scheme 23) (84). Later on, another group reported the isolation of 81b from P.comosa, and was able to convert 3-epischelhammerine (80b) to 81b by chlorination and reduction, as shown in Scheme 23 (87). Cephalotaxus harringtonia var. harring ton ia has also yielded 3-epischelhammericine ( 9I ) .
(9 -.::-::Cy+ 0
-
CH,O,-
’
CH,O,’
CH,O,’
,
OH 77b 3-Epischelhammeridine
Slb 3-Epischelhammericine
80b 3-Epischelhammerine
SCHEME 23
Other alkaloids in the Al(6)-alkene series have been reported. Two isomeric alkaloids (C,,H,,NO,) were obtained from Cephalotaxus harringtonia K. Koch var. harringtonia. Their spectroscopic properties closely resembled those of schelhammericine except that their NMR spectra revealed the presence of two aromatic methoxyl groups in place of the methylenedioxy group of schelhammericine. The alkaloids were therefore 3-epihomo-2,7-
1.
E R YTHR/.\ 1 A N D RELATED ALKALOIDS
37
dihydroerysotrine and homo-2,7-dihydroerysotrine, with structures 82a and 82b, respectively. Distinction between the two epimers was made on the basis of the NMR data (see Section III,C,l). The configuration at C-5 was considered the same as that in schelhammericine, since their optical rotations were of the same sign and magnitude (89).
R4
82a R ' = R 2 = CH,, R3 = CH,O, R 4 = H 82b R' = R Z = CH,, R 3 = H, R4 = CH,O 83 R ' = CH,, R2 = R' = H, R4 = CH,O
An alkaloid (C,,H,,NO,, alkaloid B) isolated from S. pedunculutu exhibited UV characteristics similar to those of schelhammerine (80a) and an IR absorbance at 3600 cm-' suggested a phenolic hydroxyl group. The NMR spectrum was similar to that of 3-epischelhammericine and revealed the presence of one aromatic methoxyl group, a phenolic proton, and paraoriented aromatic protons. The position of the phenol group was located at C-15 by an NMR experiment that involved deuterium exchange of the aromatic proton ortho to the phenol group. The remaining aromatic proton was broadened because of benzylic coupling and was therefore at C-17. The stereochemistry at C-3 was deduced from the observation of a large value for J3,4ax, and the configuration at C-5 was assigned by the sign and magnitude of the optical rotation. The data were consistent with structure 83 for this alkaloid, which is therefore homo-2,7-dihydroerysovine (84). This same alkaloid was found in S. undulutu (85)and has also been isolated from C. harringtoniu var. hurringtoniu along with a similar base which, from its NMR spectrum was epimeric at C-3. However, the positions of the aromatic methoxyl and hydroxyl groups could not be defined because of a lack of pure sample, and partial structure 96 was proposed (89). H
CH,O' 96
97
38
S . F. D Y K E A N D S . N. QUESSY
An alkaloid (C2,H19N04, alkaloid 5 ) , isolated from Plicllinr c o m u a Labill., has a MS fragmentation of the A1(6)-alkene type. The N M R spectrum revealed the presence of three aromatic methoxyl groups, and the methoxyl group at C-3 was found to be equatorial from the large value of J3,4ax(1 1.5 Hz). The configuration at C-5 was assumed to be 5s on the basis of the sign and magnitude of the optical rotation. The partial structure 97 was proposed and it was suggested, on steric and biogenetic grounds, that the aromatic substitution pattern was 15,16,17-trimethoxy.
5. A2(1)-Alkene Series The first alkaloid of the A2(1)-alkenetype was obtained from S.peduncufata (84). An alkaloid (CI9H,,NO3, alkaloid A) was isolated that was isomeric
with both schelhammericine (81a) and 3-epischelhammericine (Sib), but which clearly contained an allylic methoxyl group, as indicated by the NMR spectrum and the ease of hydrolysis of the methoxyl group. Hydrolysis proceeded with inversion of configuration at C-3 to give alcohol 98 (see Scheme 24), the structure of which was supported by its NMR spectrum. Structure 84a was proposed for the alkaloid, and this was further supported by its reduction to a product identical with tetrahydroschelhammeridine 95 (see Scheme 25), which fixed the configurations a t C-3 and C-5, but the 6ci-configuration was assumed. The alkaloid 84a is therefore 3-epi-6~,7dihydrohomoerythraline. The C-3 epimer 84b ( 6 4 7-dihydrohomoerythraline) was not reported in S. pedunculata but was later isolated from P. C O ~ O S U(87). From its NMR 10"" HCI
10" HCI
A
(35"")
0
'H
'H
84a
98
84b
SCHEME 24. Relationship bertveen 84a and 84b.
84a
77a
95 SCHEME
25
1.
39
ER YTHRI.VA A N D RELATED ALKALOIDS
spectrum this alkaloid (alkaloid 1) was found to contain an allylic methoxyl group, and the coupling data suggested that the C-3 proton was axial. Hydrolysis of 84b gave the allylic alcohol 98 as the major product; this product had properties identical to those reported for the demethylation product of 84a (84)(see Scheme 24). The interconversion reactions outlined in Schemes 24 and 25 allowed the complete stereochemistry of 84b to be assigned. In addition, it was found that the von Braun degradation product of 84b was identical to that of 3-epischelhammeridine 81b (87),as shown in Scheme 26.
84b
81b
SCHEME 26
From the same plant a similar alkaloid (C,,H,,NO,, alkaloid 2) was isolated and found to differ from 84b in that it contained two aromatic methoxyl groups in place of the methylenedioxy group. The C-3 proton was, from the N M R coupling constants, found to be axial, and structure 85 was consistent with the data. The configuration at C-5 was assumed, although its CD curve was the inverse of that of 84b in the region 235 nm. Structure 85 corresponds to 6~~,7-dihydrohomoerysotrine. Two alkaloids, C,,H,,NO, and C,,H,,NO, (alkaloids 6 and 7), isolated from P.comosa exhibited similar NMR characteristics (87).Both contained an allylic methoxyl group, a disubstituted double bond, and para-oriented aromatic protons ; however, the former contained a methylenedioxy group and the latter two aromatic methoxyl groups. Their IR spectra showed the absence of hydroxyl or carbonyl functions, which suggested that the fourth oxygen atom was contained in a ring. The MS fragmentation patterns of the two alkaloids were almost identical, showing that they differed only in the aromatic substituents. Structures 86 and 87b, respectively, were assigned
CH,O. 85
R' 86
87a R' = CH,O. R Z = H 87b R' = H , R 2 = CH,O
40
S. F. DYKE A N D S. N. QUESSY
to the two alkaloids from the spectroscopic evidence and on the basis of the transformations summarized in Schemes 27 and 28. Reduction of 87b using LAH gave the tertiary alcohol 99 with preservation of the double bond (Scheme 27). The position of both the double bond and the hydroxyl group was clear from the NMR and MS data of 99. The downfield shift experienced by the proton at C-14 (A6 1.36 ppm) could be accounted for if the hydroxyl group had the 68-configuration as this would place it spatially near the aromatic proton at C-14. Similar reduction of 86 gave the corresponding tertiary alcohol 100. Catalytic reduction of 87b gave rise to a secondary alcohol 101 as the major product. The MS and NMR data clearly revealed that isomerization of the double bond to the A1(6)-position had occurred. The signal for the methine to which the hydroxyl group was attached (i.e., C-7 proton) was located at 6 4.53 ppm by the use of N M R experiments involving deuterium exchange and acetylation. Irradiation of this signal produced a small (< 1 Hz) decoupling effect on the olefinic signal and a significant decoupling effect at the methylene protons attached to C-8. The data were consistent only with the hydroxyl group being attached at C-7, but the coupling values of 5.0 and 6.7 Hz for J7,* did not permit assignment of configuration. A similar reduction of 86 gave the secondary alcohol 102 which exhibited spectroscopic properties similar to those of 101. Further support for the structure of 102 was obtained from its
86 R + R = C H z 87b R = CH,
RO
OH CH,O”
OH
/
99 R = C H , 100 R + R = C H ,
101 R = CH,
102 R
+ R = CH2
1.
41
E R Y T H R l N A A N D RELATED ALKALOIDS I,) SOCI, 111)
LAH
A
(9 CH,O"
81b 3-Epischelhammericine
102 SCHEME 28
transformation to 3-epischelhammericine (Slb), as outlined in Scheme 28, which established the configurations at C-3 and C-5. That the original alkaloids 86 and 87b contained a 6,7-epoxy group was an inescapable conclusion of the reduction experiments; and the presence of such a group poses an interesting biogenetic problem. The stereochemistry of the epoxide remains uncertain. The alkaloid 87b was later isolated from C. wilsoniunu along with its C-3 epimer 87a (90). The name wilsonine has been given to 87a and 3-epiwilsonine to 87b. Since the alkaloid 86 has no trivial name and is not related to any members of the Erythrinu group, it is referred to here as 6,7-epoxy-3a-methoxy-15,16-methylenedioxy-C-homoerythrinan2(1)-ene.The structure of wilsonine was established in the way just described. 6. Homoerythroidines The two major alkaloids from P . billurdieri were found to have the chemical compositions C,,H2,N03 and C1,H2,N03. Their NMR spectra were similar, both contained a trisubstituted double bond but no aromatic protons. The former alkaloid exhibited one exchangeable hydroxyl proton, whereas the latter contained an aliphatic methoxyl group. The relationship between the two alkaloids was established when demethylation of the C,, alkaloid gave the C,, alkaloid. An absorbance at 1745 cm-' in the IR spectra suggested a 6- or elactone, an observation which was supported by LAH reduction to a diol (v,,,3450 cm-') in quantitative yield. The MS data suggested a A1(6)-alkene structure, and from the combined spectroscopic and degradative data the partial structures 103a and 103b were proposed
RO
-
103a R 103b R
=H = CH,
90
104
42
S. F. DYKE AND S. N . QUESSY
for the alkaloids. It was found that 103a isomerized on column chromatography to a product for which either the partial structure 90 (without the stereochemistry) or 104 was deduced. Structure 90 was favored on biogenetic grounds and on consideration of the N M R spectrum (88). The complete structure of this base, named phellibiline, was established by X-ray analysis, which revealed the absolute configurations at C-3, C-5, and C-12 as shown in stereostructure 90 (93).Since 90 was derived from the naturally occurring hydroxylic alkaloid and since this alkaloid has been related to its 0-methyl analog, structures 88 and 89 could be assigned to them. Aland the two major kaloid 89 is therefore 2,7-dihydrohomo-P-erythroidine,
88 R = H 89 R = CH,
alkaloids from P. billardieri are the only examples of the homoerythroidine series yet isolated.
IV. Cephalotaxus Alkaloids A. OCCURRENCE AND ISOLATION Cephalotaxus is a genus of plum yew natural to Eastern Asia, although it is now cultivated in many parts of the world (94). There are about seven species and most have been examined for alkaloids, which have been obtained from all parts of the plants. Since the alkaloidal extracts were reported in 1969 to exhibit antitumor activity (95), an intense investigation of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation work, structural elucidation, and pharmacological assay has come from the Northern Regional Research Laboratory in Illinois (8). The alkaloids were best isolated from the ethanol extract of the plant material, partially fractionated by counter-current distribution, and subsequently purified by preparative chromatography. Of the 11 known Cephalotasus alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a)is ubiquitous and the most abundant (up to 64% of the total alkaloid extract) in all species examined. C. wilsoniana Hay., which yields only minor quantities of cephalotaxine, is the exception, however ; it is rich in Homoerythrina alkaloids,
1.
43
E R Y T H R I Y A AND RELATED ALKALOIDS
OR3
Cephalotaxine Epicephalotaxine Acetylcephalo taxine Harringtonine Homoharringtonine Isoharringtonine Deox yharringtonine Desme thylcephalotaxine Cephalotaxinone
105a 105b 106 107 108 109 110 111 112
R’
R2
R3
HO H CH,CO a b
H HO H H H H H H
CH, CH, CH, CH, CH3 CH, CH, H CH3
C
d HO
0
co-o-
“ t
a = CH,-C-(CH,),
OH
CH,
OH b
= CH,-C-(CH,),+OH
I
CH,CO,CH,
CH,COzCH,
CH, b
U
CO-O-
H
= CH,-~--(CH,),&OH
CH,
CO-O-
H
H d
9
CO-O-
= CH,-C-(CH,),-OH
OH
I
CH,
CH,COzCH3
CO,CH, d
1
F I ~8.. Ceptiaiofa.xus alkaloids.
OCH, 113 Desmethylcephalotaxinone
OCH, 114 1I-Hydroxycephalotaxine
FIG.9. Ceplialotauus alkaloids.
OCH, 115 Drupacine
44
S. F. DYKE AND S. N. QUESSY
companion alkaloids in Cephalotaxus species (90).Seven Homoerythrina alkaloids have been identified in Cephalotaxus, including 3-epischelhammericine (Sob), wilsonine (87a), 3-epiwilsonine (87b), and structures 82a, 82b, 83, and 96 (8). The other Cephalotaxus alkaloids are structurally related to cephalotaxine (105a)and the most important group are the harringtonines 107-1 10, which are C-3 esters of cephalotaxine, since they have antitumor activity (see Section VII). The harringtonines constitute less than 10% of the total alkaloid extract and are in greatest abundance in C. harringtonia K. Koch var. harringtonia (89). The demand for the harringtonines for use in clinical trials has exceeded their supply from natural sources, resulting in many attempts to synthesize them from the more abundant cephalotaxine (see Section V1,C). In a very recent examination of C. msnii Hook., a new antitumor alkaloid was isolated but found to be structurally unrelated to the usual Cephalotaxus alkaloids. In view of the chemical results the botanical classification of the plant is being reexamined (96). Recently, a GC-MS method for the separation and quantitative identification of extracts from Cephalotaxus species (97)has been described. Most of the alkaloids were resolved, particularly the biologically active esters. The seven Homoerythrina alkaloids were only resolved into two groups of five and two components, respectively, under the conditions described. Acetylcephalotaxine (106), 1 1-hydroxycephalotaxine (114), and desmethylcephalotaxinone (113) were not resolved by retention time, but could be identified within the mixture by their MS fragmentation patterns. Cephalotaxinone (112) gave two GC peaks after silylation, presumably due to a contribution from the enol component. The artifact peak overlaps partly with the peak for drupacine (115) and hence introduces a slight error for this component and makes it difficult to quantify cephalotaxinone. It has been observed that the melting points and optical rotations of several alkaloids differ by more than can be attributed to experimental variation and must thus depend on the plant source (9,89,98).The most striking example is cephalotaxinone which has [mID-57" (0.3 c/g cmP3, CHCI,), from C. harringtonia var. drupacea and [.ID - 125' (0.6 c/g cm-,, CHC1,) from C. harringronia var. harringtonia, but that obtained by oxidation of cephalotaxine has [.I, -155" (0.63 c/g ern-,, CHCI, (89, 98). It has been suggested that Cephalotaxus alkaloids may occur as partial racemates. Although cephalotaxine is optically active ([.], - 183"),its crystalline methiodide is racemic. The amorphous residue was found to be optically active ( [ a ] , 1127, and it was suggested that racemization occurred during recrystallization from hot methanol (99).It is not clear whether Cephalotaxus alkaloids do occur as partial racemates or whether some racemization occurs
+
1.
ER YTHRINA AND RELATED ALKALOIDS
45
during the isolation and purification procedures. It has been noted that cephalotaxine obtained by transesterification of deoxyharringtonine (110) has the same optical rotation as natural cephalotaxine, and yet the harringtonines do not occur as diastereomers. If cephalotaxine does occur as a partial racemate, then the acyl portion of the harringtonines should also be partly racemic, and this would have some significance in structure-activity studies (9, 100).
B. STRUCTURE DETERMINATION 1. Cephalotaxine and Epicephalotaxine Pure cephalotaxine was first isolated from C. fortunei Hook. and C. harringtoniu var. drupacea [formerly referred to as C. drupacea ( I O l ) ] (102). The pioneering work on the structure of cephalotaxine (C,,H,,NO,) was reported in 1963 by Paudler et ul. (102, 103), and on the basis of chemical and spectroscopic evidence structure 116 was tentatively proposed. The fact that the olefinic proton appeared as a singlet in the NMR spectrum was rationalized by proposing a dihedral angle with the adjacent proton of 90" and hence zero coupling. Powell et al. (104) reexamined the structure of cephalotaxine and suggested two structures, 105 and 117, which accommodated all the data, although the former structure was favored on biogenetic grounds.
116
OCH, 105
117
46
S . F. DYKE AND S . N. QUESSY
In an accompanying publication (105), the X-ray crysial structure of cephalotaxine methiodide, which proved structure 105 for cephalotaxine, was reported. Although the methiodide was prepared from optically active ([.ID - 183”) cephalotaxine, the crystalline product was racemic, so that only the relative stereochemistry was obtained. It appears that all four chiral sites in the methiodide undergo inversion, presumably by facile cleavage and re-formation of the N-C-5 bond. This could also explain the early difficulties in the structural elucidation by chemical transformation. Recently, the absolute configuration has been established by X-ray analysis of cephalotaxine p-bromobenzoate (99, 106) as 3S,4S,5R (as shown in 105a). The seven-membered heterocyclic ring exists in a boat conformation with the nitrogen atom at the prow. 17
11
OCH, 105a Cephalotaxine
A minor alkaloid from C. fortunei (98) showed an IR spectrum identical to that of cephalotaxine, but its melting point was depressed by it. The physical properties of this alkaloid were found to be identical to the minor product obtained by reduction of cephalotaxinone (112) using LAH (102). The alkaloid was therefore 3-epicephalotaxine (105b). Although a small amount of 105b was produced on reduction of cephalotaxinone with LAH, the use of borohydride or DIBAL-H gave only cephalotaxine (98). 2. Esters of Cephalotaxine During the structure elucidation work, cephalotaxine was shown to form a mono-0-acetate (106) (102), and this compound was later found as a minor alkaloid in C.fortunei (98).An impure sample of acetylcephalotaxine was also obtained from C. wilsoniana Hay. (90). When the alkaloidal extracts of C. harringtonia var. harringtonia were found to possess antileukemia properties, a search for the responsible alkaloids was initiated, since the major component, cephalotaxine, was inactive. Four alkaloids (the harringtonines) that exhibited anticancer properties were isolated. The structures of harringtonine, isoharringtonine, and homoharringtonine were reported in 1970 (107),and that of deoxyharringtonine was reported in 1972 (108).
1.
47
E R Y T H R I N A A N D RELATED ALKALOIDS
Examination of the NMR spectra of the harringtonines revealed a spectrum nearly identical to that of cephalotaxine as well as the presence of signals arising from a side chain. This observation led to the discovery that alkaline hydrolysis of the harringtonines gave cephalotaxine in each case, plus a complex dicarboxylic acid. This was further supported by the MS data, since each alkaloid exhibited a prominent fragmentation ion with nz/e 298, due to loss of the side chain (M' -OR). The same peak was observed in the MS of cephalotaxine (M' -OH). It was therefore established that the harringtonines were C-3 esters of cephalotaxine, differing only in the nature of the ester side chain. The structures of these side chains were deduced from a careful examination of the NMR spectra of their dimethyl esters, obtained from the natural alkaloids by transesterification using sodium methoxide in methanol (100, 107, 108). The number and nature of free hydroxyl groups was determined by examination of the NMR spectra in DMSO-d, before and after deuterium exchange. The N M R spectra of the esters obtained from harringtonine and homoharringtonine exhibited two equivalent methyl groups and two different carboxymethyl signals, two tertiary hydroxyl groups, and an isolated methylene group. The spectra were consistent with structures 118 and 119, respectively, for these diesters. The spectrum of the diester obtained from isoharringtonine differed in that it contained an isopropyl function, a singlet due to an isolated methine bearing a hydroxyl group, and only one tertiary hydroxyl group. Structure 120 was proposed for this diester. By a combination of IR and NMR evidence the diester obtained from deoxyharringtonine was found to contain only one hydroxyl group, which was tertiary, and structure 121 was consistent with the data. The structures of these diesters were confirmed by synthesis (see Section V1,C). C0,CH3
OH
CH,OZCpCH,-C~~(CH,),pCpCH,
OH
CH 3
118
H
C02CH3
CH,O,C-C-C-(CH,),
OH
OH 120
CO,CH, CHAOIC
CH,
7
OH
ICHZ),pCpCHA
OH
CHS
119
H -C-CH, CH,
C0,CH3
H
CH,O,C-CH,~C~(CH~),~~~CH; OH
CH,
121
The problem now remained as to which carboxyl group was attached to the cephalotaxine skeleton. The two possible half-esters, 122 and 123, were synthesized (see Section VI,C), and esterification of cephalotaxine with 122 gave rise to a mixture of diastereomers, neither of which was
48
S. F. DYKE AND S . N. QUESSY
CO,CH,
HO,C-CH,--C
(CH,), OH
H C - CH3
CH30,C-CHZ
CH3
122
CO,H
H
C-(CH2),
C -CH,
OH
CH,
123
CH,02C-CH,
H
CO
-
C
(CH,),-C-CH,
,
OH
CH3
124
identical to deoxyharringtonine (108). This result suggested that the tertiary carboxyl group was linked to cephalotaxine in deoxyharringtonine ; but all attempts to esterify cephalotaxine with the half-ester 123 failed, and it was concluded that both reactants were sterically hindered. It was found that in the MS fragmentation patterns of the half-esters, cleavage at the tertiary center was preferred. Thus, 122 and 123 exhibited M-CO,H (m/e 173) and M-CO,CH, (m/e 159) fragmentation ions in the ratios 1 :8 and 3: 1, respectively. Deoxyharringtonine showed a ratio ofmle 1731159 of 3:1, suggesting linkage through the tertiary carboxyl group (108). The structures of deoxyharringtonine and the other harringtonines have been proved by partial syntheses from cephalotaxine and are discussed in Section V1,C. The absolute configurations of the acyl side chains are also discussed in that section as they depend, in part, on stereospecific synthesis. Recently, tissue cultures of C. harringtonia var. harringtonia were found to yield Cephalotaxus alkaloids in the same ratio as the parent plant, although in lower total yield. It was hoped that this method would help to offset the shortage of harringtonines, since the alkaloids could be obtained after six months, whereas the Cephalotaxus tree was slow to mature. A new harringtonine was discovered in the culture. The GC-MS evidence suggested that it was a homolog of deoxyharringtonine, and structure 124 was proposed for the side chain from the MS data. The name homodeoxyharringtonine was suggested for the alkaloid (109). 3. 11-Hydroxycephalotaxine and Drupacine Two minor alkaloids (C1,H,,NO,), obtained from C. harringtonia var. drupacea (Sieb and Zucc) Koidz., were deduced to be 1 l-hydroxycephalotaxine (114) and its related ketal drupacine (115) (101, 104). The NMR spectrum of the former exhibited features similar to that of cephalotaxine, with the addition of a triplet at 6 4.78 ppm, which was part of an ABX system. The alkaloid formed a diacetate wherein the position of the methine
1.
49
ER YTHR1,VA A N D RELATED ALKALOIDS
triplet in the NMR spectrum shifted to 6 6.09 ppm. The AB part at b 3.26 ppm was assigned to the protons at C-10, hence the hydroxyl group was located at C-1 1. It did not prove possible to prepare 1 l-hydroxycephalotaxine from cephalotaxine because of the sensitivity of the C-3 hydroxyl group to oxidation, and therefore the configurations at C-4 and C-5 were assumed. Drupacine also exhibited an ABX pattern in its NMR spectrum, with a triplet centered at 6 4.87ppm. The position of this signal remained unchanged upon acetylation, which gave a mono-0-acetate. There was no olefinic signal in the NMR spectrum but geminal coupling in the methylene signals attributable to C-1 was observed. That drupacine is the 2,ll-bridged structure 115 was demonstrated by its preparation under mild acid conditions from 1 1-hydroxycephalotaxine (see Scheme 29). Furthermore, treatment of 114 with tosyl chloride in pyridine gave the 3,ll-bridged ether 125. These reactions require a cis relationship between the 1 1-hydroxyl group and the cyclopentene ring, so that the stereochemistry of the hydroxyl group in 11-hydroxycephalotaxine must be as shown in 114, where the hydroxyl groups are in close proximity. Further support for this assignment came from the finding that the diacetate of 114 could be readily epimerized at C-1 1, a reaction which obviously relieves the steric congestion.
OCH,
OCH,
114
11s
I OCH, 12s
SCHEME 29
50
S. F. DYKE AND S. N. QUESSY
The ready conversion of 114 to 115 suggested that drupacine might be an artifact produced during the isolation procedure. However, it was demonstrated that the isolation conditions could not account for all the material, so that some drupacine must be present in the plant (101). Both alkaloids are unique to C. harringtonia var. drupacea, and an alkaloid with properties similar to those of drupacine was also reported by Asada in the same species, although no structure was given (110). 4. Cephalotaxinone, Desmethylcephalotaxine, and Desmeth ylcephalo taxinone Cephalotaxinone (C, ,H ,NO,) was first isolated and characterized from C. harringtonia var. harringtonia (89) and later from C. fortunei (98). In the IR spectrum of this material, the hydroxyl group of cephalotaxine was absent but a carbonyl absorbance at 1720 cm-' was present. A shift in the olefinic absorbance from 1665 to 1625 cm-' suggested an enone structure. Cephalotaxinone was found to be identical to the product 112 formed by Oppenauer oxidation of cephalotaxine (105a) (see Scheme 30). This also established the stereochemistry of 112 at C-4 and C-5.
OCH,
OCH,
105a Cephalotaxine
112 Cephalotaxinone
SCHEME 30
Desmethylcephalotaxine (111) was first prepared by mild acid hydrolysis of cephalotaxine, during the early structure elucidation work (102). The same workers later identified this material as a minor constituent of C. fortunei (98). Desmethylcephalotaxine is not an artifact, since pure cephalotaxine can be subjected to the isolation procedure without loss. It was noted that chromatography of Ceplra~otasus alkaloid fractions over neutral alumina resulted in considerable losses (111). Further elution with dilute aqueous acetic acid resulted in the isolation of a new alkaloid, desmethylcephalotaxinone ([.ID + 2.3"). The IR spectrum of this alkaloid was consistent with the presence of a vinylic hydroxyl group (3520 cm-l) and a conjugated carbonyl group (1690 cm-I). The NMR spectrum obtained in deuterochloroform contained features of the cephalotaxine structure, but included a singlet attributable to an isolated methylene (6 2.54 ppm). In DMSO-d, this resonance appeared as an AB quartet. Acetylation
1.
51
ER Y 7 H R I N A A N D RELATED ALKALOIDS
produced an enol acetate, which exhibited a signal due to an isolated methylene at 6 2.59 ppm in the NMR spectrum. Structure 113 was established by interconversion reactions. Cephalotaxine was oxidized to cephalotaxinone (112) (as in Scheme 30) which, on vigorous hydrolysis in acid, gave desmethylcephalotaxinone ([.ID 40") in less than 30% yield after 3 hr at 80' (see Scheme 31). This material was identical to the natural product except for its optical rotation. It appeared that the natural product was nearly racemic since methylation gave optically inactive cephalotaxinone (see Scheme 31) plus a small quantity of the isomeric ether 126. The spectroscopic evidence suggested that desmethylcephalotaxinone exists in the tautomeric structure 113. The possibility that 113 was an artifact was considered unlikely under the conditions of isolation. The alkaloid has been found as a minor component in C. harringtonia var. harringtonia and in C. harringtonia var. drupacea ( I l l ) .
+
vigorous H *
'CH ,CH,CHIOCH,), , H
> +
0
OCH,
113 R = H Desmethoxycephalotaxinone 126 R = CH,
112 Cephalotaxinone
SCHEME 31
V. Biosynthesis A.
E R Y T H R ~ N AALKALOIDS
At the time of the last review in this treatise ( I ) very little was known about the biosynthesis of the Erythrina alkaloids. The essential postulate was that the aromatic bases are derived from tyrosine, with a phenolic coupling as a key step (Scheme 32) involving the symmetrical intermediate (127a) derived from 3,4-dihydroxyphenylalanine (DOPA). In one suggestion. oxidation of 127a to 128 (route 1, Scheme 32) and ring closure to 129, followed by cyclization to 132a was envisaged, whereas in the alternative proposal (route 2, Scheme 32) 127a undergoes phenolic coupling to 130a, followed by oxidation to the diphenoquinone (131a) and cyclization to 132a. The overall scheme was supported by the observation (66,112) that when 127a was oxidized with alkaline potassium ferricyanide ( )-erysodienone (58) was isolated in 35% yield. Mondon and Ehrhardt (66) also described the further in aitro conversion of (58)to ( f)-erysodine (7) via 133.
+
Tyrosine
L
DOPA
I
OH
R20
OH
OH
130
128
RZO
I
0
steps
131
HO 0
129 0
132
a : R, = R, = H b : R, = R, = Me
H
Me0 R'O 7
OH 133
SCHEME 32. A postulated biosynrhetic whet?ir.forErythrinu alkaloids
Hoq-$H 1.
58
-
53
E R YTHRf.VA A N D RELATED ALKALOIDS
%: :M
Me0
< H
Me0
/
Me0
QH 133
7
Since that time dramatic advances have been made in our understanding of the biosynthetic pathways to these alkaloids, almost entirely as a result of I4C-labeled feeding experiments. In an early study (113) [2-14C]tyrosine (34)was found to be incorporated equally at C-8 and C-10 of /l-erythroidine (60),a type of Erythrina alkaloid always believed (114)to arise from aromatictype compounds. This observation was regarded as a strong piece of evidence in favor of Scheme 32. Barton et al. (115) found acceptable levels of incorporation of 134 into erythraline (4), but when 127b, tritiated in the otherwise unsubstituted
mH;zH
HO
---+
o%*
-
MeO,'
134
60
4
positions ortho and para to the phenolic hydroxyl groups, was fed to E. crista galli very low levels of incorporation were found. It was concluded that a secondary amine such as 127 is not a precursor of the aromatic Erythrina alkaloids and an alternative biosynthetic route (Scheme 33) was proposed (115). In a key experiment (115) it was shown that (+)-(S)-norprotosinomenine (135) was incorporated into 4 100 times more efficiently than its enantiomer, strong evidence that 135 is a specific precursor of 4 (19,61,116).The intermediacy of 130b was also established (68).Interestingly, dibenzazonine alkaloids have been isolated from various erythrina species (21, 23). Furthermore, erysodienone (58) has been isolated (22, 23,34),
DOPA
Tyrosine
OMe
OH 136
135
I OH
OH
M
Me0
e/
o
g
\
H
Meox& /
Me0
OH
\
OH
130b
137
Me0 Me0 58 Erysodienone
138
Me0 OH SCHEME 3 3 . The biosynthetic route to the Erythrina alkaloids
1.
55
E R YTHRlh'A A N D RELATED ALKALOIDS
Me0
Me0
MeO"
0
Me0
0 48 Erysotrine
Me0
MeO'
MeO'
OH 42 Erythratine
140
I
I
i
J
Erysovine (5)
Erythraline (4)
+ Erysopine (9) + etc. SCHEME 33 (continued)
together with (S)-norprotosinomenine, from E. lithosperma (but see Section II,A about this species). When ['4C]4-methoxynorprotosinomenine was fed to E. crista galli, the erythraline (4) that was isolated was found to be equally labeled at the methoxyl and methylenedioxy group carbon atoms, thus confirming the involvement of a symmetrical intermediate such as 130b.
56
S. F. DYKE A N D S. N. QUESSY
The important point concerning stereochemistry was also considered by Barton et al. (117, 118), who pointed out that the conversion of chiral 136 to 130b, thence into chiral erysodienone (as 139), must either involve an
139
inversion of configuration or a symmetrical intermediate. They showed (118) that chiral 130b is very rapidly racemized at room temperature and that only (-)-(55’)-erysodienone is the precursor of erythraline and of both a- and P-erythroidine. The biosynthesis of the “unusual” Erythrina alkaloids such as isococculidine (36), cocculidine (54),and cocculine (56) proceeds (119, 120) from (+)-
54 R = M e 56 R = H
(S)-norprotosinomenine (135).This was established (120) in feeding experiments with C. laurifolius DC. The proposed route is summarized in Scheme 34, where reduction of 136 to 141 was originally thought to occur, followed by a dienol-benzene rearrangement to 142. However, cyclization of 142 to isococculidine (36) is hard to visualize, although intermediate 143 was postulated. An alternative route (11a) involves reduction of the diphenoquinone 144 to 145, followed by cyclization to 146 and further elaboration to 36. The biosynthesis of z-and p-erythroidines has been investigated (118)by feeding 17-rnonotritioerysodine, 14,17-ditritioerysopine, and 1,17-ditritioerysodienone, when high levels of incorporation were observed, thus confirming that these lactonic alkaloids are derived in vivo from the aromatic compounds. The remaining point of ambiguity concerns the position of cleavage of ring D; the feeding experiments are compatible with either C-15-C-16 or C-16-C-17 cleavage, with the loss of C-16 and retention of tritium at C-17.
135
I 4
Me0 Me0
0 144
OH 141
I /
M Meo%H e0
\ OH 142
J.
/
M eO
MeO,'
0 143
36
58
S . F. DYKE AND S.
N. QUESSY
B. HOMOERYTHRINA ALKALOIDS The first two homoerythrina alkaloids to be isolated (82)were schelhammerine (80a) and schelhammeridine (77a), and since various species of
OH
80a
17a
Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested (82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view; ( +)-[2-14C]tyrosine causes specific labeling of C-8 in 77a. ?H Me0
OH
I
OH
1.
59
E R Y T H R I N A AND RELATED ALKALOIDS
C. C E P H A L O T AALKALOIDS XCS Arguing from structural similarities, it was originally suggested (10)that the Cephalotaxus alkaloids could be derived in viuo from the same precursor as the aromatic erythrina bases, but since Cephalotaxus and homoerythrina alkaloids have been isolated (90)from E. wilsoniana, it has been postulated (lob, 89) that both groups have a 1-phenethyltetrahydroisoquinoline as a common precursor (Scheme 36). Tyrosine is incorporated (122)into cephalotaxine, but the labeling pattern did not seem to be consistent with a
benzilic
rearrangement
RO
HO CO,H
0
.L
etc
SCHEME 36. Possible biosynrhetic route to the Ci~phulotaxusalkaloids.
60
S. F. D Y K E A N D S. N. QUESSY
OMe 105a
CO,H OH
0
acetyl-Co A
*C02H
&COZH
CO,H cephalotaxine
1
\COZH 110
S C H ~37. M ~Bios.vnthrsi3 uf dro.iy/turrittylottirtr
0
1.
E R YTHRl’VA AND RELATED ALKALOIDS
61
l-phenethylisoquinoline intermediate. Thus, [3-14C]tyrosine gave cephalotaxine (105a) with 68% of the activity at C-11 and 32% at C-4, but [2-14C]tyrosine labeled C-10 (37% of the activity); no label was found at C-7 or C-8. However, it was realized subsequently (123) that tyrosine was being catabolized, and the aromatic ring was not being incorporated into cephalotaxine. It was found (123)that phenylalanine is the precursor, in line with the derivation of other l-phenethylisoquinolines,and that ring D is derived from the aromatic ring of phenylalanine with the loss of one carbon atom. The biosynthesis of the acyl side chain of deoxyharringtonine (110) has been found (124) to involve L-leucine (Scheme 37).
VI. Synthesis A. ERYTHRINA ALKALOIDS A synthesis of erysotrine (1) was achieved by Mondon and his associates and reported in preliminary form in the previous review in this treatise (1). This work, which has now been published in full (125-129), is summarized in Scheme 38. Condensation of homoveratrylamine with the glyoxalate derivative of 4-methoxycyclohexanone gave the enamide (147) which, with phosphoric acid, was cyclized to the tetracyclic material (148). Reduction with Raney nickel followed by treatment with sulfuric acid gave the oxide (149) in which the rings A/B must be cis-fused. When 149 was subjected, after O-acetylation, to acid treatment, a mixture of two alkenes (150) was formed. These were separated and the correct one epoxidized to 151. Ring opening of 151 with dimethylamine yielded 152 which, on Cope elimination from the derived N-oxide, gave the alkene (153). Allylic rearrangement occurred when 153 was treated with acidified methanol to yield 154 as a mixture of epimers. These were separated by chromatography and each was carried through the remainder of the synthesis. Reduction of the amide carbonyl group of 154 gave 155, and this was followed by dehydration to 1. Finally, resolution of 1 was effected with dibenzoyltartaric acid to provide the (+)-isomer, identical with erysotrine obtained from natural sources. Mondon (125) was also able to convert the isomers (150), where the cis-A/B ring junction is established, to the dihydro derivative (156). This was then reduced to 157, where the A/B ring junction must be cis. Later, Kametani et al. (130, 131) reported that the tetracyclic compound (160) could be obtained as a mixture of cis-trans isomers merely by heating together the amine (158) and the ketoester (159). However, Mondon (132, 133) has cast doubt on this work and concludes that Karnetani’s product is
62
S. F. D Y K E A N D S. N. QUESSY
147 \
149
150
148
151
Me0
,
'OH
NMe,
153
152 SCHEME38. The ,first sythesis of erysotrine
1.
63
ER Y T H R I X A A N D RELATED ALKALOIDS
1.53
HC I !&OH
A
Me0
M e O ‘ U
154
I
( 1 1 separation 01 cpimeis
(111
LAH
Me0
“OH
155
1
SCHEME 38 (continued)
150
% Meo% Me0 ‘OH
Me0 Meo%
156
157
a mixture of the cis isomer (157) and the uncyclized material (161). Kametani et al. (131) also described the condensation of 158 with 162 and with 163 to form 164 and 165, respectively, but Mondon (132) concludes that these structures too are incorrectly assigned. HO Me0
159
160
64
S. F. DYKE AND S. N. QUESSY
Me0
U 161 158
164
165
A new approach to the synthesis of the Erythrina alkaloids involves (134) a Birch reduction of the amide (166) to 167, followed by cyclization, first to 168 with sulfuric acid in DMF, then to the ketolactam (169) with formic BzO
HO
Me0
Me0
T
N
M eO d
Me0 166
H
M
167
I
H,SO, DMF
98" HCO H
&
Me0
169
168
0
Y
e
1.
65
ER Y T H R I X A A N D RELATED ALKALOIDS
acid. When the isomeric amide (170)was subjected (135)to a similar sequence, the overall yield of 172 reached 90%. Ketalization of 172 with ethylene
Me0
170
171
I Me0e
O
y
$
+K;z:xFJ
MHe 0
(
H,SO,. DM F
O
0
0
L/ 172
173
/
(il Li+NR, lii) 0,
3'"' '
THF
(I)
M e0
e
0
Oxidation
f;":',
9 H
Me0
Me0
OH
H "OAc 0
LJ
175
174
i Me0
V
e
0
-9
+---
35""
MeO% Me0 'OAc
MeO"
/
1 Erysotrine
/
176
(I,) ill
m+ Meo%
HC'I MeSO,CI dcelone
Me0
Me0 OS0,Me
OH
O w 0
O w 0
177
174
85",,
!
NdOH MeOH
178
180
\
Zn HOAc
PhSeCl
";"-::6,. Me0
Y
Me0 CI
w
0
SePh C
I SCH,Ph
I
I
W
182
181
*
15"" H,Oi ps
loo",
i
Me0 182
179
SCH,Ph
Me0
4gYO. MrOH
RdNl
MeO"
MeO"
1.
67
ER YTHRINA A N D RELATED ALKALOIDS
glycol followed by 0-methylation gave 173, the lithium enolate of which was hydroxylated with oxygen to yield 174, which has the wrong stereochemistry at C-7. Epimerization was achieved by oxidation followed by reduction. Acetylation of the hydroxyl group and deketalization then yielded the ketoamide (175), which was reduced and dehydrated to 176. The conversion of 176 to erysotrine had been reported previously by Mondon and Nestler (136). The total synthesis of (+)-Erysotramidine (2) has been described by Ito et al. (137) starting from the amide (174) (Scheme 39). After 0-mesylation to 177, base-catalyzed reaction gave the cyclopropane derivative (178) which with zinc in acetic acid was reduced to 179, which was identical to the product (135) of 0-methylation of 172. Conversion of 178 to the thioketal(l80) was followed by reaction with phenylselenyl chloride. A mixture of two compounds, 181 and 182, was produced; the former could be transformed quantitatively to the latter. Finally, treatment of 182 with silver nitrate in methanol gave 183, which was then desulfurized to yield erysotramidine (2). An interesting short synthesis of the erythrane skeleton has been achieved by Wilkens and Troxler (138). Ethyl cyclohexanone-2-carboxylate was MeO.
L
M
o
e
w
,
Et 184
185
alkylated with ethyl bromoacetate, followed by condensation with homoveratrylamine to yield 184. Cyclization of 184 with phosphoric acid yielded 185. Stevens and Wentland (139) have prepared the erythrane derivative (187) by reacting the endocyclic enamine (186) with methyl vinyl ketone.
Me Meor rn i Meo”i-. -Meo +M e 0
Me0
O
POCI,
Me0
Me0
H
0 187
186
f
l
68
S. F. D Y K E AND S. N. QUESSY
The enamine (186) was itself prepared from homoveratrylamine and y butyrolactone. Yet another approach to the erythrane skeleton (140)involved Birch reduction of 6-methoxyindoline to 188, followed by N-acylation with 3,4-dimethoxyphenylacetyl chloride to yield 189. When this product was reacted with POCl, the ketoamide (190) was obtained in poor yield; the major product was 191.
Me0
rn 188
I 189
191
Synthetic studies along the biosynthetic route have attracted considerable attention. A very early success mentioned in the previous review ( I ) and in the biosynthesis section of this chapter (Section V,A) involved the oxidation of the diphenol(127a) with alkaline potassium ferricyanide to erysodienone (132a) via the benzocene (13Oa) and the diphenoquinone (131a) (Scheme 32). The mechanism of this reaction has been discussed by Barton et al. (68).The
1.
69
E R Y T H R I N A AND RELATED ALKALOIDS
dienone (132a) has been converted to erythratine and dihydroerysodine (see Section V,A). A particularly interesting and useful synthesis of 130b has been described by Kupchan et al. (141-143), who oxidized the l-bemyltetrahydroisoquinoline (192, R = COCF,) with vanadium oxyfluoride (Scheme 40). Earlier Kametani et al. (144) had oxidized 192 (R = C0,Et) with potassium ferricyanide and had obtained 193 (R = C0,Et) in 2% yield. HO Me0
R
OH
OH
192
193
I
NaOH
130b
NaBH,
194
SCHEME 40. Kupchan's sjnthesis of bcvrxcenes
Oxidation of the 1-benzyltetrahydroisoquinoline(195) with VOCl, (145) yielded the dienone (196) in 34% yield; reaction of this with boron trifluoride etherate provided 197, and this was converted, as shown in Scheme 41, to 14-methoxyerysodienone (199). Oxidation of the secondary amine (200) gave (146)the methoxyerysodienone (201) in only 6% yield. The alternative mode of oxidation, leading to 202, was not observed.
70
S. F. DYKE AND S.
N. QUESSY
HO
Ms
Me0
Me0
OH
OH
195
196
I
63",, BF,IEt,O
OH
Meek ?H
Me0
M
e
o
w
\ Ms
w OH
OH 198
197
J
I99 SCHEME 41. Preparation of 14-metho~q.erq.sodienone.
A photochemical method has been employed by Ito and Tanaka (147) to synthesize erybidine (62) (Scheme 42). Irradiation of the bromoamide (203) gave a mixture of lactams 204 and 205. After chromatographic separation, the former was reduced and N-methylated to erybidine. Alkaloids of the erythroidine type have not yet been synthesized, but the parent ring system has been obtained (148) by the method summarized in Scheme 43.
1.
71
E R YTHRI.CA A N D RELATED ALKALOIDS
K,FelCNI,
Me0
Me0 OH 200
OMe
Hoq 201
Me0 \
0 202
OH I
Me0
Me0
\
Me0
SCHEME 42. S~ttrltesisof Er.rhidiltc. by pliorolFsis.
72
S. F. DYKE AND S. N. QUESSY
C:r
C0,Et
I
PhCHO
(iiJ HCILMeOH
v SCHEME 43. Preparation oj rlir e r j tliroidiiie skelerori.
B. HOMOERYTHRINA ALKALOIDS The ring system of the homoerythrina alkaloids has been prepared (149)by oxidative coupling of the 1-phenethyltetrahydroisoquinoline (206, R = COCF,) (Scheme 44). The diphenol (208) was obtained in 76% yield from 207, but all attempts to oxidize the N-trifluoroacetate of 208 to a diphenoquinone failed-probably because the two aromatic rings are orthogonal to each other. However, oxidation of the secondary arnine (208) itself with potassium ferricyanide gave a mixture of 209 (45”/d yield) and 210 (15%);
1.
73
ER YTHRINA AND RELATED ALKALOIDS
5?M:e
‘OCF3
Me0 Me0
\
‘ OH
OH 201
206
I
(I) NaOH (11)
(111)
HCI NdBH,
OH
208
0 209
HO
M
e
00
9
210
SCHEME 44. Preparatiori of’ a honioer~.rl~ritia bF ozridarice coupling
these were separated by preparative thin layer chromatography. Sometime previously, Kametani and Fukumoto (150) described the oxidation of 206 (R = H) with potassium ferricyanide and assigned structure 210 to the product, but later they (151)altered this to 209.
74
S. F. DYKE AND S. N. QUESSY
The dienone (210) has also been prepared (152, 153) by oxidation of the amide (211) with potassium ferricyanide, when 212 was obtained in 67% yield. After protection of the phenolic hydroxyl group, reduction with LAH
211
212
removed the amide carbonyl and reduced the dienone to the dienol. Reoxidation and removal of the 0-benzyl group then yielded 210. An alternative preparation of 209 was described (152) in which 210 was converted (I) (11) (111)
BrCl LAH CrO,
Me0
210
89"o
eH
?H
I
chromous chloride
\
209 SCHEME 45. A n alternative preparation of 209
1.
75
E R Y T H R I N A A N D RELATED ALKALOIDS
to the amide (213)in 89% yield by reaction with chromous chloride; the amide (213), after 0-benzylation, reduction with LAH, and de-0-benzylation, gave the amine (208) in 53% yield. Finally, a 60% yield of 209 was realized when the diphenol 208 was oxidized with alkaline potassium ferricyanide (Scheme 45). Interestingly, when the dienone (207) is treated with BF,/etherate (154), rearrangement occurs to give the homoaporphine (214). Oxidation of the tetramethoxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (215) with VOF, gave (142) a little of the dienone (210, together with a 64% yield of 217. However, when each was treated with acid, rearrangement occurred to give 218 and 219, respectively.
M::ycoc Me0Y Me0
Me0
\
OH
Me0
.6' OMe 215
214
OMe 0
M e 0P \ C
O
C
OMe
OMe
M:Ip 217
216
M
e
o
COCF,
Me0 OMr 218
OMe 219
w
F
3
76
S. F. DYKE AND S. N. QUESSY
c. CEPH.4LOTAXL.S
ALKALOIDS
1. Cephalotaxine The total synthesis of alkaloids of the cephalotaxine type has attracted considerable attention (75) because of the anticancer activity reported for certain derivatives (100) (see Section IV,A). The first synthesis of cephalotaxine (105a) was reported by Auerbach and Weinreb (155,156),closely
OMe 105a
followed by that of Semmelhack et al. (157-159) by a very different route. The former method can be conveniently divided into two stages, with the tricyclic enamine (225) as the first target; the route adopted is summarized
220
224
\
225 SCHEME 46. The prc'paration of the tricyclic enamine (225).
1.
77
ER Y T H R I N A A N D RELATED ALKALOIDS
in Scheme 46. Acylation of 1-prolinol (221) with 3,4-methylenedioxyphenacetyl chloride (220) at - 20" in acetonitrile solution gave the N-acylated compound (222), with only minor amounts of the 0-N-diacyl derivative. Oxidation of 222 to 223 was effected with dimethyl sulfoxide, dicyclohexylcarbodiimide, and dichloracetic acid. Cyclization of 223 to the tricyclic amide (224) was achieved using boron trifluoride etherate. The required enamine (225) was obtained in quantitative yield by reducing 224 with lithium aluminium hydride. The second phaseof the synthesis by Auerbach and Weinreb wasconcerned with the construction of ring D. This proved to be rather difficult and initial attempts failed. Thus, alkylation of 225 with propargyl bromide gave 226, which upon hydration with aqueous mercuric sulfate yielded the expected ketone 227. However, all attempts to cyclize 227 failed. In a modified 225
(9 (9 0
226
I
Me0
C0,Et
228
0A C H ,
227
approach, 225 was alkylated with 4-bromo-3-methoxycrotonate, but again the alkylated material (228) could not be cyclized. The a-dicarbonyl compound (230)was prepared (Scheme 47) by acylating 225 with a 2-acetoxypropionyl chloride in acetonitrile to give 229, which, after hydrolysis with potassium carbonate, was oxidized to 230 with lead dioxide. In a better procedure, wherein 230 was obtained directly in 73% yield, the tricyclic enamine (225) was treated with the mixed anhydride obtained from the interaction of pyruvic acid with ethyl chloroformate. An intramolecular Michael addition was achieved by treating 230 with magnesium methoxide,
78
S. F. DYKE AND S. N. QUESSY
(yq-&-<W 0
0
AcO
P-
229
&Me 0 230 52“,
I
Mg(OMe),
0
231
112 Cephalotaxinone
SCHEME 47. Auerharh and Weinreb‘s synthesis of rrp/ialora\-ine.
leading to demethylcephalotaxinone (113). A study of the N MR spectrum revealed that none of the tautomer (231) was present. Demethylcephalotaxinone has been isolated from C. harringtonia ( I l l ) , and the synthetic product was found to be identical to the natural product. However, when 113 was heated under reflux with an excess of 2,2-dimethoxypropane in methanol/ dioxan, cephalotaxinone (112) was formed and isolated in 40% yield. Finally, reduction of 112 with sodium borohydride proceeded in a stereospecific fashion to give racemic cephalotaxine (105a). An alternative route (Scheme 48) was used by Dolby et al. (160)to prepare the tricyclic enamine (225).A Vilsmejer reaction between 3,4-methylenedioxyN,N-dimethylbenzamide (232),and pyrrole gave the amide (233)in 80% yield. Reduction with sodium borohydride provided the benzyl pyrrole (234),which
1.
ER YTHRINA AND RELATED ALKALOIDS
232
233
235
234
236
79
231
lLAH 238
SCHEME 48. Dolbj's preparation o/ enaminc2 225.
was further reduced to 235 catalytically over a rhodium-alumina catalyst. N-Acylation with chloroacetyl chloride gave 236 which on irradiation was cyclized to the tricyclic amide (237). Reduction with 1ithiu.m aluminium hydride yielded the saturated amine (238), and this was converted to the required enamine (225)by treatment with mercuric acetate. A chelating ionexchange resin was used to remove excess of mercuric acetate-a procedure superior to precipitation of the sulfide with hydrogen sulfide. Attempted annulation of 225 with ethyl x-bromoacetoacetate led to the rearranged tetracyclic compound 239 (R = C0,Et) and not to the expected product (240). Hydrolysis and decarboxylation of 239 (R = C0,Et) gave the ketone (239, R = H) which on further reduction yielded the amine (241). identical to the material prepared some years ago (161) by an independent route.
80
S. F. DYKE AND S. N. QUESSY
240
241
239
Alkylation of 225 with bromoacetone (160)gave the expected product 227, but attempts to cyclize this material gave the rearranged compound 239 (R = H) once more. It was postulated by Dolby et al. that the initially formed product was the desired compound 240 which then rearranged to the observed product 239 (R = C0,Et) by the mechanism summarized in Scheme 49. 0
I1
225
BrCH,~-C--CH,CO,El f
240
I 0
0
239 R = C0,Et
SCHEME 49. Dolby's mec~huiiisnt.fbr reurraizgeimwt of' 240
to
239.
1.
81
ER )ITHRI.VA AND RELATED ALKALOIDS
242
243 (I)
TFAA
(iil SnCI,
238
244
1
Hg(OAc1,
225
SCHEME 50. A n alternatice preparation of enaminr 225
Yet another method has been described (162)(Scheme 50) for the preparation of the tricyclic enamine (225). N-Alkylation of ethyl pyrrole-2-carboxylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156)but contrasting with the report of Dolby et al. (160). A photochemical route to the key amine (238) has been described by Tse and Snieckus (163) (Scheme 51). The maleimide (245) was iodinated in the
245
246
241 SCHEME 5 1. A photochemical prc,parution of tricyclic amine 238
82
S . F. DYKE AND S . N. QUESSY
presence of silver trifluoroacetate at the 6-position, then treatment with methyl magnesium iodide, followed by dehydration gave 246. A 40% yield of 247 was obtained on irradiation of the alkene 246, and reduction then gave 238. The second total synthesis of cephalotaxine (157-159) was very different conceptually since it was a convergent synthesis involving the two intermediates 248 and 249. The azabicyclic intermediate (248) was prepared from pyrrolidone (250) (Scheme 52), which with the Meerwein reagent gave 251. The latter was treated with an excess of ally1 Grignard reagent to yield 252.
248
249a X = C1 249b X = I
251
250
n
254
253
Me,SiCI
Me,SiO
i
1
+H
Z 0 -
3
248
OSiMe,
L
J
255
256
SCHEME 52 Seriimelhach's synthesis of cephalota.uine
1.
ER Y T H R I N A AND RELATED ALKALOIDS
83
N-Acylation with tert-butoxycarbonyl azide to 253 was followed by oxidative ozonolysis and esterification to 254. The yield of 254 from 252 was 61% in a procedure whereby the intermediates were not isolated. The diester (254) was subjected to the acyloin condensation with a potassium-sodium alloy and the product was isolated as the O,O,N-trisilyl compound (255). This was oxidized immediately with bromine to 256 and treatment with diazomethane gave 248. The yield of 248 from 254 was 55%. Intermediates 249a and 249b were obtained from piperonal by standard methods. The essential intermediate 257 required for ring closure to the cephalotaxus skeleton was obtained (about 60% yield) by combining 248 and 249 in acetonitrile solution. A number of methods of cyclization of 257 was studied (Scheme 53). In the first approach 257a was treated with sodium triphenylmethide, when a 13-16% yield of cephalotaxinone (112) could be isolated
257a X 257b X
= C1
112
=I
7
258 SCHEME 53. The cyc1i;atiorr rcvictions t o cephalotasinone
NCOCF,
'$
*
NCOCF,
"OF,
BzO
/
\
OMe
\
BzO
OMe 26 1
260
INaOH
OMe
GMe
OMe
OMe
263
M
e
O
I
262
( I ) TFA In) CH,N,
g
/ (1)
OMe Meo$~
Pd C H,
1111 K K O ,
NCOCF,
HO
/
\
OMe BzO
\
265
OMe 264
.i
266 SCHEME 54. A hii~genriicull.vputteriicd approach to cc~phali~rurinr.
1.
E R Y T H R I X A AND RELATED ALKALOIDS
85
from the complex mixture. The reaction was presumed to involve the benzyne anion (258) as an intermediate. No improvement in yields could be gained by using the iodo compound (257b) or by variation of the conditions. The yield of 112 was raised to 35% when the anion (259) derived from 257b was treated with a Ni(0) complex to induce nucleophilic displacement of iodine. In an alternative procedure, the anion (259) was treated with a sodiumpotassium alloy to form cephalotaxinone (112) in 45% yield. However cephalotaxinone was obtained in 94% yield when 25713 was treated with potassium tert-butoxide in refluxing ammonia with simultaneous irradiation with a Hanovia 450-W medium pressure lamp. These conditions caused radical cleavage of the aromatic ring-iodine bond in the anion (259),followed by coupling of the aromatic radical with the nucleophilic center. Finally, reduction of 112 with diisobutyl aluminium hydride gave ( -t)-cephalotaxine (105a) An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the I-phenethylisoquinoline derivative (260) with VOF, (Scheme 54). Alkaline cleavage of the dienone (261)gave 262 which, as the hydrochloride salt, was reduced 263. N-trifluoroacetylation followed by 0-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 2. Esters of Cephalotaxine Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against L1210 and P388 leukemias in mice (89, 100, 108), and so some attention has been devoted to the synthesis of the dicarboxylic acid side chains (see also Section IV,A). The hydroxydicarboxylic acid (270), derived by hydrolysis of deoxyharringtonine, was synthesized by the method shown in Scheme 55 to confirm the structure deduced by spectral methods (see Section IV,A). Conventional chemistry was employed; methyl isopentyl ketone (267)was reacted with diethylcarbonate in the presence of sodium hydride to yield the ketoester (268).Addition of HCN gave 269, hydrolysis of which provided the hydroxydicarboxylic acid (270). The overall yield was 48%. Esterification with diazomethane gave the diester, which was partially hydrolyzed to the halfester (122), the most hindered ester function remaining intact. This, after conversion to the half-ester acid chloride, was used to acylate cephalotaxine. A pair of diastereomorphs was produced, neither of which proved to be identical to deoxyharringtonine. It was concluded that the latter must have structure 110 in which the ester linkage to cephalotaxine involves the tertiary,
86
S. F . DYKE AND S. N. QUESSY
0
261
268
OMe 0 %OH 122
0
123
SCHEME 55. S.vnthetic proof of structure of deoxyharringtonine.
rather than the primary carboxyl group. However, when the isomeric halfester (123) was prepared, acylation of cephalotaxine could not be achieved, presumably because of steric hindrance at the carboxyl group. An alternative synthesis of 123 (165) (Scheme 56) started from the commercially available dimethyl itaconate (271, R = Me). Epoxidation to 272 (R = Me) was achieved with trifluorperacetic acid, and this, with isobutyllithium and cuprous iodide, gave the diester (273, R = Me). The benzyl ester (273, R = CH,Ph) was prepared in a similar way from 271 (R = CH,Ph) and 272 (R = CH,Ph). Catalytic hydrogenolysis of 273 (R = CH,Ph) gave the required half-ester (123). Finally 123 was resolved with ephedrine. Auerbach et d. (165)also failed in their attempts to acylate cephalotaxine to deoxyharringtonine. However, deoxyharringtonine (110)has been synthesized (166-168) by the method summarized in Scheme 57. The lithium salt (274) of 3-methyl-lbutyne was condensed with ethyl tert-butyloxalate to give 275 which, after
1.
87
E R Y T H R I X A AND RELATED ALKALOIDS
CF,CO,H
'C0,Me 271
272
C0,Me 273 ( R = Me = 121) 273 (R = H = 123)
SCHEME 56. A n alternatioe synthesis of the acid 123.
reduction and hydrolysis, yielded the cc-ketoacid (276). Conversion of 276 to the acid chloride followed by reaction with cephalotaxine provided the ester (277). Deoxyharringtonine (110)was produced when 277 was condensed
Ll+-C-c
i i
EtO CC0,t-Bu
0 P
o=c-c-c= 1
0-t-Bu
274
275
1
(i) HJPdiC (ii) TFA
(i) SOCI, (ii) cephalotaxine
HO,C
276
"
I
/I
-c'
+
OMe 0 277
\
MeC0,Me;LDA
110
SCHEME 57. Synthesis of deoxyharringtonine
88
S. F. DYKE AND S. N. QUESSY
with the lithium salt of methyl acetate. The mixture of diastereomorphs was separated by thin layer chromatography. The hydroxyacid (118) obtained by the hydrolysis of harringtonine was synthesized (169) by the route shown in Scheme 58. Condensation of the lithium salt (278) with ethyl tert-butyloxalate gave 279, which with the lithium salt of methyl acetate was converted to 280. Hydrolysis with trifluoracetic acid yielded 281 (R = H) which with diazomethane gave the dimethyl ester (281, R = Me). Catalytic hydrogenation and hydrogenolysis with 10% palladium on carbon yielded 118 which, apart from optical rotation, was found to be identical to material obtained from harringtonine, thus confirming the structure of harringtonine deduced by spectral methods (see Section IV,A). When the half-ester (281, R = H) was treated with hydrogen over palladium on charcoal, the lactone (282)was produced. Harringtonine (107) has been synthesizcd (170) by the method shown in Scheme 59. Claisen condensation between 283 and ethyl oxalate in the presence of NaH gave 284 which, when heated under reflux with aqueous HCl, was converted to a mixture from which the oxide (285) was isolated. Without purification, 285 was treated with HCl/MeOH to yield 286, saponification of which yielded the unsaturated acid as its sodium salt 287. After conversion to the acid chloride, reaction with cephalotaxine yielded 288.
Li+-Cec
4Me,COCOCO,Et
t-Bu0,C
"--J? C=C
1
219
218
MeCO:g,LDA
OBz
OH
OBz +
t-BuOZC \CO,Me
281
280
H, Pd C EtOAc
w
0
2
M
e
&H
C0,Me C0,Me 118
282
SCHEME58. Synthetic proof o j structure of harrinytonine
1.
E R YTHRINA A N D RELATED ALKALOIDS
89
Hydration of the double bond of 288 gave 289, on which a Reformatski reaction was performed to yield harringtonine (107) together with epiharringtonine (because of the two modes of hydration of the double bond in 288) (Scheme 59). The required ester (283) was prepared by first condensing isobutyraldehyde with malonic acid to form 290, followed by isomerizing with 0 CHCH2C02Et
283
286
(CO,Et), NaH
’
I1
)
I
CHCHCC0,Et C02Et 284
285
LCO*Me 107 SCHEME 59. S?;nthesis of harringronine
90
S. F. DYKE A N D S. N. QUESSY
base to 291 and then by esterifying to 283. A very similar route to harringtonine has been described by Chinese workers (171).
: i-x CHO
CH=CHCO,H 290
1 -
283
BF, EtOH
KOH H,O
>,:HCH2COzH 29 1
In the structural analysis of isoharringtonine (109),the relative configuration of the diacid side chain was solved (172) by a synthesis (Scheme 60).
_j____l_
C0,Et COMe
-!(LL!?KOH %,
WCozH
292
/ *o
293
H
C0,Me
d%C02Me =5 . 8 5 3
CO,H
C0,Me
0 294
H? 6 = 6.8 295
297
I
OSO, H,O,
.."..x
0 5 0 ,
0,Me
, C0,Me OH
296
I
MeO,C&H OH 298
SCHEME 60. Relatiue configuration of side chain of i.so/zarringtorzine.
H,O,
1.
ERYTHRI,VA AND RELATED ALKALOIDS
91
Trans-esterification of the alkaloid with sodium methoxide gave a single dimethyl ester which possessed either the threo (298) or the erythro configuration (296). Ethyl isoamylacetoacetate (292) was converted to 293 by a method developed by Vaughn and Anderson (173). Esterification of 293 gave the trans-dimethyl ester (297) which, with osmium tetroxide and hydrogen peroxide, yielded the single diol (298). This was assigned the threo configuration, in view of the known cis-hydroxylation achieved by osmium tetroxide. In an alternative sequence, the diacid (293)was dehydrated with P,O, to the anhydride (294), which in turn was esterified to the cisdiester (295). The vinyl proton absorption at 6 5.85 for 295 compares with the value of 6 6.8 for the trans structure (297). Cis-hydroxylation of the cis-diester (295) yielded the erythro compound (296). The PMR spectrum of 296 was found to be identical with that of the diol diester derived from isoharringtonine. The absolute configuration of the side chain of isoharringtonine has been deduced (174)to be 2R,3S(299)by comparing the C D spectra of its molybdate complexes with those of piscidic acid (300)of known absolute configuration.
COzH
CO,H
299
300
An alternative synthesis of 295 involves (175)the addition of diisoamyllithium cuprate to dimethylacetylene dicarboxylate. The major product (89%) was the required 295 together with some 297. The mixture was separated by chromatography.
VII. Pharmacology Many Erythrina alkaloids possess curare-like action. Alkaloidal extracts from different parts of Erythrina species have been used in indigenous medicine, particularly in India ( 176).Many pharmacological effects, including astringent, sedative, hypotensive, neuromuscular blocking, CNS depressant, laxative, and diuretic properties, have been recorded for total alkaloid extracts, although not all these properties can be associated with the erythrinane structure alone (38, 177, I78). A few purified Erythrina alkaloids have been shown to have useful pharmacological properties. Cocculine (56) and cocculidine (54) nitrates have been
92
S . F. DYKE AND S . N. QUESSY
reported to show hypotensive action in dogs, due mainly to ganglionic blocking action. Neither alkaloid had a significant effect on the CNS (179). Isococculidine (37)was shown to be a weak blocking agent at the cholinergic receptor in frogs (180).The juice of the leaf and bark of E. suberosa Roxb. was reported to have antitumor activity and the major alkaloid isolated was erysotrine (1)(181).Erysotrine was found to exhibit properties consistent with those of a competitive neuromuscular blocking agent in anaesthetized dogs (182). Cocculolidine (61) was reported to be an insecticidal alkaloid (76). Analogs of Erythrina alkaloids that lack the aromatic ring have been prepared for structure-activity studies (183). Antitumor activity in P388 and L1210 experimental leukemia systems was detected in extracts from the seeds of C. harringtonia K. Koch var. harringtonia (8,95).It was soon discovered that the major component, cephalotaxine (105a), was inactive and that the activity resided in the esters 107-110 (the harringtonines) ( 184187). Harringtonine (107) and homoharringtonine (108) had about the same activity in the P388 system and both were more active than deoxyharringtonine (110) and isoharringtonine (109).The latter two were only marginally active in the L1210 system (8).The optimum dose (for mice) was in the range 2-12 mg/kg by intraperitoneal injection over a period of 9 days (186, 187). Harringtonine appears to be the most effective agent and recent studies in the People’s Republic of China have shown that it is effective against L615 leukemia, L7212 leukemia, sarcoma 180, and Walker carcinosarcoma 256 (188).Harringtonine also appeared to be effective in the treatment of acute and chronic myelocytic leukemia in humans (189). The mode of action of the harringtonines has been investigated. All inhibit protein synthesis in eukaryotic cells (190-192). The principal effect of harringtonine was inhibition of protein biosynthesis in HeLa cells (193). Homoharringtonine, a potential antineoplastic alkaloid ( 194, was cytotoxic in HeLa, KB, and L cells growing in monolayer cell cultures (194). In view of the difficulty in obtaining a sufficient supply of the active esters for biological screening, considerable effort has been applied to the problem of preparing the esters from the more readily available cephalotaxine (105a) (see Section V1,C). This effort has also resulted in the preparation of many analogs containing ester groups that do not occur in the natural alkaloids and that have been used to obtain structure-activity relationships (168, 171, 195). Although some degree of structural variation must be tolerated, since homo-, iso-, and deoxyharringtonine show activity, most of the synthetic esters were found to be inactive (195).From a large number of cephalotaxine esters, the only synthetic ones to show significant activity in the P388 systems are those having the side-chain structures 301-304 (196).There appears to be little rationality in the structure-activity relationship.
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E R Y T H R l N A AND RELATED ALKALOIDS
93
OCH, 301 R = COC(=CH,)CH,CO,Me 302 R = COCH=CHCO,Me(trans) 303 R
=
H ,,,, ,OCO,CH2CC1, CO-C, Ph
304 R = CO2CH2CCI3
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173. W. R. Vaughn and K. S. Anderson, J . A m . Chem. Soc. 77,6702 (1955). 174. S. Brandange, S. Josephson, S. Vallen, and R. G. Powell, Acra Chem. Scand. Ser. B 28, 1237 (1974). 175. R. B. Bates, R. S. Cutler, and R. M. Freeman, J . Org. Chem. 42, 4162 (1977). 176. R. N. Chopra, S. L. Naylor, and I. C. Chopra, “Glossary of Indian Medicinal Plants,” p. 111. Counc. Ind. Sci. Res., New Delhi, India, 1956. 177. G. S. G. Barrors, F. J. A. Matos, J. E. V. Vieira, M. P. Sousa, and M. C. Medeiros, J . Pharm. Pharmacol. 22, 116 (1970). 178. S. K. Bhattacharya, P. K. Debnath, A. K. Sanyal, and S. Ghosal, J . Res. Indian Med. 6, 235 (1971); CA 78, 52895a (1973). 179. U. B. Zakirov, K. U. Aliev, and N. V. Abdumalikova, Farmakol. Alkaloido Serdechnykh Glikozidou 197 (1971); CA 77, 135092s (1972). 180. K. Kar, K. C. Mukherjee, and B. N. Dhawan, Indian J . Exp. Biol. 15, 547 (1977); CA 88, 293q (1978). 181. G. A. Miana, M. Ikram, F. Sultana, and M. I. Khan, Lloydia 35,92 (1972). 182. A. Qayum, K. Khanum, and G. A. Miana, Pak. Med. Forum 6,35 (1971); CA 77,148526m (1972). 183. E. D. Bergmann and Y. Migron, Tetrahedron 32, 2617, 2621 (1976). 184. R. E. Perdue, L. A. Spetzman, and R. G. Powell, Am. Hortic. Mag. 49, 12 (1970). 185. R. G. Powell, S. P. Rogovin, and C. R. Smith, Ind. Eng. Chem., Prod. Res. Deu. 13, 129 (1974); CA 8 1 , 4 1 3 2 3 ~(1974). 186. R. G. Powell and C. R. Smith, U.S. Patent 3,793,454 (1974); C A 80, 11261511(1974). 187. R. G. Powell and C. R. Smith, U.S. Patent 3,870,727 (1975); C A 83, 33023b (1975). 188. Anonymous, Chin. Med. J . (Peking, Engl. Ed.) 3, 131 (1977); CA 87, 111593m (1977). 189. Anonymous, Hua Hsueh Hsueh Pa0 34,283 (1976); CA 88, 1262564. (1978). 190. M. Fresno, A. Jimenez, and D. Vasquez, Eur. J. Biochem. 72,323 (1977); CA 86, 133384a (1977). 191. D. M. Baaske, Ph.D. Thesis, Purdue University, Lafayette, Indiana, 1976; Diss. Abstr. Int. B 37, 3972 (1977). 192. N. E. Delfel and J. A. Rothfus, U.S. Patent 840,423 (1977); C A 89, 3963111(1978). 193. M.-T. Huang, J . Mol. Pharmacol. 11, 511 (1975); CA 83, 201780s (1975). 194. D. M. Baaske and P. Heinstein, Antimicrob. Agents & Chemother. 12, 298 (1977); C A 87, 177505r (1977). 195. K. L. Mikolajczak, C. R. Smith, and R. G. Powell, J . Pharm. Sci. 63, 1280 (1974). 196. K. L. Mikolajczak, C. R. Smith, and D. Weisleder, J . Med. Chem. 20, 328 (1977).
CHAPTER2-
THE CHEMISTRY OF C... DITERPENOID ALKALOIDS S . WILLIAM PELLETIER AND NARESH V . MODY Institute f o r Naturul Products Research and Department of Chemistry. University of Georgia. Athens. Georgia
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............ I1. Vedtchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Veatchine and Garryine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Garryfoline, Ovatine, and Lindheimerine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Cuauchichicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Garryfoline-Cuauchichicine Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Napelline (Luciculine), Isopapelline, Lucidusculine, and 12-Acetylnapelline F. Songorine (Napellonine or Shimoburo Base I), Norsongorine, Songorine N-Oxide, and Songoramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Anopterine, Anopterimine, Anopterimine N-Oxide, Hydroxyanopterine, and Dihydroxydnopterine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. Atisine-Type Alkaloids . . . . . . . . . ..... ....... A . Atisine and Isoatisine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Dihydroatisine and Atidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Ajaconine and Dihydroajaconine . . . . . . . . . . . . . . . . . . . ........... D . Kobusine and Pseudokobusine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Ignavine and Anhydroignavinol ............................. F . Hypognavine and Hypognavin ...................... G . Isohypognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Denudatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... I . Vakognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J . Hetisine (Delatine) and Hetisinone . . . . . . K . Hetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L . Miyaconitine and Miyaconitinone ............................. M . Delnudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N . Spiradine A, Spiradine B, and Spiradine C . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Spiradine D and Spiredine . . . . . . . . . . . . ........ ......... P . Spiradine F and Spiradine G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Q . Spireine . . . . . . . . . .......................................... IV . Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . A . Staphisine and Staphidine . . . . . . . . . . . . . . . . B . Staphinine and Staphimine . . . . . . . . . . . . . . . . ................... C . Staphigine and Staphirine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Staphisagnine and Staphisagrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Behavior and Formation of the Carbinolamine Ether Linkage in Diterpenoid Alkaloids: The Baldwin Cyclization Rules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lr1. "C-NMR Spzctroszopy of C,,- Diterpenoid Alkaloida. . . . . . . . . . . . . . VII . Mass Spectral Analysis of C,,- Diterpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . .
100 102 102 104 106 109 112
114 116 122 122 124 124 125 128 129 130 131 1-32 133 135 136 138 139 140 142 143 144 144 146 147 148 149 160 163
THE ALKALOIDS. VOL. X V I l l Copyright @ 1981 by Academic Press. Inc. All rights of reproduction in any farm reserved. ISBN 0 12 469518 3
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S . WILLIAM PELLETIER AND NARESH V. MODY
VIII. Synthetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Total Synthesis of Optically Active Veatchine. . . . . . . . . . . . . . . . . . . . . . . . . . B. Total Synthesis of Napelline . . . . . . . . . . . . . . . . . C. Construction of the Denudatine Skeleton. . . . . . D. A Synthetic Approach to Ajaconine and Atidine.. . . . . . . . . . . . . . . . . . . . . . . E. Intermediates for the Veatchine- and Atisine-Type Alkaloids. . . . . . F. Construction, Degradation. and Selective Reduction of the Oxazolidine Ring of C,,-Diterpenoid Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. A Catalog of C,,-D kaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . ........................................
168 I68
179
194 196 211
I. Introduction The diterpenoid alkaloids, isolated mainly from Aconitum and Delphinium species (Ranunculaceae), have been of great interest since the early 1800s because of their pharmacological properties. Extracts of Aconitum species were used in ancient times for treatment of gout, hypertension, neuralgia, rheumatism, and even toothache. Extracts have also been used as arrow poisons. Some Delphinium species are extremely toxic and constitute a serious threat to livestock in the western United States and Canada. Delphinium extractsalso manifest insecticidal properties. In the last 30 to 40 years, interest in the diterpenoid alkaloids has increased because of the complex structures and interesting chemistry involved. The diterpenoid alkaloids may be divided into two broad categories : those based on a hexacyclic C,,-skeleton and those based on a C,,-skeleton. The highly toxic C, ,-diterpenoid alkaloids, commonly known as aconitines, have been reviewed ( I ) in Volume XVII of this treatise. The C,,-diterpenoid alkaloids contain three basic skeletons : Atisine-type (i), Veatchine-type (ii), and Delnudine-type (iii). The atisine skeleton incorporates an ent-atisane nucleus and does not obey the isoprene rule. The veatchine skeleton, which occurs in the Garrya alkaloids, is modeled on an ent-kaurane nucleus and obeys the isoprene rule. It differs from the atisine skeleton in that ring D is five- rather than six-membered. Biogenetically, these alkaloids are probably derived from tetracyclic or pentacyclic diterpenes in which the nitrogen atom of methylamine, ethylamine, or P-aminoethanol is linked to C-19 and C-20 in the diterpenoid skeleton to form a substituted piperidine ring. There have been no detailed biogenetic studies on these alkaloids. The delnudine skeleton is an interesting curiosity in that it is difficult to explain how delnudine is derived from an atisine skeleton or from a pimaric acid skeleton. Recently, a new class of diterpenoid alkaloids, known as bisditerpenoid alkaloids, has been isolated from the seeds of Delphinium staphisagria (2). The bisditerpenoid alkaloids (e.g., staphisine, iv) may be formally derived by
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
( i ) Atisine skeleton
101
(ii) Veatchine skeleton
(iii) Delnudine
attachment of two different molecules of C,,-diterpenoid alkaloids at the C-16 position. y
3
19./N\,20. H3FyJ2'
6'
\
10'
H,C--
(iv) Stdphisine
The numbering system for the alkaloids with the basic atisine (i), veatchine (ii), and delnudine (iii) skeletons used in this chapter is in accord with proposals initiated by Dr. J. w. Rowe and cosponsored by the author (3). The earlier work on the chemistry of C20-diterpenoid alkaloids has been reviewed in Volumes IV(4), VII(5), and XIl(6) of this treatise, in books on
102
S. WILLIAM PELLETIER AND NARESH V. MODY
alkaloids by Boit (7) and Pelletier (8),in The Alkaloids, Specialist Periodical Reports (9-11) and in other reviews (12-18). This chapter deals with the chemistry of C,,-diterpenoid alkaloids reported in the literature available to us since the last review in Volume XI1 of this treatise, as well as certain unpublished works from our institute. Included in this chapter is a catalog of ali known C,,-diterpenoid alkaloids showing the correct structures, physical properties, plant sources, and key references. Previously published books (19-21) and recent reviews (15-16) have reported incorrect structures for several well-known C,,-diterpenoid alkaloids. This catalog should be very useful for it presents in a single place important structural information on the C,,-diterpenoid alkaloids that has been scattered through hundreds of papers and dozens of review articles.
11. Veatchine-Type Alkaloids The veatchine-type alkaloids are also known as the Garrya alkaloids because they were first isolated from Garrya species. In 1946, Oneto reported (22)the isolation of two isomeric crystalline alkaloids, veatchine and garryine, from the bark of Garrya veatchii Kellogg. Later, Karel Wiesner and co-workers at New Brunswick initiated work on the structure elucidation of veatchine and garryine and pointed out the striking similarity between the chemistry of atisine and veatchine. They elucidated the structures of veatchine and garryine, and their results greatly assisted progress in the structure elucidation of both veatchine- and atisine-type alkaloids. Since structures of the veatchine-type alkaloids were first to be completed, their chemistry will be reviewed first.
A. VEATCHINE AND GARRYINE Veatchine, the major alkaloid of G. veatcliii Kellogg, is a strong tertiary base (pK, 11S)that undergoes a facile isomerization of the oxazolidine ring to garryine (pK, 8.7) by treatment with base or even by simple refluxing in methanol. Veatchine forms the ternary immonium salt known as veatchinium chloride by treatment with hydrochloric acid and may be regenerated from veatchinium chloride by treatment with cold base. On the basis of chemical and degradation studies, Wiesner and co-workers elegantly established (23, 24) the structures of veatchine and garryine as l b and 2, respectively. Early work on the chemistry of veatchine and garryine has been reviewed by Wiesner and Valenta (12),and later by Pelletier and Keith (6,8). The stereochemistry of the normal-type oxazolidine ring in veatchine, atisine, and other related alkaloids was ill-defined in the literature (2j),
2.
THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS
103
for example, the P-configuration was assigned to the C-20 proton in veatchine (lb) and related alkaloids without any evidence (26). Recently, Pelletier and Mody reported (27,28) unusual findings about the conformation of the oxazolidine ring of veatchine and related alkaloids by 13C-NMR spectroscopy. The I3C-NMR spectrum of veatchine shows two sets of signals for the oxazolidine ring and the piperidine ring carbons in CDCl, solution at room temperature. On the basis of this unusual observation they concluded that veatchine exists as a mixture of C-20 epimers ( l a major and l b minor) in solution. When veatchine is regenerated from veatchinium chloride (3), in which C-20 is trigonal, by treatment with base, formation of the oxazolidine ring takes place from both sides of the trigonal C-20 carbon to give epimers l a and lb.
lb
2 Garryine
la
1 Veatchine
3 Vedtchinium chloride
These findings were confirmed (29,30)by demonstrating the coexistence of C-20 epimers in the same crystal of veatchine by a single-crystal X-ray analysis. Crystallization of two epimers in a disordered relationship is a highly unusual observation. Even though veatchine exists as a mixture of
104
S. WILLIAM PELLETIER AND NARESH
V.
MODY
epimers, separation of these epimers would be extremely difficult because veatchine is not particularly stable in hydroxylic solvents such as methanol (see Section V). Because of the inconvenience of presenting two structures each time veatchine is referred to, structure 1 will be used to represent both epimers l a and l b .
4 Atisine
5 Atisinium chloride
Veatchine has been chemically related to atisine (4) by conversion to a common intermediate (34,and the absolute configuration of atisine has been established by a single-crystal X-ray analysis of atisinium chloride (30) (5). Therefore, the absolute configuration of veatchine is assigned as 4S, 5S, 8R, 9S, 10R, 13R, 15R, and 20SR. The designation of the absolute configuration of C-20 as “SR” was chosen to indicate that, in any given sample of veatchine, both epimers exist and that the 20s (ex0 configuration of the oxazolidine ring) epimer predominates. The 3C-NMR spectrum of garryine (2)exhibits (28)only one set of signals for the oxazolidine ring carbons, the piperidine ring carbons, and the C-4 methyl group, a fact which indicates that garryine does not exist as a pair of C-19 epimers. During recent work on the isolation of veatchine from the bark of G. veatchii (32), the presence of garryine was not detected. This observation suggests that veatchine may have isomerized to garryine during the earlier isolation work and that garryine may be an artifact.
B. GARRYFOLINE, OVATINE, AND LINDHEIMERINE Ovatine (6) and lindheimerine (7) have been isolated (33)for the first time from the bark and leaves of G. ocata var. lindheimeri Torr., a plant that has shown confirmed antitumor activity in vivo. These two new alkaloids are accompanied by the known alkaloid, garryfoline (S), which also occurs in the Mexican tree, G. laurifolia Hartw (34). The structure of the major alkaloid, ovatine (6),was assigned on the basis of ‘H- and 13C-NMR data of ovatine and garryfoline and was confirmed by conversion of ovatine to garryfoline and vice versa. The ‘H-NMR data of ovatine revealed the presence of two different sets of signals for the C-4
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
105
methyl group and the C-20 proton in a 1 :3 ratio and one set of signals for an aceloxy group, the N-CH,-C group, and the exocyclic double bond. The 13C-NMR spectrum of ovatine in CDCl, at room temperature also exhibited the presence of two different sets of signals for the oxazolidine ring F, the piperidine ring E, the C-4 methyl group, and certain other carbon atoms. Comparison of the 'H- and 13C-NMR spectra of ovatine with those of garryfoline revealed that the only difference between these alkaloids was the presence of an acetoxyl group at C-15. Each of these alkaloids exists as a mixture of C-20 epimers in solution. It is worth noting that in the structure assigned to garryfoline (6B) (25,26),a P-configuration was assumed without evidence for the C-20 hydrogen.
6 R = Ac Ovatine 8 R = H Garryfoline
6a R = Ac 8a R = H
9
7 Lindheimerine
6b R = AC 8b R = H
10
Mild hydrolysis of ovatine at room temperature gave the known alkaloid garryfoline, a fact which indicates that the acetoxyl group is present at C-15 in ovatine. Garryfoline afforded the unusual immonium salt (9) instead of ovatine on treatment with acetic anhydride and pyridine at room temperature. Treatment of ovatine with acetic anhydride and pyridine also gave 9
106
S. WILLIAM PELLETIER AND NARESH V . MODY
in quantitative yield. Garryfoline was converted to ovatine via lindheimerine (7) in two steps. Refluxing 9 in chloroform yielded lindheimerine (7) in 90% yield. Treatment of 7 with ethylene oxide in acetic acid gave ovatine in almost quantitative yield. Thus, the structures of ovatine and garryfoline can be represented as an epimeric mixture at C-20 of 6a and 6b for ovatine and 8a and 8b for garryfoline, with the a epimer predominating. Structure 7 was assigned to the minor alkaloid, lindheimerine, from spectral data. The ‘H- and I3C-NMR spectra revealed the presence of one acetoxyl group, a C-4 methyl group, an exocyclic double bond, and a C-20 imine group on a veatchine-type skeleton. Comparison of the 13C-NMR spectrum of lindheimerine with that of veatchine azomethine acetate (10) gave evidence for the presence of the C-15 6-acetoxyl group in lindheimerine. The structure of lindheimerine (7)was confirmed by comparison with the degradation product of compound 9, which was identical with lindheimerine. Lindheimerine occurs in extremely small quantity by comparison with ovatine. Since these two alkaloids are closely related chemically, we suggest that lindheimerine may be a biogenetic precursor of ovatine. These alkaloids did not exhibit any antitumor activity in uiuo or in uitro. C. CUAUCHICHICINE During investigation of the constituents of G . ouatu var. lindheimeri, two well-known alkaloids, garryfoline (8) and cauchichicine, as well as ovatine and lindheimerine, were isolated (33); Djerassi and co-workers (25, 34) had previously isolated the former alkaloids from the Mexican tree, G. luurifoliu, and established their gross structures. Treatment of garryfoline with dilute hydrochloric acid at room temperature results in rapid isomerization to cuauchichicine. The latter was assigned structure 11 by Vorbrueggen and Djerassi in 1962 (25,35).They assigned the a-configuration for the C-16 methyl group in cuauchichicine on the basis of chemical correlation of cuauchichicine azomethine (12) with ( dihydrokaurene (13). The structure of the latter, a minor hydrogenation product of ent-kaurene (14),was based on the behavior of ent-kaurene during catalytic hydrogenation. A a-configuration was assigned for the C-20 hydrogen in cuauchichicine without any evidence. Recently, Pelletier and co-workers (36) revised the structure of cuauchichicine to 15 on the basis of I3C-NMR spectral analysis and X-ray crystallography. A 3C-NMR study of cuauchichicine indicated that it exists as a single C-20 epimer unlike other normal-type oxazolidine ring-containing diterpenoid alkaloids such as veatchine, ovatine, garryfoline, and atisine. An a-configuration was assigned to the C-20 hydrogen on the basis of comparison of the I3C-NMR spectrum of cuauchichicine with those of veatchine and
)-“a”-
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
11
107
12
I c
c
13 “p”-Dihydrokaurene 4%
I
H,. NI
14 ent-Kaurene
18 “r”-Dihydrokaurene
atisine. To establish the stereochemistry of the C-16 methyl group in cuauchichicine by I3C-NMR spectral analysis, a pair of stable C-16 epimers was prepared. Cuauchichicine was heated at reflux in methanol to afford isocuauchichicine (16) in quantitative yield. During this rearrangement the C-16 methyl group did not epimerize. Heating of cuauchichicine o r isocuauchichicine in a methanolic solution of 2% sodium hydroxide at reflux gave a mixture of (2-16 methyl epimers of isocuauchichicine. These epimers were separated by chromatography over alumina using hexane and benzene as the eluting system to yield pure samples of isocuauchichicine (16) and epiisocuauchichicine (17).Comparison of molecular models of 16 and its epimer 17 revealed that the methyl group at C-16 is partially crowded in the pposition in contrast to the @-position.Steric compression would be expected to cause the p-methyl group to appear at higher field in the I3C-NMR spectrum than the r-methyl group. Accordingly, the signal a t 10.1 ppm was assigned to the p-methyl group in 16, and the signal at 15.9 ppm was assigned
108
S. WILLIAM PELLETIER AND NARESH V. MODY
15 Cuauchichicine
19
13a R = CH,OH 13b R = CHO 13c R = CH, “8”-Dihydrokaurene
2.
THE CHEMISTRY OF C ~ O- DI T E R P EN O I DALKALOIDS
109
to the sc-methyl group in 17. These results afforded evidence for the presence of the 8-methyl group at C-16 in cuauchichicine (10.1 ppm) and therefore structure 15 was assigned to cuauchichicine. Subsequently, this structure was confirmed by a single-crystal X-ray analysis of cuauchichicine (36). The incorrect structure 11 originally assigned to cuauchichicine requires that either the structure of the final degradation product, ( - )-“P”-dihydrokaurene (13), is incorrect or that the C-16 methyl group must have epimerized somewhere in the six-step correlation sequence. Because the structural assignments of more than 100 natural products depend on ( -)-“P”-dihydrokaurene, the structure of this important diterpene was reinvestigated. Catalytic hydrogenation of ent-kaurene (14) afforded a mixture of ent-kauranes consisting mainly of ( - )-“a”-dihydrokaurene. The ‘‘P’-epimer was produced in too small a yield to permit its isolation in a pure state. X-ray crystallography of ( -)-“a”-dihydrokaurene demonstrated the structure to be 18. Therefore, the structure previously assigned for ( - )-“P”-dihydrokaurene (13) is correct. These results indicate that epimerization of the C-16 methyl group must have taken place during degradation of cuauchichicine to (-)“P”-dihydrokaurene. This unanticipated epimerization most likely occurred during Wolff-Kishner reduction of the intermediate ketone 19 and accounts for the error in the assignment of configuration of the C-16 methyl group in cuauchichicine. The absolute configuration of cuauchichicine was determined as 4.9, 5S, 8R,10R, 16R, and 20s. It is worth noting that cuauchichicine is the first normal-type oxazolidine ring-containing alkaloid that does not exist as a pair of epimers at C-20, either in solution or in the solid state.
D. GARRYFOLINE-CUAUCHICHICINE REARRANGEMENT In 1955, Djerassi and co-workers reported (34) that the treatment of garryfoline (8) with dilute mineral acid at room temperature results in rapid isomerization to cuauchichicine (15). A similar rearrangement has been also observed in atisine, kobusine, napelline, and other terpenoids containing a methylene group at C-16 and a C-15 P-hydroxyl group. In contrast to the facile rearrangement of garryfoline, the C-15 epimer, veatchine (1), is stable even when heated in dilute hydrochloric acid. To explain the striking difference in the behavior of these two epimers toward acid treatment, a nonclassical structure for the intermediate carbonium ion has been suggested (12). Barnes and MacMillan reported (37)an investigation of this rearrangement using the epimeric (-)-kaur-16-en-l5-01~ as models. The 158-01 (20) rearranged rapidly to 16-(-)-kaur-l5-one (21) in mineral acid at room temperature whereas the 15a-01(22)was stable under these conditions. The English workers proposed a 15 + 16 hydride-shift mechanism on the basis of the
110
S. WILLIAM PELLETIER AND NARESH V. MODY
20 R = H 23 R = D
21 R = H
22
24 R = D
rearrangement of [15-~]-(-)-kaur-l6-en-15P-ol (23) to (16R)-[16-~]-(-)kaur-15-one (24) in hydrochloric acid. Later work by the same group, however, demonstrated (38)that compound 24 exchanges deuterium at C-16 with hydrogen in dilute acid with complete retention of configuration to give 21. Pelletier, Desai, and Mody prepared (39)several deuterated derivatives of garryfoline and cuauchichicine and studied the mechanism by I3C-NMR spectroscopy. Deuterated (C- 15) dihydrogarryfoline diacetate (26) was prepared from veatchinone (25) in three steps. Compound 26 in 10% HCl at
25
28
26 R' 27 R'
= OAc; R 2 = D = D; RL = OAc
Major Minor
31
D'
32
29
30
SCHEME 1
33
112
S . WILLIAM PELLETIER AND NARESH V. MODY
room temperature rearranged to 28, a compound which showed no deuterium incorporation at C-16 on the basis of 13C-NMR spectral analysis. These results indicated that the C-15 deuterium did not shift to C-16 during the rearrangement and therefore the garryfoline-cuauchichicine rearrangement does not take place via a 15 -+ 16 hydride-shift mechanism. Treatment of isogarryfoline (29) with 10% DCI in D,O at room temperature followed by treatment with base, afforded deuterated isocuauchichicine (30) in quantitative yield. Analysis of the I3C-NMRspectrum of 30 revealed the presence of deuterium at C-16 and C-17. In dilute hydrochloric acid no exchange of deuterium by hydrogen in compound 30 was detected in 24 hr, but after 96 hr, exchange was observed to give compound 31. On the basis of these results, the mechanism outlined in Scheme 1 was suggested. The mechanism involving the enol accounts for incorporation of deuterium at C-16 and C-17 and also explains the C-16 a-D, /3-CH2D stereochemistry observed. During ketonization of the enol 32, transfer of D + would be expected to occur from the less-hindered exo side of the molecule to give compound 33 containing the C-16 a-D and C-16 P-CH,D groups. These results demonstrated (39) that a 15 + 16 hydride shift is not involved but rather a mechanism involving formation of an enol followed by exopro tonation.
E. NAPELLINE (LUCICULINE), ISONAPELLINE, LUCIDUSCULINE, AND 12-ACETYLNAPELLINE Napelline (34) was isolated by Freudenberg and Roger (40) in 1937 from the poisonous roots of Aconitum napellus L. Recently, napelline has been isolated (41) from the tubers and roots of A . karakolicum, which were collected in the Terskei Ala-Tau ranges of the Kirghiz S.S.R. Early work on the chemistry of napelline has been reviewed by Wiesner and Valenta (12)and later by Pelletier and Keith (6).On the basis of extensive chemical work (42-47) and X-ray analysis (48, 49) of lucidusculine (35), structure 34 was assigned to napelline. Recently, Wiesner and co-workers OH
34 Napelline
OH
35 Lucidusculine
2.
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
36
113
37 Isonapelline
reported an elegant total synthesis of napelline and thus confirmed its structure. The synthesis of napelline is discussed in Section VII1,B. Treatment of napelline with dilute mineral acid results in rapid isomerization to isonapelline (42,43). The structure of isonapelline was represented as 36 with undetermined stereochemistry at C- 16. Recently, we established the stereochemistry of the C-16 methyl group in the related alkaloid, cuauchichicine, an acid-catalyzed rearrangement product of garryfoline. By analogy, the acid-catalyzed rearrangement of napelline to isonapelline should result in a C-16 P-methyl group in isonapelline. Thus structure 37 can be assigned to isonapelline. Lucidusculine was first isolated in 1931 by Japanese chemists (50, 51) from the roots of A . lucidusculurn Nakai, which is also known as A . yesoense var. Structural work on this alkaloid was carried out by Suginome and co-workers (52-57) from 1950to 1961.The structure of lucidusculine (35)was established in 1965 by a Japanese group by X-ray crystal analysis of its hydriodide (48, 49). Basic hydrolysis of lucidusculine afforded the parent alkamine known as luciculine. The latter was found to be the same as napelline. The X-ray crystal structure of lucidusculine provided a basic foundation for elucidating the structures of related alkaloids, e.g., napelline, songorine, songoramine. The chemistry of lucidusculine has been reviewed in detail earlier by Stern ( 4 , 5 ) and later in Volume XI1 of this treatise (6). 12-Acetylnapelline has been isolated by Soviet chemists (58, 59) from the epigeal parts of A . karakolicum collected in the upper reaches of the R. Tyup (Kirghiz S.S.R.) during the budding period. Chemical transformations and mass spectral analyses of 12-acetylnapelline and its derivatives have led to the assignment of structure 38. Alkaline hydrolysis of 12-acetylnapelline (38) yielded an amino alcohol identical to napelline (34). This result indicated that the new alkaloid was napelline monoacetate. Treatment of 12-acetylnapelline with acetic anhydride and pyridine gave the triacetate 39. The latter was selectively hydrolyzed by alkali to afford l-acetylnapelline (40). Oxidation of 38 with silver oxide yielded dehydro derivative 41, a result that revealed the presence of an ahydroxy group at C-1 in 38. Hydrogenation of 12-acetylnapelline over a
114
S. WILLIAM PELLETIER A N D NARESH V. MODY
OR
0Ac
38 12-Acetylnapelline
39 R = AC 40 R = H
0Ac
OAc
41
42
platinum catalyst afforded dihydroacetylnapelline (42). Formation of isoacetylnapelline (43)from 38 indicated that the hydroxy group at C-15 is not acetylated. On the basis of these chemical transformations, structure 38 was assigned to 12-acetylnapelline. In the earlier papers (58, 59) on the structure of 12-acetylnapelline, the choice between attachment of the acetyl group at position 12 or 15 was made on the basis of the mass spectral data of 12-acetylnapelline, l-acetylnapelline, and triacetylnapelline. The detailed mass spectral analysis of 12-acetylnapelline and its derivatives is discussed in Section VII.
F. SONGORINE (NAPELLONINE OR SHIMOBURO BASEI), NORSONGORINE, SONGORINE N-OXIDE, AND SONGORAMINE Songorine (44)was isolated as the major alkaloid of A . soongoricum Stapf by Yunsov (60) in 1948. This alkaloid was also found (61) in a Japanese Aconitum variety ( A . japonicum var.) and was provisionally named “Shimoburo Base 1.” Recently, Soviet workers reported the occurrence of songorine in the epigeal parts and tubers of A. karakolicurn (41,59, 58, 62) and the roots of A . monticola (63).The structure of songorine was intensively investigated by Canadian (42, 43), Japanese (46, 47), and Soviet (44, 45, 60, 64) groups between 1950 and 1960. Finally, in 1961, Sugasawa (47)proposed the correct structure of songorine. Later, in 1965, the structure of songorine (44) was confirmed (48)by direct comparison of its lithium aluminum hydride
2.
115
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
reduction product with napelline (34).The chemical work on songorine has been reviewed in detail by Pelletier and Keith (6) in Volume XI1 of this treatise.
CH,
OH 43
&CH2 H... -.N
,,
44 Songorine
- -H
..
OH ‘
CH,
C H -..-.-N oY&CH2 \ ;‘ ,^. ~ . \ \
2
,
5
’
45 Norsongorine
- -H
OH CH,
46 Songorine N-oxide
In 1974, Soviet researchers reported (63)the isolation of “norsongorine” (45), a known derivative of songorine, from the roots of A . monticolu. No physical properies or spectral data for norsongorine were reported by the authors. Recently, songorine N-oxide (46) has been isolated (65)for the first time from A . monticola collected in the Dzhungarian Ala-Tau on the Kuyandysai River. The structure of songorine N-oxide was elucidated from the ‘H-NMR and mass spectral data and on the basis of reduction of 46 to songorine (44) by zinc and 10% hydrochloric acid at room temperature. In 1970, Yunusov and co-workers reported (62)the isolation and structure elucidation of a new alkaloid, songoramine (47), from the tubers of A . karakolicum, collected in the upper reaches of the Tyup River (Terskei Ala-
,&CH2 , .T.. ,, , C H .+---.N I
2
5 ,
,
.
,
,
4..:.:
- -H OH
CH3
47 Songoramine
&
C2 H 5 ... ..N ”
*, . ,,~ .
CH,
48
,’
‘H
--H OH
H3
116
S. WILLIAM PELLETIER AND NARESH V. MODY
49 R = AC 50 R = H
Tau range). Occurrence of the same alkaloid was also reported earlier in the roots of A . soongoricum Stapf (66,67). The structure of songoramine was established on the basis of mass spectral analyses and conversion to songorint: (44).The spectral and chemical properties of songoramine are very similar to those of songorine. Hydrogenation of songoramine over platinum yielded a tetrahydro derivative (48), which proved to be identical to dihydrosongorine. Acetylation of 47 with acetic anhydride and pyridine gave an unusual immonium salt (49). Treatment of songoramine with hydrochloric acid also gave a quaternary immonium salt (SO). Thus, the presence of a carbinolamine ether in 47 was demonstrated by reductive opening and immonium salt formation. Finally, oxidation of songorine with silver oxide afforded songoramine, which confirmed its structure. The mass spectral data of songoramine, songorine, dihydrosongorine, and their acetate derivatives were analyzed. These results are discussed in Section VII.
G. ANOPTERINE, ANOPTERIMINE, ANOPTERIMINE N-OXIDE, A N D DIHYDROXYANOPTERINE HYDROXYANOPTERINE, Anopterine (Sl),the major alkaloid of the leaf and bark of Anopterus macleayanus F. Meull and bark of A . glandulosus Labill., has been isolated (68,69) by Lamberton and co-workers. Crude extracts of both Anopterus species have shown some preliminary antitumor activity in a number of test systems. The structures of anopterine and its hydrolysis product, anopteryl alcohol (S2), were assigned on the basis of a single-crystal X-ray analysis (68) of the azomethine iodide (53). The latter was formed on treatment of tetraacetylanopteryl alcohol (54) with methyl iodide in acetone after several weeks. Anopterine fails to form salts with mineral acids and simple organic acids because one of the C-2 and C-5 hydroxyl groups is strongly hydrogen bonded to the nitrogen. In order to confirm that no other change apart from the formation of the C-19 imine bond had occurred during the transformation of the tetraacetate
2.
THE CHEMISTRY OF C ~ ~ - D I T E R P E N O IALKALOIDS D
H3 7 H A ,
,c=c
p
H 2H. ?HO.. ;:- '
3
H,C------N '
,CH3
0-CO-c=c,
OR
'H
co-0..
117
OH
CH,OH 51 Anopterine
52 R = H 54 R = AC
OAc
53
54 to the azomethine iodide 53, the conversion of the azomethine iodide to anopteryl alcohol was attempted. Reaction of the azomethine iodide with aqueous ammonia or sodium bicarbonate yielded the C-19 epimers (5: 1) of compound 55. Alkaline hydrolysis of 55 gave a major product containing the carbinolamine ether linkage having either structure 56 or 57. Interestingly, the hydrolysis product (56 or 57) of compound 55 can not be reduced to anopteryl alcohol by treatment with sodium borohydride. On acetylation with acetic anhydride and pyridine followed by the usual work-up, the carbinolamine ether (56 or 57) gave back the epimeric alcohol 55. However, reduction of the azomethine iodide (53) with cold sodium borohydride gave tetraacetylanopteryl alcohol (54). The latter on alkaline hydrolysis afforded anopteryl alcohol in good yield. Thus, conversion of 53 to anopteryl alcohol
55
56
118
S. WILLIAM PELLETIER AND NARESH
V.
MODY
(52) confirmed that no skeletal rearrangement had occurred other than the formation of an imine bond during the transformation of 54 to 53. These results also confirmed the structure of anopteryl alcohol and its tetraacetate.
::;,5:--CH2 OH
H,C------N HO..
'~
OH
CH,;
\--
.....0
57
H O . @CH2 ~
,
-,
-. . ......
H C... ..N
AcO.. @CH2 ,
9, --- --
H,C------N
OH
,
... .......
2
CH,
CH, O A c
58
59
Oxidation of anopteryl alcohol with alkaline potassium ferricyanide yielded the carbinolamine ether (56 or 57) as a minor product (8%) and compound 58 as the major product. The structure of 58 was elucidated by an X-ray crystal analysis. Compound 58 was isolated from the oxidation reaction mixture only after acetylating the mixture, from which the carbinolamine ether was first removed, and then hydrolyzing the acetylated product. Acetylation of compound 58 gave triacetyl derivative 59, in which the epoxide ring was opened. Treatment of anopteryl alcohol with acetic anhydride and pyridine at 100" for 4 hr or longer gave tetraacetylanopteryl alcohol (54) in high yield. Less drastic acetylation conditions gave a mixture of compound 54, triacetyl derivatives 60 and 61, and diacetylanopteryl alcohol 62. The structures of these acetylated derivatives were based on 'H-NMR data. The presence of two tigloyl groups at C-1 1 and C-12 in anopterine was established on the basis of oxidation products of anopterine and anopteryl alcohol. Oxidation of anopterine with chromic acid in pyridine gave a diketone ditiglate, which on alkaline hydrolysis afforded the diketone 63. On the basis of the 'H-NMR spectra of the diketone 63 and its diacetate derivative 64,the authors established that the carbonyl group was not present at either C-1 1 or C-12 in 63. These results indicated that two tigloyl groups were present at C-1 1 and C-12 in anopterine.
2.
THE CHEMISTRY OF C,-,-DITERPENOID
OAc
ALKALOIDS
OR
&CHz
" ... .......,
0
R'O..
119
H,C------N
OH
CH, 0 54 60 61 62
R' = R 2 = AC R' = Ac, R 2 = H R' = H, RZ = AC R' = R 2 = H
63 R = H 64 R = A c
OH
65
Oxidation of anopterine with Jones reagent followed by alkaline hydrolysis afforded a monoketone, which was assigned probable structure 65. Reduction of the monoketone with sodium borohydride in methanol at room temperature gave a 4:1 mixture of two products, with anopteryl alcohol as the major product. Oxidation of anopteryl alcohol with Jones reagent yielded a yellow triketone and a diketone. The latter was not identical with the diketone 63. Structure 66 was assigned to the yellow triketone. Partial structure 67 was assigned to the diketone that was obtained from Jones oxidation of anopteryl alcohol. Further oxidation of 63 with chromic acid by the Jones method gave the yellow tetraketone 68.
67
68
120
S. WILLIAM PELLETIER AND NARESH V. MODY
On treatment with acetic anhydride in pyridine, the yellow tetraketone (68), the yellow triketone (66), and the diketone (67) afforded monoacetyl, diacetyl, and triacetyl derivatives, respectively. All these derivatives contained a tertiary acetoxyl group. However, comparisons of 'H-NMR spectra of the parent ketones with those of the acetyl derivatives indicated that a rearrangement of the molecule or a major conformational change must have occurred. On the basis of extensive 'H-NMR spectral analysis, structure 69 was proposed for the diacetyl derivative which was derived from the triketone 66. Structure 69 was justified on the basis of conformational arguments. 0
CH, OAc 69
Formation of the diacetyl compound (69) from the triketone (66) indicated that all of the ketones which underwent this anomalous acetylation reaction must have a C-2 0x0 group. Evidently a C-6 hydroxyl group is not necessary for this unusual acetylation reaction to form compounds such as 69. This idea was supported by the formation of only a monoacetyl derivative from the tetraketone (68). The conformational argument was that if ring A assumed a boat form, formation of an acetal at C-2 with an oxygen bridge between C-2 and C-5 could occur by reaction of the C-5 hydroxyl group with the C-2 0x0 group. Then ring B could assume a boat conformation with the piperidine ring changing from boat to chair form to minimize ring strain. On the basis of the arguments presented above, the tertiary acetoxyl group was assigned to C-2 in 69. Mild hydrolysis of 69 in dilute methanolic potassium hydroxide regenerated the original ketone 66, a result that indicated that no skeletal rearrangement was involved during this anomalous acetylation reaction. All the reaction products reported here were supported by detailed 'H-, 13C-NMR,and mass spectral data. In 1976, Lamberton and his colleagues reported (70)the isolation of two minor alkaloids, anopterimine and anopterimine N-oxide, from the leaves of A . macleuyanus F. Muell. These alkaloids were not encountered in the related species, A . glandulosus Labill. On the basis of extensive 'H- and 13 C-NMR analyses, structures 70 and 71 were assigned to anopterimine and anopterimine N-oxide, respectively.
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
70 Anopterimine
121
71 Anopterimine N-oxide
During the isolation of anopterine, the Australian chemists isolated a new alkaloid, hydroxyanopterine, from the bark and leaves of A . macleayanus and A . glandulosus. A closely related new alkaloid, dihydroxyanopterine, was also encountered as a minor component in the bark of A. macleayanus. Comparison of the ‘H- and 3C-NMR spectral data of hydroxyanopterine and dihydroxyanopterine with those of anopterine afforded evidence for the partial structures 72 and 73 for hydroxyanopterine and dihydroxyanopterine, respectively. Each of these alkaloids has a hydroxyl group at C-1 or C-3 on the A ring. On the basis of the 13C-NMR assignments. the presence of the additional skeletal hydroxyl substituent was preferred at the C- 1 position. The presence of another hydroxyl group in an acid moiety of dihydroxyanopterine was confirmed by hydrolysis. Alkaline hydrolysis of hydroxyanopterine and dihydroxyanopterine gave the identical amino alcohol, a result which confirmed that the second hydroxyl group in dihydroxyanopterine was a part of a new hydroxytiglic acid moiety. A biosynthetic pathway for the Anopterus alkaloids has been proposed involving a hetisine-type precursor.
’
CH, OH 72 Hydroxyanopterine
73 Dihydroxyanopterine
122
S . WILLIAM PELLETIER AND NARESH V. MODY
111. Atishe-Type Alkaloids
A. ATISINE AND ISOATISINE Atisine, the principal alkaloid of the rhizomes of A . heterophyllum Wall, has been the subject of extensive study since 1942 because of its interesting chemical features and complex structure (72). In 1954, Wiesner and coworkers (72)proposed a gross structure for atisine and subsequently Pelletier and Jacobs (73) supported this structure independently. Later, the structure of atisine as 74 was confirmed by two total syntheses (74, 75). Recently, atisine has been isolated from A . heterophylloides (76),A . gigas Ler. et Van. (77)and A . antharu (16).Atisine is an amorphous strong base (pK, 12.5) that undergoes a facile isomerization of the oxazolidine ring to isoatisine (75) (pK, 10.3) by treatment with alkali or even by simple refluxing in methanol. Atisine and isoatisine form the corresponding quaternary immonium salts 5 and 76, respectively, by treatment with hydrochloric acid. Atisine and isoatisine can be regenerated from the corresponding immonium salts by treatment with base. Atisinium chloride (5) is more stable in refluxing polar solvents than isoatisinium chloride (76). One can quantitatively isomerize isoatisinium chloride to atisinium chloride by refluxing in DMSO, DMF, or high-boiling alcohols. Thus, depending on reaction conditions, atisine, and isoatisine can be interconverted easily. The stereochemistry of the oxazolidine ring of atisine has been of great interest for a long time. In 1968, Pelletier and Oeltmann (78) postulated on
5 Atisinium Chloride
76 Isoatisinium Chloride
2.
123
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
the basis of a 'H-NMR study that atisine exists as two different conformers of the piperidine ring (chair 77a and boat 77b) in 1 : 2 ratio, respectively, in CDC1, solution at room temperature. Subsequently, on the basis of a deuterium study, Pradhan and Girijavallabhan (79) suggested that atisine in solution is a mixture of isomers which differ in configuration at C-20 and which are interconvertible via a zwitterion. On the basis of a 13C-NMR study of atisine and related alkaloids, Pelletier and Mody (27, 28) demonstrated that atisine exists as a mixture of C-20 epimers 4a and 4b in nonionic solvents (e.g., chloroform, benzene etc.). The presence of two different sets of signals for the oxazolidine and piperidine rings in the I3C-NMRspectrum of atisine in CDCI, solution at room temperature suggested the existence of a pair of epimers. The fact that the oxazolidine ring of atisine is regenerated from atisinium chloride (5), in which (2-20 is trigonal, by treatment with base suggested that formation of the oxazolidine ring takes place from both sides of the trigonal C-20 carbon to give epimers 4a and 4b. Thus, atisine can be represented by structure 4, indicating the presence of both C-20 epimers in the same formula.
77b
77a
4 Atisine
y '
CH,
'
4a
CH,
CH, 4b
The structure of atisinium chloride as 5 was confirmed recently by a single-crystal X-ray analysis (30). The absolute configuration of atisinium chloride was determined as 4S, 5S, 8R, 10R, 12R, and 1 5 s by Hamilton's method and confirmed by examination of sensitive Friedel pairs. A recent X-ray crystallographic study of isoatisine confirmed the assigned structure 75. The absolute configuration was established as 4S, 5S, 8R,10R, 12R, 15S, and 19s for isoatisine. It is worth noting that isoatisine does not exist as a mixture of C - 19 epimers. Early work on the chemistry of atisine and isoatisine
124
S. WILLIAM PELLETIER AND NARESH V. MODY
has been described in detail in several reviews (6, 8, 13) published between 1960 and 1970.
B. DIHYDROATISINE AND ATIDINE Dihydroatisine, a minor alkaloid of the roots of A . heterophyllum Wall, was isolated (80) from the strong base fraction and its structure (78) was established by comparison with the sodium borohydride reduction product of atisine or isoatisine. Recently, an X-ray analysis of dihydroatisine confirmed (30)its structure and determined the absolute configuration as 4S, 5S, 8R, 10R, 12R, and 15s. So far dihydroatisine has not been reported in any other plant.
78 Dihydroatisine
79 Atidine
The isolation and structure elucidation of atidine (79), a minor alkaloid of the roots of A . heterophyllum Wall, was reported in 1965 (81).Atidine was chemically correlated with dihydroatisine (78) and dihydroajaconine, a reduction product of ajaconine (80).Reduction of atidine with sodium borohydride in 80% methanol afforded dihydroatidine, which was identical to dihydroajaconine. Huang-Minlon reduction of atidine furnished dihydroatisine. A I3C-NMR analysis of various C,,-diterpenoid alkaloids established (28) that the carbonyl group in atidine is present at C-7. Recentiy, the structure of atidine as 79 was confirmed by a single-crystal X-ray analysis (82). It is worth noting that there are intermolecular hydrogen bonds between the hydrogen of the C-22 OH group and oxygen of the C-7 group and between the hydrogen of C-15 OH and oxygen of C-22 in crystalline atidine. AND DIHYDROAJACONINE C. AJACONINE
Ajaconine, the major alkaloid of the seeds of Delphinium ajacis syn. Consolida ambigua (garden larkspur) and D. consolida, has been known since 1913 (83).Recently, ajaconine has been isolated from the whole plants of D . virescens Nutt (84)and D. carolinianum (85),two relatively rare plants native to the southeastern United States. In 1961, Dvornik and Edwards (86) reported a full account of the structure elucidation of ajaconine as 80.
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
125
The chemical work on ajaconine has been reviewed ( 6 )in Volume XI1 of this treatise. Recently, Pelletier and Mody reported (87) an unusual rearrangement of ajaconine to 7%-hydroxyisoatisine(82) via a disfavored 5-endotrigonal ring closure, which is discussed in Section V.
81 Dihydroajaconine
80 Ajaconine
In 1978, dihydroajaconine was isolated (88) from the mother liquors accumulated during the isolation of ajaconine from garden larkspur (C. ambigua). On the basis of I3C- and 'H-NMR analysis, structure 81 was assigned to dihydroajaconine. Reduction of ajaconine with sodium borohydride in aqueous methanol gave a product that was identical with natural dihydroajaconine. 3C-NMR spectra of ajaconine, dihydroajaconine, and related alkaloids were also reported. It was suggested that dihydroajaconine may be an intermediate between ajaconine and atidine in the plant. In 1972, Sastry and Waller (89)reported the presence of dihydroajaconine during GC-MS studies of ajaconine isolated from D. ajucis. A sample of what had been earlier identified as pure ajaconine furnished a mixture of five compounds when the deuterated trimethylsilyl derivative was analyzed on the GC-MS. The temperature on the GC column (215") and the time required for elution (12.7-27.8 min) may have given rise to rearrangement products.
D. KOBUSINE AND PSEUDOKOBUSINE Kobusine has been isolated (52, 90-92) from A . sachalinense, A . yesoense Nakai, A . lucidusculunq and A . kamtschaticum, Aconitum species native to Japan. Okamoto and co-workers (93) initially assigned structure 83 or 84
126
S. WILLIAM PELLETIER A N D NARESH V. MODY
to kobusine on the basis of extensive chemical and spectral studies. Later, the same group revised (94)the structure of kobusine to 85 without presentation of evidence to eliminate structure 84. After unsuccessful attempts to correlate hetisine with kobusine, in 1970 Pelletier and co-workers (95) reported the structure of kobusine as 86 on the basis of a single-crystal X-ray analysis of its methiodide. R2
?. .,
~..-
"'
N--- ..
OH
''
CH 3 83 R' 84
R'
CH 3
= OH,
R2 = H
85
= H. R2 = OH
2 : $
N - - - .~
OH
CH, R 86 R = H Kohusine 87 R = OH Pseudokobusine
By virtue of the previous correlation (93)of kobusine with pseudokobusine, structure 87 was assigned to pseudokobusine. The latter was also isolated along with kobusine from A . yesoense Nakai and A . lucidusculum Nakai (91). The chemistry of kobusine and pseudokobusine has been discussed ( 6 )in a previous chapter in this treatise. Japanese chemists (96)have reported the chemical conversion of kobusine into the chloramine (95). The latter was treated with sodium methoxide in methanol to afford compound 96 in which the bridged C-14-C-20 bond was cleaved. Reduction of kobusine with sodium in n-propanol, followed by acetylation afforded compound 88. Treatment of 88 with excess phenyl chloroformate in refluxing o-dichlorobenzene gave the carbamate 89. The latter was hydrogenated over Pd-C in methanol to obtain compound 90 in 94% yield. Further hydrogenation of 90 in the presence of platinum in acidic solution gave 91. Acidic hydrolysis of 91 afforded compound 92. The carbamate 92 was converted to the benzyl derivative 93 by treating with
2.
127
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
benzyl alcohol and sodium hydride in dimethoxyethane. Hydrogenation of 93 over Pd-C in acidic methanol yielded 94 in 95% yield. The latter was chlorinated with N-chlorosuccinimide to afford the chloramine 95 in good yield.
86
88
90
89
I 91 R’ = Ac, R 2 = C6H5
92 R’ 93 R’
= H,
RZ = C,H5 = H, RZ = CHzC6H5
94 R = H 95 R = CI
Treatment of the chloramine 95 with sodium methoxide in refluxing methanol afforded a mixture of products 96,97, and 98 in 36%, 28%, and 13% yield, respectively. The structure and stereochemistry of 96 was established by X-ray analysis. Reduction of 96 with sodium borohydride in methanol afforded 99. The latter was acetylated with acetic anhydride in pyridine and subsequently hydrolyzed with hydrochloric acid to give the
128
S. WILLIAM PELLETIER AND NARESH
V.
MODY
N-acetate 100. Dechlorination of 100 was effected by Raney nickel hydrogenolysis to afford compound 101 in 50% yield. The cleavage of the C-14C-20 bond in the chloramine 95 is a novel fragmention for which no satisfactory mechanism has been offered.
96
91
,.CH,
99 R'
= C1,
R2 = H
98
100 R' = C1, R2 = AC 101 R' = H, R 2 = AC
E. IGNAVINE AND ANHYDROIGNAVINOL Ignavine was isolated by Okamoto and co-workers (97) in 1952 from the roots of A . sayoense Nakai. Subsequently, this alkaloid was also isolated from the roots of A . tasiromontanum Nakai (97, 98) and A . japonicum (99). Alkaline hydrolysis of ignavine gave an amino alcohol, anhydroignavinol, and benzoic acid. On the basis of spectral and chemical studies (loo),the tentative structures 102 and 103 were assigned to ignavine and anhydroignavinol, respectively. Anhydroignavinol was reported to have a molecular formula of C20H25N04 (MW 343) and was assumed to arise from hydrolysis of the benzoate ester
102
103
2.
THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS
129
at C-3 and the formation of an ether group by dehydration of two hydroxyl groups of ignavine. A high-resolution mass spectral study by Pelletier's group (101) indicated that the molecular ion of anhydroignavinol was m/e 345.1936 and therefore the molecular formula must be C,oH27N0,. In 1970, Pelletier, Page, and Newton (101) reported the correct structure 104 for anhydroignavinol from a single-crystal X-ray analysis of its methiodide.
104 Anhydroignavinol
Since previous work led to assignment of the benzoate group at C-3 in ignavine, the position and functionality of the remaining oxygen required by the ignavine formula, C2,H3,N06, requires explanation. Either the molecular formula originally assigned to ignavine is incorrect and should be C2,H3,N0, or an unusual rearrangement occurs during the hydrolysis of ignavine to anhydroignavinol. Considering the correct structure for anhydroignavinol, ignavine may be a hydrate of the benzoate ester of anhydroignavinol. The position of the benzoate group in ignavine still needs to be determined. Earlier work on ignavine and anhydroignavinol has been reviewed in Volume XI1 of this treatise (6).
F. HYPOCNAVINE AND HYPOGNAVINOL Hypognavine was first isolated from certain varieties of A . sanyoense Nakai in 1953 by Okamoto and co-workers (102). Alkaline hydrolysis of hypognavine afforded an alkamine, hypognavinol. On the basis of extensive chemical studies and spectral data, the Japanese chemists (102-104) assigned either structure 105a or 105b for hypognavine and structure 106a or 106b for hypognavinol. Since PMR spectral examination of hypognavinol was unsuccessful in differentiating structures 106a and 106b, the structure of hypognavinol was established as 107 (105) from a single-crystal X-ray analysis of its methiodide. On the basis of steric effects, Sakai (104) proposed that the benzoate group of hypognavine is in a /?-configuration. A careful examination of models suggested that the steric difference between a C-1 P-benzoate group and a C-2 a-benzoate group would be slight. Therefore, the location of the benzoyl group in hypognavine remains uncertain.
130
S. WILLIAM PELLETIER AND NARESH V. MODY
105a R = Bz 106a R = H
105b R = Bz 106b R = H
OH 1
CH, 107 Hypognavinol
G. ISOHYPOGNAVINE
Isohypognavine has been isolated (99, 106) from the roots of A . majijai Nakai and A . juponicurn Thumb. Its name is unfortunate since it is not an isomer of hypognavine. This alkaloid has not been isolated from any other Aconitum species. On alkaline hydrolysis, isohypognavine gave an alkamine known as isohypognavinol. On the basis of chemical correlation (107) of isohypognavine with kobusine, the partial structures 108 and 109 were HO.
,CH,
108
109
110 R = Bz Isohypognavine 111 R = H Isohypognavinol
2.
THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS
131
assigned to isohypognavine and isohypognavinol, respectively. Although isohypognavine has been known more than 30 years, the complete structure has not been established. Early chemical work on these two compounds is discussed in Volume XI1 of this treatise (6). On the basis of the stereochemistry of the C-11 and C-15 hydroxyl groups in related alkaloids (e.g., kobusine, pseudokobusine), the C-1 1 and C-15 hydroxyl groups are most likely in a p-configuration in isohypognavine and isohypognavinol. We can therefore tentatively suggest structures 110 and 111 for isohypognavine and isohypognavinol, respectively.
H. DENUDATINE In 1961, Singh (108) isolated denudatine (C,,H,,NO,, MW 331) as a minor alkaloid of the roots provisionally identified as D.denudutum Wall. On the basis of chemical and spectral evidence, Indian chemists (109, 110) tentatively assigned structure 112 to denudatine. Later work indicated that the 'H NMR and mass spectra of denudatine did not agree with the assigned structure. Canadian (111) and American (112) chemists independently showed that the correct molecular formula for denudatine is CZ2H3,NO2as evidenced by the mass spectrum (mle 343). The 'H-NMR spectrum of denudatine revealed the absence of an N-methyl group. On the basis of spectral and degradation studies, Wiesner and Gotz (111) indicated that denudatine can be assigned any one of four possible structures 113,114,115, or 116, in which C-20 could be connected to C-7 or C-14 and the secondary hydroxyl group can be at C-1 1 or C-13. Subsequently, Brisse (113) and the American investigators (112) reported independently a single-crystal X-ray diffraction analysis of denudatine and its methiodide and established the structure and stereochemistry of denudatine as 117. It is noteworthy that denudatine is the first C,,-diterpenoid alkaloid with an atisine skeleton possessing both an N-ethyl and a C-7-C-20 bridge. The biosynthetic implications of this alkaloid were mentioned by the Canadian chemists (212). RZ
OH
112
113 114
R' = OH, RZ = H R' = H. RZ = OH
132
S. WILLIAM PELLETIER A N D NARESH V. MODY
115 R’ = OH, R2 = H 116 R’ = H . R 2 = OH
117 Denudatine
I. VAKOGNAVINE Vakognavine has been isolated by Singh and Singh (114)from the indigenous crude drug known as “uakhma”, which was identified as the roots of A . palmatum Don. On the basis of the isolation of 1,9-dimethyl-7-ethylphenanthrene from the selenium dehydrogenation products, Singh and Jaswal (115) postulated a songorine-type skeleton (118) for vakognavine. Spectral data revealed the presence of a tertiary methyl, an N-methyl, a benzoate, and three acetate groups in vakognavine. They also mentioned (115)that vakognavine is an highly oxygenated alkaloid of the atisine group. In 1971, Pelletier and co-workers (116) reported a single-crystal X-ray analysis of vakognavine hydriodide (119) and established the structure of vakognavine to be 120. The presence of the C-19 aldehyde in vakognavine was indicated by a singlet at 6 9.43 in the ‘H-NMR spectrum in chloroform solution. The aldehyde singlet disappeared on the addition of trifluoroacetic acid and the unchanged free base was recovered on basification. Later Singh and co-workers (117) published additional chemical and spectral data supporting structure 120 for vakognavine. On hydrogenation with Adams catalyst, vakognavine gave the hexahydro compound 121 in which the exocyclic double bond and both the carbonyl groups were reduced. Vakognavine formed a bishydrazone, which was characterized as the
118
119
2.
THE CHEMISTRY OF Cz,-DITERPENOID ALKALOIDS
133
BzO..
120 Vakognavine
OH
'5.
OH 121
0
\\
122 R' = Bz, R Z = Ac 123 R' = H, R 2 = Ac 124 R' = R 2 = H
reineckate salt. Selective hydrolysis of vakognavine with 50% sulfuric acid yielded compound 122 after 4.5 min, the monoacetate 123 after 13.5 min and the completely hydrolyzed product 124 after 2 hr. The structures of the hydrolysis products were based on 'H-NMR data. Vakognavine is the first example of an N, C- 19-seco-diterpenoid alkaloid reported and an interesting alkaloid for biogenetic speculation. The authors (116) suggested that the C-19 aldehyde may be a plausible alternate to the pseudokobusine structure as an intermediate in the biosynthesis of the modified atisine-type skeletons such as hetisine. The C-19 hydroxyl of vakognavine hydriodide (119) is reminiscent of the oxazolidine oxygen of isoatisine. J. HETISINE (DELATINE) AND HETISINONE Hetisine (125) was isolated as a minor alkaloid from the roots of A . heterophyllurn Wall (80)in 1942 by Jacobs and Craig (118, 119). Later it was also isolated from D.cardinale Hook (120).Several papers were published (121, 122) regarding the chemistry and structure elucidation of hetisine, but the structure of hetisine (125) was eventually established by an X-ray diffraction study (123. 124). Earlier work on the chemistry of hetisine has been reviewed in Volume XI1 of this treatise (6).
134
S. WILLIAM PELLETIER A N D NARESH V. MODY
RO
om RO\
R 0 . . H H 2
N---
HO H O . . e Z
__
:, CH3 125 R 126 R
H Hetisine = AC =
127 R 128 R
=
AC Hetisinone
=H
RO
130 R = H 131 R = MS
133
During an attempted chemical correlation of hetisine and kobusine, Wright, Newton, and Pelletier (125) observed an unusual rearrangement of a hetisine derivative to a cyclopropane derivative by lithium aluminium hydride reduction. The correlation route involved oxidation of hetisine diacetate (126) to the ketodiacetate 127, and hydrolysis to hetisinone (128). Wolff-Kishner reduction of hetisinone gave the diol 129. Selective Sarett oxidation of 129 yielded compound 130, which was converted into the mesylate 131. Theoretically, reduction of the latter and introduction of an allylic hydroxy group should have produced kobusine (86).However, lithium aluminium hydride reduction of 131 afforded the cyclopropane derivative 132. The 'H-NMR spectrum of 132 indicated the presence of an extra tertiary methyl group at 6 1.18, which was considerably more deshielded than any of the tertiary methyl groups previously encountered in this type of alkaloid. The structure of 132 was established (125) by an X-ray analysis of its methiodide. The authors suggested that coordination of the oxygen of the mesylate group with some aluminium species provided at least partial ionization, and then hydride attack on species 133 could have occurred at C-17 to give the cyclopropyl compound 132. This reaction represented the first reported example of this type of skeletal rearrangement among the C,,-diterpenoid alkaloids.
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
135
Hetisinone (128) has been reported to occur in D . cardinale (120), D . denudatum (126),and A . heterophyllum (80).Structure 128 originally assigned for hetisinone was confirmed (127) by ‘H-NMR and mass spectral studies. Two other possible structures for hetisinone (134 and 135) were discarded on the basis of the following arguments.
134
135
Dehydration of hetisine diacetate (126) with phosphorus oxychloride and pyridine followed by basic hydrolysis afforded a mixture of olefins 136 and 137, whose structures were analyzed by ‘H-NMR spectroscopy. These olefins can only be derived from hetisine diacetate if its structure is 126, a fact requiring the structure of hetisinone to be 128. Furthermore, hetisinone is stable to bases, behavior that is consistent with the assigned structure but less likely for either of the alternative B-ketoalcohols 134 and 135. When hetisinone was heated in D,O-CH,OD containing sodium deuteroxide, a mixture of deuterated hetisinones was obtained. Mass spectral analysis revealed the presence of 14% d , , 53% d,, 24% d , , and 6% d4 species. These data further confirmed that hetisinone is correctly represented as 128.
K. HETIDINE Hetidine has been isolated (80) in very small quantity from the strongly basic fraction of the extracts of the roots of A . heterophyllwn Wall. The presence of an N-methyl group, a tertiary methyl group, two acetylable hydroxyl functions, two ketones, and an exocyclic double bond in hetidine
136
S . WILLIAM PELLETIER AND NARESH V. MODY
was revealed by chemical and spectral data. Because hetidine was not available in sufficient quantity, the structure of this alkaloid was established by a single-crystal X-ray analysis of hetidine hydriodide (128). The latter was prepared by prolonged treatment of hetidine with methyl iodide in dimethylformamide. The structure of hetidine hydriodide was established as 138; thus hetidine was assigned structure 139. The masked aminoketone group of hetidine hydroiodide is analogous to that existing in pseudokobusine and miyaconitine.
HO..
138
139 Hetidine
L. MIYACONITINE AND MIYACONITINONE Miyaconitine and miyaconitinone, two highly oxygenated alkaloids, were isolated from the Japanese species A . miyabei Nakai in 1946 (129).On the basis of chemical and spectral data (54, 129-132) and biogenetic considerations, structures 140 and 141 were assigned to miyaconitine and miyaconitinone, respectively. High-resolution mass spectra confirmed the earlier established molecular formula, C,,H,,NO, , for miyaconitine and C,,H,,NO, for miyaconitinone. Both alkaloids failed to form acetylation products with either acetyl chloride or acetic anhydride in pyridine. These alkaloids have been correlated by converting miyaconitine to miyaconitinone by oxidation with CrO, or Bi,O, in acetic acid. Hydrogenation of miyaconitine over platinum in ethanol gave its dihydro derivative. Acidic hydrolysis of miyaconitinone afforded miyaconinone (143). The latter was reconverted to 141 by acetylation with acetyl chloride. Oxidation of 143 with CrO, in sulfuric acid or MnO, in chloroform yields the dehydro derivative 144. On formation of the perchlorates of miyaconitine and miyaconitinone, the remarkably low frequency (1678and 1676 cm-') IR carbonyl maxima disappeared. In addition, the absorption at 2 ,,,432 nm (log E l.6),which is characteristic of an x-diketone moiety, also disappeared in the W spectrum of miyaconitinone perchlorate. Miyaconitine has been shown to contain an a-ketol group, whereas miyaconitinone contains an x-diketone moiety. On the basis of spectral analysis of compound 144, the authors suggested that the new
2.
THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS
137
carbonyl formed in compound 144 by oxidation of 143 has an adjacent active methylene group and is near the nitrogen atom. On the basis of spectral data and the color tests, the Japanese chemists (132)represented structures 140 and 141 for miyaconitine and miyaconitinone, respectively. Subsequently, the structure of miyaconitine was confirmed by a single-crystal X-ray analysis of its hydrobromide (142) (133). 0
\\
140 Miydconitine
141 R = Ac Miyaconitinone 143 R = H
144
0 &H2 HRO..@ C . . ...N 5
'OR
:, H CH,
0
145 R = H Miyaconine
146 R
=
Ac
147 R = H Apomiyaconine 148 R = Ac
In 1974, the same workers (134)reported an unusual skeletal rearrangement of miyaconitine. Treatment of miyaconitine (140)with 1 N methanolic potassium hydroxide for 1 hr yielded miyaconine (145). The latter on acetylation with acetyl chloride afforded diacetylmiyaconine (146). Reaction of miyaconine with 1 N methanolic potassium hydroxide under reflux for 2 hr yielded apomiyaconine (147).Acetylation of the latter with acetic anhydride in the presence of a catalytic amount of p-toluensulfonic acid on a steam
138
S. WILLIAM PELLETIER AND NARESH V. MODY
bath for 1 hr afforded diacetylapomiyaconine (148).Treatment of compound 143 with 5% hydrochloric acid under reflux for 2 hr also afforded miyaconine (145). The latter was also obtained by mild oxidation of miyaconitine (140) with an alkaline solution of triphenyltetrazolium chloride (TTC) at room temperature. The structures of miyaconine (145) and apomiyaconine (147) were assigned on the basis of 'H- and 13C-NMRdata. Complete assignments of 3C chemical shifts of 145 and 147 are also presented by the authors. On the basis of I3C-NMR data and Dreiding models, the Japanese workers assigned a P-configuration to the hydrogen at C-5 in 145 and 147. Miyaconitine and miyaconitinone were postulated as biogenetic intermediates in the formation of the modified atisine-type compounds from the normal atisine-type system.
'
M. DELNUDINE During the isolation of denudatine, Gotz and Wiesner (135)also isolated a new alkaloid, designated as delnudine (149),from the seeds of D.denudutum. Preliminary spectral data revealed the presence of two hydroxyls, a cyclohexanone, and an exocyclic double bond in proximity with the ketone. The presence of the tertiary carbinolamine moiety was demonstrated by the formation of a basic diacetate (150) and a neutral 0,N-diacetate (151) on acetylation with acetic anhydride in pyridine. They demonstrated that one of the ketones in compound 151 was derived from the carbinolamine moiety. Finally, the structure of delnudine was established as 149 by a single-crystal
HO..
149 Delnudine
151
150
125 Hetisine
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
139
X-ray analysis (136) of delnudine hydrochloride. It is worth noting that delnudine represents a novel type of skeleton. The Canadian chemists (135) speculated that delnudine may be biogenetically derived from hetisine (125) by the concerted rearrangement portrayed by the arrows in structure 125 and by introduction of the carbinolamine moiety.
N. SPIRADINE A, SPIRADINE B, AND SPIRADINE C In 1964 Molodozhnikov and co-workers (137) reported the isolation of several diterpenoid alkaloids from the shrub Spiraea japonica L. fil. of the Roseaceae family. Later Goto and co-workers (138) examined alkaloids of the same plant (Japanese name “Shimotsuke”) and isolated 10 new alkaloids. The structures of 3 of these, spiradine A (152), spiradine B (153), and spiradine C (154) have been determined by chemical correlations coupled with a single-crystal X-ray analysis (139) of spiradine A methiodide (155). Reduction of spiradine A with sodium borohydride in methanol at room temperature afforded spiradine B. Oxidation of the latter with CrO, in pyridine regenerated spiradine A. Hydrolysis of spiradine C with potassium hydroxide in ethanol yielded spiradine B. Treatment of spiradine A with acetic anhydride in pyridine gave an 0-acetate (156) and an N-acetate (157). The structures of these acetylation products were based on IR and ‘H-NMR data. When treated with methyl iodide in methanol, spiradine A gave a
152 R = H Spiradine A 156 R = AC
153 R = H Spiradine B 154 R = Ac Spiradine C
0
CH, 0 155
157
140
S. WILLIAM PELLETIER AND NARESH
V.
MODY
methiodide (155), which was treated with silver oxide in 50% aqueous methanol to yield an N-methyl diketone (158). The latter was heated with methyl iodide at 100" in a sealed tube followed by treatment with silver oxide to afford 159. These transformations provided evidence for the I -N-C-CH,-& functionality in spiradine A. Finally, the structure OH
of spiradine A was determined by an X-ray analysis (138, 139). With the structure of spiradine A elucidated as 152, the structures of spiradine B (153), and spiradine C (154) were assigned accordingly.
0. SPIRADINE D AND SPIREDINE Spiradine D was also isolated from S. japonica by Goto and Hirata (140) in 1968. The structure of spiradine D (160) was elucidated by chemical correlation between spiradines A and D.
160 Spiradine D
161
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
141
Spiradine D formed a quaternary salt (161)on treatment with methanolic hydrochloric acid at 0'. This salt was reconverted to spiradine D by shaking with silver oxide in methanol. This experiment suggested that spiradine D has a masked aminoketone group as exists in other diterpenoid alkaloids (e.g., hetidine). The presence of a carbinolamine ether (N-C-0-C) linkage in spiradine D was detected by the following chemical transformations. Reduction of spiradine D with sodium borohydride in methanol afforded compound 162. The latter was hydrogenated in ethanol to give the dihydro derivative 163. Spiradine D was correlated with spiradine A through this dihydro derivative. Spiradine A was converted to the azine 164 by treatment with hydrazine in diethylene glycol at 180" and then with
164
166
165
167
acetone at 20'. Wolff-Kishner reduction of 164 gave a mixture of compounds 165 and 166. When this mixture was heated at reflux with ethylene chlorohydrin and methanol in the presence of potassium carbonate, the N-P-hydroxyethyl derivative 167 was obtained. Catalytic hydrogenation of 167 in ethanol gave the dihydro derivative 163. The latter was identical to one prepared from spiradine D. On the basis of this chemical correlation, structure 160 was assigned for spiradine D. Spiredine has been isolated recently from S. juponicu by Gorbunov and co-workers (141). On the basis of spectral data and chemical correlation with spiradine A, structure 168 was assigned to this new alkaloid. Catalytic hydrogenation of spiredine in a mixture of ethanol and acetic acid afforded tetrahydrospiredine (169). The latter was identical with the compound obtained by the addition of ethylene oxide to dihydrospiradine A (170).
142
S. WILLIAM PELLETIER AND NARESH V. MODY
P. SPIRADINE F AND SPIRADINE G In 1968, Toda and Hirata (142) reported the isolation and structure determination of two major alkaloids of S. juponicu, spiradine F and spiradine G. Spiradine F is an acetate of spiradine G. On the basis of extensive chemical and spectral studies, the Japanese chemists (142) assigned structures 171 and 172 to spiradine F and spiradine G, respectively.
171 R = Ac Spiradine F 172 R = H Spiradine G
173
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
143
The presence of a tertiary methyl group and an exocyclic double bond in spiradine G was demonstrated by 'H-NMR analysis. Mild reduction of spiradine G with sodium borohydride afforded the trio1 173, which indicated that the remaining two oxygen atoms exist as a part of two carbinolamine ether (N-C-0-C) linkages in spiradine G. The presence of an exocyclic double bond in the six-membered ring was confirmed by catalytic hydrogenation of spiradine G to compound 174 and oxidation of 172 with potassium permanganate to compound 175.
177
176
178
Oxidation of 172 with chromium trioxide in pyridine gave the monoketone 176, whereas oxidation of spiradine F under the same conditions afforded the hydroxylactam 177. Catalytic hydrogenation of compound 176 afforded the a-ketol 178. The latter was treated with sodium methoxide in benzene to give an enolated a-diketone (179), which definitely fixed the position of the hydroxyl group at C-6 in spiradine G. Comparison of an ORD curve of compound 178 with that of 5a-cholestane-6-one established the indicated absolute configuration for these alkaloids. It is worth noting that these alkaloids bear many structural similarities to the earlier mentioned alkaloid ajaconine. Q. SPIREINE
In 1964, Soviet chemists (137)reported the isolation of a new alkaloid, spireine, from S. japonica and later they proposed (143) alternative structures 180 or 181 for this new alkaloid. Chemical and spectral studies
144
S. WILLIAM PELLETIER AND NARESH V. MODY
revealed the presence of two keto groups, a tertiary hydroxyl group, two tertiary methyl groups, and an exocyclic double bond in spireine.
180
181
CHO
184
On reduction, spireine afforded di- and tetrahydro derivatives. The location of two keto groups in spireine was revealed by 'H-NMR and mass spectral analysis of deuterated spireine and tetrahydrospireine. When spireine was heated with selenium at 340", a compound with molecular formula C20H2,N0, was obtained. Structure 182 was proposed for this compound on the basis of spectral data. Since the C-19 imine bond is usually unstable and cannot be isolated in that form, we suggest that the imine bond is present at C-20 rather than at C-19 in the selenium degradation product (C,oH2,N0,). Thus, structure 183 should be considered for the latter. Each of the structures considered for spireine has unusual features. The exocyclic double bond in 181 bears some resemblance to lycoctamone (184), a rearrangement product of lycoctonine.
1V. Bisditerpenoid Alkaloids
A. STAPHISINE AND STAPHIDINE In 1941, Jacobs and Craig (144) reported the isolation of a diterpenoid alkaloid designated as staphisine from the seeds of D. straphisagria. On the basis of chemical studies (144, 145), they indicated that staphisine is (Iater a diterpenoid aIkaloid dimer with molecular formula C,,H,,N,O
2.
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
145
revised to C4,H60N,0) (146), which contains two NCH, groups and no methoxyl group (despite the presence of 1.36% OCH,). During the column chromatographic separation of staphisine they found that the combustion analysis of several samples of staphisine fluctuated between the limits of 82.13 and 82.85% for carbon and 9.47 and 9.77% for hydrogen. On the basis of this observation, Jacobs and Craig cautioned that the so-called staphisine could still be a persistent mixture of bases which are very difficult to separate. Attempts to separate “staphisine” by crystallization of the hydrobromide, hydrochloride, and nitrate salts met with failure.
H,C--
185 R = OCH, Staphisine 187 R = H Staphidine
H,C--
186
From the same mother liquors, in 1972 Pelletier and co-workers (247) isolated a methoxyl group-containing bisditerpenoid alkaloid, which they named staphisine, and elucidated its structure as 185 by X-ray analysis of its monomethiodide (186). Chemical studies of staphisine were hindered by its instability to light and heat and by the fact that attempted degradation led to complex changes involving numerous unstable products. Highresolution mass spectral and elemental analysis of staphisine established its molecular formula as C,,H,,N,O,. The presence of two tertiary methyl groups, two N-methyl groups, a cyclopropyl ring, a methoxyl group, and a conjugated double bond in staphisine was revealed by I3C-NMR, PMR, IR, and UV spectal data. Jacobs’ selenium dehydration experiments had afforded pimanthrene and 1,3-dirnethyl-7-isopropylphenanthreneas degradation products, which are compatible with structure 185. Thus, the structure of staphisine (185) elucidated by X-ray analysis is in agreement with observed spectral and chemical data for Jacobs’ staphisine.
146
S . WILLIAM PELLETIER AND NARESH V. MODY
In 1976, the same group (148) found that Jacobs' "staphisine" is a mixture of alkaloid 185 and a companion nonmethoxyl-bearing alkaloid designated as staphidine, C4,H,,NZ0. The structure of staphidine (187) was elucidated by a comparison of its 'H- and I3C-NMR, IR, UV, and mass spectra with those of staphisine (185). The presence of a conjugated diene system was confirmed by observing UV absorption at i,,, 268 nm ( E 17,300). The IR spectrum exhibited no N H or OH absorption. The mass spectrum showed an intense molecular ion peak at mje 606 corresponding to the molecular formula, C4,H5,N,0. The 'H-NMR spectrum of staphidine revealed the presence of two tertiary methyl groups at 6 2.13 and 6 2.21 and a vinyl proton at 6 5.85. Comparison of its 'H-NMR spectrum with staphisine showed the absence of a methoxyl singlet at 6 3.30 and an upfield shift of one N-methyl group from 6 2.27 to 6 2.21 in staphidine. The observed change (A6 = 0.06) in the chemical shift of the N-methyl was explained by the steric interaction between the NCH, and OCH, group in the A unit of staphisine. On the basis of this observation, the chemical shift at 6 2.13 was assigned to the N-methyl group in unit B of staphisine and staphidine and that at 3 2.27 and 2.21 to the N-methyl group in unit A in staphisine (185) and staphidine (187), respectively. Further correlation of staphidine with staphisine was made through their respective I3C-NMR spectra. This comparison afforded evidence for the absence of a methoxyl group at 57.8 ppm and a C-13 methine carbon at 89.4 ppm in staphidine. Based on these data, structure 187 was assigned to staphidine.
B. STAPHININE AND STAPHIMINE Besides the two bisditerpenoid alkaloids discussed earlier, two new iminecontaining alkaloids designated as staphinine and staphimine have been isolated (148)from the seeds of D.stuphisagria. The structures of staphinine (188) and staphimine (189) were also assigned on the basis of I3C- and 'H-NMR spectral analysis. The 'H-NMR spectrum of staphinine revealed the presence of two angular methyl groups at 6 0.94 and 6 1.00, one N-methyl group at 6 2.13, a methoxyl group at 6 3.30, a vinyl proton at 6 5.85, and an imine proton at 6 7.30. The 'H-NMR spectrum of staphimine was similar except for the absence of a methoxyl singlet at 6 3.30. The 'H-NMR data indicated that these two alkaloids are very similar to each other and are related to the earlier reported alkaloids staphisine and staphidine. The presence of an imine (-N=CH-) group in staphinine and staphimine was established by comparison with 3C-NMR shifts of known atisine derivatives containing an imine group, e.g., atisine azomethine. The presence of an imine group in the A unit of these alkaloids was consistent with the observed downfield
'
2.
THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS
147
188 R = OCH, Staphinine 189 R = H Staphimine
shift of the C-4 carbon and the upfield shift of the C-20 carbon in staphinine (188) and staphimine (189) relative to the known alkaloids staphisine and staphidine, respectively. This was also confirmed on the basis of an N-methyl singlet at 6 2.13 in the 'H-NMR spectrum of both alkaloids. On the basis of these spectral data, structures 188 and 189 were assigned to staphinine and staphimine, respectively. The authors were unable to carry out any transformation of staphinine and staphimine to staphisine and staphidine, respectively, because of the instability of these alkaloids toward various mild reducing agents (e.g., sodium borohydride, sodium cyanoborohydride). Staphimine and staphinine occur in extremely small amounts in the seeds of D . stuphisagria. It has been suggested that the imine-containing alkaloids may be biogenetic precursors of staphisine and staphidine.
C. STAPHIGINE AND STAPHIRINE Staphigine and staphirine have been isolated (149) in extremely small amounts from the seeds of D. stuphisagria. Staphigine and staphirine are the C- 19 lactam derivatives of staphisine and staphidine, respectively. The structures of staphigine (190) and staphirine (191) were determined on the basis of their I3C- and 'H-NMR spectra. The IR spectra of these alkaloids revealed the presence of a lactam. The H-NMR spectrum of staphigine indicated the presence of two tertiary
'
148
S. WILLIAM PELLETIER AND NAFESH V. MODY
Y H,C--
190 R 191 R
= OCH, =H
Staphigine Staphirine
methyl groups at 6 0.94 and 1.12, two N-methyl groups at 6 2.13 and 2.98, a methoxy singlet at 6 3.30, and a vinyl proton at 6 5.85. The 'H-NMR spectrum of staphirine was identical to that of staphigine except for the absence of a methyl singlet at 6 3.30. The downfield tertiary methyl singlet at 6 1.12 in these alkaloids confirmed the presence of the lactam and this value was in perfect agreement with the value observed for the methyl singlet (6 1.12) of the atisine lactam derivative (192). The presence of the lactam in the A unit of these alkaloids was established by the appearance of an N-methyl singlet at 6 2.13 in the 'H-NMR spectra and the constant 13Cchemical shifts shown by the C-19, C-20, and NCH, carbons of staphigine and staphirine by comparison with the known alkaloids staphisine (185), staphinine (188), and staphimine (189). The authors indicated that these lactam alkaloids did not arise as artifacts by oxidation of staphisine and staphidine during isolation.
D. STAPHISAGNINE AND STAPHISAGRINE Staphisagnine (193) and staphisagrine (194) were also isolated (1.50) in extremely small amounts from the mother liquors accumulated during the isolation of delphinine from the seeds of D. stuphisagria. These alkaloids are unusual in containing an oxazolidine ring of the atisine and veatchine type in addition to many of the uncommon features of the staphisine skeleton.
2.
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
149
H,C--
193 R = OCH, Staphisagnine 194 R = H Staphisagrine
The IR and 'H- and I3C-NMR spectra of these alkaloids showed some similarity to the known alkaloids staphisine (185) and staphidine (187). The 'H-NMR spectrum of staphisagnine revealed the presence of two tertiary methyl groups at 6 0.82 and 0.93, one N-methyl group at 6 2.27, a proton as part of an oxazolidine methoxyl group at 6 3.30, an N-CH-0 ring at 6 4.06, and a vinyl proton at 6 5.93. The 'H-NMR spectrum of staphisagrine was identical to that of staphisagnine except for the absence of a methoxyl singlet at 6 3.30. The presence of the oxazolidine ring in the B unit of these alkaloids was established by 'H-NMR analysis. The latter was confirmed through a comparison of their 13C chemical shifts with those of the known oxazolidine ring-containing alkaloids, veatchine, garryine, atisine, and isoatisine. It is interesting to note that these two bisditerpenoid alkaloids did not contain the conjugated diene system, which is present in the other six bisditerpenoid alkaloids. Biogenetically, it is worth noting that all these bisditerpenoid alkaloids occur as methoxyl and desmethoxyl pairs in the seeds of D.staphisagria.
V. Behavior and Formation of the Carbinolamine Ether Linkage in Diterpenoid Alkaloids: The Baldwin Cyclization Rules Recently, Pelletier and Mody (87) reported an unusual rearrangement of ajaconine (80), via a disfavored 5-endo-trig ring closure, to the more stable oxazolidine ring-containing compound, 7cc-hydroxyisoatisine (82). They called attention to apparent violations of Baldwin's cyclization rules (151)
150
S. WILLIAM PELLETIER A N D NARESH
V.
MODY
MeOH
OH 80
82
in certain of the carbinolamine ether (N-C0-C) linkage-containing diterpenoid alkaloids and their derivatives (152). Results on 5- and 6-endotrig cyclizations involving nucleophilic attack of oxygen on immonium salts derived from C,,-diterpenoid alkaloids will be discussed in this section. Atisine, an amorphous alkaloid (pK, 12.5), is usually isolated in the form of its hydrochloride salt, a compound that is really a tertiary immonium salt (5). Atisine (4) can be regenerated from atisinium chloride by treatment with base. The fact that the oxazolidine ring closes in two different directions to give a pair of epimers suggested the operation of unusual constraints on the mechanism of ring closure. Examination of a Drieding model of atisinium chloride revealed that closure of the oxazolidine ring on the pro-20R side of the plane is sterically hindered, especially by H-14, which is situated almost directly over C-20. Across to the pro-20s side of the bond is almost equally restricted by H-2. The authors indicated that cyclization of the ternary immonium salt to form the five-membered oxazolidine ring is an example of a “disfavored” 5-endo-trig ring closure. Yet this ring closure is a very facile one. The same phenomenon was also observed during the conversion of isoatisinium chloride (76)to isoatisine (75), of veatchinium chloride (3) to veatchine (l),and of garryfoline hydrochloride to garryfoline. The formation and behavior of five- and six-membered carbinolamine ethers in various diterpenoid alkaloids were examined to determine whether any further violation of Baldwin cyclization rules occurs in these alkaloids. In 1957, Marion and co-workers (153) reported the preparation of several six-membered ring-containing carbinolamine ethers from C, ,-diterpenoid
4 Atisine
5 Atisinium chloride
2.
THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS
75 Isoatisine
151
76 Isoatisinium chloride
alkaloid derivatives. Subsequently, dehydrocondelphine (196) was prepared (152) from condelphine (195) by treatment with aqueous potassium permanganate. Dehydrocondelphine is a weak base that forms a ‘NH-type salt (197) with hydrochloric acid rather than the Schiff salt (198). This behavior is not because of a special stability of six-membered carbinolamine ethers, but due to the prohibitively high energy of the transition state for the opening of the ether (196) to the quaternary Schiff salt (198). Examination of the Drieding model for 198 indicated that this Schiff salt cannot close easily to the ether for steric and vectorial reasons. Consequently, the transition state for 0-protonation and opening of the ether linkage of dehydrocondelphine to the Schiff salt would be expected to be unfavorable.
OCH,
OCH,
196
195
OCH,
OCH, 197
198
The oxazolidine rings (199) of C,,-diterpenoid alkaloids in hydroxylic solvents such as methanol are in equilibrium with the corresponding Schiff salts (200) and consequently are strong bases. Examination of a Drieding model of such a Schiff salt indicated that it is vectorially poorly arranged for ring closure. Although such a cyclization is “disfavored” according to
152
S. WILLIAM PELLETIER AND NARESH V. MODY
Baldwin’s rules, experimental evidence demonstrated (154) that an equilibrium does exist between the oxazolidine ring (199) and the Schiff salt (200). This observation suggests that the Baldwin rules are less prohibitive for quaternary immonium salts bearing a full charge on the nitrogen. These salts resemble carbocations to a greater extent than uncharged groups. The authors indicated that an attack on a carbocation (201) exhibits less vectorial specificity than an attack on a carbonyl group (202). Because the immonium salts (200) are intermediate between an uncharged group and a carbocation, the equilibrium between oxazolidine (199) and Schiff salt is probably slower than a ring closure which is not disfavored.
Ajaconine (80) was the first example of a C,,-diterpenoid alkaloid containing an internal carbinolamine ether linkage between C-7 and C-20. An attempt by Dvornik and Edwards (86)to rearrange ajaconine in methanolic base resulted in a mixture that was not studied further. On the basis of chemical reactions and hydrogen-interaction theory, they concluded that a driving force for rearrangement of the internal carbinolamine ether is absent. The Canadian chemists (86) also mentioned that an entropy factor must favor the internal ether over the oxazolidine ring, and thus the C-7C-20 ethers should be more stable than the oxazolidine ring derivatives. Treatment of ajaconine with hydrochloric acid afforded a ternary im+
monium salt (203) instead of a protonated (-NH-) type salt. Treatment of the immonium salt (203) with base regenerated ajaconine (80) instead of 7a-hydroxyatisine (205), which would parallel the formation of atisine (4) from atisinium chloride (5). Transformation of ajaconium chloride to ajaconine is an example of a 6-exo-trig ring closure, which is a “favored” process according to Baldwin’s rules. The I3C-NMR spectral analysis of ajaconine in nonionic and ionic solvents indicated that in hydroxylic solvents the ether linkage of ajaconine ionizes and covalent solvation takes place (87). This observation accounted for the formation of the Schiff salt, with the resultant high pKa value (1 1.8) of ajaconine in aqueous solution-behavior which parallels that of atisine (pK, 12.5) and veatchine (pKa 11.5). These results suggested that ajaconine may be rearranged by refluxing in an ionic solvent to a compound in which the C-7-C-20 ether linkage is absent.
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
204
153
205
Refluxing ajaconine in methanol afforded a mixture from which a new compound identified (87) as 7a-hydroxyisoatisine (82) was isolated. The structure of the latter was established by ‘H- and I3C-NMR spectroscopy. When ajaconine was refluxed in CH,OD under nitrogen, a mixture of C-19, C-20-deuterated ajaconine (206) and C- 19,C-2O-deuterated 7a-hydroxyisoatisine (207) was formed. Incorporation of deuterium in 206 and 297 indicated that ajaconine ionized and rearranged to 207 and that these species are in equilibrium in refluxing methanol.
The authors also suggested (87) a mechanism for this rearrangement in refluxing methanol. In alkaline solution the normal-type immonium species 208 closes to ajaconine (80) and not to 7%-hydroxyatisine(205) because the latter closure, being a “disfavored” 5-endo-trig process, is much slower
154
S . WILLIAM PELLETIER A N D NARESH V. MODY
than the “favored” 6-endo-trig closure of the normal-type immonium species to ajaconine. However, species 208 undergoes an isomerization to the isoimmonium salt 209 which is known in the case of the isomerization of atisine to isoatisine and of veatchine to garryine. The intermediate 209 closes to 7%-hydroxyisoatisine(82) in spite of the closure being partially disfavored because there is no faster process in competition with this ring closure.
205
80 Ajaconine
209
82
Veatchine acetate (210) was hydrolyzed to veatchine (1) in methanol a t room temperature without using any external base (152). This unusual hydrolysis was explained by participation of methoxide ion which was formed by opening of the oxazolidine ring by methanol. Diterpenoid alkaloid derivatives lacking the oxazolidine ring, such as dihydroatisine diacetate (211) and veatchine azomethine acetate (lo), failed to give compounds 212 and 78, respectively, in methanol under these conditions.
210
1 Veatchine
2.
THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS
78 R = H 211 R = Ac
155
10 R = AC 212 R = H
The hydrolysis of veatchine acetate to veatchine suggested an examination of the behavior of 7a-acetoxyatisine acetate (213) which was prepared from ajaconine (SO) via the corresponding imine. Acetylation of ajaconine with acetic anhydride and pyridine at room temperature afforded the triacetate salt 214 in quantitative yield. A Hofmann-type degradation of the triacetate salt was achieved by heating at reflux in chloroform to give the imine 215 in 95% yield. The latter reacted with ethylene oxide in acetic acid to afford 7a-acetoxyatisine acetate (213) in quantitative yield (152). When 213 was stirred in methanol at 25", a mixture of 7a-hydroxyisoatisine (82), ajaconine (SO), and their C-15 acetates (216 and 217) was formed. No starting material was detected after 36 hr. The formation of these products was explained on the basis of opening of the oxazolidine ring by methanol and formation of methoxide ion. The latter hydrolyzes the C-7 acetate group of 7-acetoxyatisine acetate. The resulting anion can close on the immonium
80
214
I
A CHCI,
213
215
156
S. WILLIAM PELLETIER AND NARESH V. MODY
“OH
80 R 216 R
= =
H Ajaconine AC
82 R = H 217 R = AC
species at C-20 to form ajaconine. And as mentioned earlier, the normaltype oxazolidine ring derivatives isomerize readily in methanol to the isotype oxazolidines. Recently, Pelletier, Nowacki, and Mody (155) reported that treatment of alkaloid imine derivatives with ethylene oxide in acetic acid or methanol afforded the oxazolidine ring-containing alkaloids in excellent yield. Treatment of lindheimerine (7) with ethylene oxide in acetic acid afforded ovatine (6) in 98% yield. Similarly, veatchine azomethine acetate (10) afforded veatchine acetate (210) in 97% yield. Formation of the oxazolidine ring in these
7 Lindheimerine
6 Ovatine
10
210 Veatchine acetate
compounds occurs via a “disfavored” 5-endo-trig ring closure. When methanol was used instead of acetic acid, 7 gave 6 in 90% yield within 3 hr. Under longer reaction times, 7 afforded only garryfoline (8) in a yield of 96%. Comparable results were also obtained with veatchine azomethine acetate (10). Under short reaction times, veatchine acetate (210) was produced and under longer reaction times, veatchine (1) was formed. Depending on the reaction time, treatment of atisine azomethine acetate (218) with ethylene oxide afforded either atisine acetate (219), atisine (4), or
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
I R' = H, R 2 = OAc 10 R' = OAc, Rz = H
6 R'
= H,
157
R 2 = OAc Ovatine
210 R' = OAc, R 2 = H
1 R' = OH, R 2 = H Veatchine 8 R' = H, R2 = OH Garryfoline
isoatkine (75). Thus, in 3 hr atisine acetate was isolated, in 12 hr a mixture of atisine and isoatisine was formed, and in 24 hr only isoatisine was obtained.
218
4 Atisine
219 Atisine acetate
75 Isoatisine
Unlike ethylene oxide, oxetane reacted very slowly with the alkaloid imine derivatives to afford low yields of tetrahydro-l,3-oxazine derivatives. Treatment of veatchine azomethine acetate (10) with oxetane in acetic acid at 50" afforded the six-membered carbinolamine ether, homoveatchine acetate (220), in 25% yield. The latter was isolated as a mixture of C-20 epimers.
158
S. WILLIAM PELLETIER AND NARESH V. MODY
10
220
221
222
On the basis of these results, the authors designed (152) a reaction with imines in which either a five- or six-membered carbinolamine ether might be formed. Treatment of veatchine azomethine acetate with glycidol afforded compound 221 as the major product. The structure of 221 was established by 3C-NMR spectroscopy and confirmed by a single-crystal X-ray analysis. The presence of a five-membered ring containing compound 222 was not detected in the reaction mixture. In a similar reaction, atisine azomethine acetate (218) reacted with glycidol to yield a mixture of the C-20 epimers of compound 223. Surprisingly, treatment of ajaconine azomethine acetate (215) with glycidol gave the single C-20 epimer (224). This
218
223
L
“OAc
CH 3 215
224
2.
THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS
159
behavior suggested that the 7%-acetoxylgroup in 224 exerts a profound influence on the direction of closure of the carbinolamine ether linkage. In summary, certain reactions with diterpenoid alkaloid imines proceeded by a “disfavored” 5-endo-trigonal process, whereas in other cases, such as the reactions with glycidol, a “favored” 6-endo-trigonal process was followed. The Baldwin rules should be modified to accomodate the exceptional behavior of the tertiary immonium salts. Recently, examples of similar reactions demonstrating the violation of the Baldwin cyclization rules have been reported (156-158).
4a
4b
In 1970, Pradhan and Girijavallabhan (79)concluded that atisine in solution contains an equilibrium mixture of the C-20 epimers (4d and 4b), which are interconvertiable via a zwitterion. This conclusion was based on a ‘H-NMR study of atisine in different polar solvents. Later, Pelletier and Mody (154) reported that atisine in nonionic solvents exists as a mixture of C-20 epimers which do not interconvert via a zwitterion and that in ionic solvents atisine slowly isomerizes to isoatisine. This idea was supported by a I3C-NMR study of atisine in deuterated solvents. The results reported by Pelletier and Mody (154) were questioned by Pradhan (159)in 1978. The rebuttal paper was submitted prior to the publication of the X-ray crystallographic studies in which Pelletier and co-workers (30)reported additional evidence supporting their earlier conclusion. Recent work (36)on the structure of cuauchichicine further confirmed this conclusion. The normal-type oxazolidine ring of cuauchichicine does not exist as a mixture of C-20 epimers in solution. This unusual finding was confirmed (36)by a single-crystal X-ray analysis of cuauchichicine.
160
S. WILLIAM PELLETIER AND NARESH V. MODY
VI.
' 3C-NMR Spectroscopy of C,,-Diterpenoid
Alkaloids
Recent developments in instrumentation and techniques have made possible the application of 13C-NMR spectroscopy to the study of many natural products. 3C-NMR spectroscopy has become exceedingly important in the area of structure elucidation and synthesis of naturally occurring organic substances since its availability to organic chemists just over 10 years ago. Recently, 13C-NMR data have become important for the comparison of natural and synthetic compounds or degradation products. I3C-NMR spectral data have proved critically important in establishing the stereochemistry of compounds that are not available in crystalline form for X-ray analysis, such as atisine (4). The I3C-NMR spectra of diterpenoid alkaloids not only indicate the number and type of carbon atoms in the system but also reveal close structural and family resemblances and give detailed information about the sites of various functional groups. The usefulness of the I3C-NMR technique in solving difficult structural problems of complex diterpenoid alkaloids is reviewed here. In 1974, Japanese chemists (134) demonstrated the utility of 13C-NMR spectroscopy in the field of C,,-diterpenoid alkaloids. They determined the structures of miyaconine (145) and apomiyaconine (147), two rearrangement products of miyaconitine, by the aid of I3C-NMR spectroscopy. In 1976, Lamberton and co-workers (69, 70) demonstrated the use of 3C-NMR studies in elucidating the structures of several new C,,-diterpenoid alkaloids and their derivatives. The 3C-NMR spectra of several veatchine-type alkaloids and their derivatives [e.g., anopterine (51), anopteryl alcohol (52), tetraacetylanopteryl alcohol (54), triacetylanopteryl alcohol (61), compound 58, compound 59, anopterimine (70), anopterimine N-oxide (71), hydroxyanopterine (72), and dihydroanopterine (73)] were examined. The noise-decoupled and off-resonance proton-decoupled 3CNMR spectra of anopterine provided evidence for many unusual structural features and confirmed the structure of anopterine, which was established by a single-crystal X-ray analysis of tetraacetylanopteryl alcohol azomethine iodide (53). These 3C-NMR data were utilized in the structure determination of four new alkaloids (anopterimine, anopterimine N-oxide, hydroxyanopterine, and dihydroxyanopterine) isolated in small amounts from A . macleayanus and A , glandulosus. The power of the 3C-NMR spectroscopic technique was demonstrated (148-150) in the elucidation of the structures of some very complex natural products, the bisditerpenoid alkaloids, isolated from D. staphisagria. On the basis of 13C-NMR data of the known alkaloid, staphisine (185), the structures of seven new related alkaloids, staphidine (187), staphinine (1881, staphimine (189), staphigine (190), staphirine (191), staphisagnine (193),
'
'
'
2.
THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS
161
and staphisagrine (194),were determined. Partial chemical shift assignments for these alkaloids were presented in tabular form. A complete correlation of 3C- chemical shifts of staphisagnine and staphisagrine with those of staphisine and staphidine was also presented. In 1977, Pelletier and Mody (27) determined that atisine (4), veatchine (l), and related normal oxazolidine ring-containing derivatives exist as a mixture C-20 epimers in nonionic solvents with the help of 13C-NMR spectral data. Later, this claim was confirmed by a single-crystal X-ray analysis of veatchine. The same authors have also examined (154)the unusual behavior of the oxazolidine ring of atisine in ionic and nonionic solvents by 13C-NMR analysis and shown that the C-20 epimers of atisine are neither interconvertible via a zwitterion, as reported by Indian chemists (79), nor in equilibrium with each other. A comprehensive 13C-NMR study of the atisine and veatchine-type alkaloids as well as certain of their derivatives has been reported (28).The 3C-NMR spectra of atisine (4), atisinone (225),isoatisine (75), isoatisinone (226), dihydroatisine (78), dihydroatisine diacetate (211), atidine (79), atidine diacetate (227), atisine azomethine (228), atisine azomethine acetate (218), dihydroatisine azomethine (229), N-methyldihydroatisine azomethine (230), veatchine (l),garryine (2), dihydroveatchine (231), dihydroveatchine diacetate (232), veatchine azomethine (212), veatchine azomethine acetate (lo),dihydroveatchine azomethine (233); and N-methyldihydroveatchine azomethine (234) have been analyzed. Self-consistent assignments of nearly all the resonances were made in these compounds with the aid of single-frequency off-resonance proton decoupling techniques, additivity relationships, and the effectsinduced by certain structural changes.
225 Atisinone
227
226 Isoatisinone
228
162
S. WiLLIAM PELLETIER A N D NARESH V. MODY
231 R = H 232 R = Ac
229 R = H 230 R = CH3
233 R 234 R
=H = CH,
The I3C-NMR spectra of these compounds were analyzed to identify and distinguish skeletal features of the atisine and veatchine-type alkaloids for use in the structure elucidation of new C,,-diterpenoid alkaloids. The structures of two new C,,-diterpenoid alkaloids designated as ovatine (6) and lindheimerine (7), isolated from G . ovata var. Iindheimeri, have been elucidated (33)with the help of 13C-NMRspectroscopy. Similarly, the structure of dihydroajaconine (81) was also established (88) with this technique. Pelletier and Mody (87) have studied the behavior of ajaconine (88) in ionic and nonionic solvents with the aid of I3C-NMR spectroscopy. They established the structure of 7a-hydroxyisoatisine (82) and reported the 3CNMR spectra of 80,82, atisinium chloride (5), and ajaconium chloride (203). The stereochemistry of the C-16 methyl group and the oxazolidine ring in cuauchichicine was recently reassigned as a result of examining the I3CNMR spectra of isocuauchichicine (16) and its C-16 epimer (17). The oxazolidine ring of cuauchichicine was shown to exist as a single C-20 epimer in solution. Subsequently, the revised structure for cuauchichicine (15) was confirmed by X-ray analysis. 1 3C-NMR spectroscopy has proved to be a powerful technique for solving complex structural and conformational problems among the diterpenoid alkaloids. In the future we may expect an increasing use of this technique over traditional techniques such as IR, 'H-NMR, and MS for solving difficult structural problems in natural products chemistry. Unambiguous assignments of chemical shifts in these alkaloids will be useful in future biogenetic studies of C,,-diterpenoid alkaloids.
2.
163
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
VII. Mass Spectral Analysis of C,,-Diterpenoid Alkaloids The mass spectra of C,,-diterpenoid alkaloids are complex, and there is a paucity of information concerning their fragmentation patterns. The first systematic mass spectral analysis of these alkaloids was reported by Soviet chemists in 1970. Yunusov and colleagues (62) analyzed the mass spectra and their derivatives. of songorine (44),songoramine (47), napelline (M), Songorine and many related compounds give the parent ion as the base peak. In the case of some acetylated derivatives, M - 59 is the base peak. The fragmentation of these alkaloids occurs in several directions in contrast to the regular splitting pattern of the lycoctonine-type alkaloids. N-Methyl group-containing compounds exhibit a M + - 15 peak, which arises through the splitting of a methyl radical from the N-ethyl group. The cleavage of ring A is an important process in the mass spectra of songorine and related derivatives. The initial cleavage of the C-7-C-20 bond is common. The ions resulting from the cleavage of the C-7-C-20 bond of songorine are presented in pathways A and B. One of the strongest ions is m/e 298 (M' - 59), which is postulated to arise from the cleavage of the C-1-C-10 bond via the intermediate ion-radical with rnje 299. On the basis of the structure of the ionradical of mje 299, we have revised the structure of the M - 59 ion (Pathway A). Loss of rings C and D to form an ion with m/e 246 was considered to be the one-state transition. The latter was supported by a metastable peak. All the fragments containing ring C eliminate a formyl group or carbon monoxide. Formation of an ion with m/e 180 occurs directly from the molecular ion (Pathway B) by the expulsion of ring A, C, and D atoms. The metastable peak for rnje 180 ion was also observed. On the basis of the given pathway for the formation of rnje 180 ion, we have reassigned the structure of this ion. The fragmentation pattern of the mass spectrum of songorine diacetate (Pathway C) was not particularly revealing compared with that of songorine. The splitting off of the C- 15 acetyl group is manifested by the M - 43 peak (m/e 398). The strongest peak in the mass spectrum of songorine diacetate is the M f -59 peak (mje 382). This ion is further fragmented to a small extent with the expulsion of ketene or carbon monoxide as observed in the case of songorine. There are no major peaks in the lower mass region. For dihydrosongorine and its diacetate. major fragmentations were postulated to involve loss of ring D (Pathway D and E). In the case of dihydrosongorine, the ion-radical with rnje 301, in which loss of ring D has occurred, is the base peak, whereas in the diacetate mje 384 (loss of the C-1 acetoxyl group) is the strongest peak. Comparison of the mass spectrum of dihydrosongorine with that of its diacetate reveals that the presence of two acetate groups has some influence on the fragmentation patterns. Metastable peaks are observed for both transitions. +
+
+
/
44 Songorine M + 357 (100)
m / e 328 (16)
J
m / e 246
( I 3)
m/e
:Pathway A
270 (7)
2.
THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS
0 II ‘ZH5
&CH,
-
- -H
N’
0 II ‘ZH5
&CH,N‘
;!
OH
- -H
H,C’
OH
CH3
CH 3
Pathway B
m/e 441 (60)
m/e 382 (100)
\ 0 /I
m ’ e 398 ( 5 7 )
Pathway C
165
166
S. WILLIAM PELLETIER AND NARESH V. MODY
m/e 400 (8)
m/e 443 (13)
I
R R
=H
0
R = H mje 301 (100) R = Ac mle 343 (28)
nde 354 (26)
= Ac
m,’e 443 ( I 3)
I
J C,H
5-
Lq$
N/
C,H,--
I
CH 3 M
e
m
242 Pathway E
P
284
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
167
The molecular ion peak is the strongest peak in the mass spectrum of songoramine (Pathway F). The fragmentation of songoramine begins with the cleavage of the carbinolamine ether linkage and ring A. The ion-radical with m/e 299, which arises from the explusion of acrolein, fragments further into an ion with mje 122. Both transitions are confirmed by metastable peaks. The ion with mje 299 also originates from the radical-ion with mle 327 by the loss of carbon monoxide, which was confirmed by the metastable peak. Some assignments for songorine and dihydrosongorine were confirmed by deuterium labeling of the hydroxyl groups and exocyclic methylene group. 0
0
CH 3 m/e 299 (46)
I C2H5
m r 122 (29)
m,'e 327 (10)
Pathway F
In 1978 Yunusov and colleagues (59) reported the mass spectral data of napelline and several of its derivatives. The fragmentation data for napelline. 1-acetylnapelline, 12-acetylnapelline, triacetylnapelline, anhydrohydroxyacetylnapelline, isoacetynapelline, dihydronapelline, and isonapelline were tabulated showing the intensities of various ion peaks. Sastry and Waller (89, 160) analyzed a deuterated trimethylsilyl derivative of ajaconine on a gas chromatograph-mass spectrometer (GC-MS) system. They found that the crystalline sample earlier identified as pure ajaconine was a mixture of five compounds. Peak 1 with retention time (R,) of 12.7 min had a molecular ion of 477. Peaks 2 ( R , = 17.3 min), 3 (R, = 21.0 rnin), and 4 (R,= 25.5 min), all with a molecular ion of 521 (503 for the nondeuterated TMS derivatives), accounted for the di-TMS derivatives of
168
S . WILLIAM PELLETIER AND NARESH V. MODY
ajaconine. Peak 5 ( R , = 27.8 min) had a molecular ion of 604 which indicated the presence of three deuterated TMS groups. Structural assignments for the five compounds were made on the basis of their fragmentation patterns.
VIII. Synthetic Studies A. TOTALSYNTHESIS OF OPTICALLY ACTIVE VEATCHINE In 1970, Professor Wiesner and co-workers (161)reported the first total synthesis of optically active veatchine (l),the major alkaloid of G. veatchii. An improved synthesis (162) of ketones 244 and 245 from compound 235 has been reported. These ketones had been synthesized (163) previously and transformed to veatchine. Lithium aluminium hydride reduction of 235 followed by mesylation afforded 236. The latter was oxidized with osmium tetroxide and sodium metaperiodate to yield the cyclobutanone 237. Treatment of 237 with acid afforded in 48% yield the ketoacid (238), which was esterified with diazomethane to 239. The latter was converted to the ketal240 by treatment with ethylene glycol and p-toluenesulfonic acid. Compound 240 was reduced with lithium aluminium hydride to the alcohol 241. This alcohol had been synthesized previously by Nagata and co-workers (164) by an entirely different route. The azide 242 was prepared in 80% yield by mesylation of 241 and treatment of the product with sodium azide. Lithium aluminium hydride reduction of 242 gave the primary amine, which was converted to the urethane 243 by treatment with ethyl chloroformate. The ketal group of 243 was removed by acidic hydrolysis and the resulting ketone was nitrosated with N,O, and sodium acetate. Decomposition of the nitrosourethane with sodium ethoxide in refluxing ethanol afforded the ketone 244 in 65% yield. The latter had been also synthesized previously by Japanese chemists (165). The ketone 244 was converted to the ketal 246 and the latter to 247
235
236 R = CHI 231 R = 0
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
238 R = H 239 R = CH,
240 241 242 243
169
R=CO,CH, R=CH,OH R = CH,N, R = CH,NHCO,C,H,
by reduction with lithium in ammonia followed by acetylation. Deketalization of 247 afforded the desired ketone 245. The latter was identical with the optically active ketone prepared from veatchine. To complete the total synthesis of the optically active form of veatchine, the successful resolution of the synthetic racemic ketone 244 was accomplished. Compound 244 was reduced stereoselectively with sodium borohydride to give the alcohol 248. The latter was heated with succinic anhydride and pyridine in xylene to yield the racemic half-ester 249. Treatment of 249 with brucine afforded the diastereoisomeric brucine salts, which were separated by fractional crystallization. The separated salts were decomposed
R--
244 R = Ms 245 R = COCH,
248 R
=
H 0
249 R
= C(CH,),CO,H
'I
246 R 247 R
= =
MS COCH,
1 Veatchine
170
S. WILLIAM PELLETIER A N D NARESH V . MODY
and the half-esters were hydrolyzed. The resulting alcohols were oxidized to the respective ketones. The identity of the synthetic enantiomer with the same absolute configuration as the natural ketone 244 was established by mixture melting points and their ORD curves. The naturally derived ketone 244 was prepared for comparison purpose from 245 in the same manner, substituting acetylation for mesylation as mentioned earlier. The naturally derived ketone 245 had previously been prepared from veatchine by Vorbruggen and Djerassi (25). Since Canadian chemists had earlier published (163) work on the conversion of the degradation product 245 ofveatchine to garryine and veatchine, the total synthesis of the natural optically active form of these alkaloids is thus completed.
B. TOTALSYNTHESIS OF NAPELLINE In 1974, Wiesner and colleagues completed an elegant total synthesis of racemic napelline (34) (166). A series of model studies on this type of system was reported (167, 168). They developed (169)an efficient route to the intermediate ketolactam (250)and have used this compound to complete a formal synthesis of napelline (166, 170). The starting compound 251 was reduced to 252 with sodium borohydride. The latter was heated under reflux in 6% sulfuric acid in methanol to afford compound 253. Treatment of the latter with maleic anhydride at 170" for 3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter was reduced with lithium aluminium hydride to the primary alcohol 256, which was oxidized to the aldehyde 257 with N,N-dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde 257 with an excess of the Grignard reagent prepared from l-bromo-3benzyloxybutane afforded a mixture of diastereoisomers represented by the structure 258.
250
34 Napelline
2.
THE CHEMISTRY OF C2,-DITERPENOID ALKALOIDS
;-"
COZCH,
0
OCH,
OCH,
%COzCH3
QCOzCH3
HO
251
@. oc3H
171
252
253
0
0 254
258
255 R = CO,CH, 256 R = CHzOH 257 R = CHO
The mixture 258 was converted to the unstable benzenesulfonyl aziridine 259 by treatment with an excess of benzenesulfonyl azide in benzene. Acetolysis of 259 with acetic acid and sodium acetate at room temperature for several days afforded the crystalline mixture of diastereoisomers represented by the formula 260. The aziridine rearrangement was regiospecific and 260 was the only product detected during this rearrangement. Lithium aluminium hydride reduction of 260 followed by acetylation yielded the mixture 261 in 85% yield. Selective hydrolysis of 261 afforded 262 in quantitative yield. The diastereoisomeric mixture 262 was converted into the diols 263 by hydrogenolysis. The diol mixture was oxidized with chromium trioxide OCH, I
C,H,CH,O
CH,
ORZ
260 R' = H, R2 = Ac, R 3 = SO,C,H,. 261 R' = R z = R3 = AC 262 R' = R 2 = Ac. R3 = H
172
S. WILLIAM PELLETIER A N D NARESH V. MODY
in pyridine to afford the epimeric diketones 264. An aldol condensation of the mixture of the two diketones 264 in refluxing methanolic potassium carbonate gave the crystalline mixture of two epimers 265 in 88% yield. Photoaddition of vinyl acetate to 265 yielded the two epimers of compound 266. 0%
OCH,
HO CH, 263
264
OCH
CH,
0
,
0 OAc
265
266
This mixture was saponified with methanolic potassium hydroxide to give the two epimers of 267 in quantitative yield. By enol acetylation, 267 was converted to 268 which in turn was oxidized by osmium tetroxide and periodate to the noraldehydes 269. The mixture 269 was converted to 270 via oxidation, esterification, and mild alkaline hydrolysis. The hydroxyesters 270 were oxidized by the Jones' method to afford the single crystalline diketoester 271. Ketalization of 271 yielded the ketal 272 in quantitative ?CH3
?CH, R
I
I
Ac-1--r*
CH, 267 268 269 270
R' R' R' R'
H, RZ = CH,CHO R 2 = CH=CHOAc = Ac, R 2 = CHO = H, RZ = C02CH, =
= Ac,
CH, 271 R = O 272 R
=
<"I 0
2.
THE CHEMISTRY OF C2 0-DITERPENOID ALKALOIDS
173
yield. The latter was heated under reflux with methanolic sodium methoxide to yield the lactam 273 in a yield of 80%. During this reaction, the C-5 center was epimerized to form the A,B-trans-isomer as expected. Compound 273 was converted to 274 by Wolff-Kishner reduction. The desired intermediate 250 was obtained (169, 171, 172) by deketalization of 274 with a mixture of hydrobromic and acetic acids.
213 R 274 R
=0 = H,
250 R = H 275 R = CH,CH=CHCH3
The phenol 250 was converted to the crotyl derivative 275 by treatment with crotylchloride and potassium carbonate in DMF. Compound 275 was rearranged by heating at 180-185" for 2 hr to afford a mixture of methyl epimers 276 in 8 1.5"/0yield. This mixture was methylated with methyl iodide and potassium carbonate to yield the methyl ether 277. Oxidation of 277 with osmium tetroxide and sodium periodate afforded the aldehyde 278 in 80% yield. Conversion to the diketal279 and reduction of 279 with lithium in liquid ammonia followed by work-up yielded a dehydro compound, which was treated with p-toluenesulfonic acid in a mixture of benzene and acetone to give the diastereoisomeric mixture 280 in 50% yield. This mixture underwent a vinylogous aldol condensatation on treatment with methanolic potassium hydroxide. The products were isolated by preparative TLC and oxidized with chromium trioxide and pyridine in CH,C12 to yield the diketones 281, 282, 283, and 284. The diketone 281 was identical by TLC, and mass and infrared spectra with the optically active compound prepared
216 R = H 211 R = CH,
278
174
S. WILLIAM PELLETIER A N D NARESH V. MODY
R
219
FH3
280
from napelline (34) or lucidusculine (35). Hydrogenation of 282 over 10% palladium on charcoal afforded 285 in quantitative yield. The latter was identical with the corresponding optically active compound of the same structure prepared from napelline or lucidusculine.
281 R' 282 R'
285 R' 288 R'
= H,
R2 = CH, RZ = H
= CH,,
RZ = H R 2 = CH,
= CH,, = H,
283 R' 284 R'
35 R 34 R
= H,
R 2 = CH3
= CH3, R2 = H
= Ac Lucidusculine = H Napelline
Lithium aluminium hydride reduction of lucidusculine (35) afforded napelline (34) in quantitative yield. Napelline was hydrogenated with platinum oxide in acetic acid to afford dihydronapelline (286). Treatment of 286 with mercuric acetate in aqueous acetic acid followed by oxidation with chromium trioxide in pyridine afforded 287 in 16.5%yield. Ketalization of 287 yielded 285 in a yield of 71%. On refluxing 285 with methanolic base, a 4 :6 equilibrium mixture of 285 and 288 was obtained. These compounds
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
175
were separated by preparative TLC. Bromination of 288 with bromine in the presence of HCl at 0'' afforded 289 in 92% yield. Dehydrobromination of 289 with lithium bromide and lithium carbonate yielded the ketone 281. 0 II
281
0 II
289
The synthesis of napelline was completed from compound 285. Hydrolysis of the ketal 285 by treatment with aqueous acetic acid yielded compound 287. The latter was reduced with lithium aluminium hydride to afford a trihydroxyamine, which was acetylated to give compound 290 in 20% yield. The dihydroxyacetate 291 was prepared in 45% yield by hydrolysis of 290 with potassium carbonate in aqueous methanol. Acetylation of 291 afforded 292, which on oxidation with chromium trioxide in methylene chloride gave 293. Bromination of 293 with bromine in a mixture of ether and chloroform containing HCl yielded the bromoketone 294. The latter was OR'
290 R ' = R2 = AC 291 R' = R 2 = H 292 R ' = Ac. R 2 = H
OAc
293 R = H 294 R = Br
176
S. WILLIAM PELLETIER A N D NARESH V. MODY
OAc
295
dehydrobrominated with lithium bromide and lithium carbonate in DMF to give 295. Reduction of 295 with lithium aluminium hydride afforded napelline (34).
C. CONSTRUCTION OF THE DENUDATINE SKELETON The New Brunswick group's synthetic studies have led to the elaboration of the carbon skeleton of denudatine (117). The synthesis (173) of intermediate 296 from 258 should eventually lead to the total synthesis of denudatine. Compound 258 was prepared according to the procedure described during the synthesis of napelline in Section VII1,B. The hydroxyl group of 258 was removed by mesylation and subsequent lithium aluminium hydride reduction to give 297. The latter was converted to the pentacyclic aromatic intermediate 298 using a reaction sequence employed for the synthesis (169)
117 Denudatine
OH
258 R
=
291 R
=H
296
298
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
177
of an intermediate for napelline (see Section VIII,Ei). Birch reduction of 298 followed by reacetylation afforded the enol ether 299. Hydrolysis of 299 with dilute oxalic acid gave the p, punsaturated ketone 300 in 95% yield. Compound 300 was relatively unstable and therefore was immediately reduced to the alcohol 301 with sodium borohydride. Mesylation of 301 gave compound 302, which on treatment with potassium tert-butoxide in DMSO afforded the unstable diene 296. The Diels-Alder addition of 296 to maleic anhydride afforded the desired adduct 303 in a yield of 60%. In order to use this reaction sequence for the synthesis of denudatine, the cyclic diene system must contain appropriate functional groups.
299
300 0
301 R = H 302 R = SO,CH,
303
In 1976 Wiesner’s group reported (174) the synthesis, from compound 305, of the model compound 304, which contains the C-D ring system of denudatine. Alkylation of 305 with bromomethyl acetate and potassium carbonate in acetone gave compound 306 in a yield of 95:;. This compound was hydrolyzed to the acid 307, which on treatment with a solution of aqueous sodium acetate and N-bromosuccinimide in methylene chloride yielded the masked quinone 308. The latter was treated with an excess of ethyl vinyl sulfide in ether to give 309. Hydrolysis of 309 in aqueous methanolic potassium carbonate afforded the diketone 310 in 92% yield. Reaction of 310 with an excess of trimethylsilylmethyl magnesium chloride in THF gave 311. The latter was desulfurized with Raney nickel to yield 312 in
178
S. WILLIAM PELLETIER A N D NARESH V. MODY
304
305
C2H5-SvH
308
309
306 R' = Ms, R2 = CH3 307 R' = R 2 = H
C2H5-S
310
quantitative yield. Treatment of 312 with 70% perchloric acid in THF gave the a$-unsaturated ketone 313. Compound 313 was treated with an excess of methanethiol to furnish the addition product 314. Hydroboration followed by oxidation with hydrogen peroxide afforded an epimeric mixture 315 in a total yield of 85%. Acetylation of 315 with acetic anhydride and pyridine gave 316. Partial hydrolysis of 316 furnished the monoacetate 317 which was oxidized with N,N-dicyclohexylcarbodiimideand DMSO to give the ketoacetate 318. Hydrolysis of 318 to 319 and subsequent treatment with methyl iodide gave the ternary sulfonium iodide which by refluxing with aqueous potassium carbonate afforded the hydroxyketone 304. The structure of 304 was determined by a single-crystal X-ray analysis of its pbromobenzoyl derivative 320.
311 R = S C 2 H , 312 R = H
313
314
Application of this synthetic sequence to the earlier reported intermediate 321 should lead to the total synthesis of denudatine.
2.
179
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
315 R' = R2 = H 316 R' = R 2 = AC 317 R' = Ac, R 2 = H
318 R = AC 319 R = H
304 R 320 R
=H = COC,H,-p-Br
D. A SYNTHETIC APPROACH TO AJACONINE AND ATIDINE In 1971, Zalkow and co-workers reported (175) the conversion of podocarpic acid (322) to a key intermediate 323 for the synthesis of the enatiomers of ajaconine (80) and atidine (79). Compound 323 contains the
CH 3 323
CH3 80 Ajaconine
180
S. WILLIAM PELLETIER AND NARESH
V.
MODY
functionalities necessary for conversion into the enatiomers of these alkaloids. The ORD curves of a number of optically active tetracyclic intermediates (obtained during this synthesis) containing a carbonyl group at C-7 and a bicyclo[2.2.2]octane C-D ring system have been compared. Methyl 0-methyl-7-ketopodocarpate (324)was reduced with sodium borohydride to the hydroxyester 325. Birch reduction of 325 followed by acidic hydrolysis and esterification with diazomethane afforded the dienone 326. Reduction of 326 with sodium borohydride followed by acetylation and treatment of the epimeric mixture with m-chloroperbenzoic acid afforded 327. The latter was rearranged with BF, in ether to yield the ketone 328 which on chromatography over alumina gave the dienone 329. Reaction of 329 with maleic anhydride in refluxing toluene followed by esterification
d3d3
@
'~~ H
CH,O,C
H CH3
'I
CH3
CH30,C
324
\ ~ \
CH30,C
325
H
CH3 326
OAc
OAc
327
OH
328
329
afforded a mixture of the triesters 330 and 331. Compound 330 was selectively hydrolyzed with potassium hydroxide to give the monoester 332, which was hydrogenated using platinum on carbon in acetic acid to afford 333. Oxidative bisdecarboxylation of 333 with lead tetraacetate afforded the olefin 334, which was hydrolyzed to the acid 335. Treatment of 335 with thionyl chloride followed by sodium azide in aqueous dioxane furnished the azide 336. Photolysis of the azide afforded the lactam 323. This lactam is a key intermediate for the synthesis of ajaconine and atidine.
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
331
330 R = CH, 332 R = H
.....
I\\
CH,O,C CH,O,
181
CO,H
H
R02C
CH, 333
CH3
334 R = C H , 335 R = H
CH
,
0
336
323
E. INTERMEDIATES FOR THE VEATCHINEAND ATISINE-TYPE ALKALOIDS 1. A New Method for Construction of Ring A In 1973, Wiesner, Vlahov, and Muzika reported (176)a relatively simple annelation procedure for the construction of ring A as an alternative to the Robinson annelation method. 7-Methoxy-2-tetralone was methylated by the Stork method to yield 337. The latter was treated with sodium hydride and benzyl chloromethyl ether to furnish compound 338 in 60% yield. Ketalization of 338 afforded the ketal339 which was hydrogenated with palladium on calcium carbonate to give the alcohol 340 in a yield of 92%. The alcohol 340 was oxidized with chromium trioxide in pyridine to afford the aldehyde 341 in quantitative
182
S. WILLIAM PELLETIER A N D NARESH V. MODY
yield. The aldehyde was treated with the Grignard reagent prepared from 5-bromopent-1-ene in THF to give the epimers 342 and 343. These alcohols were converted to the methoxyl derivatives 344 and 345 by methylation with methyl iodine and sodium hydride in dioxane.
337 R = H 338 R = CHZOCHzC6Hs
342 R' = H, RZ= OH 343 R' = OH, R' = H 344 R' = H, RZ= OCH, 345 R' = OCH,, R' = H
339 R = CHzOCHzC6H, 340 R = CHZOH 341 R = C H O
The aldehydes 346 and 347 were prepared from the methoxyl derivatives by osmic acid-sodium chlorate oxidation and deketalization followed by base-catalyzed condensation in an overall yield of 50%. Acetalization of 346 withp-toluenesulfonic acid and ethylene glycol in refluxing benzene afforded the acetal 348. The latter has an active site at C-6 suitable for the introduction of oxygen substituents at this position. OCH,
OCH
I
I
CHO 346 R' = H, RZ = OCH, 347 R! = OCH,, RZ = H
348
2. Synthesis of the BCD Ring System Beams and Manders reported (177) the synthesis of the tricyclic dione 349 via two different synthetic routes. The Australian chemists utilized an approach analogous to one developed earlier by Masamune ( I 78) during the synthesis of atisine and kaurene. They prepared tetrahydro-7-methoxy2-naphthoic acid (350) from 7-methoxytetral- 1-one by published procedures.
2. THE CHEMISTRY OF '220-DITERPENOIDALKALOIDS
183
The acid 350 was demethylated with pyridine hydrochloride, then realkylated with benzyl bromide in aqueous potassium hydroxide to give 351. The latter was converted to the diazoketone 352 by the sequential treatment of 351 with oxalyl chloride and etheral diazomethane. Reaction of 352 with concentrated hydrobromic acid gave the bromoketone 353. The latter was reduced with sodium borohydride at pH 8 -9 to yield a mixture of diastereomeric bromohydrins 354. Protection of the free hydroxyl as a tetrahydropyranyl ether and hydrogenolysis of the benzyl residue afforded 355. The phenol 355 was heated under reflux with potassium tert-butoxide in tertbutyl alcohol for 5 hr to give a 3 : 1 epimeric mixture of dienone ethers 356 and 357 in about 507; yield. Treatment of this mixture with dilute acid gave the epimeric alcohols 358 and 359, This mixture was oxidized with Jones reagent to afford the diketone 349.
& & & /
/
0
/
RO 350 R
349
/
\
C6H,CHz0
= CH3
\
352 R = C H N , 353 R= CH , B r
351 R = CHzC6H,
CH(0R' )CH,Br
354 R' 355 R'
= H,
R Z= CH,C,H, RZ = H
356 R = THP 358 R = H
= THP,
357 R = T H P 359 R = H
The second approach to the tricyclic dione 349 was simple and direct. Acetylation of 360 was followed by sequential treatment with oxalyl chloride and diazomethane to give, after hydrolysis, the diazoketone 361. The latter YOOH
360
COCHN, I
361
184
S. WILLIAM PELLETIER AND NARESH V. MODY
was treated with boron trifluoride in nitromethane to afford 349 in 30% yield. Boron trifluoride etherate in nitromethane proved to be the best system for this cyclization. This method seems useful for providing intermediates for the synthesis of the atisine-type alkaloids. Beams, Halleday, and Mander (279)reported the preparation of the BCD ring system intermediates of the atisine- and veatchine-type alkaloids by intramolecular carbenoid addition reactions. Birch reduction of 6-methoxynaphth-2-oic acid (362) with an excess of lithium and tert-butyl alcohol afforded the hexahydro derivative 363, which was hydrolyzed to the ketoacid 364. The latter was reduced with lithium tri-tert-butoxyaluminium hydride to furnish the hydroxyacid 365 in a yield of 90%. Acetylation of 365 yielded 366. Treatment of 366 with oxalyl chloride in pyridine yielded the acid chloride, which was converted to the diazoketone 367 by reaction with diazomethane. The decomposition of 367 over copper powder afforded 368 in yields of 70-80%. Hydrolysis of 368 gave 369, which was oxidized with Jones reagent to afford the cyclopropyldiketone 370. Treatment of 370 with dilute acidic acetone gave the enedione 371, via a retrograde Michael reaction, in quantitative yield. This method was simplified by using compound 363. The latter was treated with methanol in p-toluenesulfonic acid to afford the acetal carboxylic acid 372, which was converted to the acid chloride with oxalyl chloride in pyridine. Conversion to the diazoketone 373 was affected in yields of 55-65%. Decomposition of 373 over copper powder in cyclohexane gave 374 and subsequent acidic hydrolysis afforded the enedione 371. This compound possesses the BCD ring system of the veatchine-type alkaloids.
362
365 R' 366 R' 367 R'
364
363
= H,
R Z = OH
= Ac, = Ac,
R 2 = OH RZ = CHN,
368 R = A c 369 R = H
370
2.
185
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
cH3QLj
CH,O 0
CH,O 371
CH,O
372 R = OH 373 R = C H N ,
374
To establish the generality of this procedure, the Australian chemists synthesized (179) the enedione 376 from 375 as shown in Scheme 2. Compound 376 contains the BCD ring system of the atisine-type alkaloids. CO,H
&A
CO,H
CH,O
CO,H
AcO 375
376
SCHEME 2. (a)Li, NH,, (CH,),COH; (b)CH,OH-H20-(COOH),; (c) Li, tri-t-butoxyaluminium hydride; ( d ) Ac,O, C,H,N; (e) (COCI),C,H,N, CH,N,; ( f ) Cu-C6H,,; ( g ) K,CO,( i ) HCI-H,O-CH,COCH,. H,O-CH,OH; ( h ) Cr0,-H,S04-H,0-CH,COCH,;
In 1974 Johnson and Mander (180) reported the synthesis of the tricyclic ketones 378 and 380 containing the 3.2.1 and 2.2.2-bicyclooctane ring systems incorporating a cyclohexa-2,4-dienone moiety. The Australian chemists prepared the diazoketones 377 and 379 by the earlier standardized method.
377
378
186
S. WILLIAM PELLETIER A N D NARESH V. MODY
The acid-catalyzed rearrangement of 377 and 379 afforded 378 and 380, respectively, in good yields. The tricyclic ketone 380 contains all appropriate functionality for the synthesis of the atisine-type alkaloids, ajaconine and atidine. COCHN,
319
3 . Formation of a C-N-C-6
380
Bridge
During the chemical interconversion of gibberelin-A, and enmein, Somei and Okamoto (281)investigated a nitrone photolysis reaction which gave the veatchine-type compound 381. Enmein was converted to 20-hydroxykaur-6-en-15a-pyranylether(382), which was oxidized with chromium trioxide in pyridine to afford the aldehyde 383. The latter was converted with hydroxylamine to the oxime 384. The nitrone 385 was prepared by treatment of 384 with bromine azide. Photolysis of 385 gave the desired compound 381 in 46% yield. This intermediate possesses several useful functionalities (e.g., carbinolamine ether linkage), which may be of interest for synthesis of C,,-diterpenoid alkaloids after minor changes in this scheme.
38 1
384
382 R = CH,OH 383 R = C H O
385
2.
THE CHEMISTRY OF C,,-DITERPENOID ALKALOIDS
187
In 1974, Mander and colleagues (182) synthesized the antipodal lactam 386 from podocarpic acid. This lactam contains the nitrogen bridge system of C,,-diterpenoid alkaloids. One of the routes explored was via the nitrile 387 obtained by the ethyl chloroformate dehydration of O-methylpodocarpamide followed by oxidation. Oxygenation of 387 with potassium tertbutoxide and oxygen afforded a mixture of the diosphenol 388 and the ketolactam 389 in yields of 9 and 62%, respectively. The ketolactam 389 was hydrogenated for a prolonged period to give the desired lactam 386.
386
387
388
389
4. Synthesis of the ABE Ring System
In 1975, van der Baan and Bickelhaupt (183) reported a new approach to the ABE ring system of C,,-diterpenoid alkaloids. Reaction of 390 with cyanoacetamide afforded compound 391. The latter was alkylated with ally1 bromide to give 392. A Cope-type rearrangement of 392 at 100-1 10" gave 393, which was treated with ethyl iodide in DMF to afford 394. Treatment of 394 with N-bromosuccinimide in H,O and DMSO yielded 395. Protection of the secondary hydroxyl group in 395 as the tetrahydropyranyl ether followed by treatment with NaOH in DMF gave the tricyclic product 396. Compound 397 was obtained from 396 by removal of the THF group followed by Jones oxidation. This model study suggests that synthesis of some of the complicated alkaloids can be achieved by choosing the proper starting materials.
188
S. WILLIAM PELLETIER AND NARESH V. MODY
0
0 CN CH,-CH=CH,
CN 39 1
390
392
0
Br 0
393 R = H 394 R = C,H,
395
0
0 396 CN
397 CN
CN
@o+(yJoJ3@ 0
C,H,O,C
CH,
CH, 'C0,C,C2H5
45%
+
CH, COzC,H5
55% 0
398 SCHEME 3
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
189
Meyer and co-workers reported (184) a simple synthesis of a tricyclic intermediate containing the ABE ring system. The sequence for the synthesis of 398 is outlined in Scheme 3. Compound 398 is of interest as an intermediate for synthesis of C,,-diterpenoid alkaloids containing a substituent at the C-7 position, e.g., ajaconine, atidine, and spiradine.
5. Synthesis of Tetracyclic Intermediates Containing Ring E In 1971, Mori, Saeki, and Matsui converted (185) the tricyclic acid 399, during their synthesis of kaur-16-en-19-oic acid (400), into the tetracyclic lactam 404 by the well-established photolytic method (186). The lactam 404 has previously been converted to veatchine and garryine by Wiesner's group.
@CH3
,'
R--6
11
H CH,
0
399 R = OH 401 R = C1 402 R = NHNH, 403 R = N 3
400
@cH3 NH
0
CH3 404
1 Veatchine
The racemic acid 399 was treated with oxalyl chloride to afford an acyl chloride 401, which on reaction with anhydrous hydrazine yielded the hydrazide 402. The latter was converted to the azide 403 by treatment with nitrous acid. Photolysis of 403 which a high-pressure mercury lamp afforded the lactam 404. This lactam was synthesized earlier by Japanese chemists by an entirely different method (187). In 1972, Indian chemists developed (188, 189) a method of introducing the C-20 functionality utilizing a regioselective intramolecular carbenoid
190
S. WILLIAM PELLETIER AND NARESH V. MODY
insertion reaction. The starting compound 405 was prepared earlier by Ghatak and Chatterjee (190) in work directed toward a general synthesis of diterpenoids. Compound 405 was converted to the diazoketone 406. The latter was treated with anhydrous copper sulfate in boiling cyclohexanetetrahydrofuran to give the tetracyclic ketone 407 in 20-25% yield. Condensation of 407 with ethyl formate in the presence of NaOH gave the hydroxymethylene derivative 408, which was oxidized with alkaline H,02 to afford the dicarboxylic acid 409. The latter was converted to the imide 411, via the anhydride 410, by treatment with urea. Lithium aluminium hydride reduction of 411 furnished 412, which has been used as the key intermediate in the total synthesis of racemic atisine (191) and veatchine (192) by Nagata’s group.
( $ 7 0 C H 3
RC
CH,
&OCH3 c= 0
CH,
I/ 405 R = O H 406 R = C H N ,
408
410
407
409
411 R = O
412 R
= H,
Kametani and co-workers (193, 194) have synthesized the key arnine 412 by a thermolytic intramolecular cycloaddition reaction. Methyl methylaceto-
2.
191
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
acetate (413) was alkylated with 1-bromo-3-chloropropane in the presence of NaH-DMF to give 414. Sodium borohydride reduction of 414 afforded the alcohol 415, which was dehydrated with celite and phosphorus pentoxide to afford the olefin 416. Treatment of 416 with sodium iodide in boiling methyl ethyl ketone furnished the iodide 417. Compound 418 was heated under reflux in N,N-dimethylacetamide to furnish 419. The latter was stirred with sodium amide in liquid ammonia to afford 1-cyano-4-methoxybenzocyclobutane (420).The iodide 417 was condensed with 420 to give 421 in 76% yield. Thermolysis of 421 in toluene at 230" afforded the cycloaddition product 423 in 52% yield via the intermediate 422.
c1
A
CH302C
CH3 CH,O,C
CN q \C O
C
H
CH,O,C
414 R = COCH, 415 R = CHOHCH,
413
BrV
CH3
H
3
CH3
416 X = C1 417 X = I
8
0
C
H
3
3 CH,O,C
R+ CN
CH3
420
418 R = COOH 419 R = H
CH,
421
p (p \ -
CH30,C
H CH3
422
CH30,C CH3 423
In order to obtain the trans-fused octalin, the cis-fused octaline 423 was oxidized with chromium trioxide in acetic acid to yield the ketone 424. The latter was treated with bromine in acetic acid to produce the a-bromoketone 425 in a yield of 98",. Dehydrobromination of 425 with N-phenylbenzamidine afforded the ap-unsaturated ketone 426 in 90-95% yield. The
192
S. WILLIAM PELLETIER AND NARESH V. MODY
ketone 426 was hydrogenated on 10% PdjC in ethanol to give the transfused compound 427. Reduction of 427 under high pressure gave the lactam 428 in 80% yield. Lithium aluminium hydride reduction of 428 furnished the key amine 412 that has been used in the total synthesis of veatchine, atisine, and gibberellin A, 5 . Earlier the same investigators (195) reported the synthesis of the related secondary amine 429.
424 R 425 R
426
=H = Br
NH
0
421
428
@OCH3 NH
CH3 412
429
The synthesis of the tetracyclic amide 437 has been reported by Meyer and co-workers (196) in work directed toward a general diterpenoid synthesis. The enantiomer of this amide has been prepared earlier by Tahara and colleagues (197)and converted to atisine, veatchine, and garryine. The synthesis (184) of the starting compound 430 is discussed in Section VIII,E,4. The ketone 430 was condensed with ethyl formate in the presence of NaH to give the hydroxymethylene ketone 431. Treatment of 431 with DDQ and acidic dioxane for 5 min at room temperature furnished the
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
193
aldehyde 432. Addition of the sodium enolate of tert-butyl acetoacetate to 432 yielded compound 433, which was treated with p-toluenesulfonic acid in acetic acid to give the tetracyclic product 434. Reaction of 434 with pyridine hydrobromide perbromide afforded the ketophenol 435 in good yield. Compound 435 was converted to 436 by treatment with 2-chlorobenzoxazole and potassium carbonate in acetone at reflux temperature. Hydrogenation of 436 over 30% PdjC gave the desired amide 437.
A
c
-
D
0
Ac-@
‘CH,
0HoH
‘CH, 431
430
0 t-BuO,CJ(H
pro
Ac- -N
A c - D o H ’ H
‘CH,
‘CH,
432
433
&gg
Ac--N
Ac- -N
/
0
/
0
‘CH
‘CH,
434
435
@
.
AC-
-N
0
’CH, 436
437
194
S. WILLIAM PELLETIER AND NARESH V. MODY
F. CONSTRUCTION, DEGRADATION, AND SELECTIVE REDUCTION OF THE OXAZOLIDINE RINGOF C,,-DITERPENOID ALKALOIDS Recently, Mody and Pelletier reported (198)a simple and efficient method for the degradation of the oxazolidine ring system of C,,-diterpenoid alkaloids. This method involved a one-pot reaction and proceeds with almost quantitative yield. An earlier reported (199) method for this degradation involves four steps and proceeds with erratic yields. Treatment of ovatine (6)or garryfoline (8) with acetic anydride and pyridine, followed by complete removal of the excess pyridine and acetic anhydride, afforded the chloroform-soluble diacetate salt 9. Without purification, this salt was heated under reflux in chloroform to yield lindheimerine (7) in 90% yield. In similar manner, atisine (4) and veatchine (1) were degraded to their corresponding imines 218 and 10 in yields of 90%. The analogous imines from the isooxazolidine ring containing alkaloids, isoatisine (75) and garryine (2), were formed in about 50% yields. A convenient method for constructing oxazolidine and thiazolidine rings from the imine-containing C,,-diterpenoid alkaloid derivatives has been reported by Pelletier, Nowacki, and Mody (155).Treatment of lindheimerine (7) with ethylene oxide in glacial acetic acid or with excess neat ethylene sulfide afforded the corresponding oxazolidine (6) and thiazolidine (438), respectively, in almost quantitative yields. Details of this method are discussed in Section V.
6 R=Ac 8 R=H
9
;_I$--.. --H
..*
:..
--H
OAc CH,
OAc CH,
7
438
A new method for converting the N-CH,-CH,OH group in diterpenoid alkaloid derivatives into the isooxazolidine derivatives using active manganese dioxide has been reported by Pelletier, Mody,
2.
THE CHEMISTRY OF CzO-DITERPENOID ALKALOIDS
195
and Bhattacharyya (200). For example, isoatisine (75) was prepared from dihydroatisine (78) by treatment with active MnO, in chloroform in 55-61% yields. Similarly dihydroveatchine (231), dihydrogarryfoline (439) and dihydrocuauchichicine (440)were converted to garryine (2), isogarryfoline (29)and isocuauchichicine (16), respectively, in 45 -65% yields. Interestingly, oxidative cyclization occurs in preference to oxidation of the allylic hydroxy group in compounds 78, 231, and 439. The advantages of this method over earlier reported methods using mercuric acetate and osmium tetroxide are discussed.
231 R’ = OH, R2 = H 439 R’ = H. R2 = OH
440
225
2 R’ = O H , R2 = H 29 R’ = H ; R2 = OH
16
441
Recently, a method for formation of the “iso-type” oxazolidine ring from -NCH,CH,OH group-containing alkaloids by oxidative cyclization with silver oxide was reported (201). This method afforded higher yields of the “iso-type” oxazolidine ring-containing compounds than any previously reported method, e.g., treatment of dihydroatisine (78) with silver oxide at 96°C for 2.5 hr gave isoatisine (75) in a yield of 90%. In 1980, the first one-step oxidation method for converting -NCH,CH,OH group-containing alkaloid derivatives simultaneously into
196
S. WILLIAM PELLETER AND NARESH
V.
MODY
both the “normal” and “iso-type” oxazolidine ring-containing alkaloids was reported (202). Thus, dihydroveatchine (231) was converted into veatchine (1) and garryine (2) in a total yield of 95% using alkaline ferricyanide. Compared to other methods, this high-yield procedure is simple, reliable, and uses an inexpensive oxidizing reagent. In 1979, Pelletier and co-workers reported (203) a method for selective reduction of the oxazolidine ring of C,,-diterpenoid alkaloids in the presence of a ketone or an a$-unsaturated carbonyl group. Reduction of atisinone (225) with sodium cyanoborohydride at pH 6-7 at room temperature furnished dihydroatisinone (441) in almost quantitative yield. They generalized this reduction method by using various alkaloid derivatives containing either an &unsaturated ketone or a simple ketone moiety.
IX. A Catalog of C,,-Diterpenoid Alkaloids 12-Acetylnapelline C,4H35N0,; MW 401 mp 205-206”; [a]D-Aconitum karakolicum Chemically correlated with napelline; ’H-NMR and mass spectral data Refs. 58, 59
Ajaconine
HO-. ..
_1
,\.
.r;r
.. .
o... CH,
CZ2H3,NO3;MW 359 mp 167”; [.ID - 122” (EtOH) Delphinium ajacis; D. consolida; Consolida ambigua; D. oirescens; D. carolinianum Chemically correlated with atidine; 13C-NMRand other spectral data Refs. 83-87
Anhydroignavinol C,,H,,NO,; MW 345 rnp 302-304”; [a]DHydrolysis product of ignavine Chemical and X-ray analysis Refs. 97-101
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
Anopterimine 0
I1 0-c-c=c,
/
H
C,,H,,NO,; MW 395 mp 235-238"; [.ID + 106' (Chf) Anopterus mncleuyanus 'H- and "C-NMR spectral analysis Ref. 70
Anopterimine N-oxide Cz5H3,N0,; MW 411 mp 233-235"; [ o L+95' ] ~ (Chf) Anopterus mucleuyunus 'H- and I3C-NMR spectral analysis Ref. 70
Anopterine C3,H,,N0,; MW 541 mp 222-223"; [.ID - 12" (Chf) Anopterus macleuyunus; and A . glundulosus Chemical studies; 'H- and I3C-NMR data, and X-ray analysis Refs. 68, 69
OH
Atidine C,,H,,NO,; MW 359 mp 182.5-183.5'; [.ID -47.0 (Chf) Aconitum heterophyllum Chemically correlated with ajaconine; 'H-, I3C-NMR, and X-ray analysis Refs. 28, 78, 80, 81, 82
197
198 Atisine
S. WILLIAM PELLETIER AND NARESH V. MODY
C,,H33N0,; MW 343 mp 329-331' (HCIj; [.ID + 26.6' (EtOHj HC1 salt Aconitum heterophyllum; A . heterophylloides; A . anthara Correlated with veatchine; Chemical, 'H- and I3C-NMR analysis; X-ray analysis of HCl salt Refs. 27,28,30, 71 -80
Cuauchichicine C,,H,,NO,; MW 343 mp 152-154"; [a],, -69" (Chf) Garrya laurifolia; G. ovata var. lindheirneri Chemically correlated with garryfoline; "C-NMR and X-ray analysis Refs. 25, 26, 34-36 Delnudine C,,H,,NO,; MW 327 mp 235-237"; Delphinium denuda turn Chemical, spectral, and X-ray analysis Refs. 135, 136
[@ID-
Denudatine C,,H,,NO,; MW 343 mp 248-249" C ; [.ID f0.15' (EtOHj Delphinium denudntum Chemical and X-ray analysis Refs. 109-113
Dihydroajaconine C,,H,,NO,; MW 361 mp 99-100°C; [aID -35' (EtOH) Consolida ambigua Chemically correlated with ajaconine; 13C-NMR and other spectral data Ref. 88
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
199
Dihydroatisine
HO----\
C,,H35N0,; MW 345 mp 159-161 ; [zID -44.5' (EtOH) Aconitum heterophyllum Correlated with atisine and isoatisine; 'H-, I3C-NMR, and X-ray analysis Refs. 28,30, 71, 78, 80
OH
Dihydroxyanopterine 0
11
and
/H 'CHzoH
C,,H,,NO,; MW 573 mp 242-244; [zID -9; (MeOH) Anopterus macleayanus Chemically correlated with anopterine "C-NMR and other spectral data Refs. 69, 70
C-3
Garryfoline C,,H,,NO,; MW 343 mp 130-133.'; [.ID -60:- (Chf) Garrya laurifvlia; G. ocata var. lindhrimeri Chemically correlated with veatchine; Chemical and ',C-NMR analysis Refs. 18, 25, 26, 33-36, 39 Garryine C,,H,,NO,; MW 343 - 84- (Chf) mp 74-82- (hydrate); [XI Garrva ueatchii Chemically related to veatchine; Chemical and %-NMR analysis Refs. 22-31 Heterophylloidine 0
AcO,. d
,---C -< H
CH ......N CH, 0
2
C,,H,,NO,; MW 383 resin, [.ID - 8 2 (Chf) Aconitum heterophylloides ' H and 13C NMR analysis; X-ray analysis of HBr salt. Ref. 76
200
S. WILLIAM PELLETIER AND NARESH V. MODY
Hetidine CZ1HZ7NO4; MW 357 mp 218-221'; [rIDAconitum heterophyllum Spectral and X-ray analysis Refs. 80, 128
Hetisine (Delatine) CZoH,,N03 ; MW 329 mp 256.5-259"; [aID 109' (Chf) Aconitum heterophyllum; Delphinium cardinale Chemical and X-ray analysis Refs. 80, 118-124
+
Hetisinone C,,H,,NO,; MW 327 mp 268-270"; [&ID 18" Delphinium cardinale; D. denudatum ; Aconitum heterophyllum Chemically correlated with hetisine Refs. 80, 120, 126, I27
HO
+
0
Hydroxyanopterine OTig
at
c-1
c-3
TH3 ,CH3
Tig = C-C=C 0
\
H
C3,H4,NOs; MW 557 mp 247-249; [.ID - 1 4 (MeOH) Anopterus macleayanus; A . glandulosus Chemically correlated with anopterine, I3C-NMR, and other spectral data Refs. 69, 70
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
20 1
Hypognavine C,,H,,NO,; M W 449 mp239-241'; [.ID +127.1' (MeOH) Aconitum sanyoense Correlated with hypognavinol Refs. 102-105
Hypognavinol C,,H,,NO,; MW 345 mp 307-308 : [.ID +67.7 (MeOH) Hydrolysis product of hypognavine : Chemical and X-ray analysis Refs. 102-105
Ignavine C,,H,,NO,; MW 449 mp 172-174"; [%ID f85.3" (EtOH) Aconitum sayoense: A. juponicum; A . tusiromontunum Chemically correlated with anhydroignavinol Refs. 97-101
Isoatisine C,,H,,NO,; MW 343 mp 149.5-152;; [ K ] ~-22.4 (EtOH) A conif um he terophyllum Correlated with atisine; Chemical, I3C-NMR, and X-ray analysis Refs. 27, 28,30, 71, 78, 80
Isocuauchichicine C,,H,,NO,; MW 343 mp 134-136; [.ID -84' (Chf) G a r r w luurifolia. Chemically correlated with cuauchichicine; Chemical and spectral (>
CH,
data
Refs. 18, 25,26,34-36
202
S. WILLIAM PELLETIER AND NARESH V. MODY
Isogarryfoline C,,H,,NO,; MW 343 mp 140-144.; {%ID-57 (Chf) Garrya laurifolia Chemically correlated with garryfoline; Chemical and spectral data Refs. 18, 2 5 , 2 6 , 3 3 - 3 6 , 3 9
<
Isohypognavine C,,H,,NO,; MW 433 mp 135"; [zID-Aconitum majimai; A . japonicum etc. Chemically correlated with kobusine Refs. 99, 106, 107
Kobusine C,,H,,NO,; MW 313 104.4" (MeOH) mp 267-267.5"; [a],, Aconitum sachlinense: A . yesoense, A . lucidusculum, etc. Chemical and X-ray analysis Refs. 93-95
+
Lindheimerine C,,H,,NO,; MW 341 resin; [a]* - 113.8" (Chf) Garrya ovata var. lindheimerz Chemically correlated with ovatine I3C-NMR and other spectral data Ref. 33
Lucidusculine C,,H,5N0,: MW 401 mp 170-171"; [@IDAconitum lucidusculum Chemical and X-ray analysis Refs. 48-57 0Ac
2.
THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS
203
Miyaconitine 0
C,,H,,NO,; MW 415 mp 218' (decomp.); [%ID -87.8' (Chf) Aconitum miyabei Chemical, spectral, and X-ray analysis Refs. 54. 129-133
\
Miyaconitinone CZ,Hz7NO6;MW 413 mp 285" (decomp.); [ a ] - 2 7 . 6 (AcOH) Aconitum miyabei Chemically correlated with miyaconitine Refs. 54, 129-133
Napelline (Luciculine) OH
C,,H,,NO,; MW 359 mp 116-117" (hydrate); [.ID -13" (MeOH) Aconitum napellus; A . karakolicum Chemically correlated with songorine and lucidusculine Refs. 40 -49
Norsongorine
8 I/
C20H,,N0,; MW 329 mp 284-286.; [a]DA . monticola Correlated with songorine Ref. 62.153
204
S. WILLIAM PELLETIER AND NARESH V . MODY
Ovatine C,,H,,NO,; MW 385 mp 113-114"; [dID -79.4'(Chf) Gnrrya ouata var. lindheimeri Chemically correlated with garryfoline; ',C-NMR and other chemical data Ref. 33 Pseudokobusine C,,H,,NO,; MW 329 mp 271"; [.IDAconitum yesoense ; A . lucidusculum Correlated with kobusine Refs. 93-95
Songoramine
9
C,,H,,NO,; MW 355 mp 211-212"; [.ID--A . karakolicum ; A . soongoricum Chemically correlated with songorine; Chemical and spectral analysis Refs. 62, 66, 67
0
C,,H,,NO,; MW 357 mp 212"; [EJA . soongoricum ; A . karakolicum; A . monticola Correlated with napelline; Chemical and spectral data Refs. 41 -48,60-64
Songorine
Songorine N-Oxide C,,H,,NO,; M W 373 mp 253-255"; [.ID----Aconitum moticola Chemically correlated with songorine; 'H-NMR and mass spectral data Ref. 65
2.
THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS
205
Spiradine A C,,H,,NO,; MW 311 mp 281-282'; [aID---Spiracea japonica Chemical, spectral, and X-ray analysis Refs. 137-139
Spiradine B C,,H,,NO,; MW 313 mp 259-260'; [%ID--Spiraea japonica Chemically correlated with spiradine A Refs. 137-139
Spiradine C C,,H,,NO,; MW 355 mp 248-249': [oL]~---Spiraea japonica Chemically correlated with spiradine B Refs. 137, 138
Spiradine D C2,H,,N0,; MW 339 mp 134-135-; [.IDSpiraea japonica Chemically correlated with spiradine A Ref. 140
206
S. WILLIAM PELLETIER AND NARESH V. MODY
Spiradine F C,,H,,NO,; MW 399 mp 114-1 17‘ (hydrochloride); [%ID-Spiraea juponica Chemical and spectral analysis Ref. 142 ---
‘0
Spiradine G C,,H3,N0,; MW 357 mp 168-17OC; [%IDSpiraea japonicu Chemical and spectral analysis Ref. I42
Spiredine C Z 2 H 2 , N 0 3MW ; 353 mp 163’; Spiraea japonica. Chemically correlated with spiradine A Ref. 141
Spireine (Structure 1) C22H,,N0,; MW 369 mp 230’ ; [a]DSpiraea juponica Chemical and spectral analysis Refs. 137, 143
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
Spireine (Structure 2) C,,H,,NO,. MW 369 mp 230 , [xlDSpiraea iaponica Chemical and spectral analysis Refs 137, 143 0
0
Staphidine C,,H,,N,O, MW 606 mp213-216 . [%ID-160 (C,H,) Delphinium stuphisagria 'H- and I3C-NMR analysis Ref 148
Staphigine C,3H,,N,0,; MW 650 mp 225-227 , [.ID - 116 (C,H,) Delphinium stuphisugr iu 'H- and I3C-NMR spectral analysis Ref. 149
207
208
S. WILLIAM PELLETIER AND NARESH V. MODY
Staphimine
C,,H5,N,O; MW 590 Amorphous; [xID -58.5 (C6H6) Delphinium stuphisagria ‘H- and I3C-NMR spectral analysis Ref. 148
Staphinine
C,,HS6N,0,; MW 620 Amorphous; [uID -57.5‘ (C6H6) Delphinium stuphisagria ‘H- and ‘-’C-NMR spectral analysis Ref. 148
2.
THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS
Staphirine C,,H,,N,O,: MW 620 mp 222-225 : [.Il, - 126 (C,H,) Delphinium staph isagriu 'H- and I3C-NMR spectral analysis Ref. 149
Staphisagnine
,-.,
''i
H3C$.-.
.,~. _ , -0
. \ H C H 3 0 - 0 h
%-.
C,,H,,N,O,; MW 666 Resin; - 104.5' (C,H,) Delphinium 'H- and I3C-NMR stuphisagria spectral analysis
[?I1,
Ref. I50
209
210
S. WILLIAM PELLETIER AND NARESH V. MODY
Staphisagrine
.’ .
.:
,’
C 4 3 H 6 0 N 2 0 2MW : 636 - 105.6 (C,H,) mp 229-231 , Delphinium stuphisagria ‘H- and 13C-NMR spectral analysis Ref. I50
[.ID
Staphisine
CH,
i;..
C,,H,,,N,O,: MW 636 mp 211-213’; -148.4’(C6H,) Delph iniuni s tuph isagr iu Chemical, spectral, and X-ray analysis Refs. 144-148
[%ID
H
H C... ..N
CH3 Vakognavine 0
\
C3,H3,XO,,; MW 619 mp 298.’: [%ID--Aconiturn pulnuirurn Chemical, spectral, and X-ray analysis Refs. 1I4 1 17 -
2.
THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS
21 1
Veatchine C,,H,,NO,; MW 343 mp 122-126 C ; [rID -69 (Chf) Garrya ceatchii Chemically correlated with atisine 3C-NMR and X-ray analysis Refs. 22-31
REFERENCES 1. S. W. Pelletier and N. V. Mody, in “The Alkaloids” (R. H. F. Manske and R. G . A. Rodrigo, eds.), Vol. 17, Chapter 1. Academic Press, New York, 1979. 2. S. W. Pelletier and N. V. Mody, Heterocycles 5, 771 (1976). 3. J. W. Rowe, “The Common and Systematic Nomenclature of Cyclic Diterpenes,” 3rd rev., pp. 40,41,43. Forest Products Laboratory, Forest Service, U.S. Department of Agriculture, Madison, Wisconsin, 1968. 4. E. S. Stern, in “The Alkaloids” (R. H. F. Manske and H. L. Homes, eds.), Vol. 4, Chapter 37. Academic Press, New York, 1954. 5. E. S. Stern, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 7, Chapter 22. Academic Press, New York, 1960. 6. S. W. Pelletier and L. H. Keith, in “The Alkaloids‘‘ (R. H. F. Manske, ed.), Vol. 12, Chapter 2. Academic Press, New York, 1970. 7. H. G. Boit, “Ergebnisse der Alkaloid-Chemie bis 1960,” pp. 851-905, 1009-1011. Akademie-Verlag, Berlin, 1961. 8. S. W. Pelletier and L. H. Keith, in “Chemistry of the Alkaloids” (S. W. Pelletier, ed.), Chapter 17. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 9. 0. E. Edwards, Alkaloids (London) 1, 343-381 (1971). 10. S. W. Pelletier and L. H. Wright, Alkaloids (London) 2, 247-258 (1972). 11. S. W. Pelletier and S. W. Page, Alkaloids (London)3, 232-257 (1973); 4, 323-345 (1974); 5, 230-241 (1975): 6, 256-271 (1976); 7, 247-267 (1977); 8, 219-245 (1978); 9, 221-237 (1979); 10, 211-226(1981). 12. K . Wiesner and Z. Valenta, Prog. Clrern. Org. Nar. Prod. 16, 26-89 (1958). 13. S. W. Pelletier, Q. Rev., Chem. Soc. 21, 525-548 (1967); Trrrahrdron 14, 76-112 (1961). 14. S. W. Pelletier and S. W. Page. Org. Chcrn.. Srr. TMYJ 9. 53-90. (1976). 15. A. R. Pinder, in “Rodd’s Chemistry of Carbon Compounds” (S. Coffey ed.), 2nd ed. Vol. 4, Part G, Chapter 34, pp. 323-379. Elsevier, Amsterdam, !978. 16. Y. Ichinohe, Kagaku N o Ryoiki 32. 27-42 (1978). 17. S. W. Pelletier and N. V. Mody, Synip, Pap.-IUPAC Inr. S j m p . C h r m ’ N u t . Prod., l l t h , 1978 Vol. 4, Part I , pp. 248-259 (1978). 18. S. W. Pelletier and N. V. Mody, J . Nut. Prod. 43,41 (1980). 19. K. Nakanishi, T. Goto. S. Itd, S. Natori, and S. Nozol, eds., “Natural Products Chemistry,.‘ Vol. 2, pp. 262-270. Academic Press, New York, 1975. 20. J. S. Glasby. “Encyclopedia of the Alkaloids,” Vols. I and 11. Plenum, New York. 1975. 21. T. K. Devon and A. I. Scott, “Handbook of Naturally Occurring Compounds,’‘ Vol. 2, pp. 241-248. Academic Press, New York, 1972. 22. J. F. Oneto, J . A m . Pharin. Assoc. 35, 204 (1946). 23. K Wiesner, S. K . Figdnr, M F. Bartlett, and D. R . Henderson. Car?.J . Chmt. 30. 608 (1 952).
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CHAPTER 3-
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS D. W. HUGHESAND D. B. MACLEAN Department of Chemistry, McMaster University, Hamilton, Ontario, Canada
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. 1,2,3,4-Tetrahydro- and 3-4-Dihydroisoquinolines . . . . . . . . . . . . . . . . . . . . . . . .
111. Benzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Bisbenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Cularine . . . . . . . . . . . . . . . . . .... .... ..... VI. The Morphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Pavine Alkaloids . . . . . . . . . . . . . . . . . . . .... ....... IX. Aporphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . X. Reduced and Nonreduced Proaporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XI. Tetrahydroprotoberberine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XII. Protopine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII. Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . ................... XIV. Modified Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XV. Benzo [clphenanthridine Alkalo ........................... XVI. Spirobenzylisoquinoline Alkaloi ...................... XVII. Rhoeadine . . . . . . . . . . . . . . . . . . . . . . . . ....... .............. ....... .............. XVIII. Secoberbine Alkaloids . . . . . . . . . . . . . . XIX. Emetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XX. Miscellaneous Alkaloids . . . . . . ................................. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
217 219 223 226 221 228 230 234 235 238 239 243 245 249 250 252 251 257 259 260 26 1
1. Introduction Since the late 1950s PMR spectroscopy has contributed immensely to many areas of the chemistry of alkaloids ( I ) . With the advent of Fourier transform spectrometers CMR has rapidly approached the level of PMR in its application to problems of structural elucidation and stereochemistry. In the case of the alkaloids many classes of the isoquinoline family have been studied. These alkaloids are of particular interest not only because of their widespread occurrence in nature but also because of their pharmacological activity (2-5). Wenkert et nl. (6)were the first to review progress in this area. More recently, Shamma and Hindenlang (7) have made an extensive compilation of chemical shift data on amines and alkaloids that includes many T H E ALKALOIDS, VOL X V l l l Copyright @ 1981 by Academic Press. Inc All rights of reproduction m any form reserved ISBN 0-1 2-4695 18-3
218
D. W. HUGHES A N D D. B. MACLEAN
examples from the isoquinoline group. In this chapter we have extended these reviews to cover the literature to mid-1979. We have not attempted to provide a comprehensive listing of all the data that are available. Instead, we have selected examples that are characteristic of a particular structural feature within a given class. We have attempted to show where novel experimental techniques have been used to advantage in the assignment of chemical shifts, and we have tried to show how the chemical shift of a particular carbon atom may be influenced by change in functionality, substitution, or stereochemistry at neighboring centers. We have also emphasized the value of this technique in differentiating among diastereomers and conformational isomers and its utility in structural elucidation. The chemical shifts reported here were obtained from spectra recorded using CDCl, as the solvent unless otherwise stated and are in ppm downfield from TMS. For those not familiar with CMR and the associated experimental procedures references (8-13) should be consulted.
C HO , 1 R
= R
1
2
=R3=H
2 R, = R = OCH3; Rg
=
H
OCH3; R3
=
CH 3
2
3 R,
=
5
R
2
=
4
6
7
23.9
8
FIG.1. 1,2,3,4-Tetrahydroisoquinolines and model compounds.
3.
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
219
11. 1,2,3,4-Tetrahydro- and 3,4-Dihydroisoquinolines
In a systematic examination of the CMR spectra of the isoquinoline alkaloids it is appropriate to begin with a discussion of the spectra of several simple isoquinolines (Fig. 1 and Table I) since this structural unit is common (1) to the alkaloids. The 3C spectrum of 1,2,3,4-tetrahydroisoquinoline has been reported by two groups (14,15).The chemical shift assignments of the aliphatic carbon atoms followed from comparison to piperidine (5) and tetralin (6) (8, 9, 16). In the case of the two carbon atoms adjacent to the nitrogen atom in 1, that at C-1 is at lower field because of the larger asubstituent effect of the phenyl group (8, 12). These assignments have been verified by selective ’H decoupling (17) (the chemical shifts given in reference 15 for C-1 and C-3 should therefore be reversed). Comparison of the chemical shifts of the aromatic carbon atoms of 1 with those of tetralin (6) permitted the tentative assignments given in Table I. The introduction of rnethoxyl groups at C-6 and C-7 into the tetrahydroisoquinoline system, a common substitution pattern in the alkaloids, as in TABLE I l 3 C CHEMICAL SHIFTS OF 1.2,3,4-TETRAHYDROlSOQ~lNOLlNES“
Carbon
1 3 4 4a 5 6 7 8 8a
6-OCH3 7-OCH3 8-OCH3 NCH,
1
2
3
4
48.2 43.8 29.1 136.1’ 129.2’ 125.6’ 125.9’ 126.1’ 134.8’
47.8 43.9 28.6 127.9’ 112.2 147.5’ 147.3’ 109.3 126.6’ 55.9 55.9
57.6 53.0 28.8 126.7’ 111.6 147.7’ 147.3’ 109.5 125.8’ 55.9 55.9
43.6 43.6 28.5 129.9‘ 124.4 110.8 145.5 150.3 128.0’ 55.9 60.0
46.0
Hughes et a/. (14). The chemical shifts within a vertical column are not unambiguously assigned and may be interchanged. However, some carbon atoms which have nearly identical chemical shifts such as those of o-dimethoxyl groups have not been indicated by footnotes. The original papers should he consulted in these cases.
220
D. W. HUGHES AND D. B. MACLEAN
2, deshielded these carbons and at the same time shielded C-5, C-8, C-4a, and C-8a. The chemical shifts of the aromatic carbon atoms agreed with those expected from application of empirically determined substituent parameters derived from veratrole (7) for o-dimethoxyl groups (C-1, + 20.8 ; C-2, -16.9; C-3, -7.6 ppm, relative to benzene, 128.6 ppm) (14). The specific assignment of C-5 and C-8 in 2 was achieved by selective 'H decoupling. The chemical shifts of the aliphatic carbon atoms are not significantly different from those of 1. In O-methylcorypalline (3) C-1 and C-3 are deshielded by +9.8 and +9.1 ppm, respectively, because of the N-methyl group fi to them (18). Similar results have been observed for the pair, piperidine (5) and Nmethylpiperidine (8) (8). Another common structural component of the isoquinoline alkaloids, particularly in the protoberberines, is the 7,s-disubstituted 1,2,3,4-tetrahydroisoquinoline unit. The spectrum of 7,8-dimethoxy- 1,2,3,4-tetrahydroisoquinoline (4) showed two interesting chemical shift changes other than the expected shifts in the aromatic carbon atoms (14). First, it was found that C-1 was shielded relative to the corresponding carbon atom of 2 by -4.6 ppm. This was attributed to the y steric effect of the C-8 methoxyl group on
9
Rl = OCH3, R2 = H
10 R1 =
R
2
= OCH3
11 R1 = H , R 2 = OCH3
12
R1 = R2 = OCH3, R3 = CN
13
R1 = R2 = OCH3, R3 = CONH2
14
R1 = R 2 = OCH3, R3 = CH2N02
15
R1 + R 2 = CH2, R3 = OH
0 16
17 18
R, + R 2 = CH2, R 3 = H R1
=
R2 = CH3, R3 = H
R3 = CH 3 FIG.2. C-1 substituted 1,2,3,4-tetrahydroisoquinolines and model compounds 19
R,
= R2 =
3.
221
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
C-1. Second, although the two methoxyl groups would be expected to be nonequivalent, the most sterically crowded methoxyl group at C-8 appeared at lower field (60.0 ppm). Similar observations were made by Dhami and Stothers in the case of o-disubstituted anisoles (19). Experimental verification of this assignment is provided in the discussion of canadine in Section XI. The 3C spectra of three 1-methyl-1,2,3,4-tetrahydroisoquinolines(9-11) (Fig. 2 and Table 11) were recently reported by Verchere et al. (20). The methyl substituent of 10 caused chemical shift changes relative to 2 in the aliphatic carbon atoms (C-1, f3 .5 ; C-3, -2.0; C-4, 1.0 ppm) that were similar to those observed at C-2 for the pair, piperidine, and 2-methylpiperidine (9). The deshielding of C-8a in 10 relative to 2 may be attributed to the fl effect of the C-1 substituent (8). Several N-methyl- 1,2,3,4-tetrahydroisoquinolines(12-15) substituted at C-1 (Fig. 2) have been prepared in this laboratory as synthetic intermediates and their I3C spectra recorded (Table 11). Compound 3 served as a model for evaluating the effect that these substituents had on the aliphatic carbon
+
TABLE I1
3cCHEMICAL
SHIFTS OF 1,2,3,4-TETRAHYDROISOQUINOLINESSUBSTITUTED AT
c-1
AND OF SOME ISOQUINOLONES
Carbon 1
3 4 4a 5 6 7 8 8a 6-OCH3 7-OCH3 6,7-OCH,O NCH, 1-CH 1-CN 1-CON H 1-CH zNO,
,
9"
10"
11"
12'
13'
14'
15'.d
17'
18'
19'
51.2 41.9 30.5 136.1 113.8 157.8 112.2 126.9 133.1 55.1
51.3 41.9 29.6 127.1 112.3 147.5 147.6 109.6 132.8 55.9 56.1
51.8 42.0 29.2 126.9 129.9 111.2 157.8 111.8 141.7
56.5 48.4 28.1 121.5 111.7 149.4 148.0 109.7 126.3 56.1 55.8
70.2 50.9 29.0 124.2 111.7 148.3 147.0 109.4 125.9 56.0 55.9
61.3 45.4 23.0 123.8 111.9 148.6 148.0 110.2 127.2 56.0 55.9
85.7 45.5 29.6 132.4 109.1 147.5 146.4 108.8 129.1
166.6 40.2 28.4 134.6 107.9 150.9 146.9 107.3 118.2
167.0 40.3 27.9 132.9 110.2 152.2 148.1 109.8 121.7 56.1 56.1
164.8 48.3 27.5 131.8 110.6 151.9 148.1 109.5 122.1 56.0 56.0
101.8
101.5
43.5
44.8
42.0
22.8
22.8
55.0
22.6
Verchere et ul. (20). Hughes and MacLean. (17). Manske c.t a/. (21). Solvent. DMSO-d6 ' Shamma and Hindenlang. (7) a
116.8 176.4 79.3
43.1
35.0
222
D. W. HUGHES AND D. B. MACLEAN
atoms of the isoquinoline system. With the exception of CN, these substituents deshielded C-1. In general the c( effect of nitriles on aliphatic systems is small (8, ZZ), and in 12 the magnitude of the substituent effect may be further reduced by gauche interactions with the N-methyl group. The aromatic carbon atoms of 12, 13, and 14, relative to those of 3, were not appreciably affected by the substituent at C- 1. In hydrastinine (15) the aromatic chemical shifts were assigned by comparison with the spectrum of the model compound, methylenedioxybenzene (16), from which the following substituent parameters were derived : C-1, 19.2; C-2, - 19.8; C-3, -6.8 ppm, relative to benzene (14, 21). Several isoquinolones have also been examined (17).The carbonyl group at C-1 in the isoquinolones, noroxohydrastinine (17) (7), corydaldine (18) (17), and N-methylcorydaldine (19) (17),not only affected the chemical shifts of the aliphatic carbon atoms but also influenced the chemical shifts (Table IT) of the aromatic carbon atoms through a resonance effect. The upfield shift of C-1 in 19 relative to 18 (-2.2 ppm) and of the N-methyl of 19 relative to 3 (- 1I .O ppm) indicated the presence of a steric interaction between the carbonyl and the N-methyl groups. This result is typical of an amide carbonyl existing in a cis geometry with the nitrogen substituent (8, 9). The 3,4-dihydroisoquinoline system is also encountered in this family of alkaloids. The assignment of chemical shifts to the aromatic carbon atoms of the substituted 3,4-dihydroisoquinolines(21-25 in Fig. 3 and Table 111) followed directly from the application of the appropriate substituent parameters to the shifts reported for 20 (22) and from a consideration of the resonance effect of the carbon-nitrogen double bond. This latter point is especially evident in the methiodide salts, 24 and 25, where charge delocalization causes C-4a, C-6, and C-8 to appear at lower field than their counterparts C-8a, C-7, and C-5, respectively. Carbon- 1 was readily recognized as the lowest field resonance because of its imine character.
+
20 21
R
= R = R 3 = H 1 2 R1 = R2 = OCH3, R3 = H
22
R, = R 2 = OCH3, R3 = CH 3
23
R1 = OCH3, R2
=
24
R,
=
25
R,
+ R2
H, R3 = CH3
FIG.3. 3,4-Dihydroisoquinolines.
R2
=
CH
3
= CH2
3.
THE 13C-NMR SPECTRA OF ISoOUINOLINE ALKALOIDS
223
TABLE 111 I3cCHEMICAL SHIFTS OF THE
3,4-DIHYDROISoQuINOLINES
Carbon
20"
21h
22'
23'
Uh
25d
1 3 4 4a 5 6 7 8 8a 6-OCH3 7-OCH3 6,7-OCH,O 1-CH, NCH,
159.8 47.3 25.0 136.2 126.9 130.8 127.3 126.9 128.4
159.5 47.4 24.7 129.8 110.5 151.3 147.9 110.5 121.6 56.0 56.1
163.5 47.1 25.8 131.3 110.6 151.1 147.7 109.5 122.7 56.0 56.4
163.4 46.9 26.7 139.5 111.8 161.2 112.9 127.0 123.2 55.1
164.6 50.5 25.5 132.3 111.3 157.6 148.8 115.7 117.2 57.0 57.2
164.8 49.8 25.5 136.4 109.6 155.6 147.7 112.0 119.0
23.4
23.1
103.9 48.1
47.7
Christ1 (22). Hughes et al. (14). Verchire et al. (20). Hughes and Maclean. (17).
111. Benzylisoquinoline Alkaloids The benzylisoquinoline alkaloids are widely distributed in nature and are intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not surprising therefore that several groups (6, 7, 15, 23) have examined their spectra. Among the alkaloids that have been studied are reticuline (26) (7), norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-Noxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of laudanosine are recorded in Table IV and the structures of the alkaloids may be found in Fig. 4. The assignments of the 13Cchemical shifts of laudanosine were first made by Wenkert et al. (6) and confirmed later (15). It is now apparent that compounds 2 and 3 (14) and 3,4-dimethoxyphenethylamine(6, 15) serve as satisfactory models of the isoquinoline and benzyl moieties, respectively. The substitution of a 3,4-dimethoxybenzyl group at C-1 of 3, as in laudanosine (28), caused changes to occur in the chemical shifts of the aliphatic carbon atoms of the tetrahydroisoquinoline moiety analogous to those of the compounds with substituents at C-1 listed in Table I1 (C-1, 7.9; C-3, - 6.2; C-4, -3.5; NCH,, -3.6). The chemical shift changes between 27 and 28
+
224
D. W. HUGHES AND D. B. MACLEAN
TABLE IV "C CHEMICAL SHIFTSOF LALDANWNE (28) AND ITS QUATERNARY SALT(32) Carbon
28"
32b
1 3 4 4a 5 6 7 8 8a 9 1' 2' 3' 4' 5' 6 6-OCH3 7-OCH, 3'-OCH, 4'-OCH, NCH, NCH,),
65.5 46.8 25.3 125.8 112.8 146.9 146.9 110.7 132.2 40.4 129.0 110.7 148.3 146.0 110.7 121.5 55.5' 55.5' 55.3' 55.3' 42.4
71.3 54.7 23.1 120.6 111.0 148.9 146.6 110.5 119.1 37.4 126.3 113.1 148.9 147.9 110.1 122.3 56.4' 55.4e 54.9' 54.7' 52.3, 50.3
Wenkert et al. ( 6 ) . al. (23); Solvent: CDC1, CH,OH. Assignments may be interchanged. a
* Marsaioli et
+
parallel those between 2 and 3. Except for the absence of two 0-methyl resonances, there are minimal differences between the spectra of 26 and 28. The presence of an N-oxide function in alkaloids 29 and 30 has a large deshielding effect on each of C-1, C-3, and the N-methyl group relative to 28. The results, which are of similar magnitude to those observed in other N-oxides (8. 24. 25). may be attributed to the combined inductive effect of the positively charged nitrogen atom and to the p effect of the oxygen. The important feature of these N-oxide shifts is their dependence on the stereochemistry of the nitrogen substituents. In the cis configuration 29, gauche interactions may occur between the N-methyl group and C-9, causing the signals of these carbons to appear at higher field than they appear in the trans isomer 30. The largest chemical shift difference between the two isomers is at C-3 which is shielded by 3.5 ppm in 30. This result may possibly be
3.
THE I3C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS
26
R
= R
27
R
28
R
1
1
1
4
=
R5 = CH3, R2 = R
= R2 = R3 = R = R
2
= R
3
= R
4
4
=
225
H
3 = Chi3, R5 = H
= R
5
= C H3
ee. 2
cH30TN C HO ,
a:: 'CH,
31
OCH,
FIG.4. Benzylisoquinoline alkaloids.
32
accounted for by a conformational change of ring B in order to minimize steric interactions at the pseudoaxial N-methyl group. Castedo et al. (26) have used I3C NMR to resolve the structure of an 0-denethylation product of papaverinol(31) obtained by treatment of the compound with sulfuric acid. It is known that when a phenol is transformed to its phenoxide the para carbon is shielded (8).When the spectra of the demethylation product and its anion were examined it was observed that C-1' was shielded by - 8.3 ppm in the anionic compound. It was apparent therefore that demethylation had occurred at C - 4 and not at C-3' as originally suggested.
226
D. W. HUGHES AND D. B. MACLEAN
Marsaioli et al. (23) have reported the 13C chemical shifts of several benzylisoquinoline alkaloids and their N-methyl salts. When 28 is Nmethylated to the corresponding quaternary salt 32 there was a deshielding of C-1 and C-3 whereas C-4, C-4a, and C-8a, and C-1' were shielded. The shielding of C-9 is caused by the 7 effect of the additional N-methyl group. From the similarity in chemical shifts for the carbon atoms of ring B and the corresponding carbon atoms in N-methyltetrahydroprotoberberines(27, 28), it was proposed that the B ring had a half-chair conformation in which the benzyl carbon was pseudoaxial. Additional evidence for this proposal came from the observation of a 5.0 Hz vicinal coupling between C-8 and H-1 which indicated a 45" dihedral angle between these atoms. The spectrum of 32 is recorded in Table IV.
IV. BisbenzylisoquinolineAlkaloids The bisbenzylisoquinoline alkaloid, isochondodendrine (33), (Fig. 5 and Table V) and its O-methyl and O-acetyl derivatives have been studied by 13C NMR (23). The aliphatic carbon atoms of this symmetrical molecule were assigned by comparison to the benzylisoquinoline alkaloids and by the off-resonance spectrum. The oxygen substituent at C-8 caused a shielding of C-1. In the aromatic region of the spectrum C-9 and C-12 had chemical shifts which remained essentially constant in all derivatives examined. Methylation and acetylation of the phenolic group produced characteristic shift changes which allowed the assignment of C-4a, C-6, C-7, C-8,
33
3.
THE 13C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
227
TABLE V I3cCHEMICAL SHIFTS OF
ISOCHONDODENDRINE (33)
Carbon
33".h
Carbon
334.h
1 3 4 4a 5
58.0 44.0 25.8 122.9 107.3 149.9 135.7 139.4 124.8
9 10 11 12 13
129.0 127.2 114.3 153.3 117.4 128.6 33.8 55.2 40.5
6 7 8 8a a
14
15 6-OCH3 NCH.3
Solvent CDCI, + CH,OH Marsaioli et al. (23).
and C-8a. Carbon-5 was assigned to the highest field aromatic signal, 107.3 ppm, whereas the protonated carbon atoms of the benzyl units were assigned by taking into account the substituent effect of the oxygen group at C-12. V. Cularine The I3C spectrum of cularine (34) (Fig. 6, Table VI), has been reported by Wenkert et al. (6). The chemical shifts of the aliphatic carbon atoms were assigned by comparison with those of laudanosine (28) and follow also from those of the simple isoquinolines (Section 11). In the aromatic region the resonances of the pair of protonated carbon atoms at C-5 and C-6 were differentiated from those at C-2' and C-5' by the observation of 4
.CH,
FIG.6 . Cularine (34).
CH,O
OCH, 34
228
D. W. HUGHES A N D D. B. MACLEAN
TABLE VI
’ 3C CHEMICALSHIFTSOF C U L A R ~ N E ~ Carbon
Carbon ~
1
3 4 4a 5 6 7 8 8a 9
56.7 47.5 26.0 126.3 124.3 110.4 148.9 144.8 132.5 35.3
” Wenkert et
ill.
1’
2‘ 3’ 4 5’ 6 7-OCH3 3’-OCH, 4’-OCH, NCH,
118.3 113.6 144.8 147.3 105.1 148.4 55.8 56.0 56.0 42.4
(6)
second-order coupling effects that the authors attributed to virtual coupling (12, 29,30). Carbon-6 was assigned to higher field than C-5 since it is ortho to the methoxyl group at C-7, and C-5’ to higher field than C-2’ since it is ortho to both methoxyl and aryloxy substituents. It is of interest that the study of the 13C spectrum clarified the ‘H spectrum. Thus, in correlating the I3C and ‘H chemical shifts in a series of off-resonance spectra (11, 12) the authors found that the original proton assignments at H-5’ and H-2’ (31) were in error and should be reversed. Selective irradiation of the aromatic protons allowed the assignment of the resonances to C-l’, C-4a, and C-8a by the observation of coupling to benzylic and homobenzylic protons. Carbon- 1’ appeared as a triplet being coupled to the protons at C-9 whereas C-4a and C-8a were broad multiplets. Under the same conditions the chemical shifts of the oxygenated aromatic carbons were determined from three bond coupling to methoxyl protons as well as by comparison to the laudanosine data.
VI. The Morphine Alkaloids Thc alkaloids of this group are renowned for their pharmacological activity and it is not surprising therefore that several groups have examined their spectra or those of derivatives (32-34). The first complete assignment of spectra to these alkaloids was made by Terui et a/. (32), and shortly thereafter a more comprehensive report by Carroll et a/. (33) appeared. The alkaloids and model compounds that are discussed are shown in Fig. 7 and 3C data are recorded in Table VII.
3.
THE 13C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS
229
NR
I
35
6CH,
R = H
37 38
36 R = CH3
39 R1
= CH3.
41
R,
=
42
R1 = R2 = COCH3
RE
RE = H
40
= H
FIG.7. Morphine alkaloids and model compounds
Terui et al. used 3-methoxymorphinan (35)and several derivatives of it as models in assigning the chemical shifts of the alkaloids. The data that they obtained for 35 and its N-methyl derivative (36)are listed in Table VII. The assignments were made using conventional techniques and by noting the shifts resulting from introducing various substituents at C-6 (carbonyl and a-hydroxyl), and at C-14 (hydroxyl). Compound 37 was also used as a model. The information obtained from the model studies was then applied to the spectra of sinomenine (38), codeine (39), and thebaine (40), the spectra of which are also recorded in Table VII. Except for the assignment of the quaternary carbon atoms in 39 and 40 the other assignments followed readily from model studies and from application of shift parameters. The quaternary carbon atoms of codeine had already been examined by Wehrli (35) using spin lattice relaxation time ( T I )measurements. In this way an unambiguous assignment of the signals at C-3, C-4, C-11, and C-12 was achieved. Carroll ef a/. confirmed the assignments made by Terui et a/. for codeine and thebaine and investigated a large number of related compounds. They
230
D . W . HUGHES AND D. B. MACLEAN
TABLE VII I3C CHEMICAL SHIFTSOF MORPHINE ALKALO~DS A K D MODELCOMPOVNDS
Carbon 1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 NMe 3-OMe OMe 3-m,CO 3-CH,C_O 6-=,CO 6- CH 3C_0
35"
36"
31"
38"
39"
40"
41'
42'
128.3 11 1.O' 158.0 110.6' 37.1 22.2 26.Sd 26.7d 51.3 33.8 130.1 141.7 38.4 46.2 42.9 39.2
128.2 110.9' 158.0 110.6' 36.6 22.3 26.8* 26.6d 57.9 23.4 129.7 141.5 37.2 45.4 42.1 47.2 42.7 54.9
128.3 110.9' 158.0 112.0' 49.5 197.2 130.9 149.4 56.1 23.8 128.2 138.8 39.9 45.6 39.9 46.4 42.7 55.0
117.9 109.1 145.2' 144.8' 49.1 193.4 152.3 115.3 56.6 24.4 130.3 122.1 40.5 45.7 35.8 47.1 42.5 55.8 54.6
119.3 112.8 142.0 146.2 91.3 66.4 133.2 128.1 58.7 20.4 127.0 130.9 43.0 40.7 35.8 46.4 43.0 56.2
119.1 112.9 142.7 144.6 89.0 152.3 95.8 111.3 60.7 29.5 127.6 133.1 46.0 132.3 37.0 46.0 42.3 56.2 54.7
118.6 116.4 138.5 146.3 91.5 66.4 133.4 128.5 58.1 20.2 125.5 131.0 43.0 40.6 35.6 46.1 42.8
119.1 121.6 132.0 149.1 88.5 67.9 129.2 128.2 58.7 20.4 131.5 131.2 42.6 40.4 34.9 46.3 42.8
~
55.2 ~
-
~~
~
20.4 168.2 20.4 170.2
" Terui ti a/. (32). Carroll ei a!. (33) c.d Assignments may be interchanged "
reported on the spectrum of morphine (41), its monoacetyl and its diacetyl derivative (42) (Table VII), as well as on several analogs of codeine and morphine modified in ring C. In addition several 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaineswere examined. In their work they examined dihydromorphine, dihydrocodeine, and dihydrocodeinone in order to aid the interpretation of the signals of ring C. 14-Hydroxyl derivatives of the alkaloids and their derivatives were also used for the same purpose. VII. Cancentrine Alkaloids Cancentrine (43) is a complex alkaloid that embodies within its structure a modified codeine skeleton and a cularine skeleton. Its I3C spectrum along with that of some derivatives was studied (36)in order to obtain chemical
3.
THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
231
shift data useful in structural elucidation of other alkaloids of this group. Structures and 13C data are found in Fig. 8 and Table VIII, respectively. The spectrum of cancentrine was interpreted primarily by comparison with the previously discussed spectra of cularine and the morphine alkaloids, particularly codeine. The assignments of C-10, C-15, C-16, and the NCH, of cancentrine followed by analogy from the corresponding carbon atoms of codeine and were confirmed by the off-resonance spectrum. The high-field
43
R,=R
44
R , + R 2 = 0
2
= H
= R2 = H
45
4,
46
R, + R 2 = 0
FIG.8. Cancentrine (43)and related compounds.
232
D. W. HUGHES AND D. B. MACLEAN
TABLE VIII 13C CHEMICAL SHIFTSOF CANCENTRINE (43), 10-OXOCANCENTRINE (44),CODEINONE (45), AND 10-OXOCODEINONE (46) Carbon
43"
44"
4Sb
46"
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 3-OCHx 19-OCH3 21-0CH3 NCH,
119.7 115.3 142.7 145.1 97.5 79.1 194.0 40.2 58.8 20.4 127.4 127.7 51.4 46.2 33.2 46.6 124.3 116.3 149.8 138.0 146.8 109.2 116.6 104.3 160.1 121.4 147.7 140.7 119.7 127.8 29.0 57.8 56.5 56.5 56.5 43.2
120.2 115.3 146.6 143.3 96.7 78.3 193.2 40.0 68.0 196.3 124.4 135.6 52.5 48.9 32.1 47.3 124.2 115.9 149.5 137.8 146.6 108.9 115.9 104.3 160.4 121.0 146.8 140.5 119.2 127.5 28.8 57.3 56.3 56.3 56.3 43.3
119.7 114.7 142.3 144.6 88.0 194.1 132.2 149.1 58.9 20.4 126.1 129.0 43.1 41.4 33.9 46.7
120.0 115.0 149.6 144.9 87.7 193.2 132.7 148.3 68.5 190.4 125.1 137.1 44.6 44.4 33.9 47.2
56.7
56.3
42.9
43.4
Holland ef al. (36) Terui et al. (32).
3.
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
233
position of C-10 in both the morphine and cancentrine alkaloids was atributed to the y steric effect of the NCH, group (32, 33). C-8, C-13, and C-14 were assigned from the off-resonance spectrum. Although the residual coupling patterns of C-9 and C-32 were partially obscured by the methoxyl signals in the off-resonance spectrum, C-9 was assigned to 58.8 ppm and C-32 to 57.8 ppm. The lowest field signals in the aliphatic region at 97.5 and 79.1 ppm were assigned to C-5 and C-6, respectively. The assignment of the aromatic resonances was difficult in this complex system because of the large number of signals. For purposes of study they were conveniently divided into two main spectral regions, 100-130 ppm for those aromatic carbon atoms bonded to hydrogen or another carbon, and 135-150 ppm for those aromatic carbon atoms bonded to oxygen substituents. Off-resonance decoupling differentiated the protonated carbon atoms from those bonded to another carbon atom, but there were cases where the residual coupling overlapped quaternary carbon signals and made the assignment of the latter quite difficult. This problem was solved by the technique of selective enhancement of quaternary carbon signals (37). A low power and modulated decoupling field was applied to the sample, producing a spectrum composed of only quaternary carbons. As a result of this procedure it was found that the peak at 119.7 ppm was a composite of signals arising from C-1 and C-29. The aromatic carbon atoms of the morphine moiety of cancentrine were assigned by comparison to codeine (32,33).For example, C-4 was assigned to 145.1 ppm because of its low intensity. Since this carbon atom does not have any neighboring protons to provide dipolar relaxation, it therefore should have a longer T I and a lower intensity because of partial saturation owing to the short delay between the rf pulses. The similar chemical shifts of C-11, C-12, and C-30 did not allow unambiguous assignments to be made. A similar analysis of the cularine portion of cancentrine resulted in the tentative assignment of the remaining aromatic carbon atoms (36). The signals at 194.0, 160.1, and 104.3 pprn were assigned to C-7, C-25, and C-24, respectively. The assignment of the oxygenated carbon atoms can at best be considered tentative. These data were used to good advantage in the structural elucidation of 10-oxocancentrine (44). Other physical data had suggested that the new alkaloid differed from cancentrine only at C-10. To provide additional support for these observations the 3C spectrum of 10-oxocancentrine and the model compounds, codeinone (45) and 10-oxocodeinone (46),were recorded. In the latter the carbonyl group at C-10 appears at 190.4 ppm. This change in functionality caused a deshielding of carbons C-9, C-14, C-3, and C-12 relative to codeinone.
'
234
D. W. HUGHES AND D. B. MACLEAN
In the aliphatic region of the 10-oxocancentrine spectrum the signal at 20.4 ppm corresponding to C-10 in cancentrine was absent. Both C-9 and C-14 were deshielded as in the model discussed above. These results confirmed the location of the carbonyl at C-10 in oxocancentrine. The assignments made to the quaternary aromaticand carbonyl carbons were considered to be tentative by the authors. VIII. Pavine Alkaloids The I3C chemical shifts of the symmetrical pavine alkaloids argemonine (47) (6) and eschscholtzine (48) (17) (Fig. 9) are presented in Table IX. The
difference in chemical shifts between the two alkaloids in large measure p ' m "/ OR,
Rp
2\
'CH,
12.
o l\, II
47
R
48
R, + R2 = R2 + R3 = CH2
1
= R
OR,
9
2
FIG.9. Argemonine (47) and eschscholtzine (48).
10
=R3=R4=CH
3
TABLE IX I3C CHEMICAL SHIFTS OF THE PAVINE ALKALOIDS Carbon
47"
4Sb
1,7 23 3,9 4,lO 4a,10a 5,ll 6,12 6a,12a 2,8-OCH, 3,9-OCH3 2,3-OCH,O 8,9-OCH,O NCH,
109.9 147.3 147.7 111.4 123.7 33.3 66.2 129.7 55.4 55.8
107.1 146.1 146.5 108.7 125.6 34.1 56.8 131.1
40.6
" Wenkert et al. (6). Hughes and MacLean (17).
100.6 100.6 40.8
3.
THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
235
reflect the difference in substituents on the aromatic rings. A discrepancy is present between the two alkaloids in the chemical shift of C-6 but the reason for this is not apparent.
IX. Aporphine Alkaloids
'
Several groups have examined the 3C spectra of the aporphine alkaloids (6, 7,38-40); examples are found in Fig. 10. The chemical shift assignments (Table X) for the aliphatic carbon atoms of rings B and C were made by comparison to laudanosine (28) (6) and to the reduced proaporphines (41). In the case of caaverine (49) a comparison with ( f)-lirinidine (50) revealed the p deshielding effect of the N-methyl group on C-5 and C-6a and the shielding of C-7 by a y effect. The analysis of the aromatic carbon atoms was aided by the use of selective 'H decoupling and long-range I3C-lH coupling (6, 40). For example, in thaliporphine (51) C-1 is bonded to a hydroxyl group and is split into a doublet ( 3 J z 7.0 Hz) by coupling to H-3. Carbon-2, which carries the methoxyl substituent, appeared as a broad multiplet owing to coupling to the methoxyl protons. Irradiation of H-3 caused C-1 to collapse to a singlet. When the positions of the hydroxyl and methoxyl groups are reversed as in predicentrine (52), C-1 was now broad with unresolved coupling to the methoxyl protons whereas C-2 was a singlet owing to the small ortho coupling to H-3 ( 2 J e 1.0 Hz). C-1 and C-2 in compounds such as nuciferine (53), which have ortho dimethoxyl groups at these positions, can be differentiated by measuring the changes in the width at half-peak height of the unresolved multiplets in the coupled spectra. If H-3 was irradiated the width at half height for C-1 was reduced from 16 Hz to 9 Hz whereas that for C-2 was virtually unaffected (40). Similar experiments were performed to assign the oxygenated carbon atoms of ring D. The chemical shifts of the nonoxygenated quaternary aromatic carbon atoms were more difficult to assign because of the additional coupling to benzylic protons. Only C-1l b was determined by selective proton irradiation since it was coupled through the biphenyl linkage to H-1 1. The assignment of the other carbon-substituted carbon atoms relied on comparing the effects of different substituents on these atoms. This is illustrated for C-7a and C- 1l a if one examines the series nuciferine (53), nuciferoline (54), glaucine (559, and nantenine (56). In alkaloids such as isocorydine (57) and bulbocapnine (58),which contain substituents on C- 10 and C-11, the chemical shifts of the ring D carbon atoms were determined not only by the methods discussed above but also by the observation of second-order effects in the off-resonance spectra of C-8 and C-9 (6).
236
D. W. HUGHES AND D. B. MACLEAN
49
R = H
51
R1
50
R = CH3
52
R, = H, R2 = CH
=
CH3, R p = H
3
CHO ,
R, 53
R1
= R2 = H
54
R1
=
Od, R2
= H
55
R,
56
R, +
=
R2
=
OCH3
R2 = OCHEO
57
R1 = R2 = CH
58
R1 + R2 = CH2
3
(FCH
CHO ,
\
bCH,
59
OCH, 60
FIG.10. Aporphine alkaloids
The effect of nitrogen quaternization on the chemical shifts of several aporphine alkaloids was studied by Marsaioli et al. (39). The conversion of dicentrine (59) to its methiodide salt (60)caused deshielding of C-5 and C-6a whereas C-3a, C-4, C-7, C-7a, and C-1Ic were all shielded. The shielding of the aromatic carbon atoms may be caused by the electric field effect similar to that observed in nitrogen protonation (8, 12). C-4 and C-7 were most likely experiencing the y steric effect of the new methyl group.
TABLE X -'C CHEMICAL SHIFTS OF THE APORPHINE ALKALOIDS
Carbon I 2 3 3a 4 5 6a 7 7a 8 9 10 11
lla Ilh 1 Ic 10-CH3 2-OCH3 1,2-OCH,O 9-OCH3 10-OCH3 9,lO-OCH ,O NCH, N(CH312
49a
50"
51b
52h
53'
54"
55'
56'
57'
5Sb
59"
141.6 146.5 110.9 127.3 28.4 42.1 53.2 36.8 135.7 128.1 128.1 126.2 125.9 132.4 119.7 123.5
141.6 146.5 110.3 127.4 28.4 52.9 62.1 34.4 135.7 128.1 127.5 126.2 126.0 132.4 119.2 123.5
140.7 145.8 108.7 123.9 29.0 53.5 62.7 34.5 128.9 110.9 147.6 147.1 112.0 124.8 119.5 127.2
142.3 148.2 113.5 129.6 28.7 53.3 62.5 34.2 129.2 110.7 148.1 147.6 110.0 124.1 126.3 125.8 60.3
144.0 151.4 110.3 127.0 29.0 52.9 62.1 34.9 130.4 107.8 146.0 145.9 108.4 125.1 126.4 128.2 59.8 55.4
141.7 150.8 110.8 128.8 29.1 52.4 62.6 35.6 129.6 118.6 110.7 149.0 143.6 119.8 125.4 129.8 61.7 55.5
143.1 148.5 106.4 121.8 24.0 61.8 69.8 28.7 123.3 111.6 148.8 148.2 110.2 122.0 116.7 117.9
56.0
143.9 151.5 110.1 127.0 29.1 53.1 62.3 34.4 129.1 110.6 147.7 147.1 111.4 124.2 126.5 128.6 59.8 55.5
141.2 147.2 106.4 126.2 28.7 52.9 61.9 33.4 128.3 110.7 148.2 146.0 111.9 122.6 115.8 126.5
55.8
144.3 151.3 111.6 127.7 28.7 52.5 62.3 33.5 126.6 128.4 114.5 155.7 114.0 132.1 125.9 128.6 59.6 55.5
140.4 145.9 107.7 127.4 29.3 53.0 62.8 35.4 129.7 119.2 110.8 148.3 142.9 118.5 125.8 128.9
55.8
144.6 151.4 110.9 127.5 28.9 52.8 61.9 34.8 135.9 127.1 126.7 126.4 127.3 131.6 126.3 128.1 59.7 55.3
100.2
101.3 55.9 55.9
56.0 55.9 43.6
44.0
55.5 55.7
56.0 55.8 43.8
' Ricca and Casagrdnde (40); Solvent: DMSO-d,. Shamma and Hindenkdng (7). ' Wenkert et al. ( 6 ) . Marsdioh et d.( 3 9 ) ;Solvent: CDCI, + C H 3 0 H .
43.5
43.5
43.4
100.4 43.6
55.8
56.2
100.4 55.4 55.6
43.6
44.0
43.5
60d
43.6.54.3
238
D. W . HUGHES AND D. B. MACLEAN
X. Reduced and Nonreduced Proaporphines The 3C chemical shifts of several reduced (61-64) and nonreduced (65, 66) proaporphine alkaloids (Fig. 11 and Table XI) have been reported by Ricca and Casagrande (41). The authors studied several pairs of diastereomers and found the I3C chemical shifts to be sensitive to the relative stereochemistry in these compounds. A comparison of the data for compounds 61 and 62 showed that the double bond could be located by examining the chemical shift of C-7. From molecular models it was found that when the double bond was between C-8 and C-9 a y gauche interaction existed between the axial proton on C-1 1 and the a proton on C-7. This interaction was used to explain the higher field shift of C-7 in compounds with the 8,9-double bond such as 61. When the double bond was between C-1 1 and C-12 these interactions were no longer present and C-7 appeared at lower field in 62. The chemical shift at C-7 was
62
61
63 R1 = OH, R2 = H
65
R = H
64 R1 = H, R2 = OH
66
R = CH3
FIG.11. Reduced and nonreduced proaporphines.
3.
THE 13C-NhXRSPECTRA OF ISOQUINOLINE ALKALOIDS
239
TABLE XI ,C CHEMICAL SHIFTS OF THE REDUCED AND NONREDUCED PROAPORPHINES' Carbon 1
2 3 3a 4 5 6a 7 7a 7b 7c 8 9 10 11 12 1-OCH, 2-OCH, NCH
61
62
63
64
65
66
140.9 148.0 110.0 130.3 26.9 54.6 65.3 43.0 47.0 134.0 121.5 157.5 126.8 198.9 35.2 30.7
140.8 147.9 110.2 129.2 26.8 54.6 64.6 48.8 47.8 134.5 121.5 33.1 35.2 198.5 126.8 155.1
141.5 148.5 111.2 129.3 26.7 54.7 64.4 40.4 51.4 134.1 121.0 75.5 46.0 209.2 38.4 26.1
140.9 147.6 109.4 129.7 26.8 55.0 65.1 37.9 52.7 134.5 120.9 69.0 48.5 209.6 32.0 28.7
141.5 147.6 110.7 124.7 26.8 54.6 65.2 46.7 50.5 134.8 122.0 154.7 127.7 185.5 126.7 150.8
56.3 43.4
56.4 43.4
56.2 43.5
56.3 43.5
56.4 43.3
143.7 152.7 111.9 132.9 27.0 54.3 65.0 46.9 50.7 134.8 127.5 154.3 127.7 185.3 126.6 150.9 60.2 56.1 43.2
Ricca and Casagrdnde (41).
also shown to be diagnostic of the stereochemistry of the alcohol function at C-8 in compounds 63 and 64. In 64 the hydroxyl group is in a configuration which results in a steric shielding effect at C-7. In the nonreduced proaporphines, ( -)-glaziovine (65) and ( -)-pronu& ferine (66), the additional double bond in ring D results in a shielding of the carbonyl carbon. Similar observations have been made in other crossconjugated system (8, 42).
XI. Tetrahydroprotoberberine Alkaloids The tetrahydroprotoberberine alkaloids have a tetracyclic ring structure which is based on the dibenzo [a,g]quinolizidine system (Fig. 12). Carbon- 13 NMR has been used extensively to study the quinolizidine conformation (14, 27, 28, 43-50). The chemical shift assignments (Table XII) for the majority of the carbon atoms were made by comparison with the appropriately substituted simple isoquinolines such as 2 and 4. Since the chemical shifts of the aliphatic
240
D. W. HUGHES AND D. B. MACLEAN
CH,O
OCH,
OCH, 72
R, = CH3, R p = H
74
R
75
R, = CH3,
1
73
= H , R2 = CH3
R2 = H
77
Ho”o: OCH, CH3
FIG.12. Tetrahydroprotoberberine alkaloids.
carbon atoms, in particular that at C-6, reflect changes in the quinolizidine conformation, definitive assignment of these carbon atoms was requisite. Reduction of berberine chloride with NaBD, yielded ( +)-canadhe (67) labeled with deuterium at C-8 and C-14 (14). In the spectrum of the labelled compound the signals at 59.6 and 53.4 ppm were virtually absent and these were assigned to C-14 and C-8, respectively. C-6 and C-8 were also differentiated by the observation of virtual coupling effects at C-6 (6). The
3.
13
Carbon 1 L
3 4 4a 5 6 8 8a 9 10 11 12 12a 13 14 14a 15 1-OCH, 2-OCH3 3-OCH3 9-OCH3 10-OCH, 11-OCH, 1,2-OCH,O 13-CH3 NCH,
24 1
THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
C CHEMICAL SHIFT^
TABLE XI1 TETRAHYDROPROTOBERBERINES
OF THE
61"
68"
69"
70b
71"
72"
13'
105.5 146.0 146.2 108.4 127.8 29.5 51.4 53.4 127.8 150.3 145.2 111.1 123.8 128.7 36.4 59.6 130.9
105.7 146.1 146.2 108.5 128.0 29.7 51.4 53.5 121.4 141.7 144.2 109.1 119.4 128.1 36.5 59.7 131.1
108.9 147.6 147.6 111.5 127.8 29.1 51.5 54.0 126.9 150.3 145.2 111.1 123.7 128.7 36.4 59.3 129.9
108.7 147.5 147.5 111.6 126.8 29.1 51.4 58.3 126.5 109.1 147.7 147.7 111.5 126.5 36.5 59.7 129.9
109.0 147.3 147.8 111.3 128.5 29.4 51.5 54.5 128.6 150.2 145.1 111.7 124.1 135.1 38.4 63.1 128.6
112.1 146.7 148.0 111.1 127.7 28.1 47.0 51.1 126.5 150.2 145.4 111.1 123.2 133.0 34.6 64.2 130.7
151.9 140.2 150.1 107.4 130.6 30.0 48.3 53.3 128.3 150.9 145.3 110.9 124.0 128.6 33.0 55.5 124.2
55.8 56.0
56.2
55.8 55.8 60.1 56.1
55.9 55.8 60.1 56.2
55.9 55.9 60.4 56.4
60.6 60.1 55.8 60.6 55.8
18.4
22.4
60.1 55.8
55.8 56.0
74'
75'
76'
113.0 146.1 147.9 110.9 130.0 30.7 24.9 23.9 63.8 52.1 46.3 64.0 61.6 60.9 126.9 150.7 149.6 111.7 123.6 134.2 32.9 38.7 69.0 70.8 72.9 78.3 130.0 68.7 55.9 56.0 60.9 55.9
11' 105.6 146.1 146.5 108.4 128.5 29.3 50.8 53.8 127.2 151.6 144.5 111.1 123.4 129.4 69.8 64.6 130.9
60.0 55.7 100.7
100.7 100.8 22.0 44.2 52.0
Hughes e t a / . (14). Moulis rt a/. (49). Kametani e t a / . (44). ' Takao et a/. (28). Manske et a/. (21). a
methoxyl group at C-9 of canadine was labeled with deuterium by treating nandinine (68) with diazomethane in D,O (14). The resonance at 60.1 ppm was absent in the spectrum of the labeled compound, thereby confirming the lower field position of the sterically crowded methoxyl group. Because of the similarity in chemical shift for C-2 and C-3, for C-42 and C-l4a, and for C-8a and C-12a these signals could not be unambiguously assigned. The chemical shift of C-8 may be used to determine the position of the oxygenated substituents in ring D. A comparison of the spectra of tetrahydropalmatine (69) and xylopinine (70) (49) showed that C-8 in (70) is deshielded
242
D. W. HUGHES AND D. B. MACLEAN
by +4.3 ppm. This change is caused by the removal of the steric effect of the C-9 substituent. It should also be noted that the C-9 hydroxyl group in nandinine is just as effective as a methoxyl group in shielding C-8. The conformation of the tetrahydroprotoberberine alkaloids is such that the B and C rings exist as half-chairs and the entire quinolizidine system may equilibrate between one trans and two cis forms (Fig. 13) (28, 43, 44, 47, 48). Corydaline (71) and mesocorydaline (72) are 13-methyltetrahydroprotoberberines in which the conformational equilibrium lies towards pure trans and pure cis, respectively, as shown by IR (51) and PMR spectroscopy (52). In CMR spectroscopy (14, 28) the change from a trans (in 71) to a cis (in 72) conformation is evident from the upfield shift of C-5, C-6, C-8, and C-13. This change has been attributed to the increased number of y interactions which occur in cis-quinolizidines (47, 48). Carbon- 14, however, is slightly deshielded, perhaps caused by changes in the P-substituent effect of both the C-methyl and C-6 (48). As the C-13 methyl changes from axial in corydaline to an equatorial position in mesocorydaline it is also deshielded. This is a reflection of a change in its steric environment. These chemical shift differences allow one to distinguish readily between the cis and trans conformations of the 13-methyltetrahydroprotoberberines.
FIG.13. Conformations of the BIC rings in the tetrahydroprotoberberines.
3.
THE I3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
243
Kametani and co-workers ( 4 3 , 4 4 )have used 13CNMR to study the effect of C-1 substituents on the stereochemistry of the quinolizidine system in this group of alkaloids. In 0-methylcapaurine (73), which has a methoxy group at C-1, the quinolizidine system was considered to be in the cis form. This conclusion was based on the upfield shift of C-6. Comparison of 73 with 71 and 72 revealed some interesting differences. C-5, C-6, C-8, and C-13 were all shielded in the cis form of the 13-methyltetrahydroprotoberberines relative to the trans form but only C-6 and C-13 were affected in 73. Carbon14 in 73 was shifted upfield relative to 72 in a manner analogous to that found for C-1 in compound 72, and this steric shielding is probably greater than any chemical shift change associated with cis-trans interconversion. C-5 and C-8 of 73 did not show any upfield shift as they did in the 13-methyl compounds. These results indicated a difference in the cis conformation of the two types of compounds and it has been proposed that this was caused by different cis-trans equilibrium .constants (28, 48). Other cis-trans isomers have been examined by 13C NMR; these include the 8-methyltetrahydroprotoberberines (46,47)which have also been studied by PMR spectroscopy (53),the N-oxides of tetrahydropalmatine (45),and several N-methyl salts such as the methochlorides of thalictricavine (trans) (74) and mesothalictricavine (cis) (75) (28, 45). The structure of a new tetrahydroprotoberberine alkaloid solidaline (76) was established in part by 3C NMR (21).The chemical shifts were assigned primarily by comparison with the data for ophiocarpine (77), mesocorydaline (72), and hydrastinine (15). By this procedure C-5, C-6, and C-15 were readily identified. The presence of the structural unit CH2-CH was indicated by an ABX pattern in the PMR spectrum. These carbon atoms were assigned to 68.7 ppm (CH,) and 60.9 ppm (CH) in the 13C spectrum. The quaternary carbon atom resonances at 69.0 and 78.3 ppm were assigned to C-13 and C- 14, respectively. A cis-quinolizidine conformation was evident based on the chemical shifts of C-5 (30.7 ppm) and C-6 (46.3 ppm) which are similar to those of the corresponding carbon atoms in mesocorydaline. This conformation was further supported by the methyl signal of C-13 at 22.2 ppm which was nearly identical with that in 72. It appears that any deshielding of the C-methyl group by the p-hydroxyl group at C-13 is countered by the 7 shielding effect of the C-14 oxygen substituent. XII. Protopine Alkaloids
The protopine alkaloids have a 10-membered ring containing a carbonyl group and a tertiary nitrogen atom. Even though they do not have an isoquinoline ring they are properly classified in the isoquinoline family
244
D. W. HUGHES AND D. B. MACLEAN
because of their biosynthetic derivation from the protoberberines. An interesting feature of these alkaloids is the conformational flexibility of the central ring that allows a transannular interaction between the carbonyl group and the nitrogen atom. This interaction, which is promoted by acids, has been studied by numerous physical methods (2). In a study by CMR spectroscopy (54) a number of representative alkaloids were examined, among which were protopine (78), cryptopine (79), and hunnemanine (80) (Fig. 14 and Table XIII). In addition to using standard methods of assigning chemical shifts, such as additivity relationships, selective H decoupling, and deuterium labeling, the authors used gated decoupling (55,56) to differentiate among the protonated aromatic carbon atoms. C-1 and C-1 1 appeared as doublets with lJCH= 160 Hz, whereas C-4 and C-12 showed additional coupling to the methylene protons at C-5 and C-13, respectively. In hunnemanine (80), which differs from the other alkaloids in having a phenolic hydroxyl group, the carbonyl resonance was shielded by 15-20 ppm relative to the other alkaloids and was also broadened. It was considered
78
R, + R2 = R3
79
R,
=
CH3. R3
t
80
R, + R2 =
CH2, R3
= H, R 4 =
=
R2
t
R4 = C H 2
R4 = CH2
FIG.14. Protopine alkaloids.
CH3
3.
THE
3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
245
TABLE XI11 I3C CHEMICAL SHIFTSOF THE PROTOPINE ALKALOIDS’.~
Carbon
78
19
80
1 2 3 4 4a 5 6 8 8a 9 10 11 12 12a 13 14 14a 2,3-OCH,O 9,lO-OCH20 2-OCH 3-OCH3 10-OCH, NCH,
107.5 145.9 147.5 109.9 135.8 31.2 57.4 50.4 117.5 145.5 145.4 106.1 124.6 128.5 46.0 194.1 132.2 100.6 100.3
111.8 146.7 149.0 112.2 134.3 31.8 57.2 49.9 117.1 145.9 145.6 106.2 124.5 128.9 45.7 194.7 130.8
108.1 145.5 147.5 109.7 135.0 31.0 56.7 49.8 120.7 145.0 143.5 108.5 122.3 128.0 45.4 173.8 131.8 100.6
40.9
40.8
100.3 55.4 55.4 55.4 40.5
Nakashima and Maciel(54) Shamma and Hindenlang (7).
that in the case of 80 the equilibrium between the tricyclic and tetracyclic forms shown in Fig. 14 was shifted toward the latter because of the acidic phenolic function. It was shown that the spectrum of protopine (78) was altered by the addition of an equimolar amount of phenol and that the carbonyl resonance now resembled that of 80. It is apparent therefore that CMR spectroscopy is an effective tool to study transannular reactions in these systems.
XIII. Phthalideisoquinoline Alkaloids Among the phthalideisoquinoline group of alkaloids there are several pairs of diastereoniers. It is shown below that CMR spectroscopy is an effective means of differentiating between such a pair of isomers. Spectra
246
D. W. HUGHES AND D. B. MACLEAN
/
'
OCH, 81
R = H
90
R = OCH3
83
R1 = R2 = CH
85
R, + R2 = CH 2
0 OCH,
OCH, 82
3
84
R, = R2 = CH 3
86
R1 + R 2 = C H 2
FIG.15. Phthalideisoquinoline alkaloids.
have been reported on naturally occurring a-hydrastine (81) and its diastereomer, a-hydrastine (82), and the natural diastereomers, corlumine (83) and adlumine (84)(14), and bicuculline (85) and capnoidine (86) (17)(Fig. 15 and Table XIV). The carbon resonances of rings A and B of these alkaloids were assigned by comparison to the spectra of the isoquinolines substituted at C-1 (Table 11). Phthalide (87), meconin (88), and 6,7-methylenedioxyphthalide(89) served as models in the assignment of the signals of rings C and D (Fig. 16 and Table XV). The signals of the phthalide spectrum were assigned through a study of the spectrum of 6-deuterophthalide and by selective proton decoupling experiments. The aromatic carbon atoms of 88 and 89 were
3.
THE
"C CHEMICAL SHIFTSOF Carbon 1 3 4 4a 5 6 7 8 8a 1'
3' 3'a 4 5' 6' 7' 7'a NCH, 6,7-OCH,O 4'-OCH, 5'-OCH, 6-OCH, 7-OCH3 4',5'-OCH,O 8-OCH3
247
3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
TABLE XIV PHTHALIDEISOQUIKOLIXE ALKALOIDS
THE
81"
82"
83"
84"
85ib.'
Wb
90b
66.0 49.0 26.7 124.5 108.1 146.3 145.4 107.3 130.0 82.7 167.0 119.4 147.5 152.6 118.5 117.3 140.4 44.7 100.5 62.0 56.7
66.2 51.3 29.2 125.3 108.2 146.3 145.8 107.4 130.0 81.8 168.0 119.3 147.6 152.3 118.4 118.1 141.1 44.9 100.7 62.2 56.7
65.7 49.5 26.5 123.4 111.3 148.2 147.2 110.7 129.5 84.9 167.2 110.3 144.5 149.1 113.1 115.5 140.8 45.1
65.7 51.7 29.1 123.9 111.0 147.4 146.9 110.0 128.4 82.1 167.7 109.7 144.1 148.8 112.8 116.1 140.9 44.9
66.0 49.5 27.0 124.8 108.5 146.8 146.0 107.8 130.7 85.0 167.2 110.3 144.5 149.1 113.1 115.6 140.5 45.3 101.0
66.2 51.4 29.1 125.2 108.2 146.4 146.0 107.5 130.1 82.9 167.5 110.0 144.2 148.9 112.9 116.0 140.9 45.0 100.8
60.9 50.1 28.1 132.2 102.4 148.5 134.1 141.3 117.2 81.9 168.2 120.3 147.8 152.3 118.4 117.8 140.6 46.3 100.8 62.2 55.9
55.9 55.9 103.3
55.6 55.9 103.1
103.3
103.1 59.4
Hughes et al. (14). Hughes and MacLean (17). In Sharma and Hindenlang (7) a similar set of data is ascribed to capnoidine.
87
88
FIG.16. Phthalide and substituted phthalides.
89
248
D . W. HUGHES AND D. B. MACLEAN
TABLE XV I3C CHEMICAL SHIFTS OF PHTHALIDE AKD ITS DERIVATIVES~ Carbon
87
88
89
1 3 3a 4 5 6 7 7a 6-OCH3 7-OCH3 6,7-OCH20
170.4 69.5 146.3 122.0 133.6 128.5 124.9 125.2
168.7 68.5 139.6 116.7 119.9 152.6 148.6 118.1 57.0 62.3
171.7 71.8 139.4 115.1 114.7 149.5 145.6 108.0
a
103.8
Hughes et al. (14).
assigned by applying to phthalide the additivity parameters for o-dimethoxyl groups and methylenedioxy groups, respectively. It was noted that C-7a in meconin (88) appeared at lower field by 10 ppm than its calculated value and the corresponding carbon atom of 89. This shift was attributed to steric inhibition of resonance of the C-7 methoxyl group (14, 19). A steric interaction with C-1 was invoked to explain the lower field resonance of the methoxyl group at C-7. In compounds 88 and 89 C-4 and C-5 were differentiated by selective H decoupling. When the partial structures corresponding to the substituted phthalides, 88 and 89, are incorporated into the alkaloids, 81-86 there was relatively little change in chemical shifts from those of the models except for the expected changes at the benzylic carbon atoms (C-1’). A close examination of the chemical shifts of the aliphatic carbon atoms of the diastereomeric pairs, 81 and 82,83 and 84, and 85 and 86, has shown that the diastereomers may be differentiated by CMR spectroscopy. The change in stereochemistry at C- 1’ between erythro-p-hydrastine (81) and threo-a-hydrastine (82)caused deshielding in 82 at C-3, C-4, and the N-methyl group by +2.3, +2.5 and +0.2ppm, respectively, whereas C-1’ was shielded by - 0.9 ppm. Chemical shift differences of similar magnitude were observed for the pairs, 83 and 84, and 85 and 86 except that in these systems C- 1’ underwent a slightly larger shielding. The chemical shift at C-1 was influenced by the presence of a substituent at C-8. In narcotine (90)(17) C-1 was shielded by -5.1 pprn relative to 81. This shielding was similar to that observed in 4 (Table I).
’
3.
THE I3C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
249
XIV. Modified PhthalideisoquinolineAlkaloids
A number of compounds that appear to be biogenetically derived from phthalideisoquinolines have recently been examined by CMR spectroscopy. They are bicucullinine (91) (57),fumaramine (92) (17), and the hydrated fumaramine (93) (17), an alkaloid recently isolated from F. schleicherii (58) (Table XVI, Fig. 17). In the case of 91 the carbonyl groups and the carboxylate group were easily identified by their chemical shifts. The aromatic carbon atoms of all three were tentatively assigned by comparison to aromatic systems carrying methylenedioxy groups and the aliphatic carbon atoms of the side chain by comparison to I3C data on phenethylamines (59) and by the intensity of the resonances attributed to the N-methyl groups. The 13C spectrum of 93 was particularly valuable in elucidating its structure.
TABLE XVI l 3 C CHEMICAL SHIFTSOF THE MODIFIED PHTHALIDEISCQUINOLINE ALKALOIDS Carbon
91"
92b
93*.'
1 2 3 4 4a 5 6 8 8a 9 10 11 12 12a 13 14 14a 3-OCHZO 10-OCHzO N(CH 3 12
104.9 142.5 148.9 108.8 137.8 28.0 56.2 168.0 121.4 142.0 149.8 109.4 118.9 122.4 190.4
108.6 146.8 147.5 110.3 132.6' 31.5 60.3 166.0 111.4 143.6 149.5 112.1 113.3 133.7' 131.9' 102.6 126.9' 101.4 103.1 45.2
109.2 144.7 145.7 110.8 126.9 30.3 60.6 164.9 113.8 142.6 148.7 111.0 115.8 142.2 87.6 37.0 133.1 100.5 102.4 45.0
190.0
125.1 99.3 99.7 40.5
a Solvent: alkaline D,O; aromatic carbon assignments are tentative, Ref. (57). Hughes and MacLean (17). Solvent : DMSO-d,. ' Assignment may be interchanged.
250
D. W. HUGHES AND D. B. MACLEAN
91
92
93
FIG. 17. Modified phthalide isoquinoline alkaloids.
XV. Benzo[c]phenanthridine Alkaloids Takao and co-workers (60) have examined a number of hydrobenzo[c]phenanthridine alkaloids and their derivatives by a variety of physical methods in order to determine the conformation of the BjC rings (Fig. 18). The I3C chemical shifts (Table XVII) were particularly sensitive to the influence of substituents on the conformation of the B and C rings. Chelidonine (94) for example, with a cis ring junction, has both the B and C rings as half-chairs [see Fig. 1 in (60)l. Acetylation of the hydroxyl group to form 95 shielded C-6, C-12, and C-13 relative to 94. The interpretation of these observations was that ring C in 94 adopted a twist half-chair conformation which increased the number of gauche interactions for these carbons. The chemical shift changes caused by the methyl group at C-13 in corynoline (96) were characteristic of the substituent effects for an angular methyl group at a ring junction (8, 12). The C-13 was shielded whereas C-11 and
3.
94 R 1 = R
2
,C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
THE
= R
3
= R
4
25 1
= H
95
R1 = COCH3, R2 = R3 = R
96
R1 = R3 = R4 = H, R2 = CH
97
R
98
R, = R
4
99
= H
3
1
= R
4
3
=H,R
2
=R3=CH
= H, R2 = R4 = CH
3
3
fl 36.1
"91.
0L
O
/N
1w.g 100.2
100
FIG.18. Benzo[c]phenanthridine alkaloids.
C-14 experienced the deshielding p effect of this methyl group. Since C-12 is y to the angular methyl group this would account for its higher field position in 96. The equatorial and axial 6-methylcorynolines, 97 and 98, respectively, were differentiated by observing the chemical shifts of C-6, C-14, and the methyl group at C-6. In 98 these carbon atoms underwent a strong shielding as a result of the 7 steric effect of the axial methyl group. An indication of the NCH, conformation was provided by the chemical shift of C-4. In compounds where the NCH, is axial such as 14epicorynoline (99), which has a trans BjC junction, this carbon was shielded relative to those alkaloids with an equatorial NCH,. The structural elucidation of a new benzophenanthridine alkaloid, luguine (100) was reported (61) in which the 13C spectrum confirmed both the aromatic nature of ring B and the presence of a hydroxyl group at C- 11. The spectrum showed four aliphatic carbon resonances and these were assigned by off-resonance decoupling.
252
D. W. HUGHES AND D. B. MACLEAN
TABLE XVII
l3cCHEMICAL SHIFTS OF THE HYDROBENZO[C]PHENANTHRIDINE Carbon 1
2 3 4 4a 6 6a 7 8 9 10 10a 11 12 12a 13 14 6-CH3 13-CH3 N-CH3 2,3-OCH,O 7,8-OCH,O CH3COCH3CO-
ALKALOIDS’
94
95
96
97
98
99
107.4 145.3’ 145.6‘ 111.9 128.9 53.9 117.1 143.1 148.2 109.2 120.4 131.4 72.4 39.7 125.8 42.1 62.9
108.2 145.3‘ 146.6‘ 106.4 127.6 45.4 117.3 144.1 147.0 108.2 121.5 129.5 12.7 31.3 126.6 33.1 62.0
107.7 145.2’ 145.4’ 112.8 128.0 54.4 116.9 142.9 148.2 109.4 118.7 136.2 76.1 36.8 125.3 40.8 69.8
41.6 100.9 100.9 21.4 175.4
107.8 145.3’ 145.5’ 112.5 127.9 54.8 123.3 142.9 148.0 109.4 118.9 135.8 75.7 36.6 125.5 40.3 60.5 10.6 23.3 39.2 101.0’ 101.2b
107.3 145.3’ 146.2’ 106.8 129.5 52.1 117.6 145.3 146.5 108.8 117.6 135.5 74.1 33.7 126.9 39.4 58.3
42.4 101.1’ 101.4’
107.7 145.4‘ 145.7’ 112.9 128.2 58.5 122.7 143.1 148.1 109.4 119.1 136.0 75.4 37.4 126.9 41.2 68.8 19.6 24.1 39.7 100.8’ 101.0’
23.5 43.2 101.0* 101.4’’
23.9 38.1 100.7’ 101.3*
Takao et al. (60).
’ Assignments may be reversed XVI. Spirobenzylisoquinoline Alkaloids These alkaloids are a relatively small group within the isoquinoline family. Ochotensimine (101) was the first to be studied and it and ochotensine are the only compounds of the group that have an exocyclic methylene on the five-membered ring (2, 3. 62). The most common functional groups are carbonyl, hydroxyl, or acetoxy at one or both of C-8 and C-13. The spectra of a series of these alkaloids were reported in 1977 (63)and these data were used recently in the structural elucidation of a new alkaloid (64). The structures and spectral data on the alkaloids discussed in this section may be found in Fig. 19 and Table XVIII, respectively. They are ochotensimine (101), sibiricine (102), corydaine (103), ochrobirine (104), fumaritine (105), and fumaritine N-oxide (106).
3.
THE 13C-NMR SPECTRA OF ISoQUINOLINE ALKALOIDS
253
c H30 c H,O
101
102
R, = H, R2 = OH
103
R,
=
OH, R2
=
H
104
106
FIG.19. Spirobenzylisoquinoline alkaloids.
1-Methyleneindane (107) was used as a model in the assignment of the resonances of the carbon atoms of rings C and D of 101 (Fig. 20 and Table XIX). A recent examination (65) of the spectrum of deuterated 107 has shown that the original assignments (63) of aromatic carbon atoms 3a and 7a should be reversed. In the case of the alkaloids with a carbonyl group, indanone (108), 6-deuteroindanone7 and 4,5-dimethoxy-l-indanone(109)
254
D. W. HUGHES AND D. B. MACLEAN
TABLE XVIII
' 3C CHEMICAL SHIFTS OF THE SPIROBENZYLlSoQulNOLINE ALKALOIDSn Carbon 1 2 3 4 4a 5
6 8 8a 9 10 11 12 12a 13 14 14a NCH, 2,3-OCH20 9,lO-OCH20 2-OCH3 3-OCH3 13-CH2 a
101"
102"
103"
104"
105b
lMb.'
110.5 147.5 147.7 110.5 126.1 29.1 48.1 37.0 123.8 143.0 148.2 108.0 113.6 136.1 155.5 71.9 137.2 39.0
106.9 147.4 147.4 109.6 125.0 29.2 48.9 70.3 132.7 146.1 154.8 1 10.9 119.9 132.5 201.5 77.2 130.6 39.7 101.3 103.2
105.8 146.9 146.9 108.2 129.3 29.5 50.2 75.0 134.3 144.4 154.5 110.6 119.6 131.2 202.2 72.0 129.8 41.7 101.1 103.1
109.7 146.2 146.8 110.0 126.0 22.8 47.6 73.4 121.5 144.7 148.6 107.1 116.1 140.0 79.5 75.2 129.5 37.7 101.0 101.9
111.2 144.2 146.4 112.9 127.4 23.3 47.6 82.3 125.5 144.2 147.5 108.9 113.3 135.0 44.0 74.5 127.9 38.1
117.4 156.8 153.0 112.9 118.2 27.6 64.8 77.2 124.2 145.4 148.6 110.9 117.9 135.3 38.8 90.6 127.2 53.7
101.6
103.1
56.0
57.4
101.3 56.1 55.8 106.7
Hughes et al. (63). Kiryakov et al. (64). Solvent: D,O + 2 drops 40% NaOD.
were examined as models (Fig. 20 and Table XIX). By comparison of the spectra of 108 and its deuterated analog it was possible to assign all the resonances of the aromatic carbon atoms. The signals of 109 were then assigned by application of the substituent parameters for o-dimethoxy groups to 108. There was good agreement between observed and calculated values. Accordingly the spectra of 4,5-methylenedioxy-l-methyleneindaneand
CH 3 0 107
108
FIG.20. Model indanes and indanones.
109
3.
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
255
TABLE XIX I3C CHEMICAL SHIFTSFOR MODEL COMPOUSDS 107-109 Carbon
107",*
108"
109"
1 2 3 3a 4 5 6
150.5 31.1 30.0 146.6 125.3 128.3 126.4 120.6 141.1 102.3
206.5 36.0 25.5 155.0 126.6 134.4 127.1 123.4 137.0
205.2 36.4 22.5 145.6 147.9 157.6 112.5 120.0 131.2
I 7a 1-CH, 4-OCH3 S-OCH3 a
60.3 56.3
Hughes et al. (63). Buchanan et al. (65)
4,5-methylenedioxy-I-indanonewere calculated by applying substituent parameters for the methylenedioxy group to 107 and- 108, respectively. These values were then used to aid the assignment of the signals of the aromatic carbon atoms of rings C and D in the alkaloids with similar functionalities. In the assignment of the resonances of the carbon atoms of rings A and B compound 3 served as a convenient model. However, the spiro carbon atom present in the alkaloids caused significant changes in the resonances of the carbon atoms of ring B. Thus for example in 101, C-6 and the N-methyl group were shielded by -4.9 and -7.0 ppm, respectively, as a result of y steric interactions with C-8 and C-13, and C-14 was deshielded by +14.3 ppm. Other spiro compounds are known to exhibit similar behavior (66) and qualitatively similar effects were found in other alkaloids of this series (63). Pairs of diastereomers such as 102 and 103 may be differentiated by CMR spectroscopy. In the case of the compounds in question there is hydrogen bonding between the amino group and the hydroxyl group in 103 but not in 102. This may account, through conformational changes, for the observed differences in their spectra. Thus C-6, C-8, and NMe are shielded while C-14 is deshielded in 102 relative to 103. Other pairs of diastereomers showed similar changes at these centers (63). In the dihydroxy compound 104 the chemical shifts of the two carbon atoms bearing hydroxyl groups are distinctly different. The assignments at
256
D. W. HUGHES AND D. B. MACLEAN
C-8 and C-13 were verified by selective 'H decoupling (63).It would be expected that the chemical shifts at C-8 and C-I3 would be diagnostic of the stereochemistry at these centers but this could not be verified because other isomers were not available for study. The elucidation of the structure of fumaritine N-oxide (106) was aided by the use of CMR spectroscopy (64).When the spectrum of fumaritine (105)
FIG. 21. Rhoeadine (110)
TABLE XX l3C CHEMICAL SHIFTSOF RHOEADINE (110)" Carbon
110
1 2 4 5 5a 6 7 8 9 9a 1Oa 10 11 12 13 13a 14 7,S-OCHZO 12,13-OCH20 14-OCH3 NCH,
77.6 55.5 55.1 33.2 136.5 110.5 147.5 147.3 108.3 130.9 130.9 123.0 112.2 145.8 145.5 117.2 96.2 101.8 101.1 60.6 41.5
' Tan1 and Tagahara (67).
3.
THE
3C-NMR SPECTRA OF ISCQUINOLINE ALKALOIDS
257
was compared with that of 106 it was apparent that the N-oxide function strongly deshielded the adjacent carbon centers, C-6,C- 14,and N-methyl. The differences in the resonances of the aromatic carbon atoms of ring A between 105 and 106 reflect the change from phenol to phenoxide at C-2. (The spectrum of 106 was recorded in alkaline D,O.)
XVII. Rhoeadine The structural features that characterize the rhoeadine alkaloids are a seven-membered ring B and the presence of a cyclic acetal or hemiacetal function (2,3)(Fig. 21). In the 13Cspectrum of rhoeadine (110) (67)(Table XX) both C-4and C-5appear at lower field than the corresponding carbon atoms in most of those alkaloids that have a six-membered ring B. The acetal carbon C-14is readily differentiated by its low field position relative to other resonances in the aliphatic region of the spectrum. The chemical shifts of the aromatic carbon atoms are similar to those of other classes of alkaloids that carry methylenedioxy substituents on rings A and D.
XVIII. Secoberbine Alkaloids Hypecorinine (111) (3,68) is the only example of this class of alkaloids on which 13Cdata have been reported (Fig. 22 and Table XXI) (17). Like the spirobenzylisoquinolines these alkaloids have a spiro carbon atom in the isoquinoline unit. In this system C-14is strongly deshielded because of the presence of oxygen at the spiro junction, but C-5, C-6,and N-methyl are shielded relative to the corresponding carbon atoms of the spirobenzylisoquinoline alkaloids. The shielding of C-6 and the N-methyl group may be attributed to the 7’ effect of the oxygen atom, and the upfield shift of C-5 may reflect a conformational change in ring B.
FIG.22. Hypecorinine (111)
111
258
D. W. HUGHES AND D. B. MACLEAN
TABLE XXI 3C CHEMICAL SHIFTSOF HYPECORININE (111)" Carbon
111
1 2 3 4 4a 5 6 8 8a 9 10 11 12 12a 13 14 14a 2,3-OCH,O 9,lO-OCHZO NCH,
108.2 146.0 147.8 108.2 125.5 24.9 45.8 57.6 123.2 142.1 152.2 108.8 124.3 125.9 192.4 91.8 129.8 101.1 102.7 37.7
" Hughes and MacLean (17).
?
FIG.23. Emetine (112)
OCH, 112
3.
THE 13C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
259
XIX. Emetine The I3C spectrum of emetine (112)(Fig. 23 and Table XXII) was examined by Wenkert and co-workers (69).The chemical shift assignments were made by comparison with the shifts recorded for the simple isoquinolines and protoberberine alkaloids such as tetrahydropalmatine (69) (6, 14), and with indolic analogues of emetine (69). The shifts of C-4 and C-6 are characteristic of a trans-quinolizidine conformation for this ring system by analogy
TABLE XXII l3C CHEMICAL SHIFTSOF EMETINE A N D EMETINE DIHYDROCHLORIDE Carbon 1 2 3 4 6 7 7a 8 9 10 11 lla llb 12 1' 3' 4 4'a 5' 6' 7' 8' 8'a
9-OCH3 10-OCH, 6-OCH3 7'-OCH3 CH3CH2CHSCHI__ ~
Emetine"
Emetine dihydrochlorideb
36.7 36.7 41.6 61.2 51.7 29.1 126.7 111.5 147.1 147.1 108.6 130.1 62.2 40.0 52.1 40.6 29.1 126.7 111.5 147.1 147.1 109.1 132.0 55.7 55.7 55.7 55.7 23.3 10.9
34.8 35.8 39.2 58.7 50.7 26.4 124.8 111.6 149.2 149.2 110.6 125.7 62.6 40.0 53.6 37.1 25.2 124.8 113.5 148.4 148.4 113.7 125.2 56.8 56.8 57.0 57.0 23.1 10.7
Solvent : CHCl,--Koch ct a/. (69) Solvent: D,O-Buzas er al. (70).
260
D. W . HUGHES AND D. B. MACLEAN
with the corresponding carbon resonances in the protoberberine series (14, 44,48).
Buzas et al. (70) recorded the spectrum of emetine dihydrochloride as well as several emetine analogs and synthetic intermediates. Most of the assignments correlated with Wenkert’s data; however, C-1 to C-7 and C-3’ and C - 4 were shielded upon nitrogen protonation (8, 12). It was observed that protonation of the nitrogen had an additional effect on the quinolizidine portion of emetine since C-1 lb, C-3, and C-6 were not observed at ambient temperatures; C-4 was also quite broad. These signals became visible and sharpened at higher temperatures.
XX. Miscellaneous Alkaloids The I3C spectra of several l-phenyl-3,4-dihydro-, l-phenyl-l,2,3,4-tetrahydro-, and 1-naphthyl-3,4-dihydroisoquinolines have been reported in the compilation of Shamma and Hindenlang (7). The chemical shifts that have been assigned to the isoquinoline moieties in these molecules agree with those of similar systems discussed in previous sections of this article. The chemical shifts of the carbon atoms in the 3,4-dimethoxyphenyl groups are remarkably similar to those of the same unit in laudanosine (28). In the 1naphthyl series the spectra of three compounds differently substituted in the naphthalene unit were recorded and assignments made to all carbon atoms.
Acknowledgments Much of the spectral data cited in this chapter has been published elsewhere and is reproduced here by permission of the respective publishers and authors. To the publishers listed below and to the authors whose names appear in the cited references we express our sincere gratitude. The National Research Council of Canada for 13Cdata taken from Can. J . Chem. on the following compounds: 1-4, 21, 24, 67-69, 71, 72, 81-84, 87-89 (14);15, 76, 77 (21);43, 44, 46 (36):91 (57); 101-104,107-109 (63);105,106 (64).Heyden and Sons, Inc. for 13Cdata taken from Org. Magn. Reson. on the following compounds: 9-11, 22, 23 (20);20 (22);61-66 (41);70 (49); 78-80 (54). Plenum Publishing Corp. for 13Cdata taken from “Carbon-13 N M R Shift Assignments of Amines and Alkaloids” by M. Shamma and D.M. Hindenlang on the following compounds: 17, 51, 52, 58 (7). John Wiley and Sons, Inc. for 13C data taken from “Topics in Carbon-13 NMR Spectroscopy, Vol. 2,” edited by G. C. Levy on the following compounds: 28, 34, 47, 53, 55-57 (6). Pergamon Press, Inc. for 13C data taken from Ter. Lett. and PhyrolOO(61).The American chemistry on the following compounds: 32,33(2.3);35-40,45(32);60(39); Chemical Society for 13C data taken from 1. Org. Chem. on the following compounds: 41,42 (33);73(44); 112 (69).Societa Chimicd Italiana for I3Cdata taken from Gazz. Chim. Ira/. on the following compounds: 49, SO, 54,59 (40). Pharmaceutical Society of Japan for I3C data taken from Chem. Pharm. Bull. and Yakugaku Zasshi on the following compounds: 74, 75 (28); 94-99 (60); 110 (67).
3.
THE
3C-NMR SPECTRA OF ISOQUINOLINE ALKALOIDS
26 1
REFERENCES 1. T. A. Crabb, Anmi. Rep. ~V.2.IRSpecrrosc. 6a. 249 (1975). 2. M. Shamma, “The Isoquinoline Alkaloids: Chemistry and Pharmacology.” Academic Press; New York, 1972. 3. M. Shamma and J. L. Moniot, “Isoquinoline Alkaloids Research 1972-1977.” Plenum, New York, 1978. 4. G . A. Cordell and N. R. Fransuorth, Heterocycles 4, 393 (1976). 5. R. H. F. Manske, ed., “The Alkaloids,” Vol. 5. Academic Press, New York, 1955. See also relevant sections in subsequent and previous volumes of the series. 6. E. Wenkert, B. L. Buckwalter, I . R. Bufitt, M. J. Gasic, H. E. Gottlieb, E. W. Hagaman, F. M. Schell, and P. M. Wovkulick, in “Topics in Carbon-13 NMR Spectroscopy” (G. C. Levy, ed.), Vol. 2, p. 105. Wiley (Interscience), New York, 1976. 7. M. Shamma and D. M. Hindenlang, “Carbon-13 NMR Shift Assignments of Amines and Alkaloids.” Plenum, New York, 1979. 8. J. B. Stothers, “Carbon-13 NMR Spectroscopy.” Academic Press, New York, 1972. 9. G. C. Levy and G. L. Nelson, “Carbon-13 Nuclear Magnetic Resonance for Organic Chemists.” Wiley (Interscience), New York, 1972. 10. G. C. Levy, ed., “Topics in Carbon-I 3 NMR Spectroscopy,” Vols. I , 2. Wiley (Interscience), New York, 1974, 1976, resp. 11. G . A. Gray, Anal. Cbem. 47, 546A (1975). 12. F. W. Wehrli and T. Wirthlin, “Interpretation of Carbon-13 N M R Spectra.” Heyden, New York, 1976. 13. R. J. Abraham and P. Loftus, “Proton and Carbon-13 NMR Spectroscopy-An Integrated Approach.” Heyden, London, 1978. 14. D. W. Hughes, H. L. Holland, and D. B. MacLean, Can. J . Chem. 54, 2252 (1976). 15. S. P. Singh, S. S. Parmar, V. I. Stenberg, and S. A. Farnum, J . Heterocvcl. Cbern. 15, 541 (1978). 16. E. Wenkert, J. S. Bindra, C. Chang, D. W. Cochran, and F. M. Schell, Ace. Cbem. Res. 7, 46 (1974). 17. D. W. Hughes and D. B. MacLean, unpublished results. 18. D. K. Dalling and D. M. Grant, J . Am. Cbem. Soc. 89, 6612 (1967). 19. K. S. Dhami and J. B. Stothers, Can. J . Chem. 44,2855 (1966). 20. C. Verchere, D. Rousselle, and C. Viel, Ory. Magn. Reson. 11: 395 (1978). 21. R. H. F. Manske, R. Rodrigo, H. L. Holland, D. W. Hughes, D. B. MacLean, and J. K. Saunders, Can. J . Chem. 56. 383 (1978). 22. M. Christl, Ory. Magn. Reson. 7, 349 (1975). 23. A. J. Marsaioli, E. A. Ruveda, and F. de A. M. Reis, Pbytochemistry 17, 1655 (1977). 24. R. T. LaLonde, T. N. Donvito, and A. I.-M. TSdl, f a n . J . C/iem. 53;1714(1975). 25. E. Wenkert, H. T. A. Cheung, H. E. Gottlieb, M. C. Koch, A. Rabaron, and M. M. Plat, J . Ory. Cbem. 43, 1099 (1978). 26. L. Castedo, J. M. Saa, R. Suau, and C. Villaverde, Hererocycles 9, 659 (1978). 27. K. Yoshikawa, I. Morishima, J. Kunitomo, M. Ju-ichi, and Y. Yoshida, Cbem. Letf. 961 (1975). 28. N. Takao, K. Iwasa. M. Kamigauchi, and M. Sugiura, Chmi. Pharm. Bull. 25, 1426 (1977). 29. R. A. Newmark and J. R. Hill. J . A m . Chem. Soc. 95, 4435 (1973). 30. E. W. Hagaman, Org. Mayn. Reson. 8, 389 (1976). 31. N. S. Bhacca, J . C. Craig, R. H. F. Manske, S. K . Roy, M. Shamma, and W. A. Slusarchyk, Tetrahedron 22, 1467 (1966). 32. Y. Terui, K . Tori, S. Maeda, and Y . K. Sawa, Ter. Lurr. 2853 (1975). 33. F. 1 . Carroll, C. G. Moreland, G . A. Brine, and J. A. Kepler, J . Org. Cbem. 41, 996 (1976). 34. C . Olieman, L. Maat, and H. C. Beyerman, Red. Trau. Chini. Pays-Bas 97, 31 (1978).
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D. W. HUGHES AND D. B. MACLEAN
35. F. W. Wehrli, J . Chern. Soc., Chem. Commun. 379 (1973): see also G. C. Levy. ed. “Topics in Carbon-I3 NMR Spectroscopy,” Vol. 2. Wiley (Interscience), New York, 1976. 36. H. L. Holland, D. W. Hughes, D. B. MacLean. and R. G. A . Rodrigo. Can. J . Chem. 56, 2467 (1978). 37. I. H. Sadler, J . Chem. Soc., Chem. Commun. 809 (1973). 38. S. Kano, Y . Takahagi, E. Komiyama, T. Yokomatsu, and S. Shibuya, Heterocycles 4, 1013 (1976). 39. A. J. Marsaioli, F. A. M. Reis, A. F. Magalhaes, E. A. Ruveda, and A. M. Kuck, Phytochemistry 18, 165 (1979). 40. G . S. Ricca and C. Casagrande, Gazz. Chim. Ztal. 109, 1 (1979). 41. G. S. Ricca and C. Casagrande, Org. Magn. Reson. 9, 8 (1977). 42. R. Hollenstein and W. von Philipsborn, Helo. Chin?. Acta 55, 2030 (1972). 43. T. Kametani, A. Ujiie, M. Ihara, K. Fukumoto, and H. Koizumi, Heterocycles3,371(1975). 44. T. Kametani, K. Fukumoto, M. Ihara, A. Ujiie, and H. Koizumi, J . Org. Chem. 40, 3280 (1975). 45. C. Tani, N. Nagakura, S. Hattori, and N. Masaki, Chem. Lett. 1081 (1975). 46. T. Kametani, A. Ujiie, M. Ihara, K. Fukumoto, and S.-T. Lu, J . Chem. Soc., Perkin Trans. 1 1218 (1976). 47. T. Kametani, M. Ihara, and T. Honda, Heterocycles 4, 483 (1976). 48. D. Tourwe and G. Van Binst, Heterocycles 9, 507 (1978). 49. C. Moulis, E. Stanislas, and J.-C. Rossi, Org. Magn. Reson. 11, 398 (1978). 50. M. Onda, R. Matsui, and Y. Sugama, Chem. Pharm. Bull. 25,2539 (1977). 51. N. Takao and K. Iwasa, Chem. Pharm. Bull. 24, 3185 (1976). 52. C. K. Yu, D. B. MacLean, R. G. A. Rodrigo, and R. H. F. Manske, Can. J . Chem. 48,3673 (1970). 53. D. Tourwe, G. Van Binst, and T. Kametani, Org. Magn. Reson. 9, 341 (1977). 54. T. T. Nakashima and G. E. Maciel, Org. Magn. Reson. 5, 9 (1973). 55. 0. A. Gansow and W. Schittenhelm, J . A m . Chem. Soc. 93, 4294 (1971). 56. R. Freeman and H. D. W. Hill, J . Magn. Reson. 5, 278 (1971). 57. R. G. A. Rodrigo, R. H. F. Manske, H. L. Holland, and D. B. MacLean, Can. J . Chem. 54, 471 (1976). 58. H. G. Kiryakov, unpublished results. 59. P. R. Srinivasan and R. L. Lichter, Org. Magn. Reson. 8, 198 (1976). 60. N. Takao, K. Iwasa, M. Kamigauchi, and M. Sugiura, Chem. Pharm. Bull. 26, 1880 (1978). 61. L. Castedo, D. Dominguez, J. M. Sai, and R. Suau, T e f . Lett. 2923 (1978). 62. S. McLean and J. Whelan, in “MTP International Review of Science” ( K . Wiesner. ed.), Vol. 9, p.161. University Park Press, Baltimore, Maryland, 1973. 63. D. W. Hughes, B. C. Nalliah, H. L. Holland, and D. B. MacLean, Can. J . Chem. 55, 3304 (1977). 64. H. G. Kiryakov, D. W. Hughes, B. C. Nalliah, and D. B. MacLean, Can. J . Chem. 57,53 (1979). 65. G. W. Buchanan, J. Selwyn. and B. A. Dawson, Can. J . Chem. 57, 3028 (1979). 66. D. Zimmerman, R. Ottinger, J. Reisse, H. Christol, and J. Brugidou, Org. Magn. Reson. 6, 346 (1974). 67. C. Tani and K. Tagahara, J . Pharm. Soc. 97, 93 (1977). 68. B. C. Nalliah and D. B. MacLean, Can. J . Chem. 56, 1378 (1978). 69. M. C. Koch, M. M. Plat, N. Preaux, H. E. Gottlieb, E. W. Hagaman, F. M. Schell, and E. Wenkert, J . Org. Chem. 40, 2836(1975). 70. A. Buzas, R. Cavier, F. Cossais, J.-P. Finet, J.-P. Jacquet, G. Lavielle, and N. Platzer, Helv. Chim. Acta 60, 2122 (1977).
-CHAPTER
4-
THELYTHRACEAEALKALOIDS W . MAREKGOLFBIEWSKI AND JERZY T . WROBEL Depar-tmmr of Chemistry. Unifiersit) of Warsaw. Warsaw. Poland
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Lactonic Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Lactonic Trans-Fused Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Lactonic Cis-Fused Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . General Features of the Stereochemistry of Lactonic Biphenyl Alkaloids . . . D . Chemistry of Lactonic Biphenyl Alkaloids Trans- and Cis-Fused . . . . . . . . . . 111. Lactonic Biphenyl Ether Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..... IV . Simple Phenylquinolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . V . Ester Alkaloids . . . . . . . . . . . . . . . . . . . . . . ............................. VI . Piperidine Metacyciophane Alkaloids . . . ............................. A . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Stereochemistry . . . . . . . . . . . . . . . . . . . . . . ..... ... VII . Quinolizidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Structure and Chemistry B. Stereochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Mass Spectrometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Oxoquinolizidine Metacyclophane Lythraceae Alkaloids . . . . . . . . . . . . . . . . . VIII . Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Early Synthetic Approaches B . Pelletierine-Benzaldehyde Condensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Lactonic Biphenyl Ether Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Lactonic Biphenyl Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Piperidine Metacyclophane Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX . Biosynthesis . . . . . . . . . . . . ......................................... X . Physiological Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
263 266 266 269 273 275 281 284 286 288 288 289 292 294 294 297 299 302 303 303 303 307 310 312 313 319 320
I . Introduction The plants of Lythraceae family are moderately well distributed in different regions of the world. from the tropics to the temperate zones. and are especially abundant in Latin America . The family consists of 22 genera composed of about 500 species. including several economically important THE ALKALOIDS. VOL. XVlIl Copyright 0 1981 by Academic Press Inc . All rights of reproduction in any farm reserved. ISBN 0-12-46951X-3
.
w. MAREK
264
GOEFBIEWSKI AND JERZY T. WROBEL
species of the genera Woodfordia, Lafoensia, Lythrum, Cuphea, Ammannia, Lagerstroemia, and Lawsonia (1). One reason for the early investigation of the Lythraceae plants has been the pronounced physiological activity displayed by the Heimia species. The first isolation of the Lythraceae alkaloids from Decodon fierticillatus (L) Ell was reported by Ferris in 1962 (2). Those were lactonic biphenyl alkaloids (type A) decinine, decodine, verticillatine, decamine, vertine, lactonic ether alcaloids, decaline, and vertaline. This report was followed by isolation of other lactonic alkaloids from Heimia salicifolia Link and Otto by Schwarting et al. ( I , 3) and from Heimia myrtifolia Cham and Schl. and H . salicifolia by Douglas et al. ( 4 ) . In 1967, Fujita et al. (5,6)isolated three piperidine metacyclophane alkaloids (type B) from Lythrum anceps Makino. The third structural variant of the Lythraceae alkaloids, quinolizidine metacyclophane (type C), was
13
HN
Y
*
OR
24
l1 19
1
N
9
8
24
12 23
/
22
\
12 25
120
l9
/
14
21
21
A
2
B
C
isolated by Fujita et al. from Lythrum anceps in 1971 (7, 8) and by Ferris et al. from Lythrum Ianceolatum in 1973 (9).* Forty-three alkaloids have been identified in these plants. Alkaloids were detected only in the aerial parts of the plants. The structures of almost all the bases have been established by chemical and spectroscopic data and/or X-ray analysis. Brief references to the Lythraceae alkaloids have been made in Volumes X, XII, and XIV of this treatise. A short review on the alkaloids from Lythrum anceps was published in Japanese (14). A review on the Lythraceae alkaloids has appeared recently, covering mainly structure elucidation (15). * The numbering system used for lactonic Lythraceae alkaloids is that introduced by Spenser (10) and originally employed by Schopf et al. (11).The system closely corresponds to the that introduced by Fujita et nl. (Z2,13) for metacyclophane alkaloids (B and C). The new system is attractive since the carbon atoms that correspond in biogenetic origin to the three types (A, B, C) maintain corresponding numbers.
13
TABLE I LACTONIC TRANS-FUSED BIPHENYL ALKALOIDS Compound
Formula
Lythrine (1) Decinine (2) Lyfoline (3) Sinine (4) ALC-1 ALC-2 Nesodine ( 5 )
2'
5
2 7 No 5
C26H31N06
C26H29N05 C26H29N05 C26H29N05
M P ( C)
M P of derivatives ('C)
241 -243" 241 -242 222-224
HCl, 325-331 OAc, 172-173 OAC, 197-198
223 -224
0,6-diMe,231-233
217.5-219" 335-345 309-310 190
Decodine (6)
C25H29N05
193- I97
Dehydrodecodine (7)
C25H27N05
181-183
HC1, 330 OAc, 126-128
[.I,
(CHC1,) +32.5 + 40.6 -142
- 174.2 +115.6 + 72.3
OMe, 95-1 10 0 . 0 - d i Ac, 202-203
- 97
I,,,nm
(log E )
285 (4.14) 260 (4.04) 294 (3.86) 269 (3.46) 282 (4.15) 246 (4.04) 292.5 (3.85)
281 (4.10) 258 (3.92) 287 (381) 261 (3.29) 2'77 (4.06) 262.5
Plant" Source
Ref.
b, c, f
I . 4 , 16
a, d, e
2, 17
b
3
b, c, f b b b
20 20 3
16, IN, 19
a b
2, 17 21
Corrected melting point. a, Decodon uerticillatus (L) Ell.; b, Heirnia salicifolia Link and Otto; c, H . rnyrtifolia Cham and Schl.; d, Layrrstroemia iedica L.; e. Lythrurn lanceolatum; f, Layerstrocvnia fauriei.
w.
266
MAREK GOEFBIEWSKI AND JERZY T. WROBEL
11. Lactonic Biphenyl Alkaloids
A. LACTONIC TRANS-FUSED BIPHENYLALKALOIDS Nine alkaloids belong to the trans-fused group: lythrine (l),decinine (2), lyfoline (3),sinine (4), nesodine (5),decodine (6),dehydrodecodine (7),ALC-1, and ALC-2. All of them have a trans-fused quinolizidine ring, a 12-membered lactone ring, and the biphenyl group. The p-hydroxycinnamoyl moiety is 12,13-dihydro in decinine (2)and decodine (6),and 13-hydroxy-12,13-dihydro in sinine (4). The other aromatic ring is oxygenated at C-22 and C-23 in compounds 1-4 or at C-22 and C-21 in compounds 5-7. Alkaloids of this group are listed in Table I (1-4, 16-21). The structure and relative configuration of lythrine (1) was established by chemical and X-ray crystallographic studies of 0-methyllythrine (8) hydrobromide (22). The structure of other alkaloids in the group was assigned from a combination of chemical and spectral studies as well as by correlation with the structure of lythrine. Lythrine (1) was isolated from Heimia salicifolia Link and Otto by Blomster et al. (I), from Heimia myrtifolia Cham and Schl. by Douglas et al. ( 4 ) , and from Lagerstroemia fauriei by Fuji et al. (16).The absolute configuration of the biphenyl system was established by comparison of CD curves of 0-methyldihydrolythrine (9) (0-methyldecinine), a-methyldihydrothebaine (lo), and neodihydrothebaine (11) which agreed in sign and wavelength between 200 and 250 nm. These studies have determined that the chirality of the biphenyl chromophore of all biphenyl alkaloids is the same (23).The relative configurations of all the chiral carbons in lythrine were already known. Establishing the absolute configuration at any one chiral center
@ / H
R R3"
13
9
/ l6
\
llS20,
RZ
OR^
/
\
R2 \
R'
OMe
1 R' = OMe, R 2 = R3 = H 3 R' = OH, R Z = R3 = H 5 R ' = R3 = H, R 2 = OMe 7 R' = H, R 2 = O H , R 3 = H 8 R' = OMe, R Z = H, R 3 = Me
T
/
24
'
H 4 H N
OH 2 R'
= OMe,
R'
OMe
R 2 = R3 = R4 = H
4 R' = OMe, R 2 = R3 = H, R4 = OH 6 R' = R 3 = R4 = H, R Z = OH
9 R'
= OMe,
RZ = R3 = R4 = H, 17-OMe
4.
THE LYTHRACEAE ALKALOIDS
267
Me
OCH, 10 R = M e 11 R = H
should solve the problem of absolute configuration of the quinolizidine part. The absolute configuration at C-5 was assigned by comparison of the sign of the end absorption in the 200-250-nm region of the O R D spectrum of a degradation product (12) of lythrine with L-( -)-2-methylpiperidine and
Me
OMe 12
L-alaninol (24). Decinine (2) was isolated by Ferris from Decodon uerticillutus (2, 171, from Lugerstroemiu indicu L. (25), and from Lythrum lunceolutum (9).This alkaloid was shown to be identical to the dihydro derivative of lythrine (22). Lyfoline (3) was isolated from H . salicifolia by Appel et ul. (3) who established the identity of 0,O-dimethyllyfoline and 0-methyllythrine. On the basis of this fact and biogenetic considerations(oppheno1 coupling), structure 3 was assigned to lyfoline (26). Shine (4) was isolated from H . sulicifolia by Blomster et al. (I). Later, this alkaloid was shown to be identical to lythridine isolated by Douglas et ul. ( 4 )from H . myrtifoliu and by Fuji et ul. (16)from Lagerstroemiu fuuriei. Structure 13 was proposed for this alkaloid on the basis of its mass spectrum and its dehydration to lythrine (18). However, X-ray analysis of sinine (lythridine) methiodide has verified its structure as 4 (19).
268
w. MAREK
GOLEBIEWSKI AND JERZY T. WROBEL
OMe 13
Two new alkaloids, ALC-1 and ALC-2, were isolated from H . salicifolia by Dominquez et al. (20). Mass spectral fragmentation and properties of methyl ethers suggested that they were stereomers of lythrine. Nesodine (5) and dehydrodecodine (7) were isolated from H . salicifolia by Schwarting et al. (3, 21). Decodine (6)was isolated from D. uerticillatus by Ferris (2, 17). These three alkaloids differ from the lythrine-type alkaloids (1-4) in the oxidation pattern of the aromatic nuclei This was established by comparison of UV and NMR spectra and from oxidation studies. Methyl decinine has i,,,293 ( E 7180) and methyldecodine has i,,,285 ( E 4980). The permanganate oxidation of 0-methyldecinine (9)and 0,O-dimethyldecodine (14; structure 2 with R2 = OMe and R' = R2 = R3 = H) yielded 4 3 dimethoxyphthalic acid and 3,4-dimethoxyphthalic acid, respectively, along with 4-methoxyisophthalic and succinic acid (see Scheme 3). Structure 15 was proposed for nesodine by Schwarting et al. (3) on the basis of a broad phenolic hydroxyl absorption at 2700-2500 cm-I and a
15
lack of hydroxyl reactivity. This was attributed to hydrogen bonding to the nitrogen atom. However, an alternative structure 5 was assigned to nesodine by Ferris et al. ( 2 4 ) in agreement with the above data. A phenolic hydroxyl would be unreactive because of steric effects, and its IR absorption represents partial proton transfer from oxygen to nitrogen in the solid state to give an ionic species.
4.
269
THE LYTHRACEAE ALKALOIDS
The methoxylation pattern of lactonic alkaloids was established by a combination of spectral and chemical studies. Methoxyl groups at positions ortho to the biphenyl link (at C-17 or C-21) resonate at relatively high field (6 3.8 - 3.7 ppm) because of shielding by the adjacent aromatic ring. Methoxyl groups at the other positions absorb at 6 3.95 - 3.85 ppm. Formation of an internal ether demonstrates the presence of 17-OH (24).
1-
OMe
OMe
The methoxyl groups of nesodine absorb in the NMR at 6 3.98 and 3.69 ppm. The former signal may be assigned to 22-OMe and the latter to 21-OMe. The data do not eliminate an alternative structure (16) (structure 1 with R' = H, R Z= OH, R3 = Me) for nesodine. Ferris et al. preferred 5 to 16 on the basis of the fact that no naturally occurring Lythraceae alkaloid has a 21-OMe. It would, however, be necessary to confirm this structure by internal ether formation. Decodine (6) exhibits a methoxyl resonance at 6 3.87 ppm in the NMR spectrum which was assigned to a 22-OMe since dimethyl decodine has methoxyl peaks at 3.87, 3.69, and 3.69 ppm. The presence of a 17-OH group was established by formation of an internal ether. In view of the above data structure (6)was assigned to decodine.
B. LACTONIC BIPHENYL CIS-FUSED BIPHENYLALKALOIDS Seven alkaloids belong to this group : vertine (cryogenine) (17), decamine (18), heimidine (19), verticillatine (20), dihydroverticillatine (21), sinicuichine (22), and lagerstroemine (indicamine) (23). All have a cis-fused quinolizidine system, a 12-membered lactone ring, and a biphenyl group oxygenated at C-17, C-22, and C-23 in 17-19 and at C-17, C-21, and C-22 in 20-23. These alkaloids are listed in Table 11. ( I , 2, 16, 17, 25, 27-29). Vertine (17) differs from lythrine (1) only in the configuration at C-5. The same close relationship exists between decamine (18) and decinine (2), heimidine (19) and sinine (4),
TABLE I1 LACTONIC CIS-FUSED BIPHENYL ALKALOIDS Compound Vertine (17)
Formula
MP ("C)
MP of derivatives ('C)
[.ID
(CHCI,)
+ 39
Decamine (18)
245-247 253-255" CZ6H3,NOS 223-224
HCI, 322-323 OAC, 183-185 OAC, 197-198
+61 - 145
Heimidine (19) Verticillatine (20)
CZ6H,,NO, C,,H,,NO,
221-223" 312
HCI, 316-318" HC1.240
+ 1 19b
C,,HZ9NOs
Dihydroverticillatine (21) C,,H,,NO, Sinicuichine (22) Lagerstroemine (23)
-
263
C,,H,9NO, 187-188" CZ6H3,NOs 240"
HCI, 265-266" CH,I, 266
+77.8 - 137
i,,,nm
(log c) Plant' source
285 (4.13) 260 (4.09) 294 (3.87) 268 (3.51) 292 (3.8) 292 (4.07) 260 (3.91) 288 (3.83) 266 (3.57) 285 (4.01) 294(3.68)
Ref.
a, b, c, e
I , 2, 16, 27
a,d
2, 17
b a
28 2, 17
d
25
b d
29 25
'Corrected melting point.
DI.[
of verticillatine hydrochloride measured in methanol. a, Decodon verticillatus (L) Ell. ;b, Heimia salicifolia Link and Otto; c, H . myrtifoliu Cham and Schl. I. d, Lagerstroemiu indicu: e, L.,/uuriei.
4.
THE LYTHRACEAE ALKALOIDS
27 1
U
Q
L A \
OH
OMe OMe
17 R = H, A"
18 R = H 19 R = O H
-U
20 21 22 23 24
OMe
R ' = R 2 = H, A12 R' = R2 = H R' = Me, R 2 = H, A12 R' = Me, R2 = H R' = R 2 = Me, A''
verticillatine (20) and dehydrodecodine (7), dehydroverticillatine (21) and decodine (6), as well as sinicuichine (22) and nesodine (5). These pairs of trans- and cis-fused alkaloids have the same UV spectra and O RD curves and very similar IR (apart from the Bohlmann bands region) and mass spectra. These data demonstrate that both groups have the same skeleton and the same aromatic substitution pattern, as well as identical configuration at the biphenyl linkage. Vertine (17) was first isolated by Ferris from Decodon verticillutus (2) and then by Douglas et al. from Heimia myrtijolia and H. salicifoliu (4). Independently, Blomster et al. isolated cryogenine from H . salicifolia (1);its identity with vertine was shown later (22). This alkaloid was extracted recently by Fuji et al. (16) from Lagerstroemiu fauriei. Enantiomerism of lythrine (1) and vertine (17) at C-5 was established as discussed in Section II,C by spectroscopic and chemical criteria and conclusively confirmed by two series of degradations carried out on both alkaloids. In the first series (see Scheme 2) lythrine (1) was transformed to N-methylpiperidine (44). The optical rotation was -31' in 43 and +31' in the corresponding derivative of vertine. The plain positive OR D curve of the 0-methyl derivative of the latter compound corresponded to those of D(+ )-coniine and D-( )-2-methylpiperidine. Comparison of physical properties of compound 41 (in Scheme 2 ) with the corresponding product from vertine showed that both compounds were diastereomers as predicted (24). There were significant differences in the NMR and IR spectra, and the melting point of 41 (84-85') was depressed (77-92") on admixture with the corresponding derivative from vertine. In the second degradation shown for dihydrolythrine (see Scheme 1 ) both lythrine and vertine were converted to N-nitrosamine derivatives (38) and an
+
272
w. MAREK
WFBIEWSKI
AND JERZY T. WROBEL
epimer at C-5, respectively. ORD and CD effects of the biphenyl system and the N-nitroso group can be observedindependently as the absorption maxima of both chromophores are sufficiently removed from one another [290 mm ( E 7000) and 350 nm ( E 200), respectively]. The Cotton effect at 350 nm reflects the configuration at C-5. The ORD and CD curves are opposite in sign in this region, thus confirming that the two types of alkaloids differ in configuration at C-5 (24). Decamine (18) was isolated by Ferris from D. verticiffatus (2) and from Lagerstroemia indica by Ferris et a f . (25). Ferris established the identity of decamine with dihydrovertine. Heimidine (19), a minor alkaloid isolated from Heimia saficifofia by El-Olemy et al. (28),is hydroxydihydrovertine. Dehydration of heimidine on alumina gives vertine (17). Structure 19 was assigned on the basis of similar mass, NMR (aromatic region), and Ik spectra (apart from the lack of Bohlmann bands) to those of sinine (4). The absolute configuration of the C-13 OH group was not established. Verticillatine (20) was isolated by Ferris from Decodon verticiflatus (2). Dihydroverticillatine (21) and lagerstroemine (23) were isolated by Ferris et a f . from Lagerstroemia indica (25)and sinicuichine (22) by Blomster et al. from H . saficifolia (1).Lagerstroemine was also detected in Plantago psylium (30, 31). These four alkaloids have the same aromatic oxygenation pattern as decodine (6)and nesodine (5). The methoxylation pattern of verticillatine was established in the same way as described for decodine. Enantiomerism of the dimethyl ethers of dihydroverticillatine (25) and decodine at C-5 was demonstrated by a parallel series of degradations to N-nitroso derivatives
OMe 25
OMe 26a 26b 26c 26d
R = Me R = CN R =H R=NO
4.
273
THE LYTHRACEAE ALKALOIDS
shown for 25 (cf Scheme 1). The ORD curves of 26d and the corresponding product from decodine show extrema opposite in sign at 350 nm (24). 0methylsinicuichine proved to be identical to 0,O-dimethylverticillatine (24). (29). Lagerstroemine (23), on methylation with diazomethane, afforded 0,Odimethyldihydroverticillatine (25). Lagerstroemine has two methoxyl and one phenolic hydroxyl group. The methoxylation pattern was established by conversion of the alkaloid to the benzopyran (27) via the methiodide of the diol (28). Me
I
OMe
OMe 21
28
C. GENERAL FEATURES OF THE STEREOCHEMISTRY OF LACTONIC BIPHENYL ALKALOIDS The Lythraceae alkaloids have four centers of chirality-three chiral carbon atoms at the quinolizidine ring C-1, C-3, and C-5, and the dissymetric biphenyl or biphenyl ether link. The chirality of the biphenyl system in all alkaloids of the group is the same. The chirality of the biphenyl ether link is also the same for all alkaloids in this class (22,23, 32). All lactonic alkaloids have the same absolute configuration at C-1 and at C-3. The C-1 phenyl substituent is always equatorial. The C-1 hydrogen appears in the N M R spectra as a doublet of doublets with large (10-12 Hz) and small (1-2 Hz) coupling constants. The coupling requires that this hydrogen be axially oriented. The lactonic oxygen at C-3 is always axial. The C-3 hydrogen absorbs at 6 5.0-5.4 ppm with the half-height width of 7.5-9 Hz. This result indicates that H-3 is equatorial in all alkaloids (24). The axial nature of the C-2 oxygen substituent was confirmed by its epimerization to the equatorial configuration. Treatment of methyldecinine
274
w. MAREK
G ~ E F B I E W S K IAND JERZY T. W R ~ B E L
1 OMe 29
and methyldecamine with phenylmagnesium bromide followed by dehydration with formic acid yielded 29. The acetate of 29 showed an H-2 signal with a half-height width of 13-14 Hz for trans- as well as cis-fused alkaloids. This result indicates the axial configuration of this proton. The quinolizidine ring of Lythraceae alkaloids can exist in both trans and cis configurations. Both forms are clearly identifiable by combination of spectral and chemical criteria. First, Bohlmann bands are present in the IR spectra of trans-fused alkaloids and absent in the spectra of cis forms (33, 34). When the lactone ring of the trans alkaloids is cleaved by lithium aluminium hydride the Bohlmann bands are still present, but they do not appear on cleavage of the lactone ring in the cis alkaloids. Hence, the conformation of the quinolizidine ring remains unchanged in the products of lactone opening in both trans and cis bases, confirming the equatorial configuration of phenyl group. Second, the diagnostic benzylic proton at C-1 absorbs in lower field in the NMR spectra of cis-fused alkaloids (6 3.324.60 ppm) than in the corresponding trans isomers (6 2.95-3.75 ppm). This difference for the natural alkaloids (or their derivatives) is equal to 0.371.O ppm (24).These results correspond well with the data of Bohlmann et al. (35) for simple 4-phenylquinolizidines where resonance of H-4 is at lower field in the cis-fused isomer. The NMR spectra of the methiodides showed a similar relationship. NMethyl resonances of cis-fused alkaloids are about 0.4 ppm at lower field than in the corresponding trans forms. The NMR spectra of N-oxides of biphenyl lactonic alkaloids (0-methyl and 0-acetyl derivatives) show the signal of low-field aromatic proton H-24 at 6 8.1-8.7 ppm. The Dreiding models indicate that this proton is deshielded by the N-0 group. H-24 resonates in the cis-fused derivatives at 0.13-0.28 pprn lower field than in the corresponding trans forms (24).The same relation is observed in the NMR spectra of biphenyl ether alkaloids where H-24 absorbs at 6 7.6-8.2 ppm (25, 36).
4.
275
THE LYTHRACEAE ALKALOIDS
The stereochemistry at C-5 is also reflected by relative rates of quarternization. The cis-fused bases react much faster than the trans stereomers. Inspection of models shows that the trans-quinolizidine has four axial hydrogens blocking axial attack of the alkylating agent whereas the cisquinolizidine shows only two 1,3-diaxial interactions (24, 37, 38).
D. THECHEMISTRY OF LACTONIC BIPHENYLALKALOIDS TRANSAND CIS-FUSED 1. Cleavage of the Lactone Ring Hydrolysis of the lactone ring in dimethyldecodine (14) was carried out by prolonged refluxing of the alkaloid in aqueous methanolic sodium hydroxide (17). Ferris reported that the starting material could be recovered in 18% yield using thionyl chloride in chloroform. However, in the total synthesis of the biphenyl ether alkaloid decaline, the yield of lactonization of the corresponding hydroxyacid did not exceed 5% (39,40). This reaction was usually carried out in much better yield in benzene with p-toluenesulfonic acid (39). The lactone ring of dimethylodecodine (14) was cleaved by lithium aluminium hydride reduction to the corresponding diol. The same diol was formed from the lithium aluminium hydride reduction of the hydroxyester prepared from the product of alkaline hydrolysis (I7). Reductive cleavage of the lactone in methyldecinine (9)followed by formic acid dehydration afforded the olefin (29).
(i)PhMgBr (ii) HCO,H+
I
OMe 9
OMe 29
Cleavage of the lactone was observed in methylation of phenolic hydroxyl group. In the alkylation of lythrine with dimethyl sulfate the major product was the betaine (30). In the case of dihydrolythrine (decinine) the lactone ring was not opened and the product was isolated as the 0, N-dimethylmethyl sulfate salt (31)(27).
276
W . MAREK W E B I E W S K I A N D JERZY T. WROBEL
1-
Me,SO,
MeOSO;
I
I
OMe
OMe 31
30
Methylation of the phenolic OH in the product of Emde degradation of decinine (32) with trimethylanilinium hydroxide (24) resulted in cleavage of the lactone ring to yield derivative 33. Me
Me
OMe 32
OMe 33
2. Degradation of the Quinolizidine Ring The quinolizidine system of Lythrdceae alkaloids does not lend itself very readily to the reactions commonly employed to degrade the carbon skeleton of a molecule. Hofmann degradation of several decodine derivatives was unsuccessful ( 2 4 ) , and the attempted Hofmann degradation of lythrine yielded a complex mixture of products that failed to yield a definable compound. It was possible to cleave the quinolizidine ring in decinine methiodide via an Emde degradation where, as expected, the bond between nitrogen and benzylic carbon was ruptured to yield 29. This reaction proceeds most efficiently when a free phenolic hydroxyl group is present. Presumably, the negative charge on the phenoxide anion protects the biphenyl system from reduction (24). The lactone ring in decinine (2) was reduced to the cyclic ether (34)with diborane generated from sodium borohydride and boron trifluoride. The Emde degradation of (34) afforded a piperidine derivative (3%). The Cyanogen bromide N-demethylation of the methyl ether (3Sb)followed by
4. THE
277
LYTHRACEAE ALKALOIDS
ye
H
2 -
NaBH, BF,
(ii)
BrCN LAH
(1111
HNO,
(I) (1)
Me0
I
I
OMe
OMe
34
35a R = H
35b R
=
Me
OMMe 36 R = C N 37 R = H 38 R = N O
SCHEME 1
lithium aluminium reduction resulted in the secondary amine (37).Treatment with nitrous acid yielded crystalline N-nitrosamine derivatives in both trans and cis series (Scheme 1) (24). A further interesting cleavage of the quinolizidine ring in a degradation product of lythrine (1) proceeded with an internal SN2 displacement of the quarternary nitrogen by the C-17 phenoxide anion to chroman (41). The N-propyl derivative (40) was prepared by catalytic hydrogenolysis of the cinnamyl alcohol (39) resulting from the LAH reduction of lythrine (1). Higher yields were obtained by using lithium aluminium hydride-aluminium trichloride directly on lythrine or by hydrogenolysis of 39 with sodiumammonia-ethanol followed by catalytic hydrogenation. The latter procedure was more efficient as it did not involve separation of the reaction products from aluminium salts. The hydroxyl group of the chroman (41) was eliminated via the mesyl derivative to yield a trans olefin (42). Hydrogenolysis of the allylic benzylic ether of 42 followed by hydrogenation of the olefin afforded 43 (Scheme 2) (24).
278
1 -
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MAREK GQLFBIEWSKI AND JERZY T. WROBEL
LAH
($1
Na-EtOH NH,
(iij HI,'Pt
OMc
OMc
40
39
41
Me
Me
(i) Na-EtOHiNH, (1;)
H, Pt
[iii) PhNMe,OH-
0Me
43 R = H 44 R = M e
42
SCHEME 2
3. Oxidation N-oxides of alkaloids could be easily prepared using m-chloroperbenzoic or peracetic acids (17, 24). On pyrolysis of the N-oxide of dimethylodecodine a mixture of products was obtained, and only dimethyldecodine (14) could be characterized.
4.
279
THE LYTHRACEAE ALKALOIDS
Attempts at mild oxidation of dimethyldecodine (14) to the lactam with neutral potassium permanganate in acetone or chromic anhydride in pyridine were unsuccessful and only the starting material was recovered. Vigorous permanganate oxidation of dimethyldecodine gave 4-methoxyisophthalic acid (45) and 3,4-dimethoxyphthalic acid (a), isolated as the anhydride, along with succinic acid. The same reaction with decinine afforded 45 and 4,5-dimethoxyphthalic acid (47) (17). Oxidation of lythrine (1) and vertine (17) afforded lactone (48) along with (47) (Scheme 3) (27).
OMe
OMe
OMe 45
14
-
46
CO,H I
KMnO,
OMe
OMe OMe 45
9
47
H
KMnO, ___f
CO,H /
'OMe
1
OMe 48
1
SCHEME 3
TABLE 111 LACTONIC BIPHENYL ETHERALKALOIDS Compound
Formula
MP ("C)
Decaline (49)
CZ6H31N0,
102-118
Demethyldecaline (50) Vertaline (51)
C, H, NO, C,6H,,NO,
Demethylvertaline (52) Lagerine (53)
C2SH29N0S
Methyllagerine (54) Heimine a
,
C2,HZ9NO,
C26H31N05
C,6H,,N05
-
[c(ID(CHCI,) ~
136 -
194-196
- 170
120-160 210
- 184
~
247.5-249
-
-
+43
i.,,,nm
(log E )
Plant" source
Ref.
a
2, 17, 36, 41
a a
36 2, 36, 41
a C
36 25
C
25, 42
b
1
293 (3.79) 264 (3.28) ~
293 (3.81) 264 (3.29) ~
275 (3.49) 232.5 (4.31) ~
~
a, Decodon uerticillatus (L) Ell; b, Heimia salicifolia Link and Otto; c, Lagerstroeniia indica L.
4.
281
THE LYTHRACEAE ALKALOIDS
4. Etherification of Phenolic Hydroxyl Group Phenolic methyl ethers were usually prepared by treatment of the alkaloid with dimethyl sulfate and sodium hydroxide or with diazomethane (17). In the first case a side reaction was N-methylation or even cleavage of the lactone (3). In decodine (6) the C-17 OH group was methylated on treatment with ethereal diazomethane. The hindered C-21 OH group was alkylated with methanolic CH,N, (17).
111. Lactonic Biphenyl Ether Alkaloids
Six alkaloids belong to this group : decaline (49), demethyldecaline (50), vertaline (51), demethylvertaline (52), lagerine (53),and methyllagerine (54). In the first two alkaloids the quinolizidine ring is trans-fused and in the latter four it is cis-fused. These compounds are listed in Table I11 (1, 2, 17, 25, 36, 41, 4 2 ) . Decaline and vertaline were isolated by Ferris from Decodon verticillatus (2). An X-ray study of vertaline hydrobromide established the structure and absolute stereochemistry of vertaline as shown in 51 (32, 43). The relative stereochemistry at C-1 and C-3 in all alkaloids in the group is the same as in the biphenyl alkaloids; for example, the biphenyl ether and lactone group are linked to the quinolizidine ring in axial and equatorial configurations, respectively. On the basis of the previously described spectroscopic and chemical criteria (Section I1,C) Ferris et al. (36) showed that decaline had the same structure as vertaline with the exception of opposite configuration at C-5. This assignment was verified by degradation studies. Sodium-ammonia
OR2 OMe 49 50 51 52
R' = BH, R2 = Me R' R' R'
= BH, = rH,
RZ = H R 2 = Me = aH, R 2 = H
yooq TOT OMe
53 R = H 54 R = M e
RO 55 R = H 56 R = M e
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282
MAREK GOLEBIEWSKI AND JERZY T. W R ~ B E L
reduction of the methiodides of decaline and vertaline yielded 3-phenylpropanol and N-methylpiperidine derivatives (57 for decaline) resulting from cleavage of three bonds. Decaline and vertaline were not degraded under the conditions wherein methiodides were cleaved. Consequently,, the cleavage of the C,-N bond must trigger the scission of the biphenyl ether and ester bonds. A mechanism proposed by Ferris et al. (36) is shown for the case of decaline methiodide.
Y
O
M
Y
e
O
M
e
OMe
OMe 49
Me
I!
Me
-
4r
2e 3H
OMe
7z OMe Me
I!
L
O
H
RoA I
OMe 57 R = H 58 R = Me
The optical rotation of 58 was -36' and the corresponding product from vertaline showed [.ID +59". This result demonstrated that the pro-
4.
283
THE LYTHRACEAE ALKALOIDS
ducts were diastereomers. Consequently, these data confirmed the assignment of absolute structure 49 for decaline. The de-0-methyl derivatives of decaline and vertaline were isolated by Ferris et ul. from D. uerticillatus (36,41)and assigned structures 50 and 52, respectively, on biogenetic grounds. The proposed structure for demethyldecaline was confirmed by total synthesis (44). Lagerine was isolated by Ferris et al. from Lagerstroemiu indicu (17), and methyllagerine was isolated by Hanaoka et al. (42) from L. indica grown in Japan. The structure of lagerine is unique since it was not possible to convert this base to any known Lythraceae alkaloid. The basic skeletons of 0-methyllagerine and vertaline are the same since the mass spectra of the two alkaloids are almost identical. The alkaloids differ in the substitution pattern on the biphenyl ether chromophore, a fact which is reflected in the UV spectra. Structure 55 was proposed for lagerine by Ferris et al. (25) mainly on the basis of sodium-ammonia cleavage of 0-methyllagerine methiodide. This reaction afforded p-methoxyhydrocinnamyl alcohol (59) and the Nmethylpiperidine, for which structure 60 was proposed by a combination of chemical and spectral methods.
l+ Rob \
Me0
OMe 55 R = H 56 R = Me
59
60 R = H 61 R = M e
The same N-methylpiperidine derivative was obtained by sodiumammonia degradation of 0-acetyllagerine methiodide. It was difficult, however, to distinguish the NMR spectra of 61 from an isomer with 4alkylpyrocatechol structure. This possibility could not be excluded by analysis of UV spectrum of the N-oxide of 61. The relative stereochemistry of lagerine is the same as that of vertaline. Compound 55, proposed as the structure of lagerine, was synthesized by Hanaoka et al. (45)and shown not to be identical to the natural alkaloid. On the basis of the NMR spectrum and biogenetic considerations, structure 53 are assigned to lagerine and confirmed by total synthesis (42, 46). Therefore, the Emde degradation of 0-methyllagerine can be depicted as follows
284
w. MAREK
GOLFBIEWSKI AND JERZY T. W R ~ B E L
(the reaction must proceed with methyl transfer from C-21 to C-17 oxygens to yield 59 and 62): Me
HO OMe
Q
OMe
OMe
59
54
62
Heimine was isolated by Schwarting et al. (1) from Heinzia saliciJblia, but its structure has not been established.
1V. Simple Phenylquinolizidine Alkaloids
Extracts from young seedlings of Heirnia salicifolia plants were the source of three minor alkaloids. Rother and Schwarting have isolated two isomeric 1-(12-hydroxy-l3-methoxy)phenylquinolizid-3-ols (63a) and (@a) and detected 1-(12-hydroxy- 13-methoxy)phenylquinolizid-3-one(65a or 65b or both) (47, 48).* These alkaloids were absent in extracts of plants obtained at later stages of growth (49). These three compounds are intermediates in the current biogenetic hypothesis.
OMe 63a R = H 63b R = Me
OMe 64a 64b 64c 64d 64e
R' = R' = H R1 = H. R' = Me R ' = .4c. R' = Me R' = R' = AC R ' = Ac, R' = H
OMe
H 6Sa
{
=
BH
=
XH
H 65b
{
* The absolute stereochemistry of nonlactonic alkaloids (63-70) has not been established
TABLE IV SIMPLE QUINOLIZIDINE A N D ESTERALKALOIDS Compound Demethyllasubine-I (64a)" Demethyllasubine-II(63a) Lasubine-I (64b) Lasubine-II(63b) Abresoline (66)
Formula
MP ("C) -
C16H23N03 16
2
3
C,,HZ3N03 C17H23N03 C26H31N06
-
120.5-122 -
[.ID
(MeOH) ~
-_
-
- 8.8 - 34.7 -
279.5 (3.5) 279.5 (3.6) 284 (3.73) 323 (3.76)
-
-
C25HZ9N05 C28H35N06
f68.0
Subcosine-I1 (67)
c2 8
+85.3
35N06
nm (log E)
-
Demethoxyabresoline (68) 10-Epidemethoxyabresoline(70) Subcosine-I (69)
c 2 5H29N05
I.,,,
~
We use the name demethyllasubine-I and -11 for quinolizidols 64a and 65b. a, Heirnia salicifolia Link and Otto; b, Lagerstroemia subcosiaia Koehne.
232.5 (4.7) 287.5 (4.1) 323.5 (4.2) 232.5 (4.3) 287.0 (4.1) 323.0 (4.2)
Planth source
Ref. 47.48 48 16 16
SO 51 51 16
16
286
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MAREK ~ ~ E F B I E W S KAND I JERZY T. WROBEL
The structures of both quinolizidols (63a and 64a) have been established by analysis of NMR, IR, and MS data and by comparison with synthetic compounds. The hydroxyl group is axial in the trans-fused quinolizidol (63a) and the phenyl group is equatorial. The NMR signal of H-3 in 63a appears as multiplet at 6 4.1 ppm with a 1/4-height (W1,,) band-width of about 11 Hz. In the synthetic equatorial epimer this proton absorbs at 6 3.6 ppm with W, 32 Hz. The NMR spectrum of the cis-fused quinolizidol(64a) and its derivatives showed the presence of an equilibrium mixture of conformers where the form with an axial OH and equatorial phenyl group was only a minor component. The signal of H-1 in 64b-d appears at 6 4.0-4.1 ppm as a triplet with a coupling constant of 4-5 Hz and W1,, of 13-14 Hz. H-3 was in part unresolved from H-1 in 64a,e and in 64c,d was a broad multiplet (a triplet of triplets with J 8-9 and 4.5 Hz) with W,,, equal to 25-28 Hz. These couplings of H-1 and H-3 favor that conformation with an axial phenyl and an equatorial hydroxyl. Compound 64a was synthesized by reduction of cis-fused quinolizidone (65b) with NaBH, to yield mixture of 64a and its epimer in 1.3: 1 ratio or with lithium tri-sec-butylborohydride, where 65% conversion to axial alcohol was observed. The identity of natural and synthetic quinolizidols (63a and 64a) was conclussively established by radioactive dilution analysis. This technique made it possible to detect 1-( 12-hydroxy-13-methoxy)phenylquinolizid-3one (65a or 65b or both) in the seedlings of Heimiu sulicifoliu. Fuji et al. (16) have recently isolated lasubine-I (64b) and lasubine-I1 (63b) from Lugerstroemiu subcostutu Koehne. The structures of these alkaloids have been established by correlation with synthetic compounds (63a and 64a) as well as by analysis of IR, PMR, I3C-NMR, and mass spectra. These alkaloids are listed in Table IV (16,47,48,50,51).
,
V. Ester Alkaloids Three minor ester alkaloids, abresoline (66),demethoxyabresoline (68), and 5-epidemethoxyabresoline (70), have been isolated from Heimiu sulicifoliu by Schwarting et ul. (51). Abresoline" on basic hydrolysis gave trans-4-hydroxy-3-methoxycinnamic acid (ferulic acid) and the quinolizidol(63a). The presence of these units was also apparent in the mass spectrum of the alkaloid which showed strong * Abresoline (66) was prepared recently by Quick and Ramachandra by transesterification of MB-methoxyethoxymethyl (MEM) ether of methyl ferulate with M E M derivative of quinolizidol (63a)and cleavage of protective groups with trifluoroacetic acid (10.3).
4.
287
THE LYTHRACEAE ALKALOIDS
0;: Rlo Q
R 1l 6 \ 17
ORZ
66 R' 67 R' 68 R'
= OMe, = OMe, =
OR^
zQ::
\
OMe
RZ = R3 = H RZ = R3 = Me
RZ = R 3 = H
ORZ
69 70 70a 70b
R' R' R' R'
'
OMe
= OMe, R Z = R3 = = R2 = R3 = H = H, =
OR^
H
R Z = R 3 = CH,COC,H,Br(p)
R 3 = H, R2 = CH,COC,H,Br(p)
fragment ions m/e 276 and 177, corresponding to 63a and ferulic acid. The quinolizidine ring of abresoline is trans-fused as indicated by Bohlmann bands and NMR absorption of benzylic proton H-1 at 6 3.22 ppm as double doublet ( J = 10, 1 Hz). The equatorial orientation of H-3 was deduced from NMR absorption at 6 5.18 ppm with a half-height width of 8 Hz. The proposed structure was confirmed by synthesis of its dihydroderivative from isovanillin, pelletierine, and methyl benzyloxyferulate (50). Demethoxyabresoline (67) was obtained as a noncrystalline solid. Spectroscopic investigation revealed the presence of a phenolic OH, a l-phenylquinolizidine system, and a trans-cinnamyl group. The stereochemistry at C-1, C-3, and C-5 was the same as in abresoline. The molecular formula C,,H,,NO, was established by mass spectrometry. The presence of fragment ions at mje 259 (M - 164) and 258 was characteristic of p-hydroxycinnamyl esters of the phenylquinolizidol (63a). The assigned structure 68 was confirmed by basic hydrolysis to 63a and p-hydroxycinnamic acid as well as by catalytic hydrogenation to a known dihydro derivative (52). 5-Epidemethoxyabresoline (70) shows a mass spectrum similar to that of its stereoisomer 68. The absence of Bohlmann bands and the NMR chemical shift of H-1 at 6 4.0 ppm demonstrate the presence of cis-quinolizidine system. Trans-cis isomerization of the olefinic bond of 70 has been observed on silica gel, and the conversion was accelerated by UV light, The structure of 70 was established by synthesis. Cis-fused quinolizidol 64a in which the phenolic OH was protected with a p-bromophenacyl group was esterified with trans-4-bromophenacylcinnamic acid in the presence of p-toluenesulfonic acid to yield a mixture of two major esters (70a and 70b). Removal of the protective group from both esters gave 5-epidemethoxyabresoline. Two minor ester alkaloids, subcosine-I (69) and subcodine-I1 (67), have been isolated recently by Fuji et al. (16) from Lagerstruemia subcostata.
288
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MAREK ~ ~ E E B I E W S KAND I JERZY T. WROBEL
The structure of these bases has been elucidated by spectroscopic and chemical methods. A basic hydrolysis of both subcosine-I and subcosine-I1 resulted in 3,4-dimethoxycinnamic acid as well as lasubine-I for 69 and lasubine-I1 for alkaloid 67. Occurrence of simple quinolizidone alkaloids, ester alkaloids, and lactonic alkaloids in the same Heimia salicifolia plant species provides further evidence in support of current biogenetic hypothesis.
VI. Piperidine Metacyclophane Alkaloids
A. INTRODUCTION Three piperidine alkaloids; lythranine (72), lythranidine (73), and lythramine (74) belong to this group. All have a piperidine ring disubstituted at two c( positions by two aralkyl C,-C, groups joined by a biphenyl bond. Lythramine contains an extra 0,N-methylene bridge. The alkaloids were isolated from Lythrwn anceps Makino by extraction with buffers (72 pH 4.8, 73 pH 6.0, 74 1N HC1) (5,6). These alkaloids are listed in Table V. TABLE V PIPERIDINE METACYCLOPHANE ALKALOIDS Compound
Formula
Lythranine (72)
C,,H,,NO,
Lythranidine (73) Lythramine (74)
C,,H,,NO,
a
C,,H,,NO,
MP ("') -
~
150-152
MP of derivatives
[aID (MeOH)
I,,,nm (log E)
Plant source'
Ref.
HCI, 189-191
-
278 (3.62)
a
5-7, 12
AcOH, 154-156 AcOH, 136-139
-
289(3.83)
a
5-7, 12
-85
287(3.80)
a
5-7, 12
OMe, 169-171
a, Lythrum anceps Makino.
The functional groups of these alkaloids were identified by analysis of spectral and chemical data. The major alkaloid of the group, lythranine (72), was shown to contain a secondary amine group, a secondary acetoxyl group, a phenolic hydroxyl, an aromatic methoxyl group, and six aromatic hydrogens. Lythranine was found to be an 0-acetyl derivative of lythranidine (73) by a sequence of hydrolysis and acetylation reactions. Lythramine (74) was obtained on treatment of lythranine with formalin. The presence of a methylene bridge between a hydroxyl and an amine group of lythramine was confirmed by lithium aluminium hydride reduction of U-methyldeacetyllythramine (75) to N,O-dimethyllythranidine(77) (7).
4.
THE LYTHRACEAE ALKALOIDS
289
H
72 R' = R 3 = H, R Z = AC 73 R' = R Z = R3 = H 76 R1 = R Z = H, R 3 = Me 77 R' = R3 = Me, R Z = H
74 R' = Ac, RZ = H 75 R1 = H, R2 = Me
B. CHEMISTRY Methylation of lythranidine (73) with diazomethane in methanol afforded 0-methyllythranidine (76). 0,N-Dimethyllythranidine (77) was formed on prolonged standing. Lythramine (74), on methylation with the same reagent, gave 0-methyllythramine and 0-methyldeacetyllythramine (75) (12). Acetylation of lythramine at room temperature gave O,O-diacetyllythranine, whereas the same reaction at 45" gave an amorphous O,O,N-triacetate. Acetylation of Iythranidine at room temperature afforded an O,O,O-triacetyl derivative, identical to 0,O-diacetyllythranine (7). Mild oxidation of 0-methyllythranidine (76) with permanganate under alkaline conditions afforded the symmetrically substituted biphenyl dicarboxylate characterized as its dimethyl ester 78. This reaction established the presence of a 2,2',5,5'-tetrasubstituted biphenyl system in the alkaloids. Oxidation of 0-methyldeacetyllythramine (75) with chromic anhydridepyridine complex yielded the ketone (79) which exchanged four hydrogens on treatment with sodium deuteroxide in deuterium oxide and deuteromethanol (12). Dehydrogenation of lythranine at 260" on palladium black followed by oxidation with permanganate gave a mixture of carboxylic acids. The
78
79
290
w. MAREK
GOLEBIEWSKI AND JERZY T. WROBEL
methyl esters were separated into neutral and basic fractions. From the basic fraction a dimethyl dipicolinate was isolated. Thus, the presence of a piperidine ring in these alkaloids was demonstrated (12). Hofmann degradation of 0,N-dimethyllythranidine (77) methiodide followed by catalytic hydrogenation gave a product whose methiodide underwent the same sequence of reactions yielding de-N-product 80 (mp 133.5-1 35'). Oxidation with chromic anhydride in pyridine afforded a diketone 81 (mp 116-1 18').
n
J
"
81
In the NMR spectrum of 81 the (2-12 and C-13 (C-1 and C-2) methylene protons showed an A,B,-type signal at 6 2.83 ppm. Another active methylene at C-10 (C-4) absorbed as a triplet at 6 2.32 ppm. The remaining protons resonated at 6 1.O-1.8 ppm. Compound 81 was oxidized with permangamate under the alkaline conditions to yield a mixture of C6 to C9 dicarboxylic acids. These were analyzed as methyl esters by gas chromatography. Thus, the presence in the molecule of seven methylene groups between the carbonyl groups was established. Refluxing 0-methyllythranidine (or lythranidine acetate) with ethyl orthoformate yielded an amidoacetal(82). The new singlet signal of the one central proton appeared at 6 5.26 ppm in the NMR spectrum of the product.
4.
29 1
THE LYTHRACEAE ALKALOIDS
82
The reaction of O,N,-dimethyllythranidine (77) with phosphoryl chloride in pyridine followed by catalytic hydrogenation gave a crystalline chloro compound (83) as a major product and an amorphous dichloroderivative (84). Both products underwent hydrogenolysis of the chlorine atom with sodium in iso- and n-propyl alcohol, respectively, to yield bisdeoxy-0,Ndimethyllythranidine (85). HO
17
83 R' = C1, R2 = H 84 R' = R2 = C1
85
Compound 85 was dehydrogenated at 300" over palladium black under reduced pressure to a pyridine derivative 96 which was independently synthesized by the following route. Anisaldehyde (86)was treated with iodine monochloride in acetic acid to give the 3-iodo derivative 87. The Ullmann reaction of 87 in the presence of copper bronze afforded biphenyldialdehyde (88). The Knoevenagel condensation with malonic acid yielded the unsaturated diacid 91. The methyl ester (92)was also prepared alternatively by a condensation of 3-iodoanisaldehyde with malonic acid to give the iodocinnamic acid (89), followed by the Ullmann reaction of its methyl ester (90). The cinnamic diester was catalytically hydrogenated and reduced with lithium aluminium hydride to the diol94. Reaction with phosphoryl chloride afforded an amorphous dichloro derivative (95) which was condensed with 2,6-lutidine in liquid ammonia in the presence of potassium amide to yield pyridine the derivative 96 in 27% yield (53).
w.
292
MAREK GOL~BIEWSKIAND JERZY T. WROBEL
+
h
OMe
C
H
OMe
86 R = H 87 R = I
bI
CO,R
0
88
I
CO,R
OMe
89 R = H 90 R = M e
91 R = H 92 R = M e
\
85
96
93 R = C0,Me 94 R = C H , O H 95 R = CH,C1
C. STEREOCHEMISTRY Piperidine-type metacyclophane alkaloids have four chiral carbon atoms : C-3, C-5, C-9, and C-11. With 96 in hand, Fujita et nf. hydrogenated its pyridine ring over Adams catalyst and Raney nickel in order to define the relative stereochemistry of C-5 and C-9. They obtained a single crystalline hexahydro derivative in quantitative yield. Catalytic hydrogenation of substituted pyridines generally results in cis products. Therefore, one can assume the cis relationship of C-5 and C-9 hydrogens in the foregoing
4. THE
293
LYTHRACEAE ALKALOIDS
piperidine derivative (97). Compound 97 was converted to its N-methyl derivative 98 which turned out to be different from the bisdeoxy-N,Odimethyllythranidine (85). This suggested a trans relationship for the analyzed protons in 85 and in the three piperidine alkaloids. The NMR data supported this conclusion.
91 R = H 98 R = M e
98a
85a
The chemical shift of the piperidine protons CI to the nitrogen in the synthetic cis compound 98 was lower (6 2.30 ppm) than in the trans product of degradation of lythranidine (6 2.68 ppm) (54). In the dominant conformation of N-methylpiperidine the methyl group is equatorial and the lone pair is axial. Therefore, the conformation of the piperidine ring in the cis form (98) is presumably 98a, and 85a reflects the dominant conformation in the trans isomer. In the cis stereomer 98a there are two hydrogen atoms in a trans-diaxial relationship to the free electron pair on nitrogen, and in the trans form 85a there is only one such hydrogen. Piperidine is conformationally a labile system, and the chemical shift of the protons a to nitrogen takes an average value. The greater the number of trans-diaxial protons, the lower the chemical shift of the cx hydrogens atoms. In the quinolizidines the signal of the a axial proton appears at 0.5-1 ppm higher field than the signal of equatorial r protons (55, 56). The observed chemical shifts of r protons in 85 and 98 were consistent with the assigned structures. The optical activity of 85 further demonstrated the trans relationship of H-5 to H-9. The same criterion was used to assign the relative stereochemistry of C-3 and C-11. The de-N-base (80) was optically active in contrast to the corresponding diketone (81). This means that C-3 and C-11 have the same configuration and that H-3 and H-11 are trans to one another. Finally, the relative and absolute stereochemistry of bromolythranine (99) hydrobromide was established by X-ray studies (57).The cis relationship of H-3 to H-5 and H-9 to H-11 was confirmed. The absolute configuration of piperidine Lythrum alkaloids was established by analysis of ORD and CD spectra of biphenyl compounds. The absolute structures 72, 73, and 74 were assigned to lythranine, lythranidine, and lythramine, respectively, on the basis of the positive sign
294
w.
MAREK WLFBEWSKI AND JERZY T. WROBEL
99
of the Cotton effect of lythranine hydrochloride at 232 nm due to a nwc* transition (54).
VII. Quinolizidine Metacyclophane Alkaloids A. STRUCTURE AND CHEMISTRY Ten alkaloids, lythrancine-I (loo), -11 (101), -111 (102), -1V (103),-V (104), -VI (105), -VII (106), lythrancepine-I (107), -11 (log), and -111 (109), belong to this group. All have a cis-fused quinolizidine ring and a biphenyl group. These compounds are listed in Table VI (8, 9, 58-61). Lythrancine-type alkaloids have a hydroxyl or an acetoxyl group at carbons 3, 4, and 11. Lythrancines 100-103 and lythrancines 104, 105, and 106 are epimeric at C-3. Lythrancepines 107, 108, and 109 are C-4 deoxy derivatives of lythrancines I-IV. This was demonstrated by lithium aluminium hydride reduction of the 0-tosylate of lythrancine 102 and acetylation of the product to lythrancepine 109 and its C-3 epimer. All alkaloids of the group have methoxyl groups at C-17 and C-21 and the same skeleton. The structure of these alkaloids was established by a combination of chemical and spectral methods.
13
100 R' = R' = R3 = H 101 R' = RZ = H, R3 = AC 102 R' = R3 = Ac. R' = H 103 R' = R 2 = R 3 = AC
104 R' = RZ = AC 105 R' = Ac, R' = H 106 R 1 = H, R Z = AC
107 R1
R2= H
:
108 R' = H, R 2 = AC 109 R1 = R Z = AC
QUINOLIZIDINE
Compound Lythrancine-I (100) Lythrancine-I1 (101) Lythrancine-III(lO2) Lythrancine-IV (103) Lythrancine-V (104) Lythrancine-V1 (105) Lythrancine-VII (106) Lythrancepine-1 (107) Lythrancepine-II(1OS) Lythrancepine-I11 (109) Lythramine (123) Acetyllythramine (1 24)
[.ID
Formula
TABLE VI METACYCLOPHANE ALKALOIDS
MI' ("C)
274-275 134-1 35 237-238 133-134
149 15 1 187-189 175-177 214-216 184-185 -
measured in methanol. a, Lythrum anceps Makino : b, Lythrum lanceolatum.
[.ID
(MeOH)"
+ + + + + +
65 +125 38 27 +91 25.5 f101.5 59 44 +7 - 8" - 34"
i.,,,nm (log E )
Planth source
Ref. 8 , 5 8 -60
289 (3.90) 290 (3.79) 290 (3.76) 290 (3.91) _-
290 (3.80) 290 (3.78) 290 (3.83) 294 (3.83) 292.5 (3.90)
a
8,X-60 8.58-60 8,58-60 8, 61 8, 61 8, 61 8,58-60
8,58-60 8,58-60 9 9
296
w.
MAREK ~ ~ B I E W S K AND I JERZY T. W R ~ B E L
Lythrancine 100 has no acetoxyl group as shown by IR and NMR spectra. Lythrancine 101 is the monoacetate of lythrancine 100, and lythrancines 102 and 103 are, respectively, the diacetate and triacetate of lythrancine 100. Lythrancine 101, on treatment with acetic anhydride in piperidine at room temperature, furnished the C-3 0-acetate (102). In the reaction at 110- for 3 hr the two hydroxyl groups at C-3 and C-4 were acetylated to yield lythrancine 103. Lythrancine 104 has three acetoxyl groups. The C-1 1 OH in lythrancine (105) and the C-4 OH in lythrancine 106 are unsubstituted. It was possible to establish the position of the acetoxyl group on the basis of the NMR spectrum. The H-3 signal in the 3-acetates was observed at 6 4.99-5.15 ppm. In the 11-acetates H-11 resonated at 6 5.34 i 0.01 ppm. Oxidation of lythrancine 101 with Jones reagent in acetic acid at room temperature yielded a mixture of acids which were esterified and separated into a basic and a neutral fraction. From the basic fraction methyl trans-6carbonylmethoxy-2-piperydylacetate(110) was isolated. Thus, the trans relationship of H-5 and H-9 was established ;chromatography of the neutral fraction afforded symmetrical 6,6’-dimethoxybiphenyl-3,3’-dicarboxylate (78). Mild oxidation of lythrancine 101 with chromic anhydride in acetic acid gave a dihydroxyketone (111). The Jones oxidation of lythrancine 102 yielded a monoketone (112) and a diketone (113). The UV and IR spectra of the diketone suggested the presence of a benzoyl group. The structure of 113 was established by detailed analysis of the N M R spectrum. Periodate oxidation of the cis-diol in lythrancine 101 and Hofmann degradation of lythrancine 101,102, and 103 were tried but all attempts were unsuccessful (58). Treatment of lythrancine 102 with activated neutral alumina in benzene resulted in a shift of the acetyl group from the axial C-3 acetate to the 0
Me0,C
0 H
110
CH,CO,Me
111
112 R = H , 113 R = O
4.
THE LYTHRACEAE ALKALOIDS
297
equatorial C-4 OH. The structure of the product 114 was established on the basis of NMR and mass spectra. Oxidation of 114 with the Jones reagent in acetone gave diacetoxyquinolizid-3-one, which was reduced selectively with sodium borohydride in methanol to the axial quinolizid-3-01 (115) epimeric at C-3 with 114 and lythrancine-111. Acetylation of 115 afforded lythrancine 104. This conversion was crucial in establishing the structure and absolute stereochemistry of lythrancines 104, 105, and 106 (58).
114
115
B. STEREOCHEMISTRY Lythrancepine 108 was oxidized with Jones reagent to the quinolizidone (116) which underwent a retro-Michael-type reaction to a mixture of a,Punsaturated aminoketones 117 and 118. The more polar ketone 117 readily isomerized to the less polar compound 118 either on a chromatographic column or on standing in a chloroform solution. The original mixture was then catalytically hydrogenated and the saturated ketones 119 and 120 separated by chromatography on silica gel. The quinolizidone 119 was selectively reduced and acetoxy alcohol hydrolyzed and formylated with formic acid and acetic anhydride. The crystalline N,O,O-triformate 121 (mp 211-212", [a],, 70") proved to be an enantiomer of the product of methylation and formylation of lythranidine (73). Thus, the absolute configuration of lythrancines-I and -IV, and lythrancepines-I to -111at C-5, C-9, and C-l 1 was established as S , S , and R,respectively (59). The IR spectra of quinolizidine metacyclophane alkaloids do not show the presence of Bohlmann bands (33, 34). This suggests a cis-quinolizidine ring fusion. Analysis of the NMR spectrum of lythrancine 103 led to the same conclusion. The diagnostic proton H-l absorbed at 6 4.17 ppm as a double doublet. It corresponded well to the absorption of the benzylic proton tl to the nitrogen in the cis-4-phenylquinolizidines (35) and cislactonic Lythraceae alkaloids (24) at 8 4 ppm. In the corresponding trans-fused quinolizidines this proton absorbs at 6 3 ppm. The coupling
+
-
-
H’ OAc
,
+
116
108
OAc
,OAc
,
117
118
I
I
H2
1
OAc
I
119
120
I
121
122
4.
THE LYTHRACEAE ALKALOIDS
299
Me0 A
B
of H-1 in lythrancine-IV (J 11 and 4 Hz) indicates the axial configuration given the chair-chair conformation of quinolizidine. The resonance of H-3 at 6 5.15 ppm as an octet ( J 11.5, 6 , and 3 Hz) suggested an axial configuration and a triplet at 6 4.91 ppm (J 3 Hz) due to H-4 implied an equatorial position. Thus, H-1 and H-3 are cis to one another and H-3 and H-4 have the same cis relationship. The cis relationship of acetoxyl substituents at C-3 and C-4 of lythrancine 103 was confirmed by the ease of formation of a five-membered ring carbonate in reaction of lythrancine 101 with phosgene. The trans relationship of H-5 and H-9 was established as a result of oxidation of lythrancine 101 with Jones reagent to a trans-piperidine derivative (110). Analysis of all the above results led to only two possible structures, A and B, for lythrancines I-IV and lythrancepines 1-111. Structure A is preferred because the molecular models show large interactions between the 10-methylene group and the aromatic hydrogen atoms in B and the 13membered ring is highly strained. X-ray crystallographic studies of lythrancine 101 0-brosylate confirmed stereochemistry A. Thus, the absolute stereochemistry of seven quinolizidine alkaloids was established as 100-103 and 107-109 (104). Chromatography of the mother liquors of lythrancepine 102 afforded three minor alkaloids: lythrancines 104, 105, and 106. The structure and stereochemistry of these bases was elucidated by analysis of NMR and mass spectra and by comparison with those of lythrancine 103. The assigned structure 104 for lythrancine-V was unequivocally confirmed by the previously described conversion of lythrancine 102 to this alkaloid via isomer 114 (61).
C. MASSSPECTROMETRY The mass spectra of 10 quinolizidine Lythrum alkaloids including 4epilythrancine-IV, 3-epilythrancepine-111, 4-deuterolythrancine-IV, and 3deutero-3-epilythrancepine-I11were investigated by Fujita and Saeki (60).
d
a!
N
z
/I II
I1 I1
2222222
II II II
2522222
0
-8
300
d
. N
T 0
n
ZY
II
II I/
O O T
222
!
I
C'II,C'H,
R2 / J 2
il
H
d
c 111 1'
R2 =OH R2=OAc
R2 = H
310
390 432 314
R ' = H, R 2 = OH R 1 = Ac, R 2 = OH R ' = Ac, R2 = OAC R' = R 2 = H R ' = Ac, R 2 = H
g n?:e
1ll:IC
408 450 492 392 434
R ~ = O H 295 R 2 = O A c 337 R2= H 219
302
w.
MAREK GOEFBIEWSKI AND JERZY T. WROBEL
All alkaloids of the group showed a similar fragmentation pattern. All fragmentations described were supported by the observation of the metastable ions. The constitution of the ions was determined by high-resolution mass spectra. The three observed fragmentation routes were triggered by elimination of an acetoxyl radical (hydroxyl for lythrancine-I). Elimination of acetic acid from C-2 and C-3 of the common intermediate ion a yields ion b which undergoes the retro-Diels-Alder reaction to give ion c. An alternative decomposition path consists in loss of ethylene from a by the retro-Diels-Alder cleavage to yield ion d which can further eliminate acetic acid. The third route involves cleavage of the benzylic position. The loss of acetic acid from e affords ion f. The further retro-Diels-Alder reaction off gives rise to the strong peak at m / e 82 and the remaining fragment ion g. As a result of this analysis it was possible to assign the locations of the hydroxyl and acetoxyl groups in all alkaloids of the group.
D. OXOQUINOLIZIDINE METACYCLOPHANE LYTHRACEAE ALKALOIDS Five new alkaloids have been isolated from the Lythraceae plant Lythrum Lanceolatum by Wright et al. (9). The structure and absolute configuration of two of these bases, lythrumine (123) and monoacetyllythrumine (124), were established on the basis of the X-ray analysis on lythrumine hydrobromide. On acetylation both the alkaloids yielded the same diacetate (125).
123 R' = R Z = H 124 R' = Ac, RZ = H 125 R' = R 2 = AC
The lactonic alkaloid decinine (2) was also isolated from L. lanceolatum (9). This alkaloid was found previously in the Decodon uerticillatus, Heimia salicifolia and H. myrtifolia (as the 12,13-dehydro derivative, lythrine), and Lagerstroemia iizdica. This fact supports the taxonomical grouping of Lythrum with the Decodon, Heimia, and Lagerstroemia genera in the
4.
THE LYTHRACEAE ALKALOIDS
303
Lythraceae plant family and suggests that the metacyclophane and lactonic alkaloids have a common biosynthesis.
VIII. Synthesis
A. EARLYSYNTHETIC APPROACHES The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62),Wrobel and Golebiewski condensed pelletierine (126)* with isovanillin (128) and obtained a transfused quinolizidine derivative (130, P H-5) (64) in 75% yield. A model condensation of pelletierine (126)with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52)condensed A'-piperideine (132)with P-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinnamic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful.
B. PELLETIERINE-BENZALDEHYDE CONDENSATION This is a key stage in the synthesis of lactonic Lythraceae alkaloids published by Hanaoka et al., Loev et al., and Wrobel and Golebiewski. This reaction was studied by several groups of chemists (64, 66-69). It proceeds in good yield for a variety of aromatic aldehydes usually in dilute aqueous or alcoholic solutions of sodium hydroxide to yield 2-quinolizidones. Two diastereomers, 138 and 139, defined by the relative stereochemistry at C-4 and C-10 are formed in the condensation." In the trans-quinolizidone (139) the C-4 and C-10 hydrogens are trans to one another. In the cis-quinolizidone (138) they are cis. Compound 140 is presumably the most stable conformation for diastereomers 138 and 141, or its flexible form represents the conformation of lowest energy for configuration 139 (66, 67).
* 2-Piperydylpropanone (126). known for many years as isopelletierine, is now referred to as pelletierine, following the suggestion of Gilman and Marion (63).The pelletierine originally described by Tanret was never later isolated o r synthesized. A condensation of pelletierine with aliphatic aldehydes to 2-quinolizidones has been also reported (70). +
126
132
R' 127 R' = R 2 = H 128 R' = OMe, R 2 = OH
129 R' = R2 = H 130 R' = OMe, RZ = OH 131 R' = OMe, R2 = OCH2Ph
1
K . O q C O z R '
0Me 137
134
135 R ' = R 2 = R 3 = H. A' 136 R' = H, R 2 = CH2Ph, R'
133
=
Me
4.
305
THE LYTHRACEAE ALKALOIDS
126
Ar
Ar
138
139
H
Ar 140
141
The trans- and cis-fused forms are clearly identifiable by Bohlmann bands in the IR spectra (33,34)and by the NMR chemical shifts and coupling of the benzylic proton at C-1. In the spectra of trans-fused quinolizidones the diagnostic proton absorbs in the region 6 2.70-3.30 ppm where, as in the cis-fused forms, the absorption is shifted to lower field by 0.5-2 ppm. Condensation under thermodynamic control yields mainly the trans-fused quinolizidine system whereas in a kinetically controled reaction predominantly cis products are obtained (66, 67). The latter isomerize to the corresponding trans forms in an alkaline medium. An isomerization in dilute hydrochloric acid was also reported (68).The stereoselectivity of the reaction was influenced by the solubilities of the starting aldehydes and products, since the first-formed cis-quinolizidones isomerize easier in a soluble state. Several mechanism have been suggested for this reaction. Hanaoka et al. (66) have described it as a Mannich reaction. Condensation of pelletierine and arylaldehyde affords the imminium salt (143) which is transformed to the cis-quinolizidone (141) via the unstable trans-fused quinolizidone (144).The cis form (141)comes to equilibrium with the trans isomer (140) via the unsaturated aminoketone (145) by the action of hydroxide anion. Lantos et a1. (68)suggested a modification of Hanaoka’s mechanism where an imminium intermediate (143) would undergo a retrograde conjugate addition to a Schiff base (146). Its cycloaddition reaction via the enolate would produce the cis compound selectively. Wrobel and Golqbiewski (67)interpreted the condensation in terms of a two stage reaction : a Claisen-Schmidt condensation resulting in an amino alcohol (147) followed by nucleophilic intramolecular substitution of the OH group. Quick and Oterson (69) suggested a modification of the latter
306
'= w.
MAREK C O ~ . ~ B I E W ~ AND K I JERZY T. W R ~ B E L
+ArCHO
O
126
m 1 HC-OH
-
qo-dp Ar
AI
146
141
I 140
Ar 145
hypothesis which involved a dehydration of the amino alcohol 147 followed by intramolecular Michael addition in 145. Some positive information on the mode of condensation was provided by these authors who prepared the aminoketone 145 (Ar = Ph) by an independent route. Treatment of 145 with excess aqueous sodium hydroxide afforded a mixture of quinolizidones of a similar composition, as in the condensation of pelletierine with benzaldehyde.
4.
HO"
126 ArdHO
307
THE LYTHRACEAE ALKALOIDS
/
-
Ar
Ar
kr 145
C. LACTONIC BIPHENYL ETHERALKALOIDS 1. Introduction In the lactonic alkaloid molecule one can find three synthons: pelletierine, a 4-methoxybenzaldehyde derivative, and p-hydroxycinnamic acid. In all published syntheses of lactonic Lythraceae alkaloids they are the building blocks.
'CHO
R'
2. Trans-Fused alkaloids Decaline (43)was the first synthesized Lythraceae alkaloid. The synthesis was achieved independently and concurrently by a Japanese and a Polish group. Three approaches were used in these syntheses. In the first method,
308
or w.
MAREK GOLEBIEWSKI AND JERZY T. WROBEL
Hanaoka et al. (39, 71) condensed pelletierine (126) with 6-bromoisovanillin and obtained in quantitative yield the trans-quinolizidone (149). The methyl ether (150) was selectively reduced with Henbest catalyst, and the axial (151) and equatorial (153) alcohols were separated in 9 : 1 ratio. The Ullmann condensation of the acetyl derivative (152) with methyl 4-hydroxyhydroR
' H
d:ZMe +
r
152
d
Br
Br
/
'
/
/
'
OR
OM2 151 152 153 154
R' R' R' R'
OH
= OH,
R2 = H R2 = H = H, RZ = OH = H, R Z = OAc
= OAc, =
R'
OMe 49 R = Me 50 R = H
R 2 = Me
=H
V
OMe
O
M
V
e
OM2
OM2 164
155
= OAc,
OM2 156 R' 157 R'
'
OM2
OM2
149 R = H 150 R = M e
+
158 159 160 161
R' R' R' R'
= BH,
R2 = H
= rH,
R2 = H
= BH. = rH,
R 2 = Me
R2 = Me
O
M
e
OMe
162 R' 163 R' 157 R '
= OH. RZ = H, = H, R 2 = OH,
R3 = Me R3 = Me = OH, R 2 = H, R3 = H
4.
THE LYTHFUCEAE ALKALOIDS
309
cinnamate (155) gave the biphenyl ether derivative (156) in 34% yield. Alkaline hydrolysis of 156 and lactonization of the resulting hydroxyacid (157) in benzene in the presence of toluene-p-sulfonic acid yielded (?)decaline (49) in 55% yield. In another similar approach (40, 72) Wrobel and Golcbiewski obtained the methyl ether (150) in the same way. The Ullmann condensation with methyl 4-hydroxycinnamate afforded a mixture of stereoisomers 160 and 161. Catalytic reduction of the trans-fused quinolizidone (160) gave a mixture of axial and equatorial epimers (162 and 163) in 4: 1 ratio. Hydrolysis of the axial hydroxyester (162) followed by lactonization with thionyl chloride in chloroform yielded racemic decaline. In the third approach (39,40, 72)the quinolizidone ester was alternatively prepared. The Ullmann reaction of 6-bromoveratraldehyde with methyl 4-hydroxycinnamate afforded biphenyl ether aldehyde (164)in 55% yield. The alkaline condensation of 164 with pelletierine gave a mixture of stereoisomeric quinolizidone acids (158 and 159). Esterification with dimethyl sulfate yielded a mixture of trans- and cis-fused quinolizidine esters (160 and 161) in a 13 : 1 ratio after separation on silica gel. Demethyldecaline (50) was synthesized by the first method from the 0benzyl derivative of 6-bromoisovanillin by Hanaoka et al. (44). 3. Cis-Fused Biphenyl Ether Alkaloids Vertaline (51), a cis counterpart of decaline (49),was prepared by Hanaoka et al. (73, 74). The crucial cis-fused analog of 149 was obtained in 25% yield by condensation of pelletierine with 6-bromoveratraldehyde in tetrahydrofuran. The carbonyl group was reduced with sodium borohydride in methanol to mixture of axial and equatorial alcohols in a 3: 1 ratio in 96% yield. An effective new method for the synthesis of macrocyclic lactones has been developed by Corey and Nicolau (75).In this method both the hydroxyl and the carboxyl groups have been activated by formation of a 2-pyridinethiol ester. Vertaline was obtained in 67% yield when this procedure was applied to the corresponding hydroxyacid (76). The compound proposed as having the structure of lagerine (55) was synthesized by Hanaoka et al. ( 4 5 ) in a similar way from o-vanillin (167a), pelletierine, and methyl 4-benzyloxy-3-bromohydrocinnamate. In the condensation of pelletierine with 167a in aqueous sodium hydroxide two compounds were formed, a trans-fused quinolizidone (164) and a cis-hemiacetal (165) in the ratio of 1 :3. The products were interconverted on treatment with aqueous sodium hydroxide. Reduction of 165 with sodium borohydride produced the axial
310
w . MAREK GCEFBIEWSKI AND JERZY T. WROBEL
CHO
OCH, OMe 55 R = H 56 R = M e
+ OMe 167a
O
m
53 R = H 54 R = Me
Hoa
Me0
-
126
166 R = M e 167 R = C H , P h
165
164
and equatorial alcohols in the ratio of 19:l. The synthetic product 55 was proven not to be identical with the natural lagerine. On the basis of the NMR data and biogenetic considerations structure 54 was proposed for methyllagerine. The synthesis of 54 was similarly performed from 2-bromoveratraldehyde (166), methyl 4-hydroxycinnamate, and pelletierine. The product was shown to be identical to the natural alkaloid and the structural assignment was confirmed (42). Finally, lagerine (53) was synthesized in the same way starting from the benzyl ether of 2-bromoisovanillin (167). The synthesis has demonstrated that the phenolic hydroxyl group is at C-21 (46).
D. SYNTHESIS OF LACTONIC BIPHENYL ALKALOIDS 1. Trans-Fused Alkaloids Methyldecinine (14) was synthesized independently by Loev et al. (77) and Hanaoka et al. (78, 79). The crucial unsymmetrical biphenyl aldehyde (168) was obtained by the Ullmann reaction of 6-bromoveratraldehyde with 3-iodo- or 3-bromo-4-methoxy hydrocinnamate. Condensation with pelletierine afforded the biphenyl quinolizidone (171) which was reduced with Henbest catalyst followed by hydrolysis and lactonization.
4.
31 1
THE LYTHRACEAE ALKALOIDS
Decinine (2) was prepared similarly by Lantos and Loev (80), from the biphenyl aldehyde (169). Calcium hydroxide-catalyzed condensation with pelletierine afforded biphenyl quinolizidone (172) in 20% yield. This compound was obtained in better yield from the acid-catalyzed epimerization of the cis-fused diastereomer (173) of the decamine synthesis (68). 2. Cis-Fused Biphenyl Alkaloids Methyldecamine (174) was synthesized from pelletierine and the alkaliinsoluble amide 170 by Hanaoka et al. (81). Decamine (18) was synthesized by Lantos et al. by the kinetically controlled condensation of pelletierine with biphenyl aldehyde (169) which afforded the cis-quinolizidone (173) in 50% yield. Reduction of the carbonyl group with Henbest catalyst followed by alkaline hydrolysis produced the undesirable trans-fused quinolizidols as a major product. However, hydrogenation with platinium catalyst in an alkaline solution afforded the less stable cis-fused axial carbinol, which on cyclization followed by a mild basic hydrolysis yielded decamine (18). RZOC
R3
R20,C
* *
OMe 168 R' = Me, R 2 = OMe or OEt 169 R' = SO,Me, R 2 = OMe or OEt 170 R' = Me, R2 = N(Me),
0Me 171 R' = Me, R 2 = H, R3 = BH 172 R' = SO,Me, R Z = H, R3 = PH 173 R' = SO,Me, R Z = H, R 3 = aH
I
OMe 14 2 18 174
R'
=
R'
= =
Me, R2 = BH H, RZ = PH R' H, RZ = IH R' = Me. R2 = aH
312
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MAREK GOLFBIEWSKI AND JERZY T. WROBEL
A generalized scheme has been presented wherein the cis-fused quinolizidone (173) is epimerized to the trans form (172) (68). E. PIPERIDINE METACYCLOPHANE ALKALOIDS The first total synthesis of the metacyclophane alkaloid ( f)-lythranidine (73) was achieved by Fuji et al. (82).
94 R = C H , O H 175 R = CHO
178 R = H 179 R = NO
176
I77
180
73
The Wittig reaction of dialdehyde 175, prepared by chromic anhydridepyridine oxidation of diol 94 (54, with 176 in dilute methylene chloride solution produced cyclophane 177 in 86% yield. Epoxidation of 177 with m-chloroperbemoic acid followed by hydrogenolysis over Pd/C, acetylation, and Pt0,-Raney Ni-catalyzed hydrogenation afforded the cis-substituted piperidine derivative (178). The N-nitroso compound (179) was equilibriated with tert-butoxidedimethyl sulfoxide to the trans-cis mixture which was denitrosated over Raney nickel and hydrolyzed to yield a mixture of diols (180). Refluxing 180 in ethyl orthoformate resulted in isolation of the crystalline amidoacetal which exhibited IR and NMR spectra identical to those of the amidoacetal
4.
THE LYTHRACEAE ALKALOIDS
313
(82)derived from the natural lythranidine. Monodemethylation of synthetic 82 with aluminium chloride in EtSH-CH,Cl, followed by acidic hydrolysis afforded ( +)-lythranidine.
IX. Biosynthesis Several biogenetic schemes have been suggested to account for the origin of biphenyl and biphenyl ether lactonic alkaloids (52, 62, 83, 84). The proposals differ in the mode of biogenesis of the phenylquinolizidine moiety. Steps common to all the proposals are the reduction of 0x0 group in the phenylquinolizidone (130)followed by esterification with ofp-coumaric acid (C,-C,) unit derived from phenylalanine via cinnamic acid. Most of the work on the biosynthesis of Lythraceae alkaloids has been done by Spenser et al. (10, 84-87). First, the validity of the pelletierine hypothesis (c) of Ferris et al. (62) has been tested. The pelletierine (126) nucleus is generated from L-lysine (181)via cadaverine (182),and presumably A'-piperideine (132) and its side chain originate from the acetate. Incorporation of radioactivity from 4C-labeled samples of these precursors to decodine (6) and decinine (2) in Decodon oerticilutus has been investigated (85,87). The active alkaloids isolated from the plants to which [2-14C]lysine or [6-'4C]lysine had been separately administered were partially degraded to establish a distribution of activity. Chromic acid oxidation yielded 2-piperidylacetic acid (183) containing C-5 and C-9, y-aminobutyric acid (lM),and 8-alanine (185)containing C-9. Since the entire activity of decodine and decinine was recovered in 2-piperydylacetic acid it was likely that an intact C, unit composed of C-2 to C-6 of lysine was incorporated into ring A. y-Aminobutyric acid and b-alanine contained one-half of the activity of the intact alkaloids, regardless of whether [2-14C]- or [6-14C]lysine had been the precursor. Thus, the C, fragment of the alkaloids must originate from lysine by way of a symmetrical intermediate. The carboxyl carbon of lysine does not enter the alkaloids. When [ l-'4C]lysine was administered to D. uerticillatus the alkaloid fraction was totally inactive. The chirality of a precursor-product relationship was determined by the use of doubly labeled lysine, in which one enantiomer was labeled only with tritium and the other with tritium and 14C (88).Comparison of the 3H/14C ratios of substrate and products demonstrated that decodine and decinine were derived from L-lysine, whereas pipecolic acid (186) was derived from D-lysine. Thus, pipecolic acid does not serve as a precursor of Lythraceae alkaloids (87).
w.
314
MAREK GOLFBIEWSKI AND JERZY T. WROBEL
8q;
HO
HO
OMe
\
186
OMe
132
OMe
I
OMe
I
ALKALOIDS SCHEME4
4.
315
THE LYTHRACEAE ALKALOIDS
n C o 2 H NH, N H ,
n NH, C 0 NH, 2 H
Ti NH,
NH,
OMe
2 R' = H, R 2 = OMe 6 R' = O H , R 2 = H
183
184
185
Decodine derived from [ l-14C]cadaverine showed a distribution of label identical to that of the lysine-derived samples. Activity was equally divided between C-9 (p-alanine) and C-5 (Zpiperydylacetate minus 8-alanine). In decodine, into which A'-[6-'4C]piperideine was incorporated, the label was confined to C-9. This was consistent with the established evidence that the double bond in A'-piperideine does not migrate from one side of the nitrogen to the other (89,90). In the ultimate test of hypothesis c, Decodon plants were treated with (RS)-[6,2-'4C,]- and (RS)-[6-3H,2'-'4C]pelletierine to yield inactive alkaloids, whereas in concurrent experiments labeled decodine and decinine were obtained from other substrates. The accumulated evidence favored hypothesis e (see Scheme 4). The next experiments concerned biosynthesis of the phenylalanine-derived fragments. First, Rother and Schwarting reported the specific incorporation of [3-'4C]phenylalanine (187) into cryogenine (vertine; 17) in Heimiu sulicifoliu. The lactone (48), a product of partial degradation, contained 92% of the molar activity of cryogenine. This fragment constitutes two C,-C, units: C-13 to C-19 and C-I,C-20 to C-25. 4,5-Dimethoxyphthalic anhydride (47), comprising C-1. contained 31% of the activity of the alkaloid (84). In the other experiment with [3-14C]phenylalanine, 33% of
316
w.
MAREK GOLFBIEWSKI AND JERZY T. WROBEL
Y
O OMe
M
e
CO,H
47 (31"")
OMe 48 (920,)
* C0,II
I
OMe 45 (467;)
1
OMe 47 (33",)
the activity of cryogenine was located in 47 and 46% in 4-methoxyisophthalic acid (45). p-Hydroxy- and p-methoxybenzoic acids obtained by decarboxylation of 45 showed essentially the same specific activity as 45 (91). These results indicated that the label was localized at C-13 (46 and 61%) and very probably at C-1 (33 and 31%). Thus, in conclusion, phenylalanine is the donor for both the aromatic rings and the adjacent carbon atoms C-1 and C-13. This result was consistent with any one of the five biogenetic hypotheses shown in Scheme 4. To distinguish among the hypotheses, it was essential to examine the incorporation of such other radiomers of phenylalanine as [ 1-I4C]- and [1,3-'4C,]phenylalanine. Degradation of decodine derived from [3-l4C]pheny1alanine showed that 58% of the label was located at C-13 and 33% at C-1. Thus, there is a close correspondence of the origins of the two lactonic biphenyl alkaloids of different stereochemistry at C-5 and with different oxygenation patterns. The results of experiments with radioisomers of phenylalanine are shown in Scheme 5 for decodine. For the case of decinine a very similar distribution of activity was obtained. When [l-'4C]phenylalanine was tested as a precursor, the entire activity of decinine and decodine was unequally divided between C-1 1 and C-3. The carbonyl carbon at C-11 [isolated as benzophenone oxime as a result of phenylation with the Grignard reagent, dehydration, and chromic acid
4.
317
THE LYTHRACEAE ALKALOIDS
oxidation ( 1 0 , 2 4 ) ] contained 71% of the activity of decodine and 76% of the activity of decinine. The remaining activity (28 and 20%, respectively) was present at C-3, i.e., at the carbinol carbon. This carbon was extruded as benzoic acid in the following degradation, shown for decodine. Lithium aluminium hydride (LAH) reduction of dimethyldecodine (15) resulted in a diol (188) that was selectively tosylated at the primary hydroxyl group. Reduction of the tosylate (189) with LAH afforded the desoxy derivative (190). Mild oxidation of 190 with Jones reagent to 191 followed by reaction with phenyl lithium yielded a mixture of epimeric phenylcarbinols (192) which on oxidation with permanganate gave benzoic acid.
@ , \ OMe OM>
OMe
OMe
OMe
zm-
15
188
+ Jones
189 R = OTs 190 R = H
KMnO,
191
PhC0,H *
192
When [2-'4C]phenylalanine was administered to Decodon plants about two-thirds of the activity of decodine and decinine was located at C-2. This carbon was isolated as the m-naphthylamide of acetic acid by the KuhnRoth oxidation of the n-propyl derivative. In the fourth experiment incorporation of intermolecularly doubly labeled phenylalanine (at carboxyl carbon and at the p carbon of the side chain) was investigated. The labeled decodine and decinine contained radioactivity only at the expected four carbon atoms C-1, C-3, C-1 1, and C-13 which were isolated and assayed for radioactivity. The ratios of relative specific activities calculated from these data (C-3/C-1, C- 11/C-13) were in good agreement with the activity ratio of the precursor (CO,H/B-CH,).
w.
318
MAREK WFBIEWSKI
H
AND JERZY T. W R ~ B E L
H
H
g*: 7: q HO
187
2
H
t
2
/ \
+ \ HO
H
H
/
/
\
\
OH
d
/
\ HO OH
OMe
2
45.4 - = 0.83 55.6
19 23
-=
\ OMe
0.83
2s = 0.83 30
-
SCHEME5
This body of evidence led to the conclusion that two intact C,-C, units derived from phenylalanine are incorporated into lactonic Lythraceae alkaloids. One unit is the precursor of the phenylpropanoid part of the alkaloids (C-11 to C-19) and the other gives rise to the C-3 to C-1, C-20 to C-25 segment of the phenylquinolizidine part." Thus, hypotheses a and c, which demanded participation of a C,-C, unit in the biosynthesis of the phenylquinolizidine moiety, have been disproved. The mode of incorporation of lysine and its metabolites has eliminated routes b and d. The accumulative evidence demonstrates that only path e is consistent with all experimental results. This route predicts an extension of the side chain of the phenylpropanoid precursor by a two-carbon unit supplied by a donor such as acetyl- or malonyl-Coenzyme A. The results of the final experiment with [2-'4C]malonate were consistent with hypothesis e but inconclusive. * In a preliminary communication (86)46% of the activity of intact decodine was found at C-1 in harmony with the pelletierine hypothesis. A complete reinvestigation of the degradation on the sample of original decodine derived from [1,3-14C2]phenylalanine has shown that the earlier result was in error (10).
4.
319
THE LYTHRACEAE ALKALOIDS
Although 2-piperydylacetic acid contained the entire activity of decodine, the label was not confined to C-4 and two other degradation products, a-alanine and a-aminobutyric acid, contained -40% of the activity of the alkaloid.
OH 193
OH 194
In light of the present evidence the biogenesis of metacyclophane Lythraceae alkaloids required revision, since the only published proposal (9) was based on pelletierine. A new biogenetic scheme was proposed which invoked intermediacy of A'-piperideine and two C,-C, units [derived from P-ketoester (193)]. An intermediate disubstituted piperidine (194) would give rise to two types of metacyclophane alkaloids as a result of reduction and phenol coupling as well as Michael addition in the case of the quinolizidine bases (10).
X. Physiological Activity For centuries, the American Indians used plants of Heimiu species to prepare intoxicating and stimulating beverages. The beverage prepared from H . sulicifoliu is reported to produce a mild psychosomimetic effect. This plant was used as a panaceum for a wide spectrum of diseases ranging from common indigestion to syphilis. Heimia sulicfoliu was used as an appetite stimulant, a remedy for bronchitis, dysentery, inflammation of the womb, and slow healing ulcers. The aerial parts of the plants are diaphoretic, diuretic, purgative, and show emetic, hemostatic, and astringent action ( I ) . Early work was not, however, directed toward isolation of physiologically active compounds. The preliminary biological studies on isolated Heimiu alkaloids did not confirm any central nervous system activity in rats ( 4 ) . Later biological
320
w. MAREK
GOEFBIEWSKI AND JERZY T. WROBEL
studies have demonstrated the pronounced activity of several Lythraceae alkaloids. Vertine (cryogenine) (92-96) and decinine [as a free base (97) or an alkanesulfonic acid salt (98)] are antiinflammatory agents in rats and guinea pigs (95).Decinine shows a diuretic activity in rats (97, 99) and dogs (99) and may be used as a diuretic hormone. Vertine increases blood glucose level (94)and lowers mean blood pressure (100).Vertine and nesodine show sedative activity in dogs and guinea pigs. Decamine is a fungicide (101). Decamine-modified polyethylene preparations show antithrombotic properties in rabbits (102). The capacity of the polymer to inhibit blood coagulation and clot formation was impaired by incorporation of decamine. 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.
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w. MAREK
G~EBBIEWSKIAND JERZY T. WROBEL
M. Hanaoka, N. Ogawa, and Y . Ardta, Tet. Lett. 2355 (1973). J. T. Wrobel and W. M. Golqbiewski, Tet. Lett. 4293 (1973). M. Hanaoka, N. Ogawa, and Y . Arata, Chem. Pharm. Bull. 22,973 (1974). M. Hanaoka, N. Ogawa, and Y. Arata, Chem. Pharm. Bull. 24, 1045 (1976). E. J. Corey and K. C. Nicolaou, J . Am. Chem. Soc. 96, 5614 (1974). E. J . Corey, K. C. Nicolaou, and L. S. Melvin, Jr., J . Am. Chem. Sot. 97, 654 (1975). B. Loev, I. Lantos, and H. van Hoeven, Tet. Lett. 1101 (1974). M. Hanaoka, H. Sassa, C. Shimezawa, and Y. Arata, Chem. Pharm. Bull. 22, 1216 (1974). M. Hanaoka, H. Sassa, C. Schimezawa, and Y. Arata, Chem. Pharm. Bull. 23,2478 (1975). I. Lantos and B. Loev, Tet. Lett. 2011 (1975). M. Hanaoka, K. Tanaka, and Y. Ardta, Chem. Pharm. Bull. 24,2272 (1976). K. Fuji, K. Tchikawa, and E. Fujita, Tet. Lett. 361 (1979). J. P. Rosazza, J. M. Bobbit, and A. E. Schwarting, Int. Symp. Chem. Nut. Prod. I.U.P.A.C., 5th, 1968 Abstract C8. 84. A. Rother and A. E. Schwarting, Chem. Commun. 1411 (1969). 85. S. H. Koo, R. N. Gupta, I. D. Spenser, and J. T. Wrobel, Chem. Commun. 396 (1970). 86. S. H. Koo, F. Comer, and I. D. Spenser, Chem. Commun. 897 (1970). 87. R. N. Gupta, P. Horsewood, S . H. Koo, and I. D. Spenser, Can. 1.Chem. 57, 1606 (1979). . Leistner, R. N. Gupta, and I. D. Spenser, J . A m . Chem. Soc. 95, 4040 (1973). . Leete, J . Am. Chem. Soc. 91, 1697 (1969). 90. R. N. Gupta and I. D. Spenser, Can. J . Chem. 47,445 (1969). 91. A. Rother and A. E. Schwarting, Phytochemistry 11, 2475 (1972). 92. L. De Cat0 Jr., J. K. Brown, and M. H. Malone, Eur. J . Pharmacol. 26, 22 (1974); CA 84, 84209r (1975). 93. W. C. Watson and M. H. Malone, J . Pharm. Sci. 66, 1304 (1977). 94. A. B. Kocialski, F. J. Marozzi, Jr., and M. H. Malone, J . Pharm. Sci. 61, 1202 (1972). 95. D. S. Kosersky, W. C . Watson, and M. H. Malone, Proc. West. Pharmacol. SOC.16, 249 (1973); C A 80, 33858r (1974). 96. D. S. Kosersky, J. K. Brown, and M. H. Malone, J . Pharm. Sci. 62, 1965 (1973). 97. V. D. Wiebelhaus, Ger. Offen. 2,255,226 (1973); CA 79, 23578 (1973). 98. D. W. Blackburn and H. C . Caldwell, U.S. Patent 3,960,870 (1976); C A 85,112747k (1976). 99. V. D. Wiebelhaus, G . Sosnowski, A. R. Maas, and F. T. Brennau, Recent Adv. Renal Physiol. Pharmacol., Proc. Annu. A . N . Richards Symp., I S t h , 1973, 331 (1974); C A 83, 607 (1975). 100. H. R. Kaplan and M. H. Malone, Lloydiu 29, 348 (1966). 101. G. K. Palii, Tr. Gos. Med. Inst. 55, 38 (1974); C A 84, 1600972 (1975). 102. 0. P. Buadze, K. M. Lakin, and A. N. Nazin, Vopr. Bid. Med. Tekh. 2, 131 (1974); C A 85,87246 (1976). 103. J. Quick and R. Ramachandra, Synth. Commun. 8, 51 1 (1978). 104. M. J. Barrow, P. D. Cradwick, and G. A. Sim, J. Chem. Sot., Perkin Trans. I 1812(1974).
CHAPTER 5-
MICROBIAL AND IN VITRO ENZYMIC TRANSFORMATION OF ALKALOIDS H. L. HOLLAND Department of Chemistry, Brock University, St. Catharines, Ontario, Canada
1. Introduction
............
................ ........................... ...
A. General Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Hydrolases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Oxidoreductases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...._ D. Conjugation . . . . . . . . . . . . . . . E. Practical Considerations . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Transformations of Indole Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Brucine ................................ .. B. Corynant Ikaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ........... C. Lysergic Acid and Related Alkaloids D. Vindoline and Related Alkaloids . , . , , . . . , , . , . . . . . . . . . . . . . . . . . . . . . . . . . IV. Transformations of Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Aporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Benzylisoquinolines . . . . . . . . . , , . . . . , , , . , . , , . . . . . . . . . . . . . . . . . . . . . . . . . C. Bisbenzylisoquinolines and Related Alkaloids . . . D. Morphine and Related Alkaloids . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . E. Phenethylisoquinolines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V. Transformations of Pyridine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. A. Nicotine and Related Alkaloids , , , , . , . . . . . . . . . . . . . . . . B. Arecoline . . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...............
Vl. Transformations of Pyrrolizidine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... .. .. . . . . ... .. . .. ... . .. . ... .. .. A. Monoester Alkaloids . . . . . . . . B. Diester Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Transformations of Quinoline Alkaloids . . . .............. VIII. Transformations of Steroidal Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Tomatanine-Based Alkaloids . . , , . , . . . , . , . , . . . . . . . . . . . . . . . . . . . . . . . . . . B. Solanidanine-Based Alkaloids . , . ............................ C. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... IX. Transformations of Tropane Alkaloids . . . . . . . . . . , , , References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
324 325 325 325 326 327 328 328 328 332 338 339 348 348 360 366 367 369 373 316 316 376 376 376 319 380 381 381 383 386 390 391 39 1 395
THE ALKALOIDS, VOL. XVlll Copyright @ 1981 by Academic Press, Inc. All nghts of reproduction in any form reserved. ISBN a i z - 4 6 9 ~ 1 8 - 3
324
H. L. HOLLAND
I. Introduction
Chemical transformations carried out by biological reagents such as purified enzyme preparations and by intact organisms such as fungi and bacteria have done much to ease the lot of the synthetic chemist in recent years. Regio- and stereoselective reactions such as C-hydroxylation (1, 2), S-oxidation (3, 4 ) , carbonyl reduction (5, 6 ) and oxidation (7, 8), N- and 0dealkylation (9), N-oxidation (lo),and hydrolytic reactions carried out by biological systems have been widely used in many areas of organic chemistry (11, 12). Although biological reagents have found increasing use in alkaloid chemistry, this aspect of the subject has not been recently reviewed. However, a number of reviews of the use of biological systems relevant to the chemistry of alkaloids have appeared. These include the microbial transformation of alkaloids (13-15), the use of purified enzymes in heterocyclic chemistry (16), a compendium of microbial transformations of nonsteroid cyclic compounds (11),a review of the metabolic N-oxidation of medicinal amines (lo),and articles on the use of microbial systems as models for the mammalian metabolism of drugs and other chemicals (9,17).The present chapter will discuss the use of purified enzyme preparations and of intact microorganisms in effecting transformation of alkaloid substrates. In vivo animal studies have not been included since these are of limited applicability to the alkaloid chemist. Similarly, those studies which are principally enzymic in direction and those which are concerned only with the structure or properties of enzymes that effect transformations of alkaloids will not be discussed, nor will aspects of normal biosynthesis be included. It is rather the intention of this chapter to draw attention to the possible synthetic uses of biological reagents in alkaloid chemistry, and perhaps to stimulate further research in this underdeveloped field. To this end, the literature up to and including references appearing in Volume 88 (1978) of Chemical Abstracts (with the exception of the material reviewed in references 11 and 13-16) has been surveyed. The tables in Sections III-IX summarize the transformations discussed below. Yields given are the percentage recovery of product based on total substrate used. In many cases, products were not isolated (indicated in parentheses) ; and published yields have been based on spectrophotometric analysis, on the measured release of other metabolites (e.g., formaldehyde in the case of O-demethylation), or on consumption of starting material. In these cases, yields are also given in parentheses.
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
325
11. Enzymes Involved in Alkaloid Transformations
A. GENERAL CONSIDERATIONS With the exception of ester, amide, and glycoside hydrolysis, the transformation of alkaloids by biological systems is invariably an oxidative or (less commonly) a reductive process. The enzymes involved therefore fall into only two of the six main groups of enzyme types (18), namely hydrolases and oxidoreductases. The former includes enzymes that catalyze the hydrolysis of esters, amides, glycosides, and other functional groups. The latter includes enzymes such as the dehydrogenases responsible for the reversible alcohol oxidation-carbonyl reduction reaction and CH-CH dehydrogenation, the oxygenases that perform C-hydroxylation (and hence indirectly 0-and, N-dealklyation), N-oxidation, and S-oxidation, and the peroxidases capable of performing oxidative coupling of phenols. Whether used in a purified state or in the form of the intact organism, many of the enzymes involved in the transformation of alkaloids are working on unnatural substrates. It has been assumed (17)that these biotransformations are performed largely by the detoxification systems of the organism involved, which possess oxidative, reductive, and hydrolytic capability (17). For this reason, purified enzyme systems capable of transforming alkaloids are frequently derived from mammalian livers, the major site of removal of foreign chemicals from the organism. Many microorganisms also possess enzyme systems capable of performing analogous transformations. A subsequent or parallel step in the normal detoxification process is “conjugation,” or the linking by ester, acetal, or other bond of the foreign chemical or its metabolite to a normal constituent of the organism. Such conjugative reactions involving N-acetylation by acetyl coenzyme A and an N-acetyltransferase, and N- and 0-methylation by S-adenosylmethionine and a methyltransferase are encountered in alkaloid biotransformations.
B. HYDROLASES The substrate specificity of many esterases is not high (19) and the same is true of some proteases (amide-hydrolyzing enzymes), such as a-chymotrypsin (12, 20). Amides may also serve as substrates for some esterases (21). Since esterases and proteases are widespread, hydrolysis of ester or amide linkages often accompanies other transformations by intact organisms. Soluble hydrolases are often present in supernatant fractions of mammalian microsomal preparations, and hydrolytic reactions may also occur when extracts of this type are used. Glycosidases, which catalyze the hydrolysis of
326
H. L. HOLLAND
specific glycosidic bonds, are also widespread ; and alkaloids containing these linkages are therefore susceptible to glycosidase action during biotransformation. The mechanism of action of hydrolases and their applications in organic chemistry have been reviewed recently (12).
C. OXIDOREDUCTASES
1. Monooxygenases Oxidative biotransformations account for the majority of detoxification processes and of these, reactions involving monooxygenases are the most important. Monooxygenases are responsible for hydroxylation at saturated and aromatic carbon and for N- and S-oxidation (22, 23). A characteristic feature of these enzymes is the direct introduction of one atom of molecular oxygen into the substrate, the other being incorporated into a molecule of water. Saturated carbon hydroxylation is thought to involve direct insertion of an enzymically produced electrophilic oxygen species (an enzymic equivalent of oxene) into an unactivated C-H bond of the substrate (24): activation of the substrate by enolization can also result in hydroxylation at a position CI or vinylogous to carbonyl functionality (25).The low substrate specificity normally associated with this reaction means that oxidative transformations of this type are common, and the fact that oxidation frequently occurs at a position remote from any other functionality results in products that are valuable because of their relative inaccesibility by other means. Similar hydroxylation CI to nitrogen results in the formation of a hemi-aminal and hence to N-dealkylations (26),and hydroxylation at the CL carbon of an ether leads in an analogous fashion to 0-dealkylation (27). Monooxygenase enzymes are also responsible for hydroxylation of aromatic systems to produce phenolic metabolites. The mechanism of this reaction, which involves formation of an arene oxide intermediate, has been extensively investigated (28).Less well-characterized from the mechanistic standpoint are the enzyme systems that convert sulfides to sulfoxides and sulfones and amines to Nhydroxylated metabolites (10, 17).
2. Peroxidases Enzymes of the peroxidase-type which use hydrogen peroxide as the oxidizing species, are capable of performing oxidative coupling of phenolic alkaloids (16).The commercially available horseradish peroxidase as well as peroxidase preparations from potatoes and other sources have been used in conjunction with hydrogen peroxide to perform these transformations. The
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
327
substrate specificity and regiospecificity of product formation of these systems is usually low, the enzymes apparently serving merely to catalyze the oxidation of the substrate to a phenoxyl radical, which then couples nonenzymically and therefore usually nonspecifically (29, 30).
3. Dehydrogenases Dehydrogenases capable of the introduction of an olefinic bond into a saturated substrate are present in several microorganisms. In many cases, the double bond is introduced into conjugation with a carbonyl group of the substrate, but the presence of an activating carbonyl is not a rigid requirement for dehydrogenase activity. The mechanism and stereochemistry of action of the steroid dehydrogenases has been reviewed recently (2, 12).
4. Alcohol Dehydrogenases This large and diverse group of enzymes catalyzes the reversible alcohol dehydrogenation<arbonyl reduction reaction. A detailed discussion of the utility of this enzyme-catalyzed process in organic synthesis, together with details of the mechanism and stereochemistry of the reaction, has appeared recently (12). The enzymology of alcohol dehydrogenases has also been recently discussed (31). The key role played by these enzymes in normal metabolism is reflected by their widespread occurrence (31).This, together with the low substrate specificity of several common enzymes of this type, such as the liver alcohol dehydrogenases, has ensured that alcohol-carbonyl interconversion is a frequently observed biotransformation.
D. CONJUGATION Reaction of a substrate with a common constituent chemical of an organism (“conjugation”) may occur in several ways. Generally, these reactions represent a method of detoxification by conversion of a foregin chemical to a less toxic and more polar (and therefore more water-soluble and more easily excretable) derivative. Alcohol or phenol substrates may be converted to acetals of glucuronic acid (“glucuronidation”), sulfate derivatives, or to methyl ethers. Amines may be converted to acetamide derivatives or sulfamate esters, whereas carboxylic acids can be conjugated with the amino group of glycine to give glycine conjugates (9). These reactions, which are common in intact mammals, occur much less commonly with enzyme preparations and are not observed with microorganisms.
328
H. L. HOLLAND
E. PRACTICAL CONSIDERATIONS
The methodology of preparing and working with purified enzyme preparations is often limited by the difficulty of access of the source material (especially for enzymes of mammalian origin) and by the limited stability of the enzymes themselves (32).The scale of such preparations, the low aqueous solubility of most substrates, and the inability of many of the enzymes involved to retain their activity in the presence of even moderate concentrations of organic solvents, severely limit the quantities of substrate that can be transformed. In the majority of cases, only micro- or millimole amounts can be conveniently handled, although in favorable cases gram quantities can be transformed (33, 34).For preparative-scale reactions, transformations with intact microorganisms such as fungi and bacteria are more conveniently carried out. With a growing or resting culture of a microorganism, the quantity of substrate is usually limited only by the volume of the microbial medium present: quantities of 1 mg of substrate per ml of medium are common (24, 25, 35), and higher concentrations can be used (36, 37). With little specialized equipment, transformations of up to 10 g of substrate can therefore be readily carried out in the average chemical laboratory. The techniques of enzymic (12) and microbial (17 ) transformation have been recently discussed and compared. 111. Transformation of Indole Alkaloids
A summary of the transformations of indole alkaloids is presented in Table I(38-54). A. BRUCINE Following their earlier observation that the urine collected from rabbits that had been administered brucine (1) contained the phenolic metabolites 2-methoxy-3-hydroxystrychnine(2) and 2-hydroxy-3-methoxystrychnine (3), Watabe et al. (38)obtained a rabbit liver homogenate preparation that would effect the same transformations. Incubation of 1 with the 90009 supernatant fraction of rabbit liver homogenate for 1 hr at 37" resulted in 0-demethylation to produce 2 and 3, albeit in low estimated yield. An unidentified nonphenolic metabolite was also formed in low yield. The same preparation was also capable of performing specific 0-demethylations of 4nitroveratrole and 4-acetamidoveratrole. Microbiological systems capable of 0-demethylation of brucine or strychnine have not been identified. The major route of metabolism of these alkaloids by the bacteria and fungi so far investigates is N-oxidation, which in the case of brucine can proceed in yields of up to 50% (55, 56).
TABLE I TRANSFORMATIONS OF INDOLE ALKALOIDS Substrate A. Brucine Brucine (1)
Reagent
Rabbit liver microsomes
B. Corynantheidine and related alkaloids Rabbit liver microsomes Corynantheidine (4) Dihydrocorynantheine (5) lsocorynantheidine (6) Hirsutine (7) Speciogynine (9) Mitraciliatine (10) Mitrdgynine (11) Speciociliatine (12) Paynantheine (13) Mitrajavine (javacillin) (14) Tetraphylline (15) Aricine (16) Reserpinine (17) Ajmalicine (18) Gonyronella urceolifera Polystictus versicoior Piricularia oryzae Tetrahydroalstonine (19) Rabbit liver microsomes Reserpine (21) Mouse liver homogenate
Products"
li;, Yieldb
Ref.
(2-Hydroxy-3-rnethoxystrychnine)(3) (2-Methoxy-3-hydroxystrychnine) (2) (Unidentified nonphenolic base)
38 38 38
LO-(17)-Demethylcorynantheidine] (8) LO-(17)-Demethyldihydroco rynan theine ?] [0-(17)-Demethylisocorynantheidine?]
39,40 39,40 3Y, 40 39.40 40 40 40 40 40 40 40 40 40 40 41 42 42 40 43 43 44
(Unidentified) [0-(17)-Demethylspeciogynine?] (Unidentified) [0-(17)-Demethylmitragynine?] LO-(17)-Demethylspeciociliatine?] [0-(17)-Demethylpaynantheine ?] (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) 10-Hydroxyajmalicine (20) (Unidentified) (Unidentified) (Unidentified) (3,4,5-Trimethoxybenzoicacid) (Methyl reserpate) (22) (3,4,5-Trimethoxybenzoic acid)
(continued)
TABLE I (continued) Substrate
Rescinnamine (23) Rauwolscine (a-yohimbine) (26) Corynanthine (24)
Harman (27) Harmine (28)
Reagent Rat liver homogenate Guinea pig liver homogenate Dog liver homogenate Cat liver homogenate Polystictus versicolor Piricularia oryzae Polystictus versicolor Piricularia oryzae Polystictus versicolor Gongronella urceolifera Polystictus versicolor Piricularia oryzae Polystictus versicolor Cow liver homogenate Mouse liver homogenate Rabbit liver homogenate Guinea pig liver homogenate Rat liver homogenate Cat liver homogenate Polystictits versicolor
C. Lysergic acid and related alkaloids Isolated rat liver LysLrgic acid derivatives (30) Chanoclavine (31) Pigeon liver preparation Agroclavine (33) Rat liver microsomes
Products"
<:
Yieldb
Ref.
(3,4,5-Trimethoxybenzoicacid) (3,4,5-Trimethoxybenzoicacid)
44 44
(3,4,5-Trimethoxybenzoicacid) (3,4,5-Trimethoxybenzoicacid) (Two products) (Unidentified) (Unidentified) (Unidentified) (Unidentified) 10-Hydroxycorynanthine (25) (Unidentified) (Unidentified) (Unidentified) (Harmol) (29) (Harmol) (29) (Harmol) (29) (Harmol) (29)
44 44 42 42 42 42 42 41 42 42 42 45 45 45 45
(Harmol) (29) (Harmol) (29) (Unidentified)
45 45 42
(N-Demethylation) (Elymoclavine) (32) (Noragroclavine) (34) (Elymoclavine) (32)
46 47 48 48
Guinea pig liver micromes
D. Vindoline and related alkaloids Vindoline (38)
Streptomyces sp. A17000
Streptomyces albogriseolus A17178 Streptomyces griseus UI 1158
Deacetylvindoline (39) Vinblastine (46)
3',4'-Dehydrovinblastine(51)
Streptomyces cinnamonensis A15167 Streptomyces albogriseolus A1 71 78 Streptomyces punipalus A36120 Horseradish peroxidase
(Setoclavine) (35) (isosetoclavine) (36) (Penniclavine) (37) (Noragroclavine) (34) (Elymoclavine) (32) (Setoclavine) (35) (Isosetoclavine) (36) (Penniclavine) (37)
48 48 48 48 48 48 48 48
Dihydrovindoline ether (40) 16-Dehydroxy-14,15-dihydro-15, 16-epoxy-14-0x0-3-norvindoline (43) 3-Acetonyldihydrovindoline ether (42)
49 49
N-Demethylvindoline (44) Dihydrovindoline ether (40)
50,51
Dihydrovindoline ether dimer (45) Deacetyldihydrovindoline ether (41)
52 49
N-Demethylvinblastine (47)
51
Vinbkdstine ether (50) 10-Hydroxyvinblastine (48)
53 53
Leurosine (52)
54
Parentheses indicate products not isolated. Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
49
52
332
H. L. HOLLAND
1 R' 2 R' 3 R'
R 2 = CH, Brucine R Z = H 2-Methoxy-3-hydroxystrychnine = H, R Z = CH, 2-Hydroxy-3-methoxystrychnine =
= CH,,
CH,O
H
H configuration C-20
Alkaloid
C-3
4 Corynantheidine 5 Dihydrocorynantheine 6 lsocorynantheidine
x
x
2
B
B B
B
7 Hirsutine
x
B. CORYNANTHEIDINE AND RELATED ALKALOIDS In an attempt to correlate pharmacological activity with the rate of biotransformation, Beckett and Morton have studied the metabolism of a series of indole alkaloids and related model systems by a variety of enzyme preparations of mammalian origin (39, 40, 57-59). Of the systems studied, rabbit liver microsomes were effective in performing O-demethylation ; liver microsome preparations from rat and guinea pig were not very effective in transforming alkaloids 4-7 and 9-19 (but vide infra) (40). In the case of corynantheidine (4), the product of metabolism was identified as the 0-(17)demethyl compound 8 by TLC comparison with authentic material. In all cases, the degree of metabolism was estimated by monitoring both formaldehyde production and the concentration of unmetabolized alkaloid (39, 40). The related alkaloids 5 , 6 , and 7, which differ from corynantheidine only in configuration at C-3 and/or C-20, and the 9-methoxyl analogs 9-13,
5.
333
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
also produced formaldehyde on incubation with rabbit liver microsomes, together with a single Dragendorff-positive nonphenolic metabolite on TLC, which was assumed by analogy with the corynantheidine metabolite to be an 0-(17)-demethyl compound. In the case of hirsutine (7) however, the total metabolism (21%) estimated by determination of remaining substrate was considerably greater than the degree of 0-demethylation indicated by formaldehyde production (lx),indicating appreciable metabolism of this alkaloid by another (unidentified) route. CH,O
I
CH,O
H
I
I H
CH,O
8 0-(17)-Demethylcorynantheidine
H configuration Alkaloid
c-3
c-20
9 Speciogynine
a
LO Mitraciliatine
B
B B
I1 Mitragynine 12 Speciociliatine
z
2
/I
z
The same phenomenon was observed for mitraciliatine (10) and the closed ring E alkaloids 14-19, where the percentage metabolism by 0demethylation estimated by formaldehyde production ( 1%) was much less than the degree of total metabolism (25-69%). Nevertheless, both hirsutine and mitraciliatine gave detectable amounts of a compound assumed by TLC analysis to be an 0-(17)-demethyl metabolite, whereas such was not the case with 14-19. Hirsutine and mitraciliatine were also metabolized (to unidentified products) by both rat and guinea pig liver microsomes, which did not metabolize alkaloids 4-6, 9, and 11-13. Beckett and Morton did not comment on the inability of their rabbit liver microsomal preparation to metabolize the closed ring E alkaloids 14-19. They found no correlation of partition coefficients or pK, values with the degree or type of metabolism of the corynantheidine-type alkaloids 4-7 and 9-13, but explained the observed differences on the basis of the preferred conformations of the members of this series, noting that significant metabolism by a route other than 0-demethylation occurred only with the pseudo
-
334
H. L. HOLLAND
isomers 7 and 10 (42).The preferred conformations of the normal (as in 5, 9, and 13),pseudo (as in 7 and lo), allo (as in 4 and ll),and epiallo (as in 6 and 12) configurations of these alkaloids have been investigated (60)and discussed earlier in this treatise (61): they are presented in Fig. 1. The normal and all0 members of this series show the greatest degree of metabolism, virtually all of which is by 0-demethylation. The alkaloids of epiallo configuration are metabolized to a lesser extent, but still by 0-demethylation, whereas the
normal
pseudo
R R
epiallo
is
R
FIG. 1. Preferred conformations of corynantheidine-type alkaloids
5.
335
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
pseudo alkaloids show negligible 0-demethylation, being metabolized by a different route. Beckett and Morton (40) speculate that this is due to the nonplanar nature of the latter, and postulate the existence of an active site on the 0-demethylating enzyme which prefers a more nearly planar substrate such as the normal or allo configuration provides. The epiallo configuration can approach planarity in a conformation (Fig. 1, lower) that is present to the extent of 25% or more under the conditions of the incubation (40), whereas the pseudo configuration is inevitably nonplanar. The same authors also speculate that the increased degree of metabolism observed with the 9methoxyl series 9-13 compared with the unsubstituted analogues 4-7 may be caused by a higher electron density in the indole ring of the former compounds resulting in better binding to the enzyme surface (40), but there is no direct evidence of this. CH,O
I
H
CH,O
13 Paynantheine
R' I
H configuration Alkaloid 14 15 16 17 18 19 20
Mitrajavine (Javacillin) Tetraphylline Aricine Reserpinine Ajmalicine Tetrahydroalstonine 10-Hydroxyajmalicine
C-3
C-20
B 1
B B
z
1
2
z
1
B
5(
z
2
B
R'
R2
R3
OCH, H H
H OCH, OCH, H
H H H OCH,
H
H H H
H H H H
H
OH
336
H. L. HOLLAND
Although the closed ring E alkaloids 14-20 were metabolized by the rabbit liver preparation of Beckett and Morton (40), the structures of the metabolites were not discussed beyond the observation that their metabolism was not linked to formaldehyde production. Alkaloids of this type are, however, hydroxylated by several microorganisms in the 10 or 1 l positions (11). A recent report on the incubation of ajmalicine (18) and corynanthine (24) with Gongronellu urceoliferu states that the organism introduces a 10hydroxyl group, giving 20 and 25, respectively, 10-hydroxycorynanthine (25) being produced in a yield of 68% (41). Ajmalicine is also transformed by Polystictus uersicolor to give 75% of an unidentified metabolite more polar than the starting material and by Piriculuriu oryzue to give unstated products (42). In contrast to the oxidative reactions discussed above, the only reported biotransformations of reserpine (21) and rescinnamine (23) (42-44) appear to involve hydrolytic processes. Reserpine is readily metabolized by liver homogenates from the mouse (43),rat, guinea pig, dog, and cat ( 4 4 )to yield methyl reserpate (22) and 3,4,5-trimethoxybenzoic acid in yields of up to 70% (43).The use of reserpine labeled with tritium in the 2 and 6 positions of the trimethoxybenzoate residue indicated that no significant metabolism of reserpine by another route occurred before hydrolysis, reserpine and 3,4,5-trimethoxybenzoic acid being the only detectable radioactive components of the incubation mixture at the conclusion of the reaction (44). An
CH ,O,C+OR
OCH,
a
OCH, 22 R
=
H
Methyl reserpate 0
23 R
=
--C-CH=CH
C :H
OCH,
Rescinnamine
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
337
apparent requirement of reserpine metabolism for molecular oxygen and NADPH, the normal cofactors of monooxygenase enzyme systems, is unexplained, although the formation of a short-lived intermediate by an oxidative step, which precedes the hydrolytic reaction, has been postulated (43). Resperine is also transformed by Polystictus versicolor and by Piriculariu oryzue (42), the former microorganism giving two products. In neither case were the products identified beyond the statement that Dragendorff-negative blue or green fluorescent spots were detected on TLC. The same microorganisms are capable of biotransformation of rescinnamine (23), Polystictus versicolor producing 90% of an unidentified Dragendorffpositive metabolite. This organism also transforms rauwolscine (26), giving 50% of a substance analyzed only by TLC (42). The simple indole alkaloids harman (27) and harmine (28) are also SUSceptible to biotransformation. Polystictus versicolor metabolizes both 27 and 28 to unidentified products, formed in a yield of 50% in the case of 28 (42). Mammalian liver preparations perform an oxidative 0-demethylation of harmine (28) to produce harmol(29) (45).The supernatant fraction from the 10,OOOg centrifugation of liver homogenates of cow, mouse, rabbit, guinea pig, rat, and cat were all effective in 0-demethylation, the highest yields (90%)being obtained after incubation for 30 min with the preparations from cow and mouse liver (45). No other products were detected from the biotransformation of harmine by the liver preparations mentioned above,
24 R
=
H Corynanthine
25 R = OH 10-Hydroxycorynanthine
26 Rauwolscine (r-Yohimbine)
27 R : H Harman 28 R = OCH, Harmine 29 R = OH Harmol
338
H. L. HOLLAND
although in ciuo studies on harmine metabolism have found that the initially formed harmol is subsequently conjugated to form the sulfate ester or gluconuride (62, 63).
C. LYSERGIC ACIDAND
RELATED
ALKALOIDS
Alkaloids of this group are susceptible to oxidative biotransformations by many microorganisms resulting in N-demethylation, C-hydroxylation, or ring-closure reactions (11). Many of the observed biotransformations parallel or are closely related to processes thought to occur in the normal biosynthesis of the ergot alkaloids and may indeed involve the same or similar enzyme systems to those responsible for the normal production of the alkaloids themselves (11, 64, 65). Several key reactions of this type are also performed by mammalian liver preparations. Thus, lysergic acid derivatives of type 30 are susceptible to N-(6)-demethylation and to side-chain hydroxylation by isolated rat liver preparations (46);and in a direct parallel to its normal biogenesis (66,67), elyrnoclavine (32) is produced, although in low yield, from chanoclavine (31) in the presence of a commercial preparation from pigeon liver (77, 68).
3
T
;
&;;F3
K J
J
I
1
I
/
HOH,C
;
&
\.
1
1
R'
H
H
30
3 I Cha noclavine
32 Elymoclablne
The key position of agroclavine (33) in the production of clavine-type alkaloids (69)prompted Ramstad and co-workers to investigate the metabolism of this alkaloid by preparations of rat liver and guinea pig adrenal microsomes (48). Previous work with isolated horseradish peroxidase (70) had shown that agroclavine was converted to setoclavine (35) and isosetoclavine (36) by this enzyme, and indeed these were among the products formed by the mammalian microsomal systems. The enzyme preparations from both rat and guinea pig converted agroclavine to noragroclavine (34), elymoclavine (32), setoclavine (35), isosetoclavine (36), and penniclavine (37) (48). The N-demethylation carried out by these systems was monitored by release of formaldehyde and by the conversion of [ 4C]agroclavine (produced biosynthetically from ['4C]tryptophan) to [14C]noragroclavine. The other oxidative reactions carried out by the microsomal preparations are stated
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
339
to be comparable to normal biosynthetic processes involving agroclavine (71).
Hllll
I
1 H
33 R = CH, Agroclavine
34 R
=
H Noragroclavine
H
35 R' 36 R ' 37 R'
= OH, R 2 = CH, = CH,, RZ = OH
Setoclavine Isosetoclavine = OH, R 2 = CH,OH Penniclavine
38 R 39 R
= COCH, =H
Vindoline Deacetylvindoline
D. VINDOLINE AND RELATED ALKALOIDS The pharmacological significance of the antineoplastic agents vinblastine (46) and vincristine has promoted considerable interest in biological transformations of alkaloids of this type in the search for new and more effective antitumor agents. Following an initial report of the screening of over 400 microorganisms for their capacity to transform vindoline (38) (72),the Eli Lilly group has published details of the transformations of vindoline (38) deacetylvindoline (39), and vinblastine (46) by Streptomyces species (49-51, 53). In a parallel study, Rosazza and co-workers (52) have also investigated the transformations of vindoline by Streptonzyces grisrus. The Eli Lilly workers found that incubation of vindoline with Strepproniyces sp. A1 7000 gave a complex mixture of products, from which they were able to isolate dihydrovindoline ether (40) and 16-dehydroxy-14,15-dihydro15,16-epoxy-l4-0~0-3-norvindoline (43) in low yield (49). The structure of 40 was determined by comparison of its PMR and mass spectral data with those of the previously described dcacctyldihydrovindoline ether (41) and the alkaloid cathanneine (cathoclavine) (53) (73-75). Confirmation of the
340
H. L. HOLLAND
ether linkage to C-15 was obtained by spin decoupling of the C-14 and C-15 hydrogens. Irradiation at 6 2.02 ppm (C-14 hydrogens) caused the doublet of doublets at 6 4.05 ppm assigned to the C-15 hydrogen to collapse to a singlet. The same phenomenon was observed for 41 (vide il2fua) (49). The structure of the other product isolated from this incubation 43 was assigned by a combination of spectral data. The absence of a strongly basic nitrogen atom, the presence of an additional band at 1750 cm-' in the infrared spectrum assigned to a lactam carbonyl, and the appearance in the PMR spectrum of the C-15 hydrogen as a sharp singlet all indicated the presence in 43 of the five-membered lactam ring E. This structure was also in agreement with 220-MHz PMR data, which indicated the presence of only two methylene groups (apart from that of the C-20 ethyl unit), namely those at C-5 and C-6. The mass spectrum of 43 contained several ions absent from the spectra of related compounds such as vindoline, those at mle 124 and 297 being assigned the structures shown in Fig. 2 by high-resolution analysis, and again indicating the presence in 43 of the five-membered lactam moiety (49).
niie
124 (C,HIoNO)
iw:e 297 (C,,H,,N,O,)
FIG.2. Characteristic fragment ions of 43 (49).
The same group also studied the transformation of vindoline by Streptomyces albogriseolus A1 7178 and again were able to isolate two metabolites, 3-acetonyldihydrovindoline ether (42)and N-demethylvindoline (44) (49-51). The major product of metabolism 42 contained 56 mass units more than
40 R L= H, R' = COCH, Dihydrovindoline ether 41 R ' = R 2 = H Deacetyldihydrovindoline ether
42 R'
= CH,COCH,,
R 2 = COCH, 3-Acetonyldihydrovindolineether
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
34 I
43 16-Dehydroxy-14,15-dihydro-l5,16-epoxy-14-oxo-3-norvindoline
dihydrovindoline ether and, like the latter, exhibited a one-proton multiplet in the PMR spectrum at 6 4.06 ppm which collapsed to a singlet on irradition at 6 2.0 ppm. The signal at 4.06 ppm was thus assigned to the C-15 hydrogen in a dihydrovindoline ether-type linkage and that at 6 2.0 ppm to the C-14 methylene hydrogens. The PMR spectrum of 42 also contained a threeproton singlet at 6 2.17 ppm not present in starting material or 40 and an additional carbonyl absorption in the IR spectrum at 1710 cm- The structure was thus formulated as 42, the extra 56 mass units being contributed by an acetonyl side chain. The site of attachment of the latter was determined to be C-3 by a combination of PMR and mass spectral analysis. The characteristic fragment ions of the spectrum of 42 which led to this conclusion are in Fig. 3 (49). The other product of this incubation, the N-demethyl compound 44, was again identified by spectral analysis (50).High-resolution mass spectral data led to the identification of the fragments shown in Fig. 4,
m:’e 338 (C,,H,,NO,)
m,e
353 (C2,H2,NZ02)
FIG 3. Characteristic fragment ions of 42 (49).
m e 174(CllH12NO)
w e 283 (C,,H,3N,0)
FIG.4. Characteristic fragment ions of 44 (50).
342
H. L. HOLLAND
and these, together with the appearance of N-H stretching in the IR spectrum at 3420 cm- and the lack of the N-CH, signal in the PMR spectrum, suggested that this metabolite was the N-demethyl compound 44. Final confirmation of this structure was obtained by conversion of 44 to vindoline by reaction with formaldehyde in the presence of hydrogen and palladium (50). The transformation of vindoline by a related microorganism, Srreptomyces yriseus, has also been reported (52). The major product was once again dihydrovindoline ether (40), isolated in 28% yield. A second metabolite, isolated in 10% yield, was formulated as the dihydrovindoline ether dimer 45. High-resolution MS analysis showed a molecular ion at m/e 908 of composition C,,H,,N,O,,. The mass spectral fragments of 45 which reveal the dimeric nature of this metabolite are shown in Fig. 5. The other fragment ions observed in the mass spectrum of this compound are formed by processes characteristic of related alkaloids such as vindoline and dihydrovindoline ether (49, 76). The structure of 45 was eventually determined by a combination of CMR and PMR spectral analysis (52)of the compound itself and of the sodium borohydride or hydrogen-palladium reduction product. The latter showed a molecular ion at mje 910, suggesting the presence in 45 of
'
M-C,H,
M-CH,CO,
m/e 879 (1 7) m/e
849 ( 3 3 )
a+b
A
a
mie 749 (100)
-CH,CO,
OCH, mle
661 (12)
45 m / e 908
(42) m/e 454 (52)
mle 395 (31)
FIG5. Mass spectral fragmentation of dihydrovindoline ether dimer (45) (52).
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
343
one double bond relative to starting material, and its availability by sodium borohydride reduction indicated the existence of this additional unsaturation as an enamine. The CMR spectra of dihydrovindoline ether and of the dimer 45 were tentatively assigned by Rosazza and co-workers, and their assignments are listed in Table 11. The resonances were assigned by comparison with published spectra of similar alkaloids (77, 78) and by the analysis of broad band and off-resonance data (52). The CMR data, together with a
TABLE I1 I3CMR ASSIGNMENTS OF DIHYDROVINDOLINE ETHER(40) A N D THE DIMER 45
Carbon 2 3 3-olefin 5 6 7 8 9 10
11 12 13 14 14-olefin 15 16 17 18
19 20 21 Acetyl carbonyl Ester carbonyl Aryl OCH, Ester OCH, N-CH, Acetyl-CH,
40
45
84.9 46.6*
84.8, 83.7 46.0* 136.2 52.0, 5 1. I 49.1*, 46.0" 53.3*, 51.5* 130.5, 130.3 121.7, 121.0 103.7, 103.2 161.0, 160.9 95.0, 94.7 151.7, 150.5 22.3 111.9 79.3, 76.8 88.3, 85.8 74.8, 74.1 9.1, 8.5 32.5, 29.7 48.5*, 46.6* 67.6, 66.2 170.2, 169.9 169.3, 168.9 55.3, 55.2 52.4, 53.0 36.9, 36.0 20.9, 20.9
50.9 46.3* 52.3* 130.3 120.8 103.2 160.9 94.6 150.5 22.2 77.6 88.1 74.8 9.0 24.8 41.Q 67.1 169.8 168.9 55.2 54.4 36.0 20.8
Chemcial shifts marked with asterisks may be interchanged.
344
H . L. HOLLAND
OCH,
44 N-Demethylvindoline
45 Dihydrovindohne ether dimer
detailed analysis of the PMR spectrum of 45, allowed the site of linkage of the monomer units to be identified as C-3’-C-14. The location of one site of attachment as C-14 of a vindoline ether unit was confirmed by the observation of a singlet olefinic hydrogen (that at C-3) in the PMR spectrum at 6 6.1 1 ppm and a singlet at 6 4.26 ppm, assignable to the C-15 hydrogen of the same moiety. A band at 1653 cm-’ in the infrared spectrum of 45 was attributed to the presence of an enamine unit, as was the reactivity with sodium borohydride. The conclusion that the site of attachment to the other monomer unit was C-3’ was made by analysis of the PMR signal at 6 4.1 pprn, assigned to the C-15’ hydrogen. This appeared as a broad signal whose multiplicity and breadth was attributed to the presence of two nonequivalent hydrogens at C-14’. Nevertheless, as the authors point out (52), their data does not absolutely preclude the site of attachment to this unit from being C-5’ or C-6’. Rosazza et al. (52)have proposed the mechanism shown in Fig. 6 for the formation of both dihydrovindoline ether and its dimer from vindoline. This mechanism, which proposes an intermediate enamine-immonium ion species 54-55 produced by N-oxidation, followed by intramolecular attack of the C-I6 hydroxyl oxygen, also accounts for the formation of 3-acetonyldihydrovindoline ether 42 from vindoline by Streptomyces albogriseolus (49). Reduction of the immonium ion 55 thus leads directly to dihydrovindoline ether, whereas its capture by acetoacetate or the enamine 54 (79) leads to 42 and 45, respectively.
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
345
\-oxidation
A
OAc R
R
i
38
$ OAc
(
R
R 54
acetodcetate
OAc
40
R 55
FLG.6. Mechanism of the metabolism of vindoline (38)by Streptornyces griseus
Deacetylvindoline (39) is transformed by Streptomyces cinnamonensis A151 67 in a manner analogous to the major transformation route of vindoline by similar organisms, giving deacetyldihydrovindoline ether (41) in low yield (49).The structure of 41 followed from analysis of the PMR spectrum in which decoupling of the C-14 and C-15 hydrogens at 6 1.93 and 4.22 ppm once again confirmed the presence of the C-15-C-16 ether bridge (49). Transformations of the dimeric alkaloid vinblastine (46) by Streptoniyces species have been reported which involve N-demethylation (54,aromatic hydroxylation (531,and intramolecular ether formation (53).With Streptomyces albogriseolus, N-demethylation occurs in an undisclosed yield to produce 47 (51).The same organism in the hands of the same workers is also reported to lead to the formation of vinblastine ether (50) in low yield, along
346
H. L. HOLLAND
cH3u C H&,02 : RC
7
-
46 R ' = H. R 2 = CH, Vinblastine 47 R 1 = R 2 = H N-Demethylvinblastine 48 R ' = OH, R Z = CH, 10'-Hydroxyvinblastine 49 R 1 = OCH,. R 2 = CH,
50 Vinblastine ether
with other unidentified metabolites (53). The structure of the ether 50 was determined by IR, PMR, and MS analysis. The I R spectrum of 50 revealed the absence of the N-H band characteristic of the spectrum of the starting material; this was also apparent from PMR data. Bands attributable to a strongly hydrogen bonded OH were present in both the I R (2700-2800 cm- ') and P M R (6 9-10 ppm) spectra of 50. The structure of 50 was confirmed by high-resolution MS data, which is summarized in Fig. 7. The fragmentation pattern was deduced by analogy with that established for vinblastine (46) (80). Vinblastine is also transformed by Streptomyces punipalus A361 20 to give 10'-hydroxyvinblastine (48) in 9% yield (53). Hydroxylation of indole alkaloids at C-10 had been observed previously with yohimbine and related compounds (81, 82). The structure of 48 was deduced from spectral analysis of the phenol and of the methoxyl derivative 49 produced by treatment of 48 with diazomethane (53). The appearance of signals at 6 6.91 (singlet, C-9' hydrogen) and 6.71/6.95 ppm (AB quartet, C-11' and C-12' hydrogens) in the PMR spectrum of 48 were particularly characteristic of the presence of the C-10' hydroxyl function. In a study using a commercially available horseradish peroxidase preparation, Stuart and co-workers accomplished the conversion of 3',4'anhydrovinblastine (51) to leurosine (52) in a maximum yield of 65'1, (54). This conversion can be carried out by a variety of oxidizing agents including
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
m e 749
-CH,CO, 4
50
m
347
e 808 (C,,H,,N,O,)
m)’e 352 (100) (C,,H,,N,O,)
540 (C,,H,,N,O,)
FIG.7. Mass spectral fragmentation of vinblastine ether (50)
atmospheric oxygen (83-86), an observation which led to the proposal that leurosine may be an oxidative artifact of isolation (86). However, Stuart et al. (54) were able to demonstrate that the conversion of 51 to 52 was performed efficiently by horseradish peroxidase in the presence of hydrogen peroxide and, less efficiently, by a cell-free extract of Catharanthus roseus leaves under the same conditions. Hydrogen peroxide alone did not lead to the formation of significant amounts of leurosine under the conditions of incubation. They therefore suggested that leurosine is in fact a “natural” product, and that it may be formed by the action of a peroxidase-type enzyme on 3’,4‘-anhydrovinblastine.
34 8
H. L. HOLLAND
CH,O
H
51 3’,4’-Anhydrovinblastine
52 Leurosine
53 Cathanneine (Cathoclavine)
IV. Transformations of Isoquinoline Alkaloids The transformations discussed below are summarized in Table I11 (42, 8 7- 118).
A. APORPHINES The pharmacological properties of the natural and synthetic aporphines such as apomorphine (119, 120) have ensured the thorough investigation of the ir? vivo mammalian metabolism of this class of compounds. Reported reactions include glucuronidation (124, 0-methylation (91, 122) O-demethylation ( 1 2 4 , and N-demethylation (123). Studies in vitro with enzyme preparations and in uivo with microorganisms reveal a similar pattern of metabolism. Smith and Sood (87) examined the transformations of nuciferine (57) and its IV-alkyl analogs 58-63 by liver microsomes from the rat, rabbit, and guinea pig. With the enzyme preparation from the latter source they observed
TABLE 111 TRANSFORMATIONS OF ISJQUINOLINE ALKALOIDS Substrate
Reagents
ProductQ
Yield’
Ref.
-
A. Aporphines Nornuciferine (56) Nuciferine (57)
Rat liver microsomes Rabbit liver microsomes Rat liver microsomes Rabbit liver microsomes
58
59
60 61 62 63
(S)-Boldine (65)
10,l I-Dimethoxyaporphine (72)
Guinea pig liver microsomes Rat liver microsomes Rabbit liver microsomes Guinea pig liver microsomes Rat liver microsomes Rabbit liver microsomes Guinea pig liver microsomes Guinea pig liver microsomes
Horseradish peroxidase Piricularia oryzar Cunninghamella bainieri ATCC 3065 Cunninghamella hlukeslreana ATCC 9245 Cunninghamella echinulata NRRL 3655
(Lysicamine) (64) (Lysicamine) (64) (Nornuciferine) (56) (Lysicamine) (64) (Nornuciferine) (56) (Lysicamine) (64) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) (Nornuciferine) (56) Bisboldine (68) Bisboldine ether 70 (Unidentified) (Isoapocodeine) (75) (Unidentified) (Isoapocodeine) (75) (Unidentified) (Apocodeine) (74) (Isoapocodeine) (75) (Unidentified)
x7 x7 87 87 N7 87 87 x7 87 x7 x7 x7 87 87 87 87 87 88 NU 42 X9 89 89 89 x9 89 XY
TABLE 111 (continued)
W VI
0
Substrate
Reagents Helicostylum piriforme QM 6945 Microsporum gypseum ATCC 11395 Mucor mucedo SP-WlSC 4605 Penicillium ducluuxi NRRL 2020 Sepedonium ch ryospermum ATCC 13378 Streptomyces .species SP-WISC 1158
Apocodeine (74)
Streptomyces rimosus ATCC 23955 Rat liver microsomes
lsoapocodeine (75)
Rat liver microsomes
10-Hydroxyaporphine (77) 10-Methoxyaporphine (76) Apomorphine (73)
Rat liver microsomes Rat liver microsomes Rat liver homogenate
(S)-Glaucine (66)
St,vsunus stemonites SC 2831 Penicillium cluviforme MR376 Cunninghumella echinulutu NRRL 3655
Product" (Apocodeine) (74) (Isoapocodeine) (75) (Isoapocodeine) (75) (Unidentified) (Isoapocodeine)(75) (Unidentified) (Isoapocodeine) (75) (Unidentified) (Unidentified) Apocodeine (74) Isoapocodeine (75) (Unidentified) (Apocodeine) (74) (Isoapocodeine) (75) (Apomorphine) (73) (Unidentified) (Apomorphine) (73) (Unidentified) (Unidentified) (10-Hydroxyaporphine) (77) (Apocodeine) (74) (Isoapocodeine) (75) (6a,7-Dehydroglaucine) (79) (Unidentified) (6a,7-Dehydroglaucine) (79) (Unidentified) [0-(9)-Methylboldine] (67) (Unidentified)
7" Yield'
Ref. HY HY 89 89 89 89
89 89 8')
89 89 HY HY
89 Y0 Yf)
90 90 YO
90 91 91 92 92 92 92 92 92
Cunninghamella bainieri ATCC 3065 Streptomyces punipalus NRRL 3529 Streptomyces griseus UI 1 158 Penicillium brevicompactum ATCC 10418 Fusariwn solani ATCC 12823
(RS)-Glaucine (RS)-66 B. Benzylisoquinolines N-Methylcoclaurine (81)
Norlaudanosoline (87)
Fusarium solani ATCC 12823
Potato peel homogenate Nelumbo nucifera Gartner homogenate Rat liver homogenate Rat liver homogenate
Rat brain homogenate
[0-(9)-Methylboldine] (67)
92
[0-(9)-Methylboldine] (67) (Unidentified) 0-(9)-Methylboldine (67) Norglaucine (78) (Norglaucine) (78)
92 92 92 92 92
6a,7-Dehydroglaucine (79) Oxoaporphine 80 (6a,7-Dehydroglaucine) (79) (R)-Glaucine [(R)-661
92 92 92 Y2
Dimer 82 Trimer 85 p - Hydroxybenzaldehyde
93 93 93
(Two unidentified methylated products) (90) (93) (Ring A monomethyl 93) (90)
Y4 95. 96 95, 96 95, 96 95, 96 95, 96 95. 96 97.98 99 98 99 98 99 99 100
(93)
(R,S)-Reticuline (88)
Rat liver homogenate
(Ring A monomethyl 93) (R,S)-Coreximine (91) (R,S)-Scoulerine (94)
(R,S )- N orreticuline (96)
W
Papaver rhoeas homogenate
Pallidine (98) Isoboldine (100) p-Hydroxyreticuline (141)
(continued)
TABLE 111 (continued)
W
ul
h,
Substrate
Reagents
(R,S)-Laudanosine (89)
Rat liver homogenate
Papaverine (106)
Cunninghamella blakesleeana ATCC 8688a Stysanus microsporus UI 2833 Aspergillus niger ATCC 10581 Cunninghamella echinulata ATCC 9244 Microsporum gypsewn ATCC 11395 Rat liver homogenate
Aspergillusjlavus X- 158 Aspergillus alliaceus 3 15 Cunninghamella bainieri 3065
Cunninghamella blakesleeana ATCC 8688a Cunnin$hamella echinulata NRRL 3655 ,, ~
Cunninghamella echinulata ATCC 9244
Product"
% Yieldb
Ref.
(R,S)-Xylopinine (92) (-)-Tetrahydropalmatine (95) (R,S)-Norlaudanosine (87) (R,S)-Pseudocodamine (104)
0.02 0.007 14.1 44.4
98 98 98 101
(Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified)
(-1
101 101 101 101 101
[O-(4')-Demethylpapaverine] (107) [O-(7)-Demethylpapaverine] (108) [6-(6)-Demethylpapaverine] (109) [O-(6)-Demethylpapaverine] (109) 0-(6)-Demethylpapaverine (109) [0-(3')- or -(4)-Demethylpapaverine] [O-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) [0-(3')- or -(4)-Demethylpapaverine] [O-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) [ 0 - ( 3 ' ) - or -(4)-Demethylpapaverine] [O-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) 0-(4)-Demethylpapaverine (107) [0-(7)-Demethylpapaverine] (108) [O-(6)-Demethylpapaverine] (109)
(-1 (-1 (-1
(-1 (-1 (-1 (-1
(Good) 40 (-)
(Trace) (Trace)
(-1 (Trace) (Trace)
(-1 (Trace) (Trace) 21 (Trace) (Trace)
102, 103 102, 103 102,103 103 103 103 103 103 103 103 103 103 103 103 103 103 103
Cunninghamella elegans ATCC 9245 Sepedonium chryospermum ATCC 13378 Streptomyces griseus UI 1158
Streptomyces platensis ATCC 13865
W w v1
C. Bisbenzylisoquinolines and related alkaloids (+)-tetrandrine (111) Cunninghamella blakesleeana ATCC 8688a Cunninghamella blakesleeana ATCC 9245 Cunninghamella echinulata NRRL 3655 Cunninghamella echinulata ATCC 9244 Mucor mucedo U1-4605 Penicillium brevi-compactum ATCC 10418 Streptomyces griseus UI-1 I58 Streptomyces griseus UI-L103 Streptomyces punipalus NRRL 3529 Streptomyces lincolnensis ATCC 25466 Microsporum gypseum ATCC 11395 Aspergillus ochraceus UI 398
[0-(3’)-or -(4)-Demethylpapaverine] [0-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) [043’)-or -(4)-Demethylpapaverine] [0-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) [043’)- or -(4)-Demethylpapaverine] [0-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109) [0-(3‘)- or -(4)-Demethylpapaverine] [0-(7)-Demethylpapaverine] (108) [0-(6)-Demethylpapaverine] (109)
103 103 103 103 103 103 103 103 103 103 103 103
(Unidentified) N-(2)-Nor-(+)-tetrandrine (113) (Unidentified)
101 104 104
“+‘)-Nor-( +)-tetrandrine] (112) [N-(Z)-Nor-( +)-tetrandrine] (113) [N-(T)-Nor-( +)-tetrandrine] (112)
101 104 104
[N-(2’)-Nor-(+)-tetrandrine] (112) [N-(2‘)-Nor-(+)-tetrandrine] (112)
101,104 101,104
[N-(T)-Nor-( +)-tetrandrine] (112) (Unidentified) “-@‘)-Nor-( +)-tetrandrine] (112)
101, 104 104 101,104
[N-(T)-Nor-( +)-tetrandrine] (112)
101, 104
“+‘)-Nor-( +)-tetrandrine] (112) (Unidentified) [N-(Z‘)-Nor-( -t)-tetrandrine] (112)
104 104 104
(continued)
TABLE 111 (conlinued)
W
z Substrate
Thalicarpine (114)
Hernandaline (115)
D. Morphine and related alkaloids Morphine (117)
Reagents Gliocladium deliquescens UI 1086 Streptomyces spectabilicus C632 Mucor microsporus UI-1700 Rhizopus arrhizus QM 1032 Stremphlium solani UI 1805 Streptomyces platensis ATCC 13865 Cunninghamella bainieri UI 3065 Helicostylum piriforme QM6945 Mucor paraciticus M 2652 Fusarium solani ATCC 12823 Streptomyces punipalus NRRL 3529 Strpptomyces griseus UI-1158 Cpninghamella blakesleeana ATCC 8688a Mucor mucedo UI 4605 Streptomyces punipalus NRRL 3529
Horseradish peroxidase Rat liver homogenate
Product‘
+
% Yieldb
Ref.
[N-(2’)-Nor-( )-tentrandrine] (112)
104
[N-(2’)-Nor-(+)-tetrandrine] (112)
104
(Unidentified) (Unidentified) (Unidentified) (Unidentified)
104 104 104 104
[N-(2’)-Nor-(+)-tetrandrine] (112)
104
[N-(2’)-Nor-(+)-tetrandrine] (112)
104
[N-(2’)-Nor-(+)-tetrandrine] (112) (Unidentified) (+)-Hernandalinol(116) (Unidentified) (Unidentified) (Unidentified)
104 105 105 105 105 105
(Unidentified) (Hernandalinol) (116)
105 105
(Unidentified) (Normorphine) (119) (Morphine N-oxide) (121 and/or 123) (Morphine-3-gluconuride) (126) (Morphine-3-gluconuride) (126)
106 107 107 107 108
Rat brain homogenate Guinea pig liver homogenate
Guinea pig liver microsomes
Codeine (118)
E. Phenethylisoquinolines N-Methylhomococlaurine (130)
Homoorientaline (138) F. Miscellaneous Colchicine (142)
Potato peel homogenate Wasabia japon ica Matsumura homogenate Potato peel homogenate Hamster liver microsomes
Rat liver microsomes
Mouse liver microsomes
Mouse brain homogenate
Mescaline (146) W
tn
2-Hydroxymorphine(?) (128) 2-Hydroxymorphine(?) (128) Normorphine (119) Morphine N-oxide 123 Codeine (118) Norcodeine (120) Codeine N-oxide 124 Codeine N-oxide 122 Morphine (117) Normorphine (119)
(6-7) (9-10) 9 0.9 5.3 9.1 19.5 0.1 7.9 2.4
2 3 0.3
Promelanthiodine (132) Dimer 134 Dimer 136 Unidentified 1-Hydroxyhomoorientaline (139)
4
0.5
[O-(2)-Demethylcolchicine] (144) [0-(3)-Demethylcolchicine] (143) [0-(10)-Demethylcolchicine] (145)
(1.3) (15) (Trace)
[O-(3)-Demethylcolchicine gluconuride] (Unidentified) [0-(2)-Demethylcolchicine] (144) [0-(3)-Demethylcolchicine] (143) [0-(10)-Demethylcolchicine] (145) [0-(2)-Demethylcolchicine gluconuride] [0-(2)-Demethylcolchicine] (144) [0-(3)-Demethylcolchicine] (143) [0-(10)-Demethylcolchicine] (145) (3,4,5-Trimethoxyphenylaceticacid) (3,4,5-Trimethoxyphenylacetic acid) (3,4,5-Trimethoxybenzoicacid)
(-1 (-1 (Minor) (Major) (Minor)
(-1 (Minor) (Major) (Minor) (2-8) (Major) (Minor)
107 107 109,110 109,110 109,110 109, 110 109,110 109, 110 109,110 109, 110
111 112 112 112 100 113 113 113 113 113 133 113 113 113 113 113 113 114 115 115
(continued)
TABLE 111 (continued) Substrate
Reagents Mouse liver homogenate Mouse kidney homogenate Mouse heart homogenate
D-(
-)-Ephedrine (148)
Rabbit liver microsomes
Rabbit liver homogenate supernatant L-( +)-Ephedrine
(148)
Rabbit liver microsomes
Rabbit liver homogenate supernatant Salsolinol(l52) (+)-Tubocurarine' (154) (+)-2,3-Dehydroenhetine (158) a
Parentheses indicate not isolated.
Rat liver homogenate Isolated rat liver Rat liver microsomes
Product"
% Yieldb
(3,4,5-Trimethoxybenoic acid) (3,4,5-Trimethoxyphenylacetic acid) (3,4,5-Trimethoxybenzoicacid) (3,4,5-Trimethoxyphenylaceticacid) (3,4,5-Trimethoxybenzoicacid) (3,4,5-Trimethoxyphenylaceticacid) (Norephedrine) (149) (Benzoic acid) (1 -Phenyl- 1,2-propanediol) (Norephedrine) (149) (Benzoic acid) (I-Phenyl- 1,2-propanediol) (Norephedrine) (149) (Benzoic acid) (1 -Phenyl- 1,2-propanediol) (Norephedrine) (149) (Benzoic acid) (l-Phenyl-l,2-propanediol) (Mono-0-methylsalsolinol) (No biotransformation) (No biotransformation)
* Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
Ref. 115 115 115 11.5 115 115 116 116 116 116 116 116 116 116 116 116 116 116 94 117 118
5.
357
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
R'O
56 57 58 59
60 61 62
63
R = H Nornuciferine R = CH, Nuciferine R = CH,CH, R = CHlCH2CH3 R =C H , 4 R = CH,CH=CH, R = CH2C-CH R = CH,C,H,
65 R' = R2 = H (S)-Boldine
66 R'
= R2 = CH,
(S)-Glaucine
67 R' = H, R2 = CH,
64 Lysicamine
(S)-O-(9)-Methylboldine
N-dealkylation in all cases, leading to the formation of nornuciferine (56) in low yield. The rates of N-dealkylation of 57-63 were inversely proportional to the size and complexity of the N-alkyl group. In addition to nornuciferine, both rat and rabbit liver microsomes coverted nuciferine to the oxoaporphine (64) in a yield of less than 1%. Lysicamine was identified by TLC and spectral comparisons with a sample produced by the photochemical air oxidation of nornuciferine in chloroform solution (87, 124). Although lysicamine may therefore be formed by autoxidation of nornuciferine, the use of the appropriate blanks in the enzymic studies indicated that the transformation was indeed an enzymic one under the incubation conditions used (87). No 0-demethylation was observed in the above study, but Smith and co-workers later reported (90) a preparation of rat liver microsomes which performed the 0-demethylation of apocodeine (74) to apomorphine (73),of isoapocodeine (75)to 73, and of 10-methoxyaporphine (76) to 10-hydroxyaporphine (77). The same group has also isolated a catechol 0-methyltransferase from rat liver, which was used to carry out the methylation of apomorphine to yield both apocodeine and isoapocodeine in a ratio of 81 : 1 (91).
6
CH30
OR
OR
68 R
=H
Bisboldine
69 R = AC
358
H. L. HOLLAND
OR 70 R = H Bisboldine ether 71 R = AC
The only other reported transformation of an aporphine alkaloid by a purified enzyme preparation involves the dimerization of (S)-boldine (65) by horseradish peroxidase in the presence of hydrogen peroxide (88). Two products were isolated, both in moderate yield, and were formulated as 68 (12%) and 70 (8%). In spite of the description of the major product as an (S,S)-dimer, the configurations at C-6a and C-6a’ were given as shown in structure 68 [C-6a(S), C-6a’(R)]. The (S,S)-dimer has the opposite configuration at C-6a‘ to that shown. Similar comments apply to dimer 70 which, as formulated by Stuart and Callendar (88), is an (R,R)-isomer. Irrespective of the configurations at C-6a and C-6a’, the gross structures of 68 and 70 were determined as follows. The PMR spectrum of 68 showed signals in the aromatic region at 6 6.05 (2H, C-3 and C-3’ hydrogens) and 7.56 ppm (2H, C-11 and C-11’ hydrogens), assigned by comparison with the spectrum of starting material, and indicative of a C-8-8’ linkage. The mass spectrum of 68 did not show a molecular ion, but that of a tetraacetate derivative 69 was interpreted on the basis of the mass spectral behavior of the aporphines (125, 126) as diagnostic of the carbon-carbon dimeric structure proposed. Stuart and Callendar point out that although restricted rotation about the C-8-8’ bond of 68 leads to the possibility of the existence of 68 as a pair of diastereomers, only one isomer was formed in the enzymic dimerization. The structure of dimer 70 was determined by PMR spectroscopy of 70 and the triacetate derivative 71, the appearance in the aromatic region of the spectrum of 70 of signals at 6 6.03 (2H, C-3 and C-3’ hydrogens), 7.20 (1H and C-8 hydrogen), and 7.57 ppm (2H, C-11, and C-11’ hydrogens) indicating the formation of an 0-(9)-C-8’ dimer (87). Transformations of aporphines by microorganisms involving 0- and N-demethylation (89,92) and CH-CH dehydrogenation (92) have been reported. In a preliminary screening study, Wolters reported the metabolism of boldine and a related alkaloid of undisclosed structure to unidentified products by Piricularia oryzae (42). More detailed studies with a series of microorganisms have been carried out by Rosazza and co-workers (89,92).
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
359
In a study aimed at identifing microbial systems that would mimic the mammalian metabolism of 10,ll-dimethoxyaporphine(72), they screened 65 microorganisms for their capacity to transform 72 (89). Of these, 10 produced identifiable metabolites in reasonable yield (see Table 111). These transformations involved 0-demethylation to produce apocodeine (74) and/or isoapocodeine (75), maximum isolated yields being given by Streptomyces species sp-Wisc. 1158(74,24%and 75,19.5%).Cunninghamella blakesleeana ATCC 9245 converted 72 quantitatively to isoapocodeine, assayed by spectral analysis but not isolated. Highly polar, unidentified metabolites were formed along with 74 and/or 75 by most of the microorganisms investigated.
72 R' = R2 = OCH, 10,ll-Dimethoxyaporphine 73 R' = R 2 = OH Apomorphine 74 R' = OCH,, R2 = OH Apocodeine 75 R' = OH, R2 = OCH, Isoapocodeine 76 R' = OCH,, R2 = H 10-Methoxyaporphine 77 R' = OH, R2 = H 10-hydroxyaporphine
C H , O V OCH, 78 Norglaucine
OCH, 79 6a,7-Dehydroglaucine
In a later investigation of the microbial transformation of (S)-glaucine (66), Rosazza's group identified microorganisms that performed 0- and N-demethylation as well as stereospecific CH-CH dehydrogenation (92). Maximum isolated yields of norglaucine (78) (1 1%) were produced by Streptomyces griseus UI 1158, which also produced the 0-(2)-demethyl metabolite, 0-(9)-methylboldine (67), in a yield of 14%. The site of 0demethylation in 67 could not be determined by PMR analysis of the signals for the remaining methyl hydrogens, but was confirmed by titration of a solution of 67 in DMSO-d,/D,O with NaOD. Demethylation at 0 4 2 ) relative to glaucine was indicated by the observation of a large upfield
360
H. L. HOLLAND
shift of the resonance assigned (127) to the C-3 hydrogen of 67. Further evidence for the structure of 67 was obtained by comparison with a sample produced by monomethylation of boldine (65) with diazomethane. The dehydrogenation of 66 to 6a,7-dehydroglaucine (79) proceeded in a yield of 60% with Fusarium solani ATCC 12823. This microorganism also produced a 21% yield of the oxoaporphine 80, but control experiments indicated that the latter was an artifact produced by air oxidation of 79 during the incubation. CH,O
OH
OCH, 80
81 N-Methylcoclaurine
In an attempt to determine whether the metabolism of glaucine was a stereospecific process, (R,S)-glaucine was incubated with both Streptomyces griseus (giving 67 and 78) and Fusarium solani (giving 79 and 80). In the former case, recovered starting material was not optically active, indicating no preference for either enantiomer of the substrate in either 0-or N-demethylation. However, glaucine recovered after six days incubation with F. solani, when approximately one-half of the substrate remained, was determined to be 75.4% enantiomerically pure (R). Monitoring of the incubation indicated that after seven days, the residual glaucine was essentially the pure (R) enantiomer, although at this time little substrate remained unmetabolized.
B. BENZYLIS~QUINOLINES As part of their program of study of neuroamine metabolism in mammals, Davis and co-workers investigated the biotransformations of norlaudanosoline (87) by rat liver and by brain preparations. They were successful in isolating a catechol 0-methyltransferase enzyme system from rat liver which performed methylations of 87 to give two upidentified products (94); and later they obtained soluble enzyme preparations from rat brain and liver which, in the presence of [14C]methyl-S~denosylmethionine, gave three radioactive metabolites identified by mass spectral analysis as 90, 93, and a ring A monomethyl derivative of 93 (95, 96). Other investigations of benzylisoquinoline biotransformations have been made by the groups of Kametani and Rosazza. The Japanese workers
36 1
5. ENZYMIC TRANSFORMATIONS OF ALKALOIDS
began their investigations of the biotransformations of this group of alkaloids with a study of the metabolism of N-methylcoclaurine (81) by potato peel homogenate and by homogenized rhizome of Nelumbo nucifera Gartner (93). The latter preparation gave p-hydroxybenzaldehyde as the only isolable product, a result in line with the earlier work of Baxter et al. (128)on the oxidation of related synthetic benzylisoquinolines by horseradish peroxidase-hydrogen peroxide. Incubation of 81 with potato peel homogenate-hydrogen peroxide, however, led to the formation of the head-to-tail dimer 82 and trimer 85, isolated as the corresponding acetates 83 and 86, respectively, in low yield (93). The determination of the structures of 83 and 86, obtained in only milligram quantities, relied heavily on the interpretation of mass spectral data. Major fragment ions in the spectrum of 83 were interpreted as arising from the cleavage of bonds a-d, and subsequent breakdown of fragments so produced. Cleavage of the analogous bonds a-c of 86 resulted in a fragmentation pattern which accounted for the major ions of its spectrum. Other spectral data obtained for 83 and 86 did not permit unequivocal structure determination to be made, but the structure proposed for 83 was strengthened by a detailed comparison of its mass spectrum with that of the known alkaloid neferine (a), a constituent of Nelumbo nucifera Gartner (129). CH,O R'O%
0 b\
'
/ OR2 \
OR'
82 R1 = RZ = H 83 R' = R2 = Ac 84 R' = CH,, R2 = H Neferine
NCH,
85 R = H 86 R = A c
362
H. L. HOLLAND
The tetrahydroisoquinoline alkaloids reticuline (88), a common precursor in the biogenesis of many isoquinoline and related alkaloids (130, 131), and laudanosine (89) are susceptible to biotransformation by both mammalian and microbial systems. In the case of the former it is interesting to note that many of the reported biotransformations appear to parallel reactions thought to be involved in the biosynthetic processes that involve reticuline as substrate (97-99). Following their observation that ( +)-reticuline was converted to coreximine (91) by female rats (132),Kametani and co-workers extended their investigation of reticuline biotransformation to include rat liver homogenate and were able to demonstrate the conversion of (R,S)reticuline to (R,S)-coreximine (91) (97-99), (R,S)-scoulerine (94) (98,99), (R,S)-norreticuline (96) (98), pallidine (98), and isoboldine (100) (99). No detectable amounts of the 0-0 coupled corytuberine (102) or p-o coupled salutaridine (103) were present in any of the incubations with reticuline as substrate (99).They also demonstrated the analogous conversion of (R,S)laudanosine (89) to (R,S)-xylopinine (92) (98), ( -)-tetrahydropalmatine (95) (98),and (R,S)-norlaudanosine (97) (98).
R'oqNR '
R20
OR2 87 R' = RZ = H Tetrahydropapaveroline
(Norlaudanosoline) 88 R' = CH,, R2 = H Reticuline
89 R'
=
90 R ' = R 2 = H 91 R' = CH,, RZ = H Coreximine 92 R' = R 2 = CH, Xylopinine
R2 = CH, Laudanosine
OH 93 R' = R2 = H 94 R' = CH,, R2 = H Scoulerine (Aurotensine) 95 R' = R2 = CH, Tetrahydropalmatine
100 R 101 R
=H =D
,
Isoboldine
5.
363
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
The biotransformations of reticuline involve N-demethylation (to 96), phenolic oxidative coupling in a manner analogous to that observed in alkaloid biosynthesis (to 98 and loo), and ring closure similar to that observed in protoberberine biosynthesis (to 91, 92, 94, and 95). Kametani et al. (97,98) have suggested that N-demethylation and protoberberine formation may occur through the intermediacy of an immonium cation derived from the N-methyl group of reticuline either by N-oxidation followed by rearrangement or by C-hydroxylation and loss of OH-, as shown in Fig. 8. However, in a later paper (99)they reported the biotransformation of reticuline-d, labeled with deuterium at the N-methyl group, C-1, and the attached benzylic methylene position. Mass spectral analysis of the isoboldine (101)and pallidine (99)so derived indicated that all the deuterium was retained intact during their formation. However, some of the scoulerine and coreximine produced from the same incubation contained two deuterium atoms fewer than anticipated. The characteristic mass spectral fragmentation pattern of the protoberberine alkaloids (133) indicated that the deuterium label at C-1 and the benzylic u positions had remained intact, and that loss of label had occurred from the N-methyl (now C-8) position. N-oxidation
C-hydroxylation
7=v
I
I
CH,O HO
HO
y 7 J \
U
O
OCH, OCH,
C
H
Zure
91 o r 9 4
FIG.8. Biotransformations of (+)-reticuline (88)by rat liver homogenate (97,98).
364
H. L. HOLLAND
This observation was explained by the assumption that a portion of the protoberberine was formed via norreticuline (96) present in the same incubation mixture and derived from enzymic demethylation of reticuline. Reaction of 96 with an unlabeled one-carbon fragment and subsequent ring closure would then lead to C-8 unlabeled protoberberines. The authors suggest that this one-carbon fragment may be derived from S-adenosylmethionine, and that the product of its combination with 96 may be converted directly to 91 or 94 without the intermediacy of free reticuline (99). If their assumption is correct, the conversion of norreticuline to the protoberberine alkaloids may not involve the formation of reticuline itself, a suggestion that is at variance with the known intermediacy of reticuline in the biosynthesis of alkaloids of this group. In addition to the transformations by rat liver enzymes discussed above, (R,S)-laudanosineis metabolized by a variety of microorganisms to produce products that include the 0-demethyl compound pseudocodamine (104) (101). Of over 60 microorganisms screened, Cunninghamella blakesleeana ATCC 8688a gave the highest isolable yield of 104 (44%). The structure of 104 was confirmed by a classical oxidative degradation of the 0-ethyl ether 105 to 4-ethoxy-3-methoxybenzoicacid (101). In incubations of 89 with C .
CH30
RO
OR CH,O 0 96 R = H Norreticuline 97 R = CH, Norlaudanosine
98 R = H Pallidine 99 R = D
CH30
CH,O 102 Corytuberine
103 Salutaridine
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
365
104 R = H Pseudocodamine 105 R = C,H,
blakesleeana, neither product 104 nor recovered substrate showed any optical activity, indicating that this microbial 0-demethylation is not a stereoselective process (vide supra, 92). The mammalian metabolism of the isoquinoline papaverine (106) has been studied both in vivo and in vitro (102, 103), and its microbial degradation has also been examined (103). The 0-demethylation and conjugation observed in vivo is paralleled by 0-demethylation with rat liver 0-(6)-, and 0-(7)-demethyl compounds homogenate, which gave the 0-(4)-, 107-109 (102, 103). The 0-(4',6)-didemethyl compound 110, formed in vivo (102), is not produced in vitro or in microbial degradations. Of over 60 microorganisms screened for their capacity to metabolize papaverine, 10 gave detectable 0-demethylation products (103). A good yield of 0-(6)demethylpapaverine (110) (40%) could be isolated after incubation of papaverine with Aspergillus alliaceus 3 15, and Cunninghamella echinulafa ATCC 9244 gave the 0-(4')-demethyl compound 107 in a yield of 27% (103). The phenolic metabolites formed from papaverine were all identified by comparison with authentic samples, the chemical shifts of the 0-methyl hydrogens being particularly useful in diagnosis (see Table IV).
TABLE IV CHEMICAL SHIFTSOF THE 0-METHYL HYDROGENS OF PAPAVERINE AND ITSPHENOLIC METABOLITES'
6(PP4 Compound
6-OCH3
7-OCH3
4'-OCH,
3'-OCH,
106 107 10s 109
3.99 4.00 4.02
3.89 3.89
3.81
-
3.77 3.82
3.76 3.17 3.12 3.77
a
~
From Rosazza et al. (103).
3.92
-
366
H.
'\ O
RZO R E
106 107 108 109 110
L.
HOLLAND
W
N
R' = R2 = R3 = CH, Papaverine R' = R2 = CH,, R3 = H 0-(4)-Demethylpapaverine R' = R3 = CH,, R2 = H 0-(7)-Demethylpapaverine R' = H, R2 = R3 = CH, 0-(6)-Demethylpapaverine R1 = R3 = H, RZ= CH, 0-(4', 6)-Didemethylpapaverine
111 R' = R Z = CH, (+)-Tetrandrine 112 R' = CH,, RZ= H N-(2)-Nor-(+)-tetrandrine 113 R' = H, RZ = CH, N-(2)-Nor-(+)-tetrandrine
C. BISBENZYLISOQUINOLINES AND RELATED ALKALOIDS Microbial transformations of bisbenzylisoquinoline alkaloids have been reported which include N-demethylation and oxidative removal of a substituted benzyl group from C-1 of an isoquinoline ring (ZOZ, 104, 105). The microbial N-demethylation of (+)-tetrandrine (lll),an antitumor (134) and cytotoxic (135) agent, occurs specifically at either the N-(2) or N-(2') position to give 112 or 113. The highest yield of the N-(2) nor metabolite 113 was obtained with Cunninghamella blakesleeana ATCC 8688a (104), whereas Streptomyces yriseus gave a 50% yield the N-(2')-nortetrandrine (112) (101). The structure of 112 was determined (101) by spectral comparisons with an authentic sample of synthetic origin (136), and that of 113 (104) by high-resolution MS and PMR spectral analysis. In the latter case, the absence of the signal assigned to the N-(2)methyl (136) was characteristic. The capacity of a microorganism to remove selectively one of the N-methyl groups of ( +)-tetrandrine makes microbial demethylation of this compound the method of choice for the production of either 112 or 113. Chemical N-demethylation of 111 occurs nonselectively, giving mixtures of 112, 113, and the bis-N-demethyl compound (104). The antitumor agent thalicarpine (114), a benzylisoquinoline-aporphine dimer, is metabolized by a series of microorganisms, but the only identified
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
367
product is (+)-hernandalinol (116),produced in 12% yield by Streptomyces punipalus NRRL 3529 (205).The structure of this metabolite was confirmed by comparison with an authentic sample produced by reduction of the known alkaloid hernandaline (115) (205). The observation that hernandaline is quantitatively reduced to 116 by S. punipalus under conditions identical to those used for the conversion of thalicarpine to 116 suggests that the initial product of the metabolism of thalicarpine may be the aldehyde hernandaline, which is subsequently enzymically reduced to the final product 116. Thalicarpine is therefore presumably attacked oxidatively at the benzylic position adjacent to C-l’, a reaction paralleled by its chemical oxidation which results in cleavage of the same bond (237).
OCH,
H
CH,O
OCH, 114 Thalicarpine
0 I
OR
CH30
I
OCH, 115 R = CHO Hernandaline 116 R = CH,OH Hernandalinol
D. MORPHINE AND RELATED ALKALOIDS
The metabolic fate of morphine and its derivatives in mammals has been extensively investigated, and the formation of metabolites by glucuronidation at C-3 and C-6 (to produce 125 and 126), sulfate formation at C-3 to produce 127, N-dealkylation and oxidation, and 0-methylation and
368
H. L. HOLLAND
demethylation has been reported (107,110,138).In addition, the transformation of morphine and related compounds by microorganisms has received considerable attention, and the results have been surveyed (11). Recent work in the area of morphine biotransformation has centered on the use of isolated enzyme systems and on the investigation of the properties of the enzymes themselves. In the former area, enzyme preparations from the rat liver and brain (107) and the guinea pig liver (109, 110) have been most effective in producing morphine metabolites in reasonable yield. Incubation of morphine (117) with rat liver homogenate resulted in the formation of normorphine (119) (107),morphine N-oxide of undetermined stereochemistry (121 and/or 123) (107),morphine-3-gluconuride (126) (107, 108), and a metabolite not fully characterized but thought to be 2-hydroxymorphine (128) on the basis of TLC color reactions, and the supposed formation of a similar compound on incubation of morphine with horseradish peroxidasehydrogen peroxide (106).The isolation of a morphine metabolite described as the 2,3-dihydrodiol 129 from in uiuo studies, the established enzymic oxidation of morphine at C-2 (139),and the chemical oxidation of morphine at C-2 by ferricyanide have been proposed by Misra et al. (107) as additional evidence for the structure of 128. The oxidized metabolite 128 was the only product obtained from incubation of morphine with an enzyme preparation from rat brain (107).
117 R' = H, R2 = CH, Morphine 118 R' = R2 = CH, Codeine 119 R' = R2 = H Normorphine 120 R' = CH,, R 2 = H Norcodeine
*
HO
123 R = H Morphine N-oxide 124 R = CH, Codeine N-oxide
121 R = H Morphine N-oxide 122 R = CH, Codeine N-oxide
R20 125 R' = gluconuride, R2 = H Morphine-6-gluconuride 126 R' = H, R 2 = gluconuride Morphine-3-gluconuride 127 R' = H, R 2 = sulfate Morphine-3-ether sulfate
5.
H0
HO
H;gN
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
o
gNCH,
/
HO
128 2-hydroxymorphine
369
/
129 Morphine 2,3-dihydrodiol
Phillipson and co-workers have recently investigated the metabolism of morphine and codeine (118) by a microsomal preparation from guinea pig liver (109, 110). Whereas previous in uitro studies with rat liver enzymes had revealed only traces of N-oxide formation (107), the preparation from guinea pigs carried out this conversion relatively efficiently, especially with codeine as substrate. The in uitvo N-oxidation of normorphine and norcodeine had been reported earlier (140). With morphine as substrate, the guinea pig liver microsomes produced normorphine as the major metabolite (973, in addition to codeine (5.3%) and the morphine N-oxide 123 (109,110). The N-oxides 121-124, all of which (except 122) are natural products (141), were used as reference standards for the identification of the metabolites of morphine and codeine in this study. The same enzyme preparation with codeine as substrate gave norcodeine (120), morphine, normorphine, and the isomeric codeine N-oxides 122 and 124 as products (109, 110). When compared with the yield of isomer 122 (0.1%),the formation of the N-oxide 124 in a yield of 19.5%suggests that with morphine as substrate the N-oxide (121) isomeric with that isolated (123,0.9%)may well have been present but undetected in the incubation mixture. The relatively efficient conversion of morphine to codeine by the guinea pig liver microsomes in the absence of any added methyl donor such as S-adenosylmethionine has tempted Phillipson et al. (110) to speculate that the N-methyl group of morphine N-oxide may be the source of the methyl required to methylate the C-3 phenolic function of morphine with simultaneous production of normorphine, but there is no direct evidence in support of this suggestion.
E. PHENETHYLIS~QUINOLINES Kametani et al. have studied the biotransformations of N-methylhomococlaurine (130) and homoorientaline (138) by peroxidase enzyme preparations (100, 111, 112). The peroxidase activity of a potato peel homogenate-hydrogen peroxide preparation resulted in dimer and trimer formation when benzylisoquinolines were used as substrate (Section IV,C), and
370
H. L. HOLLAND
an analogous head-to-tail dimer 132 was formed from N-methylhomococlaurine in low yield (111).The dimer 132, isolated as the triacetate 133, was characterized by a combination of PMR and mass spectral data. The molecular ion of 133 (m/e 750), underwent characteristic fragmentation at “a” to give a peak of mje 587. Additional evidence for a head-to-tail coupled structure for 133 (and hence 132) was provided by comparison of its PMR spectrum with that of related bisbenzylisoquinoline dimers. The absence of dienones as products of the enzymic coupling of 130 is noteworthy for two reasons: first, inorganic coupling reagents such as ferric chloride and ferricyanide generally lead to significant dienone formation (142); second, the enzyme preparation used in the coupling of 130 carries out the classic conversion ofp-cresol to Pummerer’s ketone in a yield comparable with that of 132 from 130 (111). In a further study involving the same substrate, but with an enzyme preparation from Wusubiu juponicu Matsumura, Kametani et ul. (112) demonstrated the formation of the head-to-head coupled dimers 134 and 136, together with an unidentified product. The 0-methyl substrate 131 was not metabolized by the enzyme preparation used in this study. The major
I
OR 130 R = H N-Methylhomococlaurine 131 R = C H ,
OR 132 R 133 R
= H Promelanthiodine = AC
OR
5.
371
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
H,
CH,N
OR
OR 134 R = H
135 R
= Ac
product 134, isolated as the triacetate 135, was characterized as a head-todimer by high-resolution mass spectral data: cleavage of head C-0-C bond a or b leads to the observed base peak at m/e 587, and subsequent cleavage of the unbroken homobenzylic bond produces a substituted bisisoquinoline ion of m/e 212 (21%). Loss of the acetyl function from m/e 212 then produces the ion at m/e 191 (51%), characteristic of bisbenzylisoquinolines with head-to-head coupling (143, 144). The minor product 136, again isolated as the acetate derivative 137, was also characterized by highresolution mass spectral data, the molecular ion (m/e 792) undergoing fragmentation at bonds a and/or b to produce fragment ions at m/e 629 and 233. As in the previous study with 130 as substrate ( I l l ) , no dienone formation was observed. The formation of head-to-tail dimers of 130 with potato peel homogenate and of head-to-head dimers with homogenate of Wasabia juponica has prompted Kametani et al. (112) to comment on the nature of the enzymes involved. However, in the absence of any definitive data on the nature of these enzymes and their mode of action, such commentary is at best speculative.
OR
OR 136 R = H
131 R
= Ac
Rzoy
372
H. L. HOLLAND
CH,O
H3
OR2 138 R' = R2 = H Homoorientaline 139 R' = OH, R2 = H 1-Hydroxyhomoorientaline 140 R' = R2 = OAc
In the absence of hydrogen peroxide, the final oxidizing agent in the peroxidase enzyme system, homoorientaline (138), is transformed to the one-hydroxy derivative 139 by potato peel homogenate (ZOO). The related benzylisoquinoline reticuline (88) is also hydroxylated at saturated carbon
-
HO
HO
oxidation
ORZ 88 (n = 1, R' = H, R Z = CH,) 138 (n = 2, R' = CH,, RZ = H)
139
155
CH,O
OR'
I
reduction
156
141
FIG.9. Enzymic oxidation c( and 138.
to nitrogen of benzyl- and phenethylisoquinolines 88 and
5.
373
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
to give B-hydroxyretixuline (141) on treatment with homogenized Papaver rhoeas and hydrogen peroxide. The latter reaction probably proceeds through an enamine intermediate 156, which would render the position B to nitrogen susceptible to attack by an electrophilic oxidizing species (25),whereas in the absence of such an oxidizing agent nucleophilic attack at the C-1 position of an immonium ion species 155 to produce 139 may occur. These proposals are summarized in Fig. 9. The initial oxidation to 155 may well involve N-oxidation followed by loss of OH- (see Fig. 8): N-oxidation by Papaver somniferum latex has been reported (145). In any event, the facile reversible oxidation-reduction of reticuline to the corresponding 1,2-dehydroisoquinolinium salt has been shown to occur in P . sonniferwn (146).The synthesis of the acetate derivative 140 by the addition of acetate to a 1,2-dehydroisoquinoliniumsalt confirmed the structure of enzymically produced 139 (ZOO) and lends credibility to the mechanistic proposals shown in Fig. 9.
141 /I-Hydroxyreticuline
ZOCH,
OR, 142 143 144 145
OCH,
R' = R 2 = R 3 = CH, Colchicine R' = H, R2 = R3 = CH, 0-(3)-Demethylcolchicine R' = R 3 = CH,, RZ = H 0-(2)-Demethylcolchicine R' = R2 = CH,, R3 = H 0-(10)-Demethylcolchicine
146 R = H Mescaline 141 R = Ac
F. MISCELLANEOUS Colchicine (142), classified as an isoquinoline alkaloid because of its biogenesis (147), undergoes oxidative demethylation at 0-(2), 0-(3), and/or 0-(10) by liver microsomes from the rat, hamster, and mouse (113). Only monodemethylation was observed, 0-(3)-dernethyl colchicine (143) being the predominantly formed isomer. In general, hamster liver microsomes
374
H. L. HOLLAND
were the most efficient of those tested for their capacity to metabolize colchicine, converting about 40% of the total substrate to metabolites : this may be related to the fact that the hamster is remarkably tolerant to colchicine poisoning (148). Colchicine is also demethylated at the 0-(10) position to give 145 by Streptomyces griseus (1491, and is susceptible to microbial oxidative attack at the nitrogen atom and to hydrolysis of the amide function (150). Although the 0-(10)demethyl compound 145 (colchiceine) may be produced from colchicine by a hydrolytic process that does not depend on oxidative 0-dealkylation ( 1 5 4 , the production of 143, 144, and 145 (113) appeared to involve a monooxygenase enzyme. The other anticipated product of enzymic demethylation, formaldehyde, was obtained in stoichiometric amounts from incubations of 0-(3)- and 0-(10)-14CH,-labeled colchicines, and no significant transformation of colchicine occurred in the absence of oxygen (113). The formation of both 143 and 144 and the variation in their relative amounts with the method of preparation and nature of the enzyme extract prompted the suggestion of the mechanisms for their formation shown in Fig. 10 (213),in which both are produced competitively from a single intermediate (157). Although arene oxides are well established as intermediates in the hydroxylation of arenes (28) and although there appears to be some evidence for the existence of an intermediate such as 157 in 0-dealkylation reactions (152),the observed formation of 143 and 144 in the oxidative degradation of colchicine can
142
-
CH,O q -
O
CH,O OCH, 157
I
I
1 144 +CH,O
OCH,
I
143 +CH,O
FIG. 10. Proposed mechanism of the 0-(2)- and 0-(3)-demethylation of colchicine by liver microsomes (113).
5.
375
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
be readily rationalized without invoking an epoxide intermediate, for which there is little direct evidence at the present time. The enzymic oxidative deamination of simple phenethylamines is exemplified by the reported biotransformations of mescaline (146) (114, 115) and ephedrine (148) (116). Mescaline is metabolized to 3,4,5-trimethoxyphenylacetic acid by tissue homogenates of mouse brain, liver, kidney, and heart (114, 115). 3,4,5-Trimethoxybenzoic acid is also formed as a minor metabolite. The formation of N-acetylmescaline (147, a significant metabolite in uiuo, was not observed in the in uitro studies. Both D-(-)and L-( + )-ephedrine have been incubated with enzyme preparations from rabbit liver ; norephedrine (149), benzoic acid, and 1-phenyl-1,Zpropanediol were characterized as metabolites (116). The D-( -)-isomer was the better substrate, being more rapidly converted. Similar results were previously reported with rabbit liver slices as the source of enzyme (153, 154). The enzymic degradation of the side chain of 8-phenethylamines has been extensively investigated with nonalkaloid substrates such as amphetamine (151) and N-methylamphetamine (150) (10, 155-157), and the reader is referred to these studies for a more comprehensive coverage of this aspect of the subject. Thd simple isoquinoline salsolinol(152), a relative of the alkaloid salsoline (153), k msno-0-methylated by an enzyme preparation from rat liver,
I , ,Jl 148 149 150 151
1
NHRZ
CH,
R' = OH, RZ= CH, Ephedrine R' = OH, RZ= H Norephedrine R' = H, R Z = CH, N-Methylamphetamine R' = RZ = H Amphetamine
154 (+)-Tubocurarine
152 R = H Salsolinol 153 R = CH, Salsoline
158 2,3-Dehydroemetine
376
H. L. HOLLAND
giving either 153 or its 0-(6)-methylated isomer (94). Salsolinol is of interest in that it represents one of the products of ethanol metabolism, the result of the reaction of ethanol-derived acetaldehyde with dopamine (158). A study of the uptake and excretion of (+)-tubocurarine (154) and its trimethyl derivative in the rat reported no evidence for biotransformation of either substrate in uiuo or in uitro with isolated perfused livers (117). A similar study with ( ? )-2,3-dehydroemetine (158) showed that although metabolism occurred in uiuo to give unidentified product(s) no in uitro biotransformation was carried out by rat liver microsomes (118).
V. Transformations of Pyridine Alkaloids A. NICOTINE AND RELATEDALKALOIDS The in uitro and in uiuo metabolism of the tobacco alkaloids has been thoroughly reviewed in recent years (159), and their microbial transformations have also been discussed (11).A detailed discussion of the biosynthesis and metabolism of tobacco alkaloids supplementary to reference 159 has also been presented (160). B. ARECOLINE
The ester function of arecoline (159) is quantitatively hydrolyzed by both rat liver and brain homogenates to produce arecaidine (160) (determined by TLC anaylsis) (161). C. MISCELLANEOUS
In preliminary communication of their work, a Russian group identified a number of Nocardia and Arthrobacter species that oxidized 3-methylpyridine to nicotinic acid (162) but did not report the use of any related alkaloids as substrates.
VI. Transformations of Pyrrolizidine Alkaloids The toxicity of plants that contain pyrrolizidine alkaloids has been discussed in an earlier volume of this series (163), and the relationship between the toxic nature of the plants and the metabolism of their alkaloids by the victim has been reviewed (164). Since the toxicity of the pyrrolizidine alkaloids in mammals seems to be due to their metabolites rather than to the alkaloids themselves (164), considerable effort has been expended in the identification of the metabolites produced both in uiuo and in uitro by mammalian systems. The material summarized in Table V (165-172) is supplementary to that discussed in reference 164.
TABLE V. TRANSFORMATIONS OF PYRROLIZIDINE ALKALOIDS Substrate A. Monoester alkaloids Heliotrine (161)
Supinine (163) Heleurine (164) Europine (165) B. Diester alkaloids Lasiocarpine (162) Retrorsine (166)
Reagent
Small Gram-ve coccus Peptococcus heliotrinreducans Small Gram-ve coccus Peptococcus heliotrinreducans Peptococcus heliotrinreducans Peptococcus heliotrinreducans
Small Gram-ve coccus Peptococcus heliotrinreducans Rat 16er microsomes
Mouse liver microsomes Hamster liver microsomes Guinea pig liver microsomes Fowl liver microsomes Quail liver microsomes Sheep liver microsomes
Product'
% Yieldb
Ref.
7a-Hydroxy-1-methylene-8cl-pyrrolizidine (173) (Heliotric acid) (7cr-Hydroxy-1-methylene-la-pyrrolizidine) (173) (Unidentified) (1-Methylene-8cr-pyrrolizidine)(174) ( 1-Methylene-lcr-pyrrolizidine) (174) (7~-Hydroxy-1-methylene-8cr-pyrrolizidine) (173)
165 165 166 165 166 166 166
(Unidentified)
165 166 167,168 167-169 168 168 168 168 168
(175)
(Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168) (Retrorsine N-oxide) (167) (Pyrrolic derivative) (168)
168 168 168 168 168 168
(continued)
TABLE V (continued) Substrate Retrorsine N-oxide (167) Monocrotaline (169)
Reagent Rat liver microsomes Guinea pig liver microsomes
a
7; Yieldb
(No metabolism to pyrrolic derivatives)
Peptococcus heliotrinreducans Hamster liver microsomes Rabbit liver microsomes Mouse liver microsomes Cattle liver microsomes Lamb liver microsomes Chicken liver microsomes Peptococcus heliotrinreducans
(Monocrotaline N-oxide) (170) (Pyrrolic derivative) (172) (Monocrotaline N-oxide) (170) (Pyrrolic derivative) (172) (Unidentified) (Pyrrolic derivative) (172) (Pyrrolic derivative) (172) (Pyrrolic derivative) (172) (Pyrrolic derivative) (172) (Pyrrolic derivative) (172) (Pyrrolic derivative) (172) (Unidentified)
Rat liver microsomes Hamster liver microsomes Rabbit liver microsomes Mouse liver microsomes Cattle liver microsomes Lamb liver microsomes Chicken liver microsomes
(Pyrrolic derivatives) (Pyrrolic derivatives) (Pyrrolic derivatives) (Pyrrolic derivatives) (Pyrrolic derivatives) (Pyrrolic derivatives) (Pyrrolic derivatives)
Rat liver microsomes
Crispatine (171) C. Miscellaneous Crude alkaloid preparation from Senecio jacobaea
Product"
Parentheses indicate not isolated. Parentheses indicate yield based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
Ref.
5.
379
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
A. M O N O E S ~ALKALOIDS R Workers in Australia, where chronic liver disease of sheep has been related to pyrrolizidine alkaloid intake (173, have isolated microorganisms from sheep rumen capable of reductive cleavage of the side-chain ester and europine function of heliotrine (161), supinine (163), heleurine (la), (165) (165,166).In the earlier report (165),a small gram-negative coccus
&
CH~O-C-C-CH-CH, 0 I1 OHOR' I I
Clm2R 1
CH,
161 R' = CH,, R2 = OH, R3 = H Heliotrine 162 R' = CH,, R2 = 0-C CH,
II'c=c/
o/
H '
CH3
R3 = H Lasiocarpint 163 R' = RZ= R3 = H Supinine 164 R' = CH,, R2 = R3 = H Heleurine 165 R' = CH,, R2 = R3= OH Europine
159 R = CH, Arecoline 160 R = H Arecaidine
CH 3
I CH, CH20H $H /I I / O=C-C-CHz-CH-C-OH I
I
y
CH3 CHzOH
/I
I
O=C-C-CH,-CH-C-OH
I
166 Retrorsine 167 Retrorsine N-oxide
3
CH
CH,-O-C=O
/ I
168
was isolated which converted heliotrine to heliotric acid and 7a-hydroxy1-methylene-8a-pyrrolizidine (173), both identified by comparison with authentic samples. The same microorganisms also metabolized supinine, but the product was not identified. In a later study, an anaerobic microorganism, Peptococcus heliotrinreducans, was obtained from sheep rumen contents. This organism also produced 173 from heliotrine (166).In addition, it produced the 1-methylenederivativesfrom supinine (163 4 174),heleurine (164 4 174), and europine (165 + 173).
380
H. L. HOLLAND
B. DJESTER ALKALOIDS
Both the microorganisms mentioned above metabolized lasiocarpine (162), the gram-negative coccus leading to unidentified product@) (165), and Peptococcus heliotrinreducans producing the 1-methylene derivative 175 (166). Metabolism of the cyclic diesters retrorsine (166), monocrotaline (169), and crispatine (171)by a variety of mammalian liver microsome preparations and by Peptococcus heliotrinreducans has been reported. Mattocks and co-workers have studied the metabolism of retrorsine by liver microsome preparations from several sources (167-169) and have demonstrated the conversion of this alkaloid to the corresponding N-oxide 167 and a pyrrolic metabolite formulated as 168. The formation of 168 via 167 and dehydration is mitigated against by the observation that retrorsine N-oxide (167) does not give rise to a pyrrolic metabolite on incubation with rat liver microsomes (167), even though the enzyme system responsible for the production of 168 from retrorsine has many of the properties of the mixed-function oxygenases capable of N-oxidation (167, 174). The metabolites of retrorsine
169 R = OH Monocrotaline 170 R = OH Monocrotaline N-oxide 171 R = H Crispatine
I
CH,-0-C=O
172
173 R = OH 174 R = H 175 R = 0-C
,CH3 Il\C=C,
o /
H3C
H
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
38 1
were identified only by specific reaction with a modified Ehrlich reagent (175).
Similar products were obtained on incubation of monocrotaline (169) with a variety of liver microsomes of mammalian origin (170, 171). The N-oxide 170 was produced by liver microsomes from the rat and guinea pig, along with a pyrrolic derivative presumed to be 172 (170, 174, whereas microsome preparations from other sources led to the production of only the pyrrolic derivative (171). Both monocrotaline and crispatine (171) were transformed to unidentified products by Peptococcus heliotrinreducans (166).
C. MISCELLANEOUS The crude alkaloid preparation from Senecio jacobaea (tangsy ragwort) is converted to pyrrolic derivatives by mammalian liver microsomes. Highest yields were obtained with microsomes from the hamster liver (171, 172).
Vn. Transformations of Quinoline Alkaloids The antitumor alkaloid acronycine (176) has been the subject of several studies employing microorganisms : these studies are summarized in Table VI (176-179). With one exception (178), all the microorganisms studied that are capable of biotransformation of 176 gave 9-hydroxyacronycine (177) as the major product, in one case (177) in an isolated yield of 30%. The minor products reported include 11-hydroxyacronycine (178), 9,lldihydroxyacronycine (179), and 3-hydroxymethyl-1l-hydroxyacronycine (181) (176-179). The microbial metabolism of acronycine is therefore closely related to its metabolism in mammals, where 177 is obtained as the major metabolite along with smaller amounts of 178 and 179 (180). The exception to this generalization is the microorganism Streptomyces spectabilicus NRRL 2494, which is reported to convert acronycine to the 3-hydroxymethyl derivative 180 in 14% yield (178). In a major study of the microbial metabolism of acronycine (177),Rosazza and co-workers examined 47 cultures for their capacity to transform this alkaloid, 10 of which were active in producing metabolites more polar than the starting material. The major metabolite was identified as the 9-hydroxy derivative 177 following isolation from the incubation of 176 with Cunninghamella echinulata NRRL 3655. This product was characterized as the acetate 182 by MS and PMR analysis, the latter technique
TABLE VI TRANSFORMATIONS OF QUINOLINE ALKALOIDS Substrate Acronycine (176)
Reagent Aspergillus niger ATCC 9142
Cunninghamellablakesleeana ATCC 8688a
Cunninghamellablakesleeana ATCC 9245 Cunninghamella blakesleeana NRRL 1369 Streptomyces rimosus ATCC 23955
Cunninghamellabainieri ATCC 9244
Cunninghamella echinulata NRRL 3655
Cunninghamella echinulata SP-WISC 1386 Cunninghamellaechinulata SP-WISC 1387 Zygorhynchus japonicus UI-1234 Aspergillus alleaceus QM 1915 Streptomyces spectabilicus NRRL 2494 a
Product"
% Yieldb
Ref.
(9-Hydroxyacronycine) (177) (11-Hydroxyacronycine) (178) (9,ll-Dihydroxyacronycine)(179) (9-Hydroxyacronycine) (177) (11-Hydroxyacronycine) (178) (9,ll-Dihydroxyacronycine)(179) (3-Hydroxymethyl- 11-hydroxyacronycine) (181) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) (11-Hydroxyacronycine) (178) (9,ll-Dihydroxyacronycine)(179) (9-Hydroxyacronycine) (177) (11-Hydroxyacronycine) (178) (9,ll-Dihydroxyacronycine)(179) (3-Hydroxymethyl- 1 1-hydroxyacronycine) (181) 9-Hydroxyacronycine (177) (11-Hydroxyacronycine) (178) (3-Hydroxymethyl-l l-hydroxyacronycine) (181) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) (9-Hydroxyacronycine) (177) 3-Hydroxymethylacronycine (180)
(Major) (Minor) (Minor) (Major) (Minor) (Minor) (-)
176,177 176 176 176 176 176 177 177 177 176,177 176 176 176, 177 176, I77 176 176 176, I77 177 177 177 177 177 178 179 178
(-1 (-1 (Major) (Minor) (Minor) (Major) (Minor) (Minor)
(-1 30
(-1 (-1 (-1 (-) (-)
80
(-1 14
Parentheses indicate not isolated. Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting materials.
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
0
383
OCH,
CH, 176 177 178 179 180 181 182
R'
= R2 = R3 = H
R'
= OH,R 2 =
Acronycine
R3= H 9-Hydroxyacronycine
R' = R3 = H,R2 = OH 1 1-Hydroxyacronycine R' = R 2 = OH, R3 = H 9,1 I-Dihydroxyacronycine R' = R Z = H,R3 = OH 3-Hydroxymethylacronycine R' = H, R2 = R3 = OH 3-Hydroxymethyl-ll-hydroxyacronycine R ' = OAc. R2 = R 3 = H
being used to confirm the position of oxygenation in ring A. The hydrogen at C-8 of both acronycine and 182 resonates at lower field than the remaining aromatic hydrogens due to the presence of the ortho carbonyl substituent, and in 182 it appears as a doublet (J = 2 Hz) at 6 7.93 ppm with meta coupling to the C-10 hydrogen. The latter hydrogen interacts with both the C-8 and C-11 hydrogens and appears as part of a well-resolved ABC spin system. The microbial hydroxylation of aromatic substrates with activating substituents appears to follow the normal rules of electrophilic substitution in that ortho and para products predominate (176, 181), and the formation of 177 (major) and 178 (minor) in both the microbial and mammalian metabolism of acronycine has been attributed (177) to the directing influence of the nitrogen atom in a process involving a monooxygenase enzyme. In spite of the investigation of the in uiuo mammalian metabolism of other alkaloids of the quinoline type, such as the biotransformations of quinidine in man (182), and the characterization of the metabolites (183, 184), there have been no other reports of microbial or in v i m enzymic transformations of other alkaloids of this group.
VIII. Transformations of Steroidal Alkaloids Although the microbial transformation of steroids is a well-developed aspect of steroid chemistry (1, 2), the corresponding branch of steroidal alkaloid chemistry has remained largely undeveloped and was last reviewed in 1968 (13). The material summarized in Table VII (35, 42, 185-189) is supplementary to that of the previous review.
TABLE VII TRANSFORMATIONS OF STEROIDAL ALKALOIDS W
E
Substrate A. Tomatanine-based alkaloids Tomatidine (183)
Reagent
Nocardia restrictus CBS 151.45
Mycobacterium phlei
Soladulcidine (solasodanol) (196)
Piricularia oryzae Trichothecium roseum Helicostylum pirijorme Arthrobacter simplex Nocardia restrictus
Dihydrotomatidine A (199) Dihydrotomatidine B (201)
Piricularia oryzae Polystictus versicolor Trichothecium roseum Nocardia restrictus Nocardia restrictus
Product"
Tomata-l,4-dienin-3-one (192) Tomatanin-3-one (189) Tomat-I-enin-3-one (190) Tomat-4-enin-3-one (191) 3-Epitomatidine (184) (Tomata-1,4-dienin-3-one) (192) (Tomatanin-3-one) (189) (Tomat-1-enin-3-one) (190) (Tomat-4-enin-3-one) (191) (Unindentified) (Unidentified) (Unidentified)
Androsta-l,4-diene-3,17-dione (208) Solasoda- 1,4-diene-3-one (198) 3-Episoladulcidine (197) (Unidentified) (Unidentified) (Unidentified) 200 202
% Yieldb
Ref.
185 186 186 186 186 187 186 186 186 186 42 42 42 188 188 187 42 42 42 188 188 187 188
(20S,22(,25()-26-Acetylamino-Sccfurostan-3P-01 (204) (25()-26-Amino-Sa-cholestane3P,168,22{-triol (206) N-Acetyltomatidine (185)
Nocardia restrictus
3-Epidihydrotomatidine B (203) ' (20S,22(,25()-26-Acetylaminofurosta1,4-diene-3-0ne (205)
Nocardia restrictus
201
188
Nocardia restrictus CBS 151.45
N-Methyltomatidine (187)
Nocardia restrictus CBS 151.45
3-Epi-N-acetyltomatidine (186) N-Acetyltomatanin-3-one (193) N-Acetyltomata-l.4-dienin-3-one (194) N-Methyltomata-l,4-dienin-3-one (195) (Unidentified)
187 189 189 189 189
Tomatidenol(209) Solasodine (210)
Tomatine (188) Solamargine (211) Solasonine (212) B. Solanidanine-based alkaloids Demissidine (213) Solanidine (216) Rubijervine/isorubijervine (218/219) Solanine (217)
C. Miscellaneous 5a-Conanin-3p-o 1 (220)
Conessine (223) Solanocapsine (224) Jervine (225)
Pseudojervine (226)
W VI W
Polystictus versicolor Trichothecium roseum Piricularia oryzae Trichothecium roseum Polystictus versicolor Heliostylum piriforme Trichothecium roseum Trichotheciwn roseum Trichothecium roseum
(Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified)
42 42 42 42 42 42 42 42 42
Nocardia restrictus CBS 157.45
Solani-l,4-diene-3-one (215) Solanid-Cene-3-one (214) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) Solanidine (216)
189 189 42 42 42 42 42 42 35
Solanidine (216) (Unidentified) Cona- 1,4-dienin-3-one (221) Con-Cenin-3-one (222) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Unidentified) (Jervine) (225) (Unidentified)
35
Trichothecium roseum Fusarium lini Trichothecium roseum Polystictus versicolor Piricularia oryzae Trichotheciwn roseum Phytophthora infestans ATCC 16981 Phytophthora infestans N B Nocardia restrictus CBS 157.45 Trichothecium roseum Trichothecium roseum Trichothecium roseum Polystictus versicolor Piricularia oryzae Trichothecium roseum
’Parentheses indicate not isolated. Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting material.
189 189 42 42 42 42 42 42 42
386
H.
L. HOLLAND
A. TOMATANINE-BASED ALKALOIDS
Belic's group in Yugoslavia has examined the metabolism of several alkaloids of this type with Nocurdia restrictus CBS 157.45, a microorganism capable of oxidative transformations of steroids (1, 195). With 3-keto steroidal substrates, introduction of A1 unsaturation constitutes a major metabolic pathway for this organism ;and with tomatidine (183)as substrate, this fungus gave rise to the formation of the corresponding 3-ketone, tomatanin-3-one (189), and the unsaturated A', A4, and A1j4 compounds 190, 191, and 192, respectively (185, 186). The biotransformation products were unambiguously identified by mass spectral, IR, and UV analysis of isolated material. Mycobacterium phlei gave a similar series of products with the same substrate, although in this case product identification was by TLC analysis only (186). The efficient steroid dehydrogenator, Fusarium soluni (194, failed to give biotransformation products with tomatidine as substrate (186).
183 184 185 186 187 1W 189 190 191 192 193 194 195
R' = OH, R z = R 3 = H Tomatidine ([22S,25S]-Sa-tornatanin-3~-01) R' = R 3 = H, R 2 = OH 3-Epitomatidine R' = OH, R2 = H, R3 = Ac N-Acetyltomatidine R' = H, R2 = OH, R 3 = Ac 3-Epi-N-acetyltomatidine R' = OH, R2 = H, R 3 = CH, N-Methyltomatidine R' = U-glycoside, R2 = R3= H Tomatine R 1+ R 2 = 0, R 3 = H Tomatanin-3-one R' + R2 = 0, R3 = H ; A' Tomat-1-enin-3-one R' + RZ = 0 , R 3 = H; A4 Tomat-4-enin-3-one R' + R2 = 0, R3 = H ; A'x4 Tomata-l,4-dienin-3-one R' + R 2 = 0, R3 = Ac N-Acetyltomatanin-3-one R' + R2 = 0, R 3 = Ac; A's4 N-Acetyltomata-l,4-dienin-3-one R' + R 2 = 0, R3 = CH,; A',4 N-Methyltomata-l,4-dienin-3-one
In a later study, the same group reported that during the early stages of the incubations with N . restrictus a metabolite was formed that did not correspond to any of the previously identified products on TLC, and that was not present at the termination of the incubation (24 hr). By stopping the incubation after only 4 hr they were able to isolate this intermediate * For details of the structure of the glycoside portion of 188 see Volume VII (p. 344) and X (p. 20) of this treatise.
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
387
in high yield (70%) and to identify it as the C-3a alcohol, 3-epitomatidine (184) (187). The mass spectrum of 184 was identical to that of tomatidine, and the structure of this metabolite was confirmed by the chemical shift of the proton attached to C-3, which now appeared at 6 4.04 ppm, downfield from its position (6 3.58 ppm) in tomatidine. This shift, along with the multiplicity observed for the new signal, was reported to be consistent with data for other Solanum alkaloids and related compounds (192, 193). Belic and co-workers (187) stated that 3-keto intermediates were observed in this and the other epimerizations described below and suggested that oxidation at C-3 may be an intermediate step in the epimerization. In addition to tomatidine (183),the N-acetyl derivate (185) was epimerized at C-3 to give 186, and both soladulcidine (solasodanol, 196) and dihydrotomatidine B (201) were transformed in a similar manner, giving 197 and 203, respectively. The Solanum alkaloid demissidine(213)was not epimerized at C-3 by N . restrictus (187). H
R'
H
196 R' = OH, R2 = H Soladulcidine (Solasodanol, [22R, 25R]-Sci-tomatanin-3~-01) 197 R' = H, R2 = OH 3-Episoladulcidine
H
O
W
198 Solasoda-1,4-diene-3-one
In an extension of their earlier work with tomatidine itself, the same group has also examined the transformations of a series of related compounds with the same microorganism (188). Soladulcidine (solasodanol, 196) is converted to the corresponding A1."-3-keto derivative 198 in unspecified yield, and both ring E-opened tomatidine derivatives 199 and 201 are similarly transformed. The ring F-opened derivative 204 underwent analogous transformation to give 205 in low yield, but the corresponding
388
H. L. HOLLAND
compound with opened rings E and F (206) was simply converted to the N-acetyl derivative 207 by N. restrictus. N. restrictus is capable of both nuclear and side-chain degradation of steroids (194), and its capacity to perform side-chain degradation of the alkaloid substrates employed in this study has been attributed by Belic et al. to the presence of the heteroatom, even though there is precedent for oxidative degradations by this organism of some steroidal substrates that do not involve reaction at the C-17 side chain (2, 194, 195). The capacity of another microorganism, Arthrobacter simplex, to degrade oxidatively the side chain of tomatidine was demonstrated by the isolation from the incubation of 183 with this microorganism of androsta-l,4-dien-3-one (208) in a yield of 2.4-4.5% (188).
HO
H
199 Dihydrotomatidine-A ([22S, 25S]-22,26-Epimino-Sa-cholestan-3~, 16P-diol) 200 A'34-3-Ketone
201 R' = OH, RZ= H Dihydrotomatidine-B ([22R,25~-22,26-Epimino-5a-cholestan-3~, 16p-diol) 202 R' + RZ = 0; A'.4-3-Ketone 203 R' = H, RZ = OH 3-Epidihydrotomatidine-B
204 [20S,22~,25~]-26-Acetylamino-Sa-furostan-3~-ol 205 ~I'-~-Diene-3-one
5.
&y HO
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
389
CH, CH-CH2-CH,-CH-CH,-NHR $
H 206 R = H [25<]-26-Amino-5~-cholestane-3/?,16/?,22<-triol 207 R = A c
In addition to the epimerization at C-3 discussed above (187), N-acetyltomatidine (185) is converted to the corresponding 3-ketone 193 and the A'.4-dien-3-one 194 by N. restrictus when the incubation times are prolonged (189). N-Methyltomatidine 187 is similarly transformed to 195 together with other unidentified metabolites (189). The structures of 193-195 were again confirmed by MS, IR, and UV analysis. The biotransformation of alkaloids of the tomatanine type has also been examined by Wolters (42).In a study with a variety of microorganisms he observed the formation of metabolites of tomatidine (183), tomatidenol (209), soladulcidine (196), solasodine (210), tomatine (188>, solamargine (211), and solasonine (212). The products were not isolated and thus no
0
208 Androsta-l,4-diene-3,17-dione
209 Tomatidenol H
RO 210 R = H Solasodine 211 R = glycoside* Solamargine 212 R = glycoside* Solasonine *See footnote. structure 188.
390
H. L. HOLLAND
structural information is available except the unsubstantiated observation that there was no liberation of aglycones during the transformations of 188, 211, and 212. B. SOLANIDANINE-BASED ALKALOIDS
Demissidine (213)is converted to the A4-3-ketoand A',4-3-keto derivatives 214 and 215, respectively, by Nocardia restrictus (189). The corresponding A5 compound, solanidine (216), is transformed to unidentified products by both Trichotheciwn rosewn and Fusarium linii, the latter microorganism producing three metabolites (42). Wolters also reports (42) the biotransformation of a rubijervine/isorubijervine mixture (218/219), and that of solanine (217) by a variety of microorganisms to unidentified products (42). The microbiological conversion of solanine (217) to solanidine (216) by hydrolysis of the glycoside substituent at C-3 has been reported (35). Two strains of the potato blight fungus Phytophthora infestans perform this reaction in low yield but are not capable of subsequent biotransformations of 216. The endogenous conversion of 217 to 216 during infection of the
213 Demissidine (Solanidan-3/l-ol) 214 A4-3-Ketone, solanid-4-ene-3-one 215 A'14-3-Ketone, solani-1,4-diene-3-one
216 R = H Solanidine 217 R = Glycoside* Solanine
CH,
I
u
HO
218 R' 219 R'
R2 = H Rubijervine = H, R2 = OH Isorubijervine = OH,
*See footnote, structure 188
220 Scc-Conanin-3~-01 221 A's4-3-Ketone, cona-l,4-dienin-3-one 222 A4-3-Ketone, con-4-enin-3-one
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
39 1
potato with P. infestans remains to be demonstrated, but the above study performed with isolated solanine and P. infestans has demonstrated that significant alteration in the solanine/solandine levels of the potato may occur on its infection with the blight fungus.
C. MISCELLANEOUS
Nocardia restrictus is capable of oxidizing the conessine derivative 5aconanin-3/3-01(220) to both the A4-3-ketone 222 and the A1,4-3-ketone221, the latter being the major product of the incubation (289). Preliminary screening experiments have demonstrated that Trichotheciwn rosewn transforms conessine (223), solanocapsine (224),jervine (225), and pseudojervine (226) (42). Transformation of the latter is claimed to produce 20-30% jervine by glycoside hydrolysis, along with an unidentified product that may be further biotransformation product of jervine. Jervine is also metabolized by Polystictus versicolor and Piricularia oryzae, but no products have been identified (42).
224 Solanocapsine
223 Conessine
225 R 226 R
=H
Jervine
= O-a-D-glUCOpyranOSylPseudojervine
IX. Transformations of Tropane Alkaloids The use of tropane alkaloids and their derivatives as medicinal agents has ensured that the investigation of the metabolism of these compounds has received considerable attention. The metabolism of tropane alkaloids in the
TABLE VIII TRANSFORMATIONS OF TROPANE ALKALOIDS Substrate Atropine (227)
Reagent Rat liver microsomes
Guinea pig liver microsomes
Aspergillus niger Cunninghamella echinulata
(-)-Hyoscamine (228) (-)-Hyoscine (237)
Aspergillus niger Guinea pig liver microsomes
Noratropine (229) Norhyoscine (238) Cocaine (241)
Guinea pig liver microsomes Guinea pig liver microsomes Rat liver microsomes
Parentheses indicate not isolated.
% Yieldb
Product" Noratropine (229) Apoatropine (233) 230 Tropine (232) Tropic acid (234) Noratropine (229) Apoatropine (233) 230 Atropine N-oxide (*)-235 Atropine N-oxide (+)-236 Unidentified (Tropine?) (232) (Noratropine?) (229) (Unidentified) Norhysocine (238) Hyoscine N-oxide (240) N-Hydroxynoratropine (231) N- Hydroxynorhyoscine (239) (Norcocaine) (242) (Benzoyl ecgonine) (243) (Unidentified)
1
Ref. 197, 198 197, 198 197, 198 197, 198 197, 198 197, 198 199 197, I98 197,198 199 199 200 200 200 200 199 199 199 199 201 201 201
* Parentheses indicate yields based on spectroscopic analysis, metabolite measurements, or consumption of starting material.
5.
393
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
animal body has been discussed in an earlier volume of this treatise (196), and the microbial transformations of tropanes has been reviewed by Kieslich (11). The material present in Table VIII (197-201) supplements that of the previous reviews. The metabolism of atropine (227) by rat and guinea pig liver microsomes has been studied (197-199). French workers noted the formation of noratropine (229), apoatropine (233), and a phenolic metabolite formulated as the ortho-phenol 230 (197, 198) by liver microsomes from the rat, and they reported that hydrolysis of the ester function of 227 did not occur with enzymes from this source (197, 198). The structure of 229 was determined by TLC comparisons of the metabolite with an authentic sample and by correlation of the formation of the metabolite with the release of formaldehyde in the incubation mixture. The structure of 233 was deduced by TLC and UV spectral comparisons of isolated metabolite with authentic sample, and the phenol 230 was identified by TLC color reactions and by comparison with a phenolic sample obtained by Udenfried oxidation of atropine. In the absence of more definitive data on the phenolic products of this reaction, the structure 230 proposed for the phenolic metabolite of atropine R'
I
N I\
0-C-CH 0
R2 227 228 229 230 231
(k),R'
= CH,, R2 = H Atropine
b
(-), R' = CH,, R2 = H Hyoscamine
R' = R2 = H Noratropine R' = CH,, R2 = OH R' = OH, R2 = H N-Hydroxynoratropine
H OR
232 R = H Tropine 233 R = COC(=CH2)C6H, Apoatropine
R2
CH-CO,H
bH 0-C-CH
II
0
234 Tropic acid
235 R' = CH,, R2 = Oe 236 R' = O e , R2 = CH,
394
H. L. HOLLAND
must be regarded as tentative. The same group also examined the metabolism of atropine by liver microsomes from the guinea pig and in addition to the products discussed above obtained the hydrolysis products tropine and tropic acid, 232 and 234, respectively (197, 198).In a more recent study of the same system, Gorrod and co-workers reported the formation of noratropine in an isolated yield of 4.3% and the formation of the isomeric atropine N-oxides 235 and 236 in a combined yield of 4.6% (199). They did not observe the formation of apotropine or the phenol 230. Similar products were obtained with hyoscine (237) as substrate, where norhyoscine (238) and the N-oxide 240 were formed (199).The capacity of the guinea pig liver microsomes to perform N-oxidation of atropine and hyoscine was confirmed by the use of the corresponding noralkaloids 229 and 238 as substrates. The products obtained were the N-hydroxy derivatives 231 and 239, respectively (199). The structures of all the metabolites formed in this study were confirmed as follows : the N-oxides 235,236, and 240 were reduced with titanous chloride to yield the corresponding parent alkaloids, atropine and hyoscine: similar reduction of the N-hydroxy derivatives 231 and 239 also produced 227 and 237. All metabolites were correlated by TLC and mass spectral comparisons with authentic samples. R
I
N
237 R = CH, Hyoscine 238 R = H Norhyoscine 239 R = OH N-Hydroxynorhyoscine
R' I
I1
0 240 Hyoscine N-oxide
241 R' = RZ = CH, Cocaine 242 R' = H, R Z = CH, Norcocaine 243 R' = CH,, RZ = H Benzoyl ecgonine
In contrast to the observation of the French group that rat liver microsomes did not possess an esterase capable of hydrolyzing tropane alkaloid
5.
ENZYMIC TRANSFORMATIONS OF ALKALOIDS
395
esters (197,198), more recent work established that cocaine (241) is hydrolyzed to benzoyl ecgonine (243) by a microsomal preparation from the rat liver (201). Norcocaine (242) was also observed as a minor product. The difference in the hydrolylic properties of liver microsomal preparations may be due to the mode of preparation, which can result in the presence or absence of the soluble esterases of the supernatant fraction of the initial centrifugate. The microbial transformation of tropane alkaloids has not received much attention in recent years. A single report (200) describes the incubation of atropine with Aspergillus niger, which resulted in the formation of one unidentified product, and with Cunninghamellaechinulata, which gave products tentatively identified as tropine and noratropine. The (-)-isomer hyoscamine (228) also gave a single product with A . niger, but this fungus was unable to metabolize tropine or scopolamine. REFERENCES 1. W. Charney and H. L. Herzog, “Microbial Transformations of Steroids: A Handbook.” Academic Press, New York, 1967. 2. L. L. Smith, Terpenoids Steroids 4, 394 11974). 3. B. J. Auret, D. R. Boyd, H. B. Henbest, and S . Ross, J. Chem. SOC.C 2371 (1968). 4. E. Abushanab, 0. Reed, F. Suzuki, and C. J. Sih, Tet. Lett. 3415 (1978). 5. A. J. Irwin and J. B. Jones, J. Am. Chem. SOC.98, 8476 (1976). 6. T. A. Van Osselaer, G. L. Lemiere, J. A. Lepoivre, and F. C. Aldenveireldt, J. Chem. SOC.,Perkin Trans. 2 1181 (1978). 7. J. B. Jones and H. B. Goodbrand, Can. J. Chem. 55,2685 (1977). 8. A. J. Irwin and J. B. Jones, J . Am. Chem. SOC.99,556 (1977). 9. R. V. Smith and J. P. Rosazza, Biotechnol. Eioeng. 17,785 (1975). 10. R. T. Coutts and A. H. Beckett, Drug Metab. Rev. 6, 51 (1977). 1 1. K. Kieslich, “Microbial Transformations of Non-Steroid Cyclic Compounds.” Thieme, Stuttgart, 1976. 12. J. B. Jones, C. J. Sih, and D. Perlman, eds., “Applications of Biological Systems in Organic Chemistry” (Techniques of Chemistry, Vol. X). Wiley, New York, 1976. 13. L. C. Vining, in “Fermentation Advances” (D. Perlman, ed.), p. 715. Academic Press, New York, 1969. 14. H. Iizuka and A. Naito, “Microbial Transformations of Steroids and Alkaloids.” University Park Press, State College, Pennsylvania, 1967. 15. C. Tamm, Angew. Chem., Znt. Ed. Engl. 1, 178 (1962). 16. K. L. Stuart, Heterocycles 5, 701 (1976). 17. R. V. Smith and J. P. Rosazza, J. Pharm. Sci.64,1737 (1975). 18. “Enzyme Nomenclature.” Elsevier, Amsterdam, 1973. 19. B. N. LaDu and H. Snady, Handb. Exp. Pharmakol. [N.S.] 28, Part 2, 477 (1971). 20. R. A. Wallace, A. N. Kurtz, and C. Niemann, Biochemistry 2, 824 (1963). 21. D. V. Parke, “The Biochemistry of Foreign Compounds.” Pergamon, Oxford, 1968. 22. 0. Hayaishi, “Oxygenases.” Academic Press, New York, 1962. 23. 0. Hayaishi, “Molecular Mechanisms of Oxygen Activation.” Academic Press, New York, 1974. 24. H. L. Holland and B. J. Auret, Can. J . Chem. 53, 845 (1975).
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INDEX
A
ALC-I, 265, 266, 268 ALC-2, 265, 266, 268 Abresoline, 285-287
3-Acetonyldihydrovindolineether, 33 1, 340 26-Acetylaminofurosta- 1,4-diene-3-one, 384 Acetylaminofurostanol, 384, 388 Acetylcephalotaxine, 43, 44, 46 Acetyll ythramine , 295 N-Acetylmescaline, 375 12-Acetylnapelline, 112-1 14, 196 N-Acetyltomata-1,4-dienin-3-one, 384, 386 N-Acetyltomalidine, 384 N-Acetyltomatidine, 386, 387 Aconitum, 100 Acontium antharu, 122, 198 Aconitum gigas, 122 Aconitum glandulosus, 116, 120, 121 Aconitum heterophylloides, 122, 198, 200 Aconitum heterophyllum, 122, 124, 133, 135, 197, 198, 199, 200, 201 Aconitum japonicum, 114, 201 Aconitum kamtschaticum, 125 Aconitum karakolicum, 112, 113, 114, 115, I%, 203, 204 Aconitum lucidusculum, 113, 125, 202, 204 Aconitum majimai, 202, 203 Aconitum miyabei, 136 Aconitum monticola, 114, 115, 128, 203,204 Aconitum napellus, 112, 203 Aconitum palmatum, 132, 210 Aconitum sachalinense, 125, 202 Aconitum sayoense, 128, 129, 201 Aconitum soongoricum, 114, 116, 204 Aconitum tasiromontanum, 128, 201 Aconitum jesoense, 113, 125, 202, 204 Acronycine, 38 1-383 Adumine, 246 Agroclavine, 330, 338, 339 Ajaconine, 124-125, 152-154, 167, 196 synthesis, 179-181, 186, 189
Ajmalicine, 329, 335, 336 Alkaloid A , 28 B, 28 1, 28 2, 28 5, 28 6, 28, 39 I , 39 Aminocholestanetriol, 384, 389 Ammannia, 264 Amphetamine, 375 Androsta-1,4-diene-3, 17-dione, 384, 388, 389 Anhydroignavinol, 128-129, 1% Anopterimine, 120-121, 197 N-oxide, 197 Anopterine, 116-121, 166, 197 N-oxide, 120-121 Anopterus glandulosus, 116, 120, 121, 160, 197, 200 Anopterus macleayanus, 116, 120, 121, 160, 197, 199, 200 Anopteryl alcohol, 116- 1 19 Antiinflammatory agent, 320 Antileukemia property, 46 Antithrombotic activity, 320 Antitumor activity, 44, 104, 366, 381 Aphorine, biotransformation, 348-360 Apoatropine, 392, 393-394 Apocodeine, 349, 350, 357, 359 Apomiyaconine, 137, 138, 160 Apomorphine, 350, 357, 359 Aporphine alkaloid, 13C spectra, 235-237 Arecaidine, 376, 379 Arecoline, 376, 376 Argemonine, 234 Aricine, 329, 335 Arrow poison, 100 Arthrobacter, 376 Arthrobacter simplex, 384, 385 Aspergillus alliaceus, 352, 382
402
INDEX
Aspergillus jlavus X - 158,352 Aspergillus niger, 352,392,395 Aspergillus ochraceus, 353
Carckosarcoma, Walker 256,92 Cathanneine, 339,348
Atidine, 124,161,197 diacetate, 161 synthesis, 179-181,186,189 Atisine, 100,101,104,122-124,150,156,
Cathoclavine, 339,348 Cephalotaxine, 42-48,59,60,92 synthesis, 76-85 Cephalotaxinone, 43,44,50-51
159,161,198 acetate, 156-157 azomethine, 161 intermediate synthesis, 181-193 Atisinium chloride, 104,122-124,150 Atisinone, 161 Atropine, 392-395 N-oxide, 392 Aurotensine, 362
B
Baldwin cyclization rule, 149 Benzoic acid, 356,375 Benzo[c]phenanthridine alkaloid, 250-252 Benzoyl ecgonine, 392,394,395 Benzylisoquinoline alkaloid, 223-226 biotransformation, 360-366 Berberine chloride, 240 Betaine, 275 Bicuculline, 246,249 Biotransformation, 325-328 see also individual alkaloids Bisbenzylisoquinoline alkaloid, 226-227 biotransformation, 366-367 Bisboldine, 349 ether, 349,358 Bisditerpenoid alkaloid, 144-149 Bohlmann band, 274 Boldine, 349,357,358 Brain, alkaloid transformation, 355,366,375 Brucine, transformation, 328,332 Bulbmapnine, 235
C Caaverine, 235 Cadaverine, 313 Canadine, 240 Cancentrine, 13C-NMR spectra, 230-234 Capnoidine, 246,247
Catharanthus roseus, 347
Cephalotaxus, 2 Cephalotaxus alkaloid,
biosynthesis, 59-61 occurrence and isolation, 42-45 structure determination, 45-51 synthesis, 76-91 Cephalotaxus fortunei, 46,50 Cephalotaxus harringtonia var. drupacea,
44,48,51 Cephalotaxus harringtonia var. harringtonia, 28,36,37,44,46,48,50, 92 Cephalotaxus manii, 44 Cephalotaxus wilsoniana, 28, 41,42,46
Chanoclavine, 330,338 Chiral, 56 erysodienone, 56 Chloramine, 126,127 Choline, 7 Cocaine, 392,394,395 Coccoline, 3, 8,15,22,26 Coccolinine, 3, 15, 22,26 Cocculidine, 4,9,11, 12,21,22,23,26,56,
91 Cocculine, 9,22,23,56,91 Cocculitine, 22,26,27 Cocculolidine, 5 , 22 Cocculus, 2, 15, 17. 18 erythrina alkaloid, 21-27 Cocculus carolinus, 21,22,23 Cocculus laurifolius, 21-27,56 Cocculus tritobus, 21,22,23,27
Coccutrine, 4,8,22,23 Coccuvine, 3,22,25 Coccuvinine, 3, 22,25-26 Codeine, 229,231,233,355,368 N-oxide, 355,368 Codeinone, 232,233 Colchicine, biotransformation, 355,373-375 Cona-I,4-dieNn-3-one, 385,390 5a-Conanin-3P-01, 385,390 Condelphine, 151 Con-Cenin-3-one, 385,390 Conessine, 385,391
INDEX
Conicine, 27 I Conjugation reaction, 327-328 Consolida ambigua, 124, 196, 198 Coreximine, 351, 362 Corlumine, 246 Corydaine, 252 Corydaline, 242 Corynantheidine, 329, 332 Corynanthine, 330, 336, 337 Crispatine, 378, 380, 381 Cryogenine, 269, 27 1, 3 15 Cryptopine, 244 Crystamidine, 4, 14 Cuauchichicine, 106-112, 159, 198 garryfoline rearrangement, 109-1 12 Cularine, 227-228 Cunninghamella bainieri, 349,35 1,352,354, 382 Cunningha mella bla kesleea nu, 349, 352, 353, 354, 359, 364, 366, 382 Cunninghamella echinulata, 349, 350, 352, 353, 381, 392, 395 Cunninghamella elegans, 353 Cuphea, 264
D
Deacetyldihydrovindoline ether, 33 1, 339, 340 Deacetylvindoline, 33 1, 339, 345 Decaline, 264, 280, 281-283 synthesis, 307-309 Decamine, 264, 269, 270, 272, 311, 320 Decinine, 264-267, 275-276, 302, 311, 320 biosynthesis, 3 13-3 19 Decodine, 264, 265, 266, 269, 272 biosynthesis, 3 13-3 19 Decodon verticillatus, 264, 265, 267, 268, 270, 280, 313 Dehydrocondelphine , 151 Dehydrodecodine, 265, 266, 268 Dehydroemetine, 356, 375, 376 l0,ll-Dehydroerysodine, 4, I5 10,ll-Dehydroerysovine, 4, 15 6a,7-Dehydroglaucine, 350, 35 1, 359, 360 3,4Dehydrovinblastine, 33 1, 346 16-Dehydroxy-14,U-dihydro- 15,16-epoxy14-0xo-3-norindoline, 33 I , 339, 341 Delatine, 133, 200
.
403
Delnudine, 100-101, 138-139, 198 Delphinium, 100 Delphinium ojacis, 124, 1% Delphinium cardinale, 133, 135, 200 Delphinium carolinianum, 124, 196 Delphinium consolida, 124, 1% Delphinium denudatum, 131, 135, 138, 198, 200 Delphinium staphisagria, 100, 144- 149, 160, 207-210 Delphinium virescens, 124, 1% Demethoxyabresoline, 285-287 3-Demethoxyerythratidinone,5 , 6, 19 Demethylcolchicine, 355, 373 0-17-Demethylcorgnantheidine,329, 333 Demethyldecaline, 280, 28 1 0-17-Demethyldihydrocorynantheine,329 0-17-Demethglisocorynantheidine, 329 Demethyllasubine-I, 285 Demethyllasubine-11, 285 0-17-Demethylmitragynine, 329 Demethylpaperine, 352-353, 365, 366 0-17-Demethylpagnantheine,329 Demethylvertaline, 280, 281 N-Demethylvindoline, 33 1, 340 0-17-Demethylspeciociliatine,329 0-17-Demethylspeciogynine,329 N-Demethylvinblastine, 33 1 Demissidine, 385, 390 Denudatine, 131, 198 synthesis, 176-179 Detoxification reactions, 326-327 Deoxyharringtonine, 43, 45, 46-48,60, 92 synthesis, 86-88
Desmethyoxycephalotaxinone , 5 1 Desmethylcephalotaxine, 43, 44, 50
Desmethylcephalotaxinone, 50-5 1 3-Desmethylerysovine, 13 Dicentrine, 236 Dihydroacetylnapelline, 114 Uihydroajaconine, 124-125, 198 Dihydroatisine, 124, 161, 195, 199 azomethine, 161 diacetate, 161 Dihydroatisinone, 196 Dihydrocorynantheine, 329, 332 Dihydroerysodine, 4, 17, 19, 20, 21, 22, 27, 69 Dihydroerysotrine, 4, 17 Dihydroerysovine, 4, 12, 17, 21, 22, 27
404
INDEX
Dihydrogarryfoline diacetate, 110-1 12 2,7-Dihydrohomoerysotrine,29 6a,7-Dihydrohomoerysotrine, 30, 39 2,7-Dihydrohomoerysovine,29 6a,7-Dihydrohomoerythraline, 30 2,7-Dihydrohorno-P-erythroidine, 42 Dihydroisoquinoline, 222 Dihydrokaurene, 107- 109 Dihydrolythrine, 271, 275 Dihydrosongorine, 163, 166 Dihydrotomatidine A, 384, 388 B, 384, 387, 388 Dihydroveachine, 161, 1% azomethine, 161 diacetate, 161 Dihydroverticillatine, 269, 270, 272 Dihydrovindoline ether, 331, 339, 340, 342344 9,11-Dihydroxyacrongcine,38 1-383 Dihydroxyanopterine, 121, 199 10,11-Dimethyoxyaporphine, 349, 359 3,4Dihydroxyphenylalanine, 5 1 Dhnethyldecodine, 275, 278-280 Dirnethyldihydroverticillatine,273 0.N-Dimethyllythranidine, 291 C2,-Diterpenoid alkaloid, 99-215 atistine-type, 122- 144 Baldwin cyclization rule, 149-159 bisditerpenoid group, 144- 149 catalog of, 196-211 mass spectral analysis, 163-168 nuclear magnetic resonance, 160-163 synthesis, 168-1% veatchine-type, 102- 122 1,17-Ditritioerysodienone,56 14,17-Ditritioerysopine,56 Diuretic, 320 Drupacine, 43, 48-50
E Elymoclavine, 330, 331, 338 Emde degradation, 276 Emetine, 259-260 Enamine, 76 D preparation, 76-77, 7%81 Enedione, 185 Enmein, 186
Ephedrine, 356, 375 3-Epi-N-acetyltomatidine,386 Epicephalotaxine, 43, 45 14-Epicorynoline, 251 5-Epidemethoxyabresoline, 286, 287 10-Epidemethoxyabresoline,285 3-Epi-2,7dihydrohomoerysotrine, 29, 36-37 3-Epi-6a ,7-dihydrohomoerythraline,30, 38 3-Epidihydrotomatidine P , 384, 388 3-Epischelhammericinene, 28, 29, 36, 41 3-Epischelhammeridine, 28, 29 3-Epischelhammerine, 28, 29, 36 3-Episoladulcidine, 384 3-Epitomatidine, 384, 386, 387 3-Epiwilsonine, 28, 36 6,7-Epoxy-k-methoxy-15,lGmethylenedioxy-C-homoerythrinan-2-ene1 41 Erybidine, 6,7, 70,71 Erysodienone, 5 , 8, 19, 21, 53-55, 56 Erysodine, 3, 5 , 7, 9, 13, 19, 20, 51 Erysoflorinone, 4, 20 Erysoline, 3, 13 Erysonine, 3, 13 Erysophorine, 3, 13 Erysopine, 3, 55 Erysopitine, 4, 8, 19, 20 Erysosalvine, 4, 8 Erysosalvinone, 4, 19, 20 Erysothiopine, 3 Erysothiovine, 3 Erysotine, 4, 8, 19, 20 Erysotinone, 4, 19, 20 Erysotramidine, 3, 14 synthesis, 6 6 6 7 Erysotrine, 1, 3, 6, 13, 19, 21, 55, 92 synthesis, 61-67 Erysovine, 3, 5 , 7, 9, 13, 55 Erythrabine, 4, 14 Erythraline, 3, 6, 14, 15, 17, 53, 55, 56 Erythramine, 4, 17, 18 Erythrartine, 3 Erythrascine, 3, 16 Erythratidine, 4, 8, 12, 18, 19, 20 Erythratidinone, 4, 6, 10, 18, 19 Erythratine, 4, 8, 12, 16, 69 Erythratinone, 4, 18 Erythravine, 3, 9, 13 Erythrina alkaloid, biosynthesis, 51-57 isolation, 6-7
405
INDEX
occurrence, 2-6 structure, 7-27 synthesis, 61-72 Erythrina arborescens, 13, 16 Erythrina crysta galli, 6,14,16,17,18,55 Erythrina falcara, 18 Erythrina folkersii, 6,13 Erythrina fusca, 17 Erythrina glauca, 17 Erythrina herbacea, 6 Erythrina indica, 5 , 15, 17 Erythrina lithosperma, 5 , 6,16,18,19,55 Erythrina orientalis, 5 Erythrina salviijlora, 6,19 Erythrina lysistemon, 6 , 15 Erythrina suberosa, 13, 92 Erythrina subumbrans, 5 Erythrina variegata, 5 , 14, 17,18, 19 Erythrina varigata var. orientalis, 5 , 6 Erythrina x bidwillii, 6 , 16 Erythrinine, 3, 6, 16 Erythristemine, 3, 8,12,15, 17 Erythroculine, 4,21,22,23 Erythroculinol, 23-25 a-Erythroidine, 5 P-Erythroidine, 5, 7,21,53, 56,72 Eschscholtzine, 234 Ester alkaloid, 286-288 Europine, 379
F
Ferulic acid, 286 Fumaramine, 249 Fumaras schleicherii, 249 Fumaritine, 252 N-oxide, 252,256 Fungicide, 320 Fusarium h i , 385,390 Fusarium solani, 351,354,360,386
G Garrya laurifolia, 104,106, 198,199,201,
202 Garrya ovata var. Lindeheimeri, 104,106,
198,199,202,204 Garrya veatchii, 102,104,199,211
Garryfoline, 104-106, 199 cuauchichicine rearrangement, 109- 112 Garryine, 102-104,189,194,1%, 199 Gibberdin-A,,, 186,192 Glaucine, 350-351,357,359-360 Glaziovine, 239 Gliocladium deliquescens, 354 Glucoerysodine, 3 Glucuronidation, 327 Gongronella urceolifera, 329,330,336 Gout, 100
H
Harman, 330,337 Harmine, 330,337 Harmol, 330,337 Harringtonine, 43,44,46-48,92 action, 92 synthesis, 88-90 HeLa cell, 92 Heimia, 264 Heimia myrtifolia, 264,265,266,270 Heimia salicifolia, 266268,270,280, 284,
285,315,319 physiological activity, 319-320 Heimidine, 269,270,272 Heimine, 280,281,284 Heleurine, 377,379 Helicostylum piriforme, 350,354,385 Heliotrine, 377,379 Hermandaline, 354,367 Hermandalinol, 354,367 Heterophylloidine, 200 Hetidine, 135-136,199 Hetisine, 133-135, 138,200 Hetisinone, 134-135, 200 Hirsutine, 329,332,333 Homo-2,7-dihydroerysotrine, 37 Homoerythrina alkaloid, 2 biosynthesis, 58 isolation, 29 nomenclature, 30-3 1 occurrence, 27-29 structure determination, 3 1-42 synthesis, 72-75 Homoharringtonine, 43,85,92 Homoorientaline, 355,369-373 Homoveatchine, 157
406
IN DEX
Hunnemanine, 244-245 Insecticide, 92, 100 Hydrastine, 246, 248 Isoapocodeine, 349, 350, 357, 359 Hydrastinine, 222 Isoatisine, 122-124, 151, 157, 195, 201 H ydrobenzo[c]phenanthridine alkaloid, Isoatisinone, 161 250-252 Isoboldine, 35 1, 362 Isochondodendrine, 226-227 1 I-Hydrocephalotaxine, 43, 44, 48-50 Isocorydine, 235 9-Hydroxyacronycine, 382, 383 Isocorynantheidine, 329, 332 9-Hydroxyacronycine, 38 1-383 Isocuauchichicine, 107-108, 112, 201 I I-Hydroxyacronycine, 381, 382 10-Hydroxyajmalicine, 329, 335, 336 Isocucculidine, 4, 21, 22, 26 lsocucculine, 4, 10, 21, 22, 26, 56, 57 Hydroxyanopterine , I2 1, 200 10-Hydroxyaporphine, 350, 359 Isogarryfoline, 112, 202 p-Hydroxybenzaldehyde, 351 Isoharringtonine, 43, 46-48, 90-91 10-Hydroxycorynanthine, 330, 337 Isohypognavine, 130-131, 202 Hydroxydihydrovertine, 272 Isohypognavinol, 130- 131 1 I-Hydroxyerysodine, 3 Isonapelline, 112-1 14 Isopelletierine, 303 1 1-Hydroxyerysotrine, 16 Isoquinoline alkaloid, Y - N M R spectra, 11-Hydroxyerysovine, 11 1-Hydroxyhomoorientaline, 355, 372 217-262 4-Hydroxy-3-methoxycinnamicacid, 286 Isorubiiervine.. 385,. 390 Isosetoclavine. 33 1. 338, 339 1-(12-H ydroxy- 13-methoxy)phenylquinolizid-3-01, 284 1-(12-Hydroxy- 13-methoxy)phenylJ quinolizid-3-one, 284, 286 2-Hydroxy-3-methoxystrychnine,328, 332 Javacillin, 329, 335 7a-Hydroxy- I-methylene-801-pyrro1izidine1 Jervine, 385, 391 377, 379 3-Hydroxymethyl-1 I-hydroxy-acronycine, 38 1 K 2-Hydroxymorphine, 355, 368, 369 N-Hydroxynoratropine, 392, 393 ent- Kaurene, 106, 107 N-Hydroxynorhyoscine, 392, 394 Kidney, alkaloid transformation, 356, 375 P-Hydroxyreticuline, 35 1 Kobusine, 125-128, 134, 202 10-Hydroxyvinblastine, 33 1 Hyoscamine, 392, 393, 395 L Hyoscine, 392, 394 N-oxide, 392, 394 Lactone ring cleavage, 275-276 Hypaphorine, 7, 14 Lactonic biphenyl alkaloid, 266-28 1 Hypecorinine, 257-258 chemistry of trans- and cis-fused, 275-281 Hypertension, 100 ether alkaloid, 281-284 Hypognavine, 129, 201 synthesis, 307-310 Hypognavinol, 129, 201 stereochemistry, 273-275 synthesis, 310-312 Lufoensiu, 264 I Lagerine, 280, 281, 283, 310 Lugerstroemiu. 264 Ignavine, 128-129, 201 Logerstroemio fuuriei, 265, 266,267, 270 Indanone, 253 Lugerstroemiu indicu, 265, 267, 270, 280 Indicamine, 269 Indole alkaloid, biotransformation, 328-348 Lugerstroemiu subcostutu, 285, 286, 287
407
INDEX
Lagerstroemine, 269, 270, 273 Larkspur, garden, 124-125 Lasiowpine, 377, 379, 380 Lasubine-I, 285, 286, 288 Lasubine-11, 285, 286, 288 Laudanosine, 223-225, 352, 362, 364 oxide, 223-225 Luwsoniu, 264 Leucine, 61 Leukemia, chronic nigelocytic, 92 L 615, 92 L 1210, 85, 92 L 7212, 92 P 388, 85 Leurosine, 331, 346-347 Lindheimerine, 104-106, 156, 194, 202 Lirinidine, 235 Liver, alkaloid transformation, 330, 332, 351, 354-356, 360, 363, 365, 368, 375, 377-380, 392-395 Luciculine, 112, 203 Lucidusculine, 112-1 14, 174, 202 Luguine, 251 Lyfoline, 265, 266, 267 Lysergic acid, 330, 338 Lysicamine, 349 Lysine, alkaloid precursor, 3 13 Lythraceae alkaloid, 263-322 biosynthesis, 3 13-3 19 ester, 286-288 lactonic biphenyl, 266-284 synthesis, 307-312 physiological activity, 3 19-320 piperidine metacyclophane, 288-294 synthesis, 312-313 quinolizidine metacyclophane, 294-303 simple quinolizidine, 284-286 Lythramine, 288, 293, 295, 312-313 Lythrancepine, 294, 295, 297-299 Lythrancine, 294-297, 299 Lythranidine, 288, 289, 293, 297 Lythranine, 288, 289-291, 293 Lythridine, 267 Lythrine, 265, 266267, 271, 275, 277, 279 Lythrum, 264 Lythrum unceps, 264, 288, 295 Lythrum lunceolutum, 264, 265, 267, 295, 302 Lythrumine, 302
M
Mass spectra, quinolizidine Lythrum alkaloid, 299-302 songorine, 163- 165 vindoline products, 339-344 Meconin, 246, 248 Mescaline, 355, 373, 375 Mesocorydaline, 242 Mesothalictricavine, 243 10-Methoxyaporphine, 350, 357, 359 Methoxycocculidine, I2 Methoxyerysodienone, 69-70 1 I-Methoxyerysodine, 3 1 I-Methoxyerysopine, 3 1 I-Methoxyerysovine, 3 1 I-Methoxyerythraline, 3, 6, 15 p-Methoxyhydrocinnamyl alcohol, 283 2-Methoxy-3-hydroxystrychnine, 328, 332 3a-Methoxy- 15,16-methylenedioxy,6,7epoxy-C-homoerythrinan-2-ene, 30 3-Methoxymorphinan, 229 Methoxynorprotosinomenine, 55 0-Methylacetyllythramine, 289 N-Methylamphetamine, 375 0-9-Methylboldine, 350-35 I 0-Methylcapaurine, 243 N-Methylcoclaurine, 351, 360, 361 N-Methylcorydaline, 222 &Methylcorynoline, 251 0-Methylcorpyalline, 220 Methyldecamine, 3 1 I Methyldecinine, 275, 3 10 N-Methyldihydroatisine azomethine, 161 N-Methyldihydroveatchine azomethine, 161 4,5-Methylenedioxy- I-methyleneindane, 254 6,7-Methylenedioxyphthalide,246 I-Methyleneindane, 253 I-Methylene-&-pyrlizidine, 377 N-Methylhomococlaurine, 355, 36%37 I Methyllagerine, 280, 281, 283-284 0-Methyllythranidine, 289, 290 2-Methylpiperidine, 27 1 N-Methylpiperidine, 220, 283 3-Methylpyridine, 376 Methyl reserpate, 329, 336 N-Methyltomatidine, 384, 386, 389 Microsome, alkaloid transformation, 329330, 332, 349-350, 355, 357, 373, 377378, 392-395
408
INDEX
Microsporum gypseum, 350, 352, 353 Mitraciliatine, 329, 333 Mitragynine, 329, 333 Mitrajavine, 329, 335 Miyaconine, 160 Miyaconite, 136-138, 203 Miyaconitinone, 136-138, 203 Monoacetyllythmmine,302 Monocrotaline, 378, 380, 381 N-oxide, 378, 380 Mono-0-methylsalsolinol,356, 375 17-Monotritioerysodine,56 Morphine, 228-230 biotransformation, 354, 367-369 N-oxide, 354, 355, 368 Morphine-3-gluconuride, 354, 368 Mucor microsporus, 354 Mucor mucedo, 350, 353, 354 Mucor puruciticus, 354 Mycobucterium phlei, 384, 386
N W-NMR spectroscopy, 160-162, 219-222 isoquinoline alkaloid, 217-262 pavine, 234-235 proaporphine, 238-239 protopine, 243-245 tetrahydroi soquinoline, 2 19-222 Nandinine, 241 Nappelline, 112-114, 203 synthesis, 170-176 Napellonine, 114 Narcotine, 248 Neferine, 361 Nelumbo nuciferu gurtner, 351, 361 Nesodine, 265, 266, 268-269, 272, 320 Neuralgia, 100 Neuromuscular blocking, 92 Nicotine, 376 Nocurdiu, 376 Nocurdiu restrictus, 384, 385,386,388, 389, 390, 391 Noragroclavine, 330, 331, 338, 339 Noratropine , 392, 393 Norcocaine, 392, 394, 395 Norephedrine, 356, 375 Norglaucine, 351, 359 Norhyoscine, 392, 394
Norlaudanosine, 223, 352 Norlaudanosoline, 35 I , 360, 362 Normorphine, 354, 355, 368 Nomuciferine, 349, 357 N-Nororientaline, 7 Noroxohydrastine, 222 N-Norprotosinomenine, 19, 53, 56 Norrecticuline, 351, 362 Norsongorine, I IS, 203 N-2’-Nortetrandrine, 353-354, 366 Nuciferine, 348, 349, 357
0
Ochotensimine, 252 Ochrobirine, 252 Ophiocarpine, 243 Ovatine, 104-106, 156, 194, 204 Oxazolidine ring, reactions of, 194-1% Oxidoreductase reaction, 326-327 Oxoaporphine, 351, 360 Oxocancentrine, 232-234 Oxocodeinone, 232, 233 I I-Oxoerysodine, 3, 1 1 1 I-Oxoerysopine, 3 1 I-Oxoerysovine, 3 I I-Oxoerythraline, 3 8-Oxoschelhammeridine, 28, 29, 35 1la-Oxoschelhammeridine, 28, 29, 35
P Pallidine, 351, 362 Papuver rhoeus, 351, 373 Papuver somniferum, 373 Papaverine, 352, 365, 366 Papaverinol, 225 Pavine alkaloid, I3C-NMR spectra, 234-235 Paynantheine, 329, 335 Pelletierine, biosynthesis, 3 13 Pelletierine-benzaldehydecondensation, 303-307 Penicillium brevicompucturn, 351, 353 Penicillium cluviforme. 350 Penicillium ducluuxi, 350 Penniclavine, 33 1, 339 Peptococcus heliotrinreducans. 377-380
409
INDEX
Pharmacology Erythrinu alkaloid, 91-93 Lythraeae alkaloid, 31S320 Phellibiline, 30, 42 Phelline, -77 Phelline billurdieri, 28, 41 Phelline comosu, 28, 36, 38, 39
Phenethylisoquinoline, bio-transformation, 369-373 Phenylalanine, alkaloid precursor, 61, 3153 18 I-Phenylisoquinoline, 58, 61 I-Phenyl-1,2-propanediol, 356, 375 Phenylquinolizidine alkaloid, simple, 284286 I-Phenyltetrahydroisoquinoline,59, 72 Phthalide, 246 Phthalideisoquinoline alkaloid, 245-249 Phyrophthoru infestuns, 385, 390 Pipecolic acid, 313 2-Piperdylpropanone, 303 Piperidine, 220, 3 19 Piperidine nietacyclophane alkaloid, 288294 chemistry, 289-292 stereochemistry , 292-294 synthesis, 312-313 2-Piperidylacetic acid, 313 Piriculuriu oryzue, 329, 330, 336337, 349, 358, 384, 385 Podocarpic acid, 187 Polysticrus versicolor, 329-330, 336-337, 384, 385 Proaporphine, 13C spectra, 238-239 Promelanthiodine, 355, 370 Pronuciferine, 239 Protoberberine, 220, 363-364 Protopine alkaloid, 13C spectra, 243-245 Protosinomenine, 19 Pseudocodamine, 352, 364 Pseudojervine, 385, 391 Pseudokobusine, 126, 204 Pyridine alkaloid, biotransformation, 376 Pyrrolizidine alkaloid, biotransformation, 376-38 1
Q Quinoline alkaloid, biotransformation, 38 1-383
Quinolizidine metacyclophane alkaloid, chemistry, 294-297 mass spectra, 299-302 oxoquinolizidine, 302-303 stereochemistry, 297-299 ring degradation, 276-278
R Rauwolscine, 330, 337 Rescinnamine, 330, 336 Reserpine, 329, 336-337 Reserpinine, 329, 335 Reticuline, 223, 351, 362-363, 372 Retrorsine, 377, 379, 380 N-oxide, 377, 378, 379 Rheumatism, 100 Rhizopus arrhizus, 354 Rhoeadine, 256, 257 Rubijervine, 385, 390
S
Salsolinol, 356, 375-376 Sarcoma 180, 92 Schelhummeru mult(floru, 28, 36 Schelhummeru pedunculutu, 27, 28, 32, 35,
36, 37, 38 Schelhummeru undulatu. 28, 37
Schelhammericine, 28, 29, 36 Schelhammeridine, 28, 32-34, 58 Schelhammerine, 28, 29, 32-34, 58 Scopolamine, 395 Scoulerine, 35 I , 362 Secoberbine alkaloid, 257-258 Senecio jucobueu, 378, 381 Sepedonium chryospermum, 350, 353 Setoclavine, 331, 338, 339 Shimoburo base I, 114 Shimotsuke, 139 Sibiricine, 252 Sinicuichine, 269, 270, 272 Shine, 265, 266, 267 Sinomenine, 229 Soladulcidine, 384, 387 Solamargine, 385, 389 Solanid-Cene-3-one, 385, 390
4 10
INDEX
Solani- 1,4-diene-3-one,385, 390 Solanine, 385, 390 Solanidanine-based alkaloid, 390-391 Solanidine, 385, 390 Solanocapsine, 385, 391 Solasodanol, 384, 387 Solasoda- 1,4-diene-3-one, 384, 387 Solasodine, 385, 389 Solasonine, 385, 389 Solidaline, 243 Songoramhe, 115-116, 167, 204 Songorine, 114-116, 204 mass spectra analysis, 163-165 N-oxide, 204 Speciocdiatine, 329, 333 Speciogynine, 329, 333 Spkdine, 189 A, 139-141, 205 B, 139-140, 205 C, 139-140, 205 D, 140-141, 205 F, 142-143, 206 G , 142-143, 206 Spiraeajaponica, 139, 140, 142, 143, 205207 Spiredine, 141-142, 206 Spireine, 143-144, 206-207 Spirobenzylisoquinoline alkaloid, 252-257 Staphidine, 144-146, 207 Staphigine, 147-148, 207 Staphimine, 146-147, 208 Staphinine, 146-147, 210 Staphirine, 147-148, 211 Staphisagnine, 148-149, 209 Staphiswine, 148-149, 210 Staphisine, 144-146, 210 Steroidal alkaloid, biotransformation, 38339 1 Stremphlium solani, 354 Streptomyces, 331, 350, 359 Streptomyces albogriseolus, 33 1, 340, 344, 345 Streptomyces cinnamonensir, 33 1, 345 Streptomyces griseus, 331, 339, 342, 351, 353, 354, 359, 366 Streptornyces lincolnensis, 353 Streptomyces platensis, 353, 354 Streptomyces punipalus, 331, 351, 353,354, 367 Streutornvces rimosus.,~350 .~
Streptomyces spectabilicus, 354, 381, 382 Stysanus rnicrosporus, 352 Stysanus stemonites, 350 Subcosine-I, 285, 287 Subcosine-11, 285, 287 Supinine, 377, 379
T Tetrahydroalstonine, 329, 335 Tetrahydroerysotrine, 25 Tetrahydroerythraline, 16 Tetrahydroisoquinoline, T - N M R spectra, 219-222 Tetrahydropalmatine, 241, 352, 362 Tetrahydropapaveroline, 362 Tetrahydroprotoberberine alkaloid, 239-243 Tetrandrine, 353, 366 Tetraphylline, 329, 335 Thalicarpine, 354, 366367 Thalictricavine, 243 Thaliporphine, 235 Thebaine, 229 Tomata- 1,4-dienin-3-one, 384, 386 Tomat-l-enin-3-one, 384, 386 Tomat-Cenin-3-one, 384, 386 Tomatidenol, 385, 389 Tomatidine, 384, 386-389 Tomatine, 385, 389 Tomatanin-3-one, 384, 386 Transformation, enzymatic, 325-328 Trichothecium roseurn, 384, 385, 390 3,4,5-Trimethoxybenzoic acid, 329-330, 336, 356, 375 3,4,5-TrimethoxyphenyIaceticacid, 356, 375 Tropane alkaloid, biotransformation, 391395 Tropic acid, 393 Tropine, 392, 393, 395 Tubocurarine, 356, 375, 376 Tyrosine, alkaloid precursor, 51, 58, 59 V
Vakognavine, 132-133, 210 Veatchine, 100, 101, 102-104, 109, 154-156, 21 1 acetate, 154-156, 157 azomethine, 161 synthesis, 168-170, 181-193, 1%
41 1
INDEX
Veatchinone, 110 Veatchinium chloride, 103 Veratrole, 220 Vertaline, 264, 280, 281-283 synthesis, 309-3 10 Verticillatine, 264, 269, 270, 272-273 Vertine, 264, 269, 270-272, 279, 320 Vinblastine, 331, 339, 345-347 ether, 331, 345 Vincdstine, 339 Vindoline, 331, 339 Vinoline, biotransformation, 339-348
X Xylopinine, 241, 352, 362
Y
Yew,plum, 42 a-Yohimbine, 330, 337 2
Zygorhynchus japonicus, 382
W Wasabia japonica, 370 Wilsonine, 28, 30, 41 Woodfordia, 264
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