THE ALKALOIDS Chemistry and Physiology
VOLUME XV
This Page Intentionally Left Blank
THE ALKALOIDS Chemistry and Physiology Edited b y
R.H. F. MANSKE Department of Chemistry, University of Waterloo Waterloo, Ontario, Canada
VOLUME XV
1975 ACADEMIC PRESS NEW YORK
SAN FRANCISCO LONDON
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT 0 1975, BY ACADEMIC PRESS, INC. ALL RIGHTS RESERVED. NO PART OF 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 IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC.
111 Fifth Avenue, New York, New York 10003
United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road. London NW1
Library of Congress Cataloging in Publication Data Manske, Richard Helmuth Fred, (date) The alkaloids: chemistry and physiology. Vols. 8- edited by R. H. F. Manske. Includes bibliographical references. 1. Alkaloids. 2. Alkaloids-Physiological effect. I. Holmes, Henry Lavergne, joint author. 11. Title. QD421.M3 541'.72 50-55 22 ISBN 0-12-469515-9 (v. 15)
PRINTED IN THE UNITED STATES OF AMERICA
CONTENTS LIST OF CONTRIBUTORS .................................................. PREFACE ............................................................... CONTENTSOF PREVIOUS VOLUMES .........................................
vii ix xi
Chapter 1 . The Ergot Alkaloids P . A. STADLER and P . STWTZ
1. Introduction ...................................................... I1 New Alkaloids .................................................... I11. Synthesis of Ergot Alkaloids ........................................
. IV. Biogenesis ........................................................ V . Biological Properties of Ergot Compounds ............................ References
.......................................................
1 2 12 19 31 36
Chapter 2 . The Daphniphyllum Alkaloids SHOSUKEYAMAMURA and YOSHIMASA HIRATA
I . Introduction ...................................................... I1 Structural Elucidations ............................................ I11. Chemistry ........................................ IV . Structural Relationship ............................................ V Biosynthesis .......................................... VI . Pharinacology .................................................... VII . Addendum ....................................... References .......................................................
.
.
41 43 70 77 80
Chapter 3 . The Amaryllidaceae Alkaloids CLAUDIOFUGANTI
. . .
I Introduction and Occurrence ....................................... I1 Lycorine-Type Alkaloids ........................................... 111. Lycorenine-Type Alkaloids ......................................... IV Galanthamine-Type Alkaloids ....................................... V. Crinine-Type Alkaloids ............................................. VI. Montanine-Type Alkaloids .......................................... VII . Cherylline ................................... ................. VIII . Narciclasiiie ...................................................... I X . Biosynthesis ...................................................... References ....................................................... V
84 88 104 111 121 137 139 141 145 160
vi
CONTENTS
Chapter 4. The Cyclopeptide Alkaloids R . TSCHESCHE and E . U . K A U ~ M A N N
I . Introduction ...................................................... I1. Occurrence and Isolation ........................................... I11. Properties ........................................................ IV . Types of Cyclopeptide Alkaloids . . ...... V . UV and I R Spectra and Circular ................. V I . NMR Spectra . . ..... ............................... VII . Mass Spectra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII . Biochemistry and Pharmacology .................................... References .......................................................
165 166 168 179 188 189 191 203 204
Chapter 5. The Pharmacology and Toxicology of the Papaveraceae Alkaloids V . PREININGER
I . Introduction ...................................................... 207 I1. Structure, Pharmacological. and Toxicological Properties of the Papaveraceae Alkaloids .......................... . . . . . . . . . . . . . . . . . . . . . . 208 References ....................................................... 243 Chapter 6. Alkaloids Unclassified and of Unknown Structure
R . H . F. MANSKE I . Introduction ...................................................... I1. Plants and their Contained Alkaloids ................................ References .......................................................
263 263 300
SUBJECT INDEX .........................................................
307
LIST OF CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin.
CLAUDIO FUGANTI, Istituto di Chimica del Politecnico, Milan, Italy (83) YOSHIMASA HIRATA,Chemical Institute, Nagoya University, Chikusaku, Nagoya, Japan (41) E. U. KAURMANN, Institut fur Organische und Biochemie der Universitat Bonn, BRD, Germany (165) R. H. F. MANSKE,Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada (263) V. PREININGER, Institute of Chemistry, Medical Faculty, Palackf University, Olomouc, Czechoslovakia (207) P. A. STADLER,Chemical Research, Pharmaceutical Department, Sandoz Ltd., Basel, Switzerland (1) P. STUTZ, Chemical Research, Pharmaceutical Department, Sandoz Ltd., Basel, Switzerland ( 1 ) R. TSCHESCHE, Institut fur Organische und Biochemie der Universitat Bonn, BRD, Germany (165) SHOSUKE YAMAMURA, Faculty of Pharmacy, Meijo University, Showaku, Nagoya, Japan (41)
Vii
This Page Intentionally Left Blank
PREFACE The literature dealing with alkaloids shows no obvious signs of abatement. The classic methods of the organic chemist employed in structural determinations have evolved into spectral methods, and chemical reactions are involved largely in confirmatory and periferal studies. Inasmuch as the spectral methods have become largely standardized we incline to limit the details in these volumes. Many new and already known alkaloids have been isolated from new and from previously examined sources. Novel syntheses are a prominent feature of recent publications. We attempt to review timely topics related to alkaloids.
R.H. F. MANSKE
This Page Intentionally Left Blank
CONTENTS OF PREVIOUS VOLUMES
Contents of Volume I CHAPTER 1. 2. 3. 4. 5. 6. 7.
Sources of Alkaloids and Their Isolation BY R . H . F. MANSKE Alkaloids in the Plant BY W . 0. JAMES. . . . . . . The Pyrrolidine Alkaloids BY LEO MARION . . . . . . Senecio Alkaloids BY NELSONJ . LEONARD. . . . . . The Pyridine Alkaloids BY LEOMARION . . . . . . The Chemistry of the Tropane Alkaloids BY H . L . HOLMES . The Strychnos Alkaloids BY H . L . HOLMES . . . . . .
. . .
. . . . . .
. . .
. . .
. . .
. . .
1 15 91 107 165 271 375
Contents of Volume I1 8.1. The Morphine Alkaloids I BY H . L . HOLMES. . . . . . . . 1 8.11. The Morphine Alkaloids BY H . L . HOLMES AND (IN PART) GILBERT STORK 161 9. Sinomenine BY H . L . HOLMES . . . . . . . . . . . . 219 10. Colchioine BY J . W . COOK AND J . D . LOUDON. . . . . . . . 261 11. Alkaloids of the Amaryllidaceae BY J . W . COOKAND J . D . LOUDON . 331 12. Acridine Alkaloids BY J . R PRICE . . . . . . . . . . . 353 13. The Indole Alkaloids BY LEOMARION . . . . . . . . . . 369 14. The Erythrina Alkaloids BY LEOMARION . . . . . . . . . 499 15. The Strychnos Alkaloids . Part I1 BY H . L . HOLMES. . . . . . 513
.
Contents of Volume 111 16. The Chemistry of the Cinchona Alkaloids BY RICHARD B . TURNER AND R . B. WOODWARD. . . . . . . . . . . . . . . 1 17. Quinoline Alkaloids. Other than Those of Cinchona BY H . T . OPENSRAW 65 18. The Quinazoline Alkaloids BY H . T. OPENSHAW . . . . . . . 101 19. Lupine Alkaloids BY NELSONJ . LEONARD. . . . . . . . . 119 AND H . T . OPENSRAW. 201 20 . The Imidazole Alkaloids BY A. R . BATTERSBY 21. The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOG AND 0. JEGER . . . . . . . . . . . . . . . . . . 247 22 . j-Phenethylamines BY L . RETI . . . . . . . . . . . . 313 23. Ephreda Bases BY L . RETI . . . . . . . . . . . . . 339 24 . The Ipecac Alkaloids BY MAURICE-MARIE JANOT . . . . . . . 363
Contents of Volume 1V 25 . The Biosynthesis of Isoquinolines BY R . H . F . MANSKE . . . . . 26 . Simple Isoquinoline Alkaloids BY L . RETI . . . . . . . . . 27 . Cactus Alkaloids BY L . RETI . . . . . . . . . . . . . 28 . The Benzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . 29 . The Protoberberine Alkaloids BY R . H . F . MANSKE AND WALTERR . ASHFORD. . . . . . . . . . . 30. The Aporphine Alkaloids BY R . H . F. MANSKE
xi
. . . . . . . . . . . . . .
1 1 23 29 71 119
xii
CONTENTS O F PREVIOUS VOLUMES
CHAPTER 31 . The Protopine Alkaloids BY R . H . F. MANSKE . . . . . . . . 32 . Phthalideisoquinoline Alkaloids BY JAROSLAV STANBKAND R . H . F . MANSKE . . . . . . . . . . . . . . . . . . 33 . Bisbenzylisoquinoline Alkaloids BY MARSHALL KULKA . . . . . 34. The Cularine Alkaloids BY R . H . F MANSKE . . . . . . . . 35 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . 36 . The Erythrophleum Alkaloids BY G. DALMA . . . . . . . . 37 . The Aconitum and Delphinium Alkaloids BY E . S. STERN . . . .
.
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 BY HUGO KRUEGER. . . . . Cardioactive Alkaloids BY E . L . MCCAWLEY . . . . . Respiratory Stimulants BY MICHAEL J . DALLEMAQNE . . Antimalarials BY L . H . SCHMIDT . . . . . . . . . Uterine Stimulants BY A. K . REYNOLDS . . . . . . Alkaloids as Local Anesthetics BY THOMAS P. CARNEY . . Pressor Alkaloids BY K . K . CHEN . . . . . . . . Mydriatic Alkaloids BY H . R . ING . . . . . . . . Curare-like Effects BY L . E . CRAIG . . . . . . . . The Lycopodium Alkaloids BY R . H . F. MANSKE . . . . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE
. . . . . . . . . . . . . . .
. . . .
. . . .
. . . .
. . . . . .
Contents of Volume V1 1 . Alkaloids in the Plant BY K . MOTHES . . . . . . . . . . 2 . The Pyrrolidine Alkaloids BY LEOMARION. . . . . . . . . 3 . Senecio Alkaloids BY NELSONJ . LEONARD. . . . . . . . . 4. 5. 6. 7. 8. 9.
The Pyridine Alkaloids BY LEOMARION . . . . . The Tropane Alkaloids BY G . FODOR . . . . . . The Strychnos Alkaloids BY J . B . HENDRICKSON . . . The Morphine Alkaloids BY GILBERT STORK . . . . Colchicine and Related Compounds BY W . C. WILDMAN. Alkaloids of the Amaryllidaceae BY W . C . WILDMAN. .
. . . . . .
. . . . . .
. . . . . .
. . . . . .
1 79 109 141 163 211 229 243 265 259 301
1 31 35 123 145 179 219 247 289
Contents of Volume V I I 10. The Indole Alkaloids BY J . E . SAXTON. . . . 11 . The Erythrina Alkaloids BY V . BOERELHEIDE
. . . . . . . . . . . . . .
1 201 12. Quinoline Alkaloids Other Than Those of Cinchona BY H . T . OPENSHAW229 13. The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . 247 14. Lupine Alkaloids BY NELSONJ. LEONARD. . . . . . . . . 253 AND V . PRELOG 15. Steroid Alkaloids: The Holarrhena Group BY 0. JEGER 319 AND 0. JEGER . 343 16 . Steroid Alkaloids: The Solanum Group BY V . PRELOG 17 . Steroid Alkaloids: Veratrum Group BY 0. JEGER . . 363 AND V . PRELOG 18. The Ipecac Alkaloids BY R . H . F. MANSKE . . . . . . . . 419 19. Isoquinoline Alkaloids BY R . H . F. MANSKE . . . . . . . . 423 STANSK . . . . . 433 20 . Phthalideisoquinoline Alkaloids BY JAROSLAV 21 . Bisbenzylisoquinoline Alkaloids BY MARSHALLKULRA . . . . . 439
...
CONTENTS OF PREVIOUS VOLUMES
Xlll
CHAPTER 22 . The Diterpenoid Alkaloids from Aconitum. Delphinium. and Garrya Species BY E . S. STERN. . . . . . . . . . . . . . 473 23 . The Lycopodium Alkaloids BY R . H . F . MANSKE . . . . . . . 505 24 . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE . . . 509
Contents of Volume V I I I 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11 .
12. 13. 14.
15. 16. 17 . 18. 19.
20 . 21 . 22 .
1 The Simple Bases BY J . E . SAXTON. . . . . . . . . . . Alkaloids of the Calabar Bean BY E . COXWORTR. . . . . . . 27 47 The Carboline Alkaloids BY R . H . F . MANSKE . . . . . . . . 55 The Quinazolinocarbolines BY R . H . F . MANSKE . . . . . . . Alkaloids of Mitraqyna and Ourouparia Species BY J . E . SAXTON . . 59 93 Alkaloids of Gelsemiurn Species BY J . E . SAXTON. . . . . . . Alkaloids of Picralima nitida BY J . E . SAXTON . . . . . . . 119 Alkaloids of Alstonia Species BY J . E . SAXTON . . . . . . . 159 The Iboga and Voacanqa Alkaloids BY W . I. TAYLOR . . . . . . 203 The Chemistry of the 2,2'.Indolylquinuclidine Alkaloids BY W . I . TAYLOR 238 The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids . . . . . . . . . . . . . . 250 BY W . I . TAYLOR . The Vinca Alkaloids BY W . I . TAYLOR. . . . . . . . . . 272 Rautuolja Alkaloids with Special Reference to the Chemistry of Reserpine BY E . SCHLITTLER. . . . . . . . . . . . . . . 287 The Alkaloids of Aspidosperma, Diplorrhyncus, Kopsia, Ochrosia, Pleiocarpa, and Related Genera BY B . GILBERT . . . . . . . . 336 Alkaloids of Calabash Curare and Strychnos Species BY A R . BATTERSBY AND H . F. HODSON. . . . . . . . . . . . . . . 515 The Alkaloids of Calycanthaceae BY R H . F. MANSKE . . . . . 581 Strychnos Alkaloids BY G. F. SMITH. . . . . . . . . . . 592 Alkaloids of Haplophyton cimicidum BY J . E . SAXTON . . . . . 673 The Alkaloids of Geissospermum Species BY R . H . F. MANSKEAND W . ASHLEYHARRISON. . . . . . . . . . . . . . . 679 Alkaloids of Pseudocinchona and Yohimbe BY R . H . F MANSKE . . 694 The Ergot Alkaloids BY A . STOLLAND A . HOFMANN . . . . . . 726 The Ajmaline-Sarpagine Alkaloids BY W . I. TAYLOR. . . . . . 789
.
.
.
Contents of Volume I X 1 1. The Aporphine Alkaloids BY MAURICESHAMMA . . . . . . . 2 . The Protoberberine Alkaloids BY P . W . JEFFS. . . . . . . . 41 STANEK . . . . . 117 3. Phthalideisoquinoline Alkaloids BY JAROSLAV 4 . Bisbenzylisoquinoline and Related Alkaloids BY M. CURCUMELLIRODOSTAMO AND MARSHALLKULKA . . . . . . . . . . 133 BOHLMANN AND DIETERSCHUMANN . 175 5 . Lupine Alkaloids BY FERDINAND 6 . Quinoline Alkaloids Other Than Those of Cinchona BY H . T . OPENSHAW223 7. The Tropane Alkaloids BY G . FODOR. . . . . . . . . . 269 8. Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V . ERN^ AND F . SORM . . . . . . . . . . . . . . . . . 305 427 HABERMEHL 9. The Steroid Alkaloids: The Salamandra Group BY GERHARD 10. Nuphar Alkaloids BY J . T . WROBEL. . . . . . . . . . . 441
xiv
CONTENTS O F PREVIOUS VOLUMES
CHAPTER AND G. LETTENBAUER . 11. The Mesembrine Alkaloids BY A. POPELAK K. HILL . . . . . . 12. The Erythrina Alkaloids BY RICHARD . . . . . . . 13. Tylophora Alkaloids BY T. R. GOVINDACHARI 14. The Gnlbulimima Alkaloids BY E. RITCHIEAND W. C. TAYLOR. . . . . . , . . . 15. The Stemona Alkaloids BY 0. E. EDWARDS
.
467
. 483 . 517 . 529
.
545
Contents of Volume X 1 1. Steroid Alkaloids: The Solanun Group BY KLAUSSCHRIEBER . . . AND 2. The Steroid Alkaloids: The Veratrum Group BY S . MORRIS KUPCHAN ARNOLDW. BY . . . . . . . . . . . . . . . . 193 B. MORIN . . . . . . . 287 3. Erythrophleum Alkaloids BY ROBERT 4. The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . . . 306 5. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . 383 6. The Benzylisoquinoline Alkaloids BY VENANCIODEULOFEU,JORGE COMIN,AND MARCELOJ. VERNENGO. . . . . . . . . . 402 7. The Cularine Alkaloids BY R. H. F. MANSKE . . . . . . . . 463 8. Papaveraceae Alkaloids BY R. H. F. MANSKE . . . . . . . . 467 9. a-Naphthaphenanthridine Alkaloids BY R. H. F. MANSKE . . . . 485 10. The Simple Indole Bases BY J. E. SAXTON. . . . . . . . . 491 11. Alkaloids of Picralima nitida BY J. E. SAXTON . . . . . . . 501 12. Alkaloids of Mitragyna and Ourouparia Species BY J. E. SAXTON . . 521 13. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 545 14. The T a r u s Alkaloids BY B. LYTHGOE . . . . . . . . . 597
.
Contents of Volume X I 1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12.
1 The Distribution of Indole Alkaloids in Plants BY V. SNIECKUS . . . The Ajmaline-Sarpagine Alkaloids BY W. I. TAYLOR. . . . . . 41 The 2,2’-IndolylquinuclidineAlkaloids BY W. I. TAYLOR. . . . . 73 The Iboga and Voacanga Alkaloids BY W. I. TAYLOR. . . , . . 79 The Vinca Alkaloids BY W. I. TAYLOR. . . . . . . . , . 99 The Eburnamine-Vincamine Alkaloids BY W. I. TAYLOR. . . . . 125 Yohimbine and Related Alkaloids BY H. J. MONTEIRO . . . . . 145 Alkaloids of Calabash Curare and Strychnos Species BY A. R. BATTERSBY AND H. F. HODSON . . . . . . . . . . . . . . . 189 The Alkaloids of Aspidosperma, Ochrosia, Pleiocarpa, Melodinus, and Related Genera BY B. GILBERT . . . . . . . . . . . 205 The Amaryllidaceae Alkaloids BY W. C. WILDMAN . . . . . . 307 Colchicineand Related Compounds BY W. C. WILDMAN AND B. A. PURSEY407 The Pyridine Alkaloids BY W. A. AYERAND T. E. HABGOOD. . . 459
Contents of Volume X I I The Diterpene Alkaloids: General Introduction BY S. W. PELLETIER AND L.H.KEITH . . . . . . . . . . . . . . . . . xv 1. Diterpene Alkaloids from Aconitum, Delphinium, and Barrya Species: AND L. H. KEITH. 2 The C1,-Diterpene Alkaloids BY S. W. PELLETIER 2. Diterpene Alkaloids from Aconitum, Delphinium, and Qarrya Species: The AND L. H. KEITH . . 136 C2,-Diterpene Alkaloids BY S. w. PELLETIER
CONTENTS OF PREVIOUS VOLUMES CHAPTER 3. 4. 5. 6. 7.
XV
Alkaloids of Alstonia Species BY J. E. SAXTON . . . . . . . 207 Scnecio Alkaloids BY FRANK L. WARREN . . . . . . . . . 246 Papaveraceae Alkaloids BY F. SANTAVY . . . . . . . . . 333 Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 455 The Forensic Chemistry of Alkaloids BY E. G. C. CLARKE . . . . 514
Contents of Volume X I I I 1 BY K. W. BENTLEY . . . . . . . . The Spirobenzylisoquinoline Alkaloids BY MAURICESHAMMA . . . 165 The Ipecac Alkaloids BY A. BROSSI,S. TEITEL,AND G. V. PARRY. . 189 Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . 213 The Galbulimima Alkaloids BY E . RITCHIEAND W. C. TAYLOR. . . 227 The Carbazole Alkaloids B Y R. S. KAPIL . , . . . . . . . 273 Bisbenylisoquinoline and Related Alkaloids BY M. CURCUMELLI-RODOSTAMO.. . . . . . . . . . . . . . . . . . 303 8. The Tropane Alkaloids BY G. FODOR . . . . . . . . . . 351 9. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 397 1. The Morphine Alkaloids
2. 3. 4. 5. 6. 7.
Contents of Volume X I V 1.
Steroid Alltaloids: The Veratrum and Buxus Groups
2. 3. 4. 5. 6. 7.
8. 9. 10. 11. 12.
.
.
.
. .
.
. .
.
BY
J. TOMKO AND
1 . . . Oxindole Alkaloids BY JASJIT S. BINDRA . . . . 83 Alkaloids of Mitraqyna and Related Genera BY J. E. SAXTON . . . 123 Alkaloids of Picralima and Alstonia Species BY J. E. SAXTON . . . 157 The Cinchona Alkaloids BY M. R. USKOKOVI~ AND G. GRETHE . . . 181 The Oxoaporphine Alkaloids BY MAURICE SHAMMA AND R. L. CASTENSON225 Phenethylisoquinoline Alkaloids BY TETSUJI KAMETANI AND MASUO KOIZUMI. . . . . . . . . . . . . . . . . . 265 Elaeocarpus Alkaloids BY S. R. JOHNS AND J. A. LAMBERTON . . . 325 The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . . . 347 The Cancentrine Alkaloids BY RUSSELLRODRIQO. . , . . . . 407 The Securineqa Alkaloids BY V. SNIECKUS. . . . . . . . . 425 Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 507 Z.VOTICKP
. . . .
. . . . . .
This Page Intentionally Left Blank
-CHAPTER
1-
THE ERGOT ALKALOIDS P. A. STADLER and P . STUTZ Chemzcal Research Pharmaceutical Department Sandoz Ltd . Basel. Switzerland
I. Introduction ....................................................... 11. New Alkaloids ..................................................... A. Introduction .................................................... B . Paspalin and Paspalicin .......................................... C. 4-Dimethylallyltryptophan....................................... D . The Chanoclavines ............................................... E . The Rugulovasines .............................................. F. Clavicipitic Acid ................................................. G . 6-Norsetoclavine ................................................ H . Cycloclavine .................................................... I. Elymoclavine.O.8.D.fructofuranoside ............................... J . 6-Methyl-8-ergolene-8-carboxylic Acid and Newly Discovered Clavines . . K . N-[N-(d-Lysergyl)-~-valyl]-~-phenylalanyl-~-pro~~ne Lactam ........... L . Dihydroergosine ................................................. M . Ergosine and Ergosinine in Higher Plants ........................... N . Ergostine ....................................................... 0. /3-Ergokryptine .................................................. I11. Synthesis of Ergot Alkaloids .......................................... A. Total Synthesis of Clavines and Lysergic Acid ....................... B . Total Synthesis of Ergot Peptide Alkaloids .......................... C . Modifications of Lysergic Acid by Partial Synthesis .................. 1V. Biogenesis ......................................................... A. Ergolenes and Lysergic Acid . . . ....... .......... B . Lysergic Acid Amides and Peptide Alkaloids ........................ V . Biological Properties of Ergot Compounds .............................. A . Structure-Activity Relationships of Peptide Alkaloids ................ B . New Semisynthetic Compounds with High Biological Activity ......... C. New Biological Effects of Ergot Derivatives ......................... References ......................................................
1 2 2 2 3 3 4 5 5 6 6 7
9 9 10 10 11 12 12 14 16 19 20 26 31 31 32 35 36
.
I Introduction The chemistry of the ergot alkaloids was last reviewed in Volume VIII of this treatise ( 1 ). A remarkable monograph appeared in 1964 covering in brief all the achievements in ergot chemistry t o that time ( 2 ).
2
P. A. STADLER
AND P. STUTZ
Ergot research of the past 10 years may be characterized as a harvesting period of intensive previous investigations. Relatively few new alkaloids have been described in the meantime, most of them being only of biogenetic significance. They all originate from parasitic fungi although certain ergot alkaloids have been known to occur also in higher plants, especially in Convolvulaceae (2). Recent progress lies mainly in the field of synthesis. Extensive work has also been done in order to gain more information about biosynthesis. It must however be emphasized that the mechanism of important biochemical transformations still remains obscure.
11. New Alkaloids
A. INTRODUCTION Since the last review on ergot alkaloids, important new alkaloids from different sources, mostly from new ergot strains, have been discovered. Their proposed structure could in some cases be confirmed by synthesis. Some of them seem to be intermediates in the biogenetic pathway from tryptophan t o the peptide alkaloids. Others are considered as end products of secondary plant metabolism. I n any case we find many interesting structures among these recently discovered substances.
B. PASPALIN AND PASPALICIN From the dried mycel of a Portuguese Claviceps paspali strain, two new indole derivatives, paspalin (1; C,,H,,NO,; mp 2 6 4 O ; [.ID -23" in chloroform) and paspalicin (2; C27H,,N0,; mp 230";,I.[ + 173" in chloroform) were isolated ( 3 ) .
-
1. Paspalin
Structure 1 had been proposed for paspalin, based mainly on biogenetic speculations (124). Extensive degradative work (225) has now confirmed this, although its stereochemistry has yet to be elucidated. Paspalin cannot be regarded as a true alkaloid, its unique structurea seco-steroid annelated to an indole nucleus-deserves, however, attention as it demonstrates the great versatility of the ergot fungus.
1. THE ERGOT
CH,
I
ALKALOIDS
3
Paspalin
2. Paspalicin
Less is known about paspalicin. It is also regarded as a 2,3-disubstituted indole derivative with four tertiary methyl groups and probably an a,P-unsaturated carbonyl group.
c. 4-DIMETHYLALLYLTRYPTOPHAN 4-Dimethylallyltryptophan (3;C,,H,,N,O,; mp 210') had already been synthesized in 1963 ( 4 ) and shortly afterward it was recognized as an important intermediate in biosynthesis of ergot alkaloids ( 5 ) .
3
4-Dimethylallylt,ryptophan
In 1968 the existence of 3 in a Penniseturn type of ergot strain, producing mainly elymoclavine, could be established after addition of ethionine to the culture broth (6).
D. THECHANOCLAVINES In 1964, two new isomers of the known chanoclavine-I (7) were isolated from the water-soluble fraction of Portuguese rye ergot (8). Interpretation of the physical data, essentially of the NMR spectra, permitted the establishment of the stereochemistry of these three isomers.
4
P. A. STADLER AND P. STUTZ
QHzOH
QH,OH
p
3
CHzOH
/ HN 4
Chanoclavine-I
5
Chanoclavine-I1
6
Isochanoclavine-I
The stereoformula 4 could be assigned t o chanoclavine-I (C,&I&,O; mp 220"; [.ID - 294" in pyridine). Chanoclavine-I1 (5; C,,H,,N,O; mp 174"; [.ID - 332" in pyridine; hydrochloride, mp 247") differs from 4 only in the cis configuration of the substituents on ring C. I t s absolute configuration could not be fixed, however; so far the formula 5 is tentative. The isolated optically active isomer of 5 was also accompanied by the racemic form. The third isomer, isochanoclavine-I (C,,H,,N,O; mp 181"; [a],, -216" in pyridine), is represented by formula 6. It differs from 4 in the position of the substituents on the isolated double bond.
E. THE RUGULOVASINES From cultures of a mold, Penicillium concavo-rugulosum, two new alkaloids as well as chanoclavine-I (4) were isolated by routine procedures (9). The new compounds were called rugulovasine-A (C,,H,,N,02; mp 138"; [a]= 0" in pyridine; hydrochloride, mp 225"; oxalate, mp 224") and rugulovasine-B (C,,H,,N,02; amorphous; [.ID 0" in pyridine; hydrochloride, mp 187"; oxalate, rnp 217"). They proved to be closely related t o each other since they were easily interconvertible when heated in alcohol solution.
8 /
:CH3
K-N Rugulovasine-A and -B
7
The accumulated information from the physical data and some
1. THE
5
ERGOT ALKALOIDS
chemical transformations (10) led to the tentative formula 7 for rugulovasine-A and -B. The steric details remain to be elucidated.
F. CLAVICIPITIC ACID From the culture filtrates of two different Claviceps species, strain SD 58 and C. fusiformis, strain 139/2/1G, a new amino acid was isolated, named clavicipitic acid, (C,,H,,N,O,; mp 262").
H
H
8
9
Formula 9 proposed a t first (11) was based mainly on mass spectral data (M+) and biosynthetic evidence since only small quantities of the new amino acid were available. Very recently, however, its structure has been revised (12) to 8, mainly on NMR studies of its crystalline N-acetylmethyl ester derivative (mp 107'; M + 326). The observed two three-proton singlets a t 1.68 and 1.82 ppm (CDC13:1,)are inconsistent with formula 9.
G. 6-NORSETOCLAVINE In the culture filtrates of two Pennisetum ergot strains 47A and 231 the first representative of 6-norclavine alkaloids was found (13) and identified as 6-norsetoclavine (10; C,,H,,N,O; mp 163-165').
10
6-Norsetoclavine
6
P. A. STADLER AND P. S T U T Z
Formula 10 was derived from physical data and confirmed unequivocally by N-methylation to the well-known setoclavine. From biogenetic reasons it is believed that it could be a secondary product arising in the fungus by demethylation of setoclavine. This might also be the case for 6-noragroclavine, the presence of which has been established in a Pennisetum strain (59).
H. CYCLOCLAVINE The detection of cycloclavine (11; C16H18N2; mp 166"; [.ID + 63" in chloroform) in the seeds of plants of the Convolvulacea family was surprising. I n Ipomoea hildebrandtii Vatke i t occurs in quantities up to 0.2%, accompanied by traces of festuclavine ( 1 4 ) .
11 Cycloclavine
The unusual structure of cycloclavine as the first known pentacyclic clavine alkaloid was derived from physical data (mass spectrum: M + 238; NMR: signals of the cyclopropyl methylene group 6 = 0.46 and 1.60) and some chemical transformations (hydrogenation, reductive ring opening, and quaternization). The remaining details of its constitution were finally determined by an X-ray analysis of the methobromide. Thus it was shown that the chirality of 11 is 5R, 8R,10R.
I. ELYMOCLAVINE-O-/3-D-FRUCTOFURANOSIDE When the Claviceps strain SD 58 was grown in a culture medium containing saccharose the slow formation of alkaloids containing polar groups was observed (15).These could not be extracted from the water phase in either alkaline or acid medium by the usual solvents. Finally, the principal alkaloid was isolated by ion exchange procedures and purified by subsequent chromatographic methods. The alkaloid was identified as elymoclavine-O-P-D-fructofuranoside (12; C,,H,,N,O,,
1. THE ERGOT ALKALOIDS
7
amorphous, M + 416) From spectroscopic data and the results of its hydrolysis. I n acidic medium or with invertase it was cleaved to elymoclavine and Fructose; emulsine had no effect and it represents the
12
Elymoclevine-O-~-~~-fructofuranoside
first glycosidic alkaloid isolated from an ergot strain. It must, however, be stated that there is good reason to believe that 12,is formed in a secondary process from elymoclavine and fructose. The latter could well result From a degradation of excess saccharose present in the culture medium.
J. 6-METHYL-8-ERClOLENE-8-cARBOXYLIC ACID In 1964 it was recognized that a strain of Claviceps paspali, grown in Portugal on the grass Paspabum dilatatum, formed only amphoteric substances instead OF the usual mixture OF simple amides OF lysergic acid. Ion exchange procedures permitted the isolation of these amphoteric substances. It turned out that they were a mixture of lysergic acid, isolysergic acid, and a new amino acid (16). The latter showed a rapid isomerization to lysergic acid in alkaline medium. Prom this observation and From its physical data (e.g., the UV spectrum showing a pure indole absorption) it was concluded that the new amino acid acid (13; C,,H,,N,O,; mp 245"; was 6-methyl-8-ergolene-8-carboxylic [.ID -208" in 0.1 N NaOH). VOOH
13
6-l\lethyl-B-ergolene-8-carboxylic acid
8
P. A. STADLER AND P. STUTZ
An unequivocal proof of this structure followed from the transformation of it to elymoclavine (54). 1. New Alkaloids from Claviceps paspali Stevens and Hall
Recently, a paper on some minor alkaloids produced by C. paspali has been published (126).Three new alkaloids could be characterized as well as the known chanoclavine-I (4) and penniclavine (14).
14
Penniclavine
15 Dihydrosetoclavine
The first new alkaloid (CI6HzoNz0; mp 276-278"; [.ID -51" in pyridine) was identical with the hydrogenation product (15) of setoclavine. The other two unknown alkaloids were called paspaclavine (16; C18H22N20;mp 204-206"; [.ID + 88" in pyridine) and paliclavine (17; CI6HzoNz0;mp 168-170"; [.ID + 3" in pyridine). CHZ
16
Paspsclavine
17
Peliclavine
A valuable hint for structure evaluation was that paspaclavine was cleaved in acidic medium to paliclavine and acetaldehyde while treatment of paliclavine with acetaldehyde yielded paspaclavine. A detailed spectroscopic analysis, especially of the NMR spectra, and some transformations finally led to formula 17 for paliclavine. Paspaclavine thus turned out to be a mixed 0,N-acetal of paliclavine. The stereochemistry at C-7 was deduced from an examination of models.
9
1. THE ERGOT ALKALOIDS
K.
N-[N-(d-LYSERGYL)-L-VALYLI-L-PHENYLALANYL-DPROLINE
LACTAM
Applying mild extraction methods t o the mycelium of an ergocristine producing Claviceps purpurea strain, an unstable peptide alkaloid of a new type was recently detected (12'). Its physical data and chemical transformations contributed to the elucidation of its structure. The fast methanolysis of the new alkaloid led t o the well-known N-lysergyl-L-valine methyl ester (18) and L-phenylalanineD-proline lactam. An amino acid analysis showed the presence of one mole each of valine, phenylalanine, and proline. Thus the new alkaloid has been characterized as N-[N-(d-lysergy1)-L-valyll-L-phenylalanylp pro line lactam (18; C,,H,,N,O,; mp 235"; [alD + 5" in chloroform).
n
18
N - [ N - ( d - L y s e r g y l ) - ~ - v a]-~-phenylalanyl-~-proline lyl lactsm
Various circumstances indicate that 18 and related hitherto overlooked substances (19) are widespread in Claviceps strains. Therefore, it seems very probable that N-lysergyl-L-valine methyl ester, claimed to be a genuine ergot alkaloid (18),is an artefact arising from methanolysis during extraction.
L. DIHYDROERGOSINE An important discovery was the observation (20) that the sclerotia of Xphacelia sorghi, grown on Xorghum vulgare in Nigeria, contained dihydroergosine (19) as the principal alkaloid. I n a recent paper (ZOa), its in vitro production in surface liquid cultures of Sphacelia sorghi has also been reported, yields exceeding 0.5 g/liter. This represents the first isolation of a dihydropeptide alkaloid from natural sources.
10
P. A. STADLER AND F. STUTZ
HN19 Dihydroergosine
M. ERGOSINE AND ERGOSININE IN HIGHER PLANTS Another observation of similar importance is the first isolation of an alkaloid of the peptide type from higher plants. Ergosine (20) (and ergosinine) as well as agroclavine were found in Ipomoea argyrophylla Vatke (21).
H'
.'CH,
I
CH H3C CH, / \
20
Ergosine
N. ERGOSTINE I n 1964 about 1% of ergostine (21) and ergostinine were found in the raw alkaloid mixture of rye ergot in addition to the principal alkaloid ergotamine. This pair is the first representative of a new group of peptide alkaloids containing, as a typical amino acid, L-ahydroxy-a-aminobutyric acid in the peptide part of the molecule (22). Ergostine could be separated from ergotamine by repeated chromatography on aluminum oxide columns. Its degradation with alkali to lysergic acid amide and a-ketobutyryl-L-phenylalanyl-L-proline and the interpretation of its physical data led t o the structure 21. It could
1. THE ERGOT ALKALOIDS
11
be confirmed by total synthesis, thus establishing the same stereochemistry as ergotamine in an unequivocal way. CH3 I 0
-
II
N-CH,
21
Ergostine
A t present, ergostine remains the only natural representative of the ergostine group of ergot peptide alkaloids, yet two analogs of this group, called ergoptine and ergonine, have been obtained by total synthesis (23).
0. /~-ERGOKR,YPTINE The development of a new, special paper chromatographic technique permitted the separation of ergokryptine into two different, but closely related isomers, designated as a-and P-ergokryptine, respectively (24). It could be shown that a-ergokryptine corresponded t o the formula formerly attributed t o ergokryptine (25); P-ergokryptine was new. I t s hydrolysis yielded d-lysergic acid, ammonia, dimethylpyruvic acid,
'A
HN
22
8-Ergokryptine
proline, and isoleucine in about equivalent proportions. From these results and from additional chemical and physical data a tentative structure 22 was proposed which was later verified by total synthesis (26).
12
P. A. STADLER AND P. STUTZ
111. Synthesis of Ergot Alkaloids The delicate structures as well as the interesting patterns of pharmacological activity of certain ergot alkaloids have received continuous attention among synthetic chemists. This is especially true of derivatives of lysergic acid, and this chapter will be devoted to the most remarkable developments in syntheses of this class of natural compounds.
A. TOTAL SYNTHESES OF CLAVINESAND LYSERGIC ACID To begin with the more classic transformations, the total synthesis of a clavine alkaloid, ( ? )-isosetoclavine (24)reported by Kornfeld and Bach (27) deserves mention. Using the same tetracyclic ketone (23) as starting material as in their famous synthesis (28) of lysergic acid (43) (cf. Vol. VIII) 24 was built up stereospecifically in two steps as demonstrated below.
23
24
The synthesis of lysergic acid by the Kornfeld group in 1954 remained the only one for a relatively long period despite some efforts in this direction (29). However, in 1968 Julia et al. published another synthesis, ingenious and entirely different in its approach (30). The author’s strategy aimed a t forming the C/D ring junction by the intramolecular attack of a stabilized allylic anion with an aryne generated from ring A (26 -+ 27). Thus, the oxindole derivative (25) which had been obtained j- two steps from 5-bromoisatin, was transformed t o a mixture of stereoisomers 26 by the sequence indicated below. Indeed, one pair of enantiomers of the formula 26 could be converted to the already known 2,3-dihydrolysergic acid methyl ester 27 in 15y0 yield by the action of sodium amide in liquid ammonia. Oxidation with activated MnO, finally led to ( k )-lysergic acid methyl ester 28.
1.
13
THE ERGOT ALKALOIDS
COOCH,
@
COOCH,
4 (3) BH QZ-CH, \ ~~~~~~~
@
\ H
HN
HN
0 26
25
hsdrolvsls isomerlzRtion
28
Julia et al. have also published some minor modifications of the sequence described above in additional patents (31) which need not be discussed here. Nevertheless, from an economical point of view, the whole process does not seem to compete favorably with fermentation processes of suitable fungi (32). In this connection it is worth mentioning that the large-scale production of peptide alkaloids, by submerged culture techniques of selectively mutated Claviceps strains, is likely t o succeed in the near future. This complex problem has been intensively studied in different laboratories for decades, but recent patents report on encouraging results (33).
14
P.
A. STADLER
AND P . STUTZ
B. TOTALSYNTHESIS OF ERGOT PEPTIDE ALKALOIDS Since the publication of the synthesis of ergotamine (34)all naturally occurring peptide alkaloids have been synthesized by analogous routes. Moreover, it has been shown that they all have the same stereochemistry and differ from each other only in their L-amino acid units and the chain length of the a-hydroxy-a-amino acid moiety a t the peptidic site. An X-ray study of a key intermediate has provided additional evidence for the correctness of the proposed absolute configuration of ergotamine ( 3 4 ~ ) . The syntheses of ergosine (20),ergovaline (35) (the latter has not yet been found in nature), ergostine (21) ( Z Z ) , and the alkaloids of the ergotoxine group (26)have been described. Two analogs of the ergostine group (called ergoptine and ergonine), of which only ergostine is known in nature, were also synthesized (23). Since all of these syntheses are very similar only that of ergocristine (38) (26) as a representative for the ergotoxine group will be discussed here in some detail. One of the main problems was the preparation of X-( i)-isopropylbenzyloxymalonic acid monoethyl ester chloride (33) as starting material. The method used in the synthesis of ergotamine, the reaction of a-alkyl-a-bromomalonic acid ester with benzylate anion, gave unsatisfactory results. However, 33 could be obtained in two ways: either by alkylation of the known 0-benzyltartronic acid ester (29) with isopropyl iodide or isopropyl sulfate, leading to 30, or by oxidation of isopropyl malonic acid ester (31) with benzoyl peroxide. I n this case the corresponding 0-benzoyltartronic acid ester (32) was obtained first which could be subsequently debenzoylated by the ethanolate anion and benzylated with benzyl bromide to yield 30. The separation of the half ester of 30 into the optical antipodes was H3C, H
I I
CSH5OOC-C-COOC,H5
\
O-CHZCBH, 29
,CH3 CH
I I
C,H,OOC-C-COOC,Hj
H H,C 31 CH,
\C/H
I
C,H5OOC-V-COOCzH5 O-CH,C,H, 30
H3C\ ,CH3 CH
/ i2c0c6H5 I I
C,H~OOC-C-COOC~H~
15
1. THE ERGOT ALKALOIDS
achieved via its ( + )-pseudoephedrine salt. I n this case the enantiomer with the correct stereochemistry was isolated and converted to the acid chloride (33) by subsequent reaction with SOCI, in dimethylformamide. Reaction Scheme I resembles that of ergotamine.
COCl
33
H
0
0\
&lysergic acid chloride. HC1
38 Ergocristine
36
39 SCHEME I
Q 35
34
37
CHz
Ergocristinine
16
P. A. STADLER AND P. STUTZ
L-Phenylalanyl-L-proline lactam (34) was acylated with 33 to the rather unstable 35 which was therefore immediately hydrogenated t o the so-called cyclolester (36)in a stereospecific reaction. The subsequent treatment entailed-as for ergotamine-a mild Curtius degradation leading to the aminocyclol (37)which itself is stable only as its salt with mineral acids. The last step was carried out essentially as in the synthesis of ergotamine to yield about equal amounts of ergocristine (38) and ergocristinine (39).Thus, it has been shown that this synthesis is widely applicable. Its scope has also been extended to the preparation of unnatural stereoisomers of ergotarnine and 9,lO-dihydroergotamine (36). The delicacy of the hitherto only synthetic pathway to the peptide alkaloids of lysergic acid is also underlined by the fact that other authors had failed to circumvent it (37). The main difficulty lies in the rapid epimerization of the L-proline containing intermediates to the D-proline isomers and the inherent instability of functionalized ahydroxy-a-amino acid derivatives. Lucente and Romeo (38)were able to isolate the N-cyclol derivatives 41 from the open chain precursor 40 by treating the latter with a slightly alkaline dioxane-aqueous buffer solution. The stereochemistry of 41 was also proved by X-ray analysis (39). NP
n
40
0
41
0
Np = p-NOs-CeH+Z = CeH5CH2-O-CO-
The scope of this reaction is, however, limited. On replacing Z by the tosyl group, only the corresponding N-acyldioxopiperazine (42) with the D-proline configuration can be isolated (40).
C . MODIFICATIONSOF LYSERGIC ACIDBY PARTIAL SYNTHESIS When the multivalent pharmacological actions of lysergic acid derivatives are taken into account, it is not surprising that many
17
1. THE ERGOT ALKALOIDS Tos
42
0
efforts have been made to modify the ergolene skeleton by partial synthesis. Some of the substitution reactions, mainly at the indole-nitrogtn as well as halogenation at C-2 have already been discussed in Volume VIII. Oxidation of 2,3-dihydrolysergic acid derivatives with Fremy’s salt leads to derivatives of 12-hydroxylysergic acid (41) which have recently been shown to be significant in metabolic studies (41a). In the meantime amides of the A*v9 isomer (13) of lysergic acid and their derivatives have been prepared (42). Homologization of lysergic acid (43)to the so-called homolysergic acid (44) has been achieved (43) as indicated below. The same reaction was also carried out later on with the 9,10-dihydro derivatives (44).
43
44
Nitration of derivatives of 9, 10-dihydrolysergic acid with fuming nitric acid in acetic anhydride in the presence of urea has been reported (44a) to lead to the 2-nitro derivatives though only in 5-20x yield. In a new reaction of the Friedel-Crafts type, using 2-methoxy-1,3dithiolane and a weak Lewis acid such as TiC1, the ester 45 could be obtained (45). This compound was either hydrolyzed to the 2-formyl derivative or desulfurized with Raney nickel to the 2-methyl compound.
18
P. A. STADLER AND P. STUTZ
Demethylation a t the nitrogen in position 6 could be realized by new modifications of the von Braun degradation. The 6-nor-6-cyano derivatives 46, obtained in the usual way by the action of cyanogen bromide on the parent compounds, could be reduced directly with zinc in acetic acid in good yield (46) to the 6-nor compounds (47). An alternative procedure was published independently by a Japanese group ( 4 7 ) ,using a two-step process via a urea-type compound 48. &C :N
H,
/
ZnIHOAc
COR
, \
\ H-N
H-N 47
46
48
The 9,lO double bond of lysergic acid has also been used for some interesting transformations; for example, hydrogenation leads stereospecifically to the 1 Oa-ergoline derivatives. The also well-known photolytic addition of water yields predominantly the 1 Oa-hydroxyergoline (48) and, when carried out in acidified methanol, mainly l0a-methoxyergolines (49) can be isolated. Hydroboration of lysergic acid and
1. THE
19
ERGOT ALKALOIDS
subsequent oxidation with H,O, is reported (50) to give Sa-hydroxy9, lo-dihydrolysergol (49).
50
49
Another remarkable reaction is the methoxymercuration which leads, when applied to derivatives of lysergic acid, to the unique 10metho~y-A~.~-ergolene derivatives (50) after treatment of the addition product with base and NaBH, (51).I n another recent paper (127) the synthesis of a new structural isomer of lysergic acid methyl ester (28) has been reported in which a novel modification of the Polonovski reaction has been used t o introduce the 7,8 double bond. Thus, the N-oxide 51 on treatment with acetic anhydride and excess base, yielded the enamino ester (52) in about 50y0 yield. COOCH, I
+
52
51
Finally, a considerable number of papers have been devoted to structure-activity relationships in order to find out the essential features for biological activity; for instance, analogs of lysergic acid minus one ring, have been synthesized from considerations formally analogous to the modifications of other biologically active molecules such as morphine. The reader is referred to the review article of Campaigne and Knapp (52).
IV. Biogenesis In recent years numerous publications dealing with the biosynthesis of ergot alkaloids have accumulated. This review intends to summarize
20
P. A. STADLER AND P. STUTZ
the most important aspects on this subject. Only those papers which support their hypotheses with experimental data by using tracer techniques will be considered here.
AND LYSERGIC ACID A. ERGOLENES
It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). I n his thorough review (385 references), Voigt (55-57') covers the literature up to 1967. The article also comprises microbiological aspects of alkaloid synthesis in saprophytic cultures as well as in vivo studies. Biogenetic interrelationships between different species of clavine alkaloids apart from the main pathway are also discussed there. According t o the more recent approaches of the groups of Arigoni (59),Groger and Floss (60-62), and Voigt (63),it could be independently shown by means of labeling experiments that chanoclavine-I (4)and not isochanoclavine-I (6) is an efficient precursor of agroclavine (53) and elymoclavine (54)in Claviceps, grown on Pennisetum typhoideum, and Claviceps paspali strains. The then established sequence of intermediates t o lysergic acid (43)is represented below. 4-Dimethylallytryptophan (3)is 5-10times more efficient as a precursor than tryptophan ( 5 ) .Its presence could be shown in anaerobic cultures of the Claviceps strain SD 58 after the addition of labeled tryptophan (64).I n another experiment, by checking the culture of an ergot strain growing on Pennisetum with ethionine ( 6 ) , a known antagonist of methionine, the isolation of 3 was achieved. I n order t o gain more information about the stereochemistry of the single steps involved, the 4R and 4X-isomers of [2-I4C, 4-3H]mevalonic acid were fed into shake cultures of Claviceps strain SD 58 (62,SS). Thereupon it could be shown that H-9 in elymoclavine (54) stems exclusively from the 4R-H of the mevalonate moiety and, surprisingly, all I4C radioactivity was located a t the methyl group of chanoclavine-I (4). Furthermore, the radioactivity of agroclavine (53)and elymoclavine (54)was unequivocally centered a t C-17 of these compounds. Thus, two isomerixations at the allylic double bond must have taken place i f 4 is a real precursor of 53 and 54. The same conclusions were reached earlier by Arigoni's group (59). Because of the great importance of
1. T H E ERGOT ALKALOIDS
21
22
P. A. STADLER AND P. STUTZ
these findings the experiment proving that 6 is not a precursor in the pathway was repeated and confirmed. Since the 4s-hydrogen of mevalonic acid is eliminated during biosynthesis, the original dimethylallyl residue would be expected t o carry the label from C-2 of the mevalonate in the trans-methyl group. The conversion of 3 to 4 therefore seems t o involve hydroxylation a t the cis-methyl group followed by cis-trans isomerization at the allylic double bond. Thus, the "apparently normal" labeling of the tetracyclic clavines in the trans (i.e., C-17) carbon after feeding with [Z-"C]mevalonate is merely the accidental result of a more complex series of reactions. COOH
I
*CH,
*CH,
--- I
L 3
R = COOH. H
The interpretation of the experimental data is further complicated by the fact that there was a reproducible decrease of up to 3007, of the 3H/14Cratio during conversion of 4 to 54. This means about 7007, retention of 3H-9. No adequate explanation for this is yet available. It must be emphasized that many biosynthetic investigatioiis have been undertaken with different species and strains of fungi and the same biogenesis is anticipated with all kinds of microorganisms. An example is the use of a Claviceps paspali strain for the production of labeled 4 as the main product, which is then fed into cultures of C. purpurea strain SD 58 in order to produce labeled 54 (65).
1. THE
23
ERGOT ALKALOIDS
The origin of H-10 of the tetracyclic alkaloids 53 and 54 was also investigated. For this purpose, ( 3RS,5R)-[5-3H]mevalonic acid was added to cultures of Claviceps on Pennisetum typhoideum (66). After 10 days of inoculation the isolated 53 and 54 did not contain any radioactivity. It was concluded therefore that H-10 must be derived from 5-pro S-H of mevalonic acid. This was later confirmed on feeding experiments with strain SD 58 (66a) using ( 3R,5S)-[5-3H]mevalonic acid as substrate. A further interesting result was obtained after separation of the chanoclavine fraction into 4 and 6 and minute amounts of chanoclavine-I1 (5). The absolute configuration of the latter has not yet been firmly established. All three chanoclavines exhibited 3H retention at C- 10. Thus, another hypothetical scheme, involving allylic oxidation of an intermediate as shown below with subsequent allylic rearrangements prior to ring C/D junction, had to be discarded since it is well known that the biological hydroxylation of methylene groups is usually stereospecific and proceeds with retention of con-
&
*.
and/or
'
H
H
N H
figuration (67). Therefore, one might assume that the 5-pro S-hydrogen of mevalonate would not be incorporated into chanoclavine-I1 (5) for example. This crucial experiment was also repeated by Arigoni's group with their Claviceps on Pennisetum typhoideum with identical results. It was also ensured that the isolated material corresponded t o natural ( - ) 5, since the characterization as its enantiomer would have required this interpretation t o be reversed. The origin of the oxygen atoms of 4 and 54 was also investigated. Using again the strain SD 58, 180-incorporation from 180-enriched water did not take place (68),indicating that the hydroxylic groups of 4 and 54 are not derived from reaction of an allylic carbonium ion with water as suggested earlier (58, 61). It was more likely that water had been directly introduced via an oxygen transferase or a mixed function oxygenase (69). Ramstad et al. (70, 71) were able to show that mycelial homogenates from strain SD 58 contained rather high catalase levels and low but measurable peroxidase activity. The 78,000 g supernatant as well as
24
P. A. STADLER AND P. STUTZ
resting cells converted chanoclavine-I (4) into elymoclavine (54) in good yield. But [14C]agroclavine (53), which is an established in vivo precursor of 54, was not converted t o the latter under these conditions. From the fact that the enzyme fraction required ATP, the sequence in Scheme I1 was envisaged in this particular system. On the contrary, CH,OH I
4
@CH,OH
/
I
54
SCHEME I1
the 6 0 4 0 % (NH,),SO, fraction of C. purpurea P R L 1980 strain was able to transform agroclavine to elymoclavine in the presence of a NADPH-producing system such as liver homogenate (72). The crude supernatant exhibited no activity in that case. Hydroxylation of clavine alkaloids in vitro can be brought about by horseradish peroxidase using hydrogen peroxide as the oxidant, and numerous other tissues (70). This leads only to 8-hydroxylation, e.g., no elymoclavine (54) can be detected from 53. On the other hand, this hydroxylation step also occurs in ergot as a minor metabolic pathway, but it will not be considered here in detail. The reader is referred to the review articles of Voigt (55-57) and of Ramstad (7’0). Recently it could be shown that, in the presence of cytochrome P-450, a special system of hepatic and adrenal microsomes from rats and guinea pigs was able to convert 53 t o 54 and to 6-noragroclavine (73).
1.
THE ERGOT ALKALOIDS
25
In an effort to avoid the confusion brought about by two allylic cis-trans isomerizations as described above, [14C,1 7-3H]chanoclavine-Ialdehyde (55) was prepared as described earlier (59). But again it was incorporated into elymoclavine (54) with retention of 3H, now found at C-7(74).
HN ‘)I 55
Voigt (75) repeated the already described (59) UV irradiation of 4 and isolated a 6% yield of agroclavine (53)besides isochanoclavine-I (6)and drew new attention t o 6 as a possible precursor despite the negative results obtained earlier (59, 65). The same author inoculated the two hydrogenation products of 4 with sclerotia from rye (75, 7 6 ) . After incubation, the corresponding tetracyclic ergolines festuclavine (56) and pyroclavine (57) were detected, showing that the dehydrating enzyme involved did not differentiate between the epimers a t C-8. I n this case a reductive cyclization step was postulated. The two dihydrochanoclavines-I were also detected in saprophytic cultures of C. paspali and C. purpurea from rye. Another contribution to the problem
-CH,
57
of ergolene biosynthesis was made by Plieninger et al. (77) who synthesized the I4C-labeled derivatives of tryptophan 58 and 59. A culture of ergot fungus J 13 from P. typhoideum incorporated them both into agroclavine and elymoclavine. From this result it was suggested that ring C is formed only after hydroxylation of the corresponding precursor 3.
26
P. A. STADLER AND P. STUTZ
@ H
58
H 59
It might be useful to summarize briefly the present status of knowledge concerning ergolene biosynthesis, although it is impossible to survey all findings which are partly contradictory t o each other. The first secured intermediate from L-tryptophan and mevalonic acid is 4-dimethylallyltryptophan (3). Ring C might be formed after an allylic hydroxylation presumably a t C-17 to establish the chanoclavines after a cis-trans isomerization of the double bond. Chanoclavine-I (4) undergoes, on ring closure another cis-trans isomerization to afford agroclavine (53) which is subsequently oxidized t o elymoclavine (54) and lysergic acid. There seems to be an independent sequence, leading from 4 directly t o 54, as shown in cell-free preparations. The hydrogens of C-9 and (2-10 of the tetracyclic ergolenes originate from the pro R-4H and pro S-5H, respectively, of the mevalonate moiety. Regarding these recent results obtained from biosynthetic experiments, one is tempted to say that matters have become rather complicated, despite the considerable amount of new information available. The main question, whether chanoclavine-I (4) is a true intermediate, remains to be solved.
B. LYSERGIC ACID AMIDESAND PEPTIDE ALKALOIDS Before dealing with biosynthetic work concerning alkaloids of the peptide type such as ergotamine (68), we shall briefly discuss the biogenesis of ergometrine (60) and lysergic acid methylcarbinolamide (61). It is now generally assumed that L-alanine or a biological equivalent such as pyruvate (78) provides the alaninol side chain of 60. The question as t o whether L-alaninol itself is an intermediate is still a matter of controversy. Two groups have reported nonincorporation of ~-[U-~~C]alaninol (7'9) or L-[ l-3H]alaninol (78) into ergometrine (60) whereas Arcamone et al. (80) observed a rather specific incorporation
1. THE ERGOT
60
27
ALKALOIDS
61
of ~-[U-l~C]alaninol into the side chain of 60. d-Ly~ergyl-[Z-~~C]-~alanine (65),on the other hand, which might be expected t o be a very close precursor of ergometrine, has an incorporation rate of only 1.77oJ, by C. paspali strain MAR 488 (81).Further experiments (82, 83) with C. purpurea strain Pepty 695 and the above strain could not provide any evidence that 65 is a natural intermediate in ergometrine biosynthesis. Studies concerning the origin of the carbinolamide side chain of 61 have revealed similar problems. Agurell (84)has shown that ethylamine is not incorporated, thus disproving a hypothesis which suggested oxidation of lysergic acid ethyl amide. This is, however, not surprising. As an alternative he proposed L-alanine as a biochemical precursor, and this has since been shown to be the case (85, 86). An efficient incorporation of ~ ~ - [ 2 - ~ ~ C ] a l aand n i n[2-14C]pyruvate e and reasonably, no incorporation of either DL-[ 1 -14C]alanineor [l-14C]pyruvate,respectively, could be observed. This indicated a decarboxylation step of C-1 during incorporation of the precursors. The amide nitrogen was specifically labeled by ~-[l~N]alanine. But since an increased l5N/I4C ratio following administration of ~ - [ l ~ C , l ~ N ] a l a n was i n e obtained, it did not seem likely that alanine was a direct precursor. Similar results were also obtained elsewhere (87). These data and the finding that d-lysergyl-L-alanine (65), which should again serve as a closer intermediate than L-alanine, is not incorporated support a hypothesis proposed by Ramstad (88): Oxidation of the open chain tetrapeptide 62 could afford 63 which on cyclization should immediately lead to ergosecaline (64), a novel type of lactone alkaloid. It was isolated only once from Spanish rye but not sufficiently characterized (89). Hydrolysis of 64 and subsequent decarboxylation would finally give the desired 61. There is no evidence that lysergic acid amide (ergine) is formed by simple amidation in ergot. From young cultures of Claviceps purpurea a partly purified enzyme could be isolated (90) which is capable of
28
P. A. STADLER AND P. STUTZ
CH3 O
H
LA-C-N
[ol
LA-C-N
OH CH-R N’ H
0
H
63
62
LA-COOH
= lysergic acid
,CH3 R = e.g., -CH \
X = amino acid residue
1
O H
II I
61 c--
CH3
LA-c-N+oYo
I
I
64
hydrolyzing amides of lysergic acid being ineffective only to 61. It has therefore been assumed (88) that every Clauiceps strain which contains measurable amounts of ergine should be devoid of this enzyme. This could be true for seeds of Ipomoea species which contain ergine and isoergine. The biosynthesis of the peptide alkaloids has not yet been studied t o a great extent, mainly because of their rather complex structure. A hypothetical sequence, based mainly on the reported isolation of d-lysergyl-~-valinemethyl ester from rye ergot (18) was proposed by Agurell (58).According to him, the biogenesis of ergotamine (68) can be represented as follows: Acylation of L-phenylalanyl-L-prolinelactam (34)with 65 should lead to 67 which, upon oxidation with retention of configuration, would lead spontaneously to 68. As to ergocristine (38), one should replace 65 by d-lysergyl-L-valine (66). Subsequent feeding experiments showed the preferential incorporation of [14C]prolineinto the dioxopiperazine part of ergocornine and ergokryptine (91). While [14C]phenylalanine specifically labels the dioxopiperazine part of ergotamine (92), the origin of the a-hydroxya-amino acid moiety of these alkaloids is less clear. Incorporation of ~-[UJ*C]alanine and also of ~ - p - ~ ~ C ] a l a n i ninto o l the a-hydroxy-aamino acid portions of ergotamine and ergokryptine has been reported
29
1. THB ERGOT ALKALOIDS
R
R = -CH
3
,CH3 R = -CH \
65
,
66
CH3
(81).But [3H]ergometrine, which had also been suggested as a precursor (82, 93) of ergotamine, was not incorporated. However, when radioactive L-valyl-L-proline lactam was fed into cultures (94) an unexpected observation was made. Degradation studies revealed that it had been hydrolyzed prior to incorporation. This fact, together with the repeatedly postulated high transaminase activity of the system, could offer an explanation for an observation of Abe (95) who noticed that in cell-free systems from a strain of Elymus type of ergot fungus, L-phenylalanine-D-proline lactam was also incorporated into ergotamine. Subsequent work was centered on d-lysergyl-L-alanine (65) or d-lysergyl-L-valine (66) (96) as key precursors of the corresponding peptide alkaloids. Again, the evidence from the feeding experiments indicated that these compounds are most unlikely t o be direct intermediates to ergotamine, ergocornine, or ergokryptine. On the other hand, alanine and valine were again very efficiently incorporated; thus, it could be concluded that the a-hydroxy-a-amino acid portion of these alkaloids was derived from these amino acids. Then it became evident that the hypothesis of Agurell (58) could not be verified. Recently, contradictory results have been reported (97'). Using a cell-free system prepared from an Elymus type of ergot strain which mainly produced ergokryptine, incorporation of d-lysergyl-~-[~H]valine
30
P.
A. STADLER
AND P. S T U T Z
as well as ~-Ieucyl-~-[~H]proline lactam was observed. This result does not however contribute to the solution of the above problems since the exact positions of labeling were not determined. It would also be conceivable to regard d-lysergic acid amide as an intermediat,e for peptide alkaloids. Groger et al. (98) however showed this hypothesis t o be improbable. I n the same paper attention is drawn to another interesting fact. Some experiments were performed in which [14C,15N]valinewas introduced into C. purpurea strain Pepty 695, a fungus known to produce ergokryptine and ergocornine as the major alkaloids. Degradation studies of the labeled alkaloids revealed that after various conditions of incubation, the a-hydroxyvaline part of ergocornine always showed a higher specific radioactivity than the valine of the dioxopiperazine moiety. This suggests that the formation of the peptide chain starts from the proline end. The recent isolation of the new alkaloid 18 might throw new light on the biogenesis of ergot peptide alkaloids. It differs from the postulated intermediate 67 only in that it has a D-proline configuration in the dioxopiperazine ring and is also very susceptible to methanolysis. After examination of the experimental conditions of isolation it was
P\H H3C LA-COOH
CH3
H
CH,
6
= lysergic acid 18
deduced that d-lysergyl-L-valylmethyl ester which had been reported to be a natural alkaloid (1) is actually an artifact. Thus, the intermediate 67 with a natural L-proline configuration is again more interesting. [It is known from the synthesis of ergotamine ( 3 4 ) that acylated 2,4-dioxopiperazines with a proline ring can undergo a facile epimerization to the D-proline isomer.] On the strength of these observations and bearing in mind that the synthesis of the peptide chain might start from the proline end, a reexamination of the hypothetical scheme proposed by Ramstad (88) would probably lead to the solution of this problem, whereas Augrell’s sequence, though similar, is not t o be regarded as likely.
1.
31
THE ERGOT ALKALOIDS
Ramstad proposed a ring closure of a linear tetrapeptide t o Agurell’s compound 67 which could either epimerize irreversibly t o the dproline compound 18 or undergo oxidative ring closure t o the peptide alkaloids as also proposed by Agurell. Any of the observations reported X
H
H (2) lting closure I(
peptide alkaloids
18
so far would fit into this reaction scheme. Thus, the synthesis of doubly labeled compounds of type 67 would give more information about this intricate problem of biochemistry.
V. Biological Properties of Ergot Compounds In their last review about ergot alkaloids, Stoll and Hofmann ( 1 ) have given a short survey of the “classic” pharmacological and clinical activities of ergot derivatives. I n the meantime some new, exciting results have been achieved which will be summarized here.
A. STRUCTURE-ACTIVITY RELATIONSHIPS OF PEPTIDE ALKALOIDS The first papers, dealing with the structure-activity relationship of peptide-type alkaloids of ergot, have revealed that biological activity is strictly related t o the stereochemistry of these compounds. The genuine alkaloids, e.g., ergotamine (68), have six asymmetric carbon atoms; the dihydro derivatives, also important in therapy, contain seven. Therefore 64 or 128 different stereoisomers a,re possible, respectively. But, a t the moment, the few stereoisomers prepared so far, show reduced biological activities. Thus, the well-known derivatives of d-isolysergic acid are almost devoid of biological potential (25, 99). Under the influence of diluted acids ergot alkaloids undergo epimerization in position 2‘ of the peptide moiety to the so-called aci-forms
32
P. A. STADLER AND P. STUTZ
(100). Again these new isomers proved to be almost ineffective in biological systems ( 101). The total synthesis of ergotamine (34) opened new possibilities for the preparation of new stereoisomers. Theoretically, almost every isomer now became accessible. Starting from the unnatural amino acids D-proline and D-phenylalanine, a peptide building block that was the antipode of ergotamine was synthesized, following the general reaction scheme of the ergotamine synthesis (34).Acylation with unnatural 1-lysergic acid then led to the antipodes of ergotamine and ergotaminine (36, 102). In addition, several diastereomers of ergotamine and ergotaminine were prepared. Using d-lysergic acid in the same condensation reaction, a new pair of stereoisomers was obtained. Another pair of diastereomers was synthesized by acylating the peptide part of natural configuration (34) with 1-lysergic acid. Finally, catalytic hydrogenation led to the corresponding diastereomers of dihydroergotamine. The antipodes of ergotamine and dihydroergotamine proved to be biologically almost ineffective, as were the diastereomers containing the unnatural form of lysergic acid. Those diastereomers, built up from natural d-lysergic acid, did however show a limited activity (102). B. NEWSEMISYNTHETIC COMPOUNDSWITH HIGHBIOLOGICAL ACTIVITY During the last few years many new compounds based on the ergolene nucleus have been prepared by partial synthesis (103,104).Some have fulfilled the expectations insofar as they seem to show more selectivity or higher activity than the ergot derivatives known before. N-(6Methyl-8-isoergolenyl)-N’,N’-diethylurea (69) is such a representative compound (105).Its pharmacological profile is dominated by a striking antagonism against serotonine (106). It is noteworthy that 69, a derivative of isolysergic acid, is distinctly more active than its 8-
II u *N-CH3
HN--J
I
69
1. THE ERGOT ALKALOIDS
33
epimer. I n therapy it is used against migraine, allergies of different origin, and hypertension (107). The reduction product of dihydrolysergic acid amide, 6-methyl8~-arninomethyl-lOa-ergoline proved to be a very fruitful starting material for the development of new active derivatives (108). Acetylation of its aminomethyl group led t o 6-methyl-8P-acetylaminomethylergoline (70) called Uterdina. This compound has a H
O
specific oxytoxic activity, comparable with that of ergometrine or methylergometrine (109, 110). Furthermore its toxicity is distinctly lower, the side effects being almost nonexistent. Another derivative of this kind is 176-dimethyl-8P-[(benzyloxycarbonyl)aminomethyl]ergoline (71) [MCE] (109, 111). It shows a H
71
O
MCE
marked and long-lasting action against serotonine and seems t o be somewhat stronger and more prolonged than that of Methysergide. l0a-Methoxydihydrolysergic acid methyl ester (49) has been another versatile starting material for structural manipulation. From a series of esters of 1-methyl-1Oa-methoxydihydrolysergol there resulted 1-methyl- 1Oa-methoxydihydrolysergol-5'-bromonicotinate (72) (MNE). It shows strong a-receptor-blocking properties, lowers systemic blood pressure, and dilates blood vessels thereby increasing peripheral blood flow (112).
34
P.
A. STADLER AND
P. STUTZ
Passing from the dihydro derivatives to those of the ergolene nucleus itself, two interesting compounds deserve mention. 1,l-Dimethyl-3[(5~,SR)-6-rnethyl-Q-ergolen-S-ylmethyl]urea (73)) the dimethylurea of lysergylamine, was found t o be a very specific and highly active agent for lowering the blood pressure (113). H
H..
@
-CH,
H-N
O
I I1 CHz-N-C-N
73
O
O
C
H
,
CH2-NwN \ 1
,CH3
‘cH3&
H-N
-CH,
74
6-Methyl-SP-[4-(p,-methoxyphenyl)1-piperazinyl)methylergolene (74) proved to be a highly active stimulator of the central nervous system (114). It potentiates (already in low doses) the excitement syndrome induced by DOPA and simultaneously annihilates the depression caused by reserpine. I n man, 74 seems to be useful in the treatment of psychoses and schizophrenia. Finally, two synthetic peptide-type alkaloids may be briefly mentioned in this chapter since both show promising pharmacological activities. Replacing L-phenylalanine in the peptide part of ergotamine by a-methylalanine, a new peptide alkaloid (75) called 5’-methylergoalanine was obtained in analogy to the synthesis of ergotamine (115). It is striking for its interesting pattern of pharmacological activities. Compared with ergotamine, its vasoconstrictor power is 50y0 higher, while unwanted side effects such as uterotonic activity and emetic power are many times weaker (116). On replacing L-phenylalanine by 0-methyl-L-tyrosine, 5’-p-methoxyergotamine (76) was obtained, a very specific uterotonic agent. I t s
1.
THE ERGOT ALKALOIDS
35
C-N-0
75
CH3
uterus contracting power was five times greater than that of ergotamine, and the intensity of other effects was clearly reduced (117).
C. NEWBIOLOGICAL EFFECTS OF ERGOT DERIVATIVES A new kind of pharmacological activity was discovered in 1954. It was observed that ergotoxine, the naturally occurring mixture of ergokryptine, ergocristine, and ergocornine, prevented the induction of deciduoma formation in pseudo-pregnant rats if injected a t the time of the traumatization of the uterus (118).On the basis of these findings, Shelesnyak suggested that ergotoxine acts via the hypothalamus and the hypophysis. Later on, ergocornine was preferentially used as an investigational tool for the study of the mechanism of ovum implantation in the rat. Further investigations made i t clear that ergocornine has a distinct endocrinological effect in the rat by lowering the level of prolactin (119). When these investigations were continued, it was found that 2-bromo-a-ergokryptine (77), is a more selective inhibitor of prolactin than ergocornine (120). It exerts its actions on female reproduction in different species of low mammals: It interrupts pseudopregnancy in rats, inhibits nidation and mammary carcinoma in rats and multiparous mice, and depresses lactation in rabbits and sows. All of these effects can be explained by its interference with the secretion of prolactin (120).The clinical evaluation of 77 showed that it is active in humans as an inhibitor of postpuerperal lactation as well as of pathological nonpuerperal galactorrhea. However, it proved t o be inefficient for the control of human fertility (121). There are some other ergot derivatives known t o suppress nidation of the fertilized egg in rats. This effect also seems to result from an inhibition of prolactin synthesis or, more specifically, from an increase
36
P. A. STADLER AND P. STUTZ
H,C
Br
CH CH,
/ \
77
of the hypothalamic concentration of prolactin-inhibiting factor of certain animal species. Of these compounds dihydrohomolysergic acid nitrile, dihydrohomolysergic acid amide, and N-(B-methyl-8-isoergoliny1)-N‘N’-diethylurea,the dihydro derivative of 69 must be mentioned (44, 122). The reader is referred to an excellent review concerning the influence of ergot alkaloids on prolactin-dependent processes (123).
REFERENCES 1. A. Stoll and A. Hofmann, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 8, Chapter 21, p. 725. Academic Press, New York, 1965. 2. A. Hofmann, “Die Mutterkornalkaloide,” Enke, Stuttgart, 1964. 3. T. Fehr and W. Acklin, Helw. Chim. Acta 49, 1907 (1966). 4. H. Plieninger, M. Hobel, and V. Liede, Ber. 96, 1618 (1963). 5. H. Plieninger, R. Fischer, and V. Liede, Ann. 672, 223 (1964); S. Agurell, Acta Pharm. Suecica 3, 11 (1966). 6. S. Agurell and J.-E. Lindgren, Tet. Lett. 5127 (1968). 7. A. Hofmann, R. Brunner, H. Kobel, and A. Brack, Helw. Chim. Acta 40,1358 (1957). 8. D. Stauffacher and H. Tscherter, Helw. Chinz. Acta 47, 2186 (1964). 9. M. Abe, S. Ohmomo, T. Ohashi, and T. Tabuchi, Agr. Bid. Chem. 33, 469 (1969). 10. S.Yamatodani, Y. Asahi, A. Metsukura, S. Ohmomo, and M. Abe, Agr. B i d . Chem. 34, 485 (1970). 11. J. E. Robbers and H. G. Floss, Tet. Lett. 1857 (1969). 12. G. S. King, P. G. Mantle, C. A. Szcyzrbak, and E . S. Waight, Tet. Lett. 215 (1973). 13. E. Ramstad, W. -N. Chan Lin, H. R. Shough, K. J. Goldner, R. P. Parikh, and E. H. Taylor, Lloydia 30, 441 (1967). 14. D. Stauffacher, P. Niklaus, H. Tscherter, H. P. Weber, and A. Hofmann, Tetruhedron 25, 5879 (1969). 15. H. G. Floss, H. Giinther, U. Mothes, and I. Becker, 2. Naturforsch. B 22, 399 (1967). 16. H. Kobel, E. Schreier, and J. Rutschmann, HeZv. Chim. Acta 47, 1052 (1964). 17. P. Stiitz, R. Brunner, and P. A. Stadler, Ezperientia 29, 936 (1973).
1. THE ERGOT ALKALOIDS
37
18. W. Schlientz, R. Brunner, and A. Hofmann, Ezperientia 19, 397 (1963). 19. T. Hohmann and H. Rochelmeyer, Arch. Pharm. (Weinheim) 299, 7 (1966). 20. P. G. Mantle and E. S. Waight, Nature (London) 218, 581 (1968). 20a. P. G. Mantle, J . Gen. Microbiol. 75, 275 (1973). 21. D. Stauffacher, H. Tscherter, and A. Hofmann, Helv. Chim. Acta 48, 1379 (1965). 22. W. Schlientz, R. Brunner, P. A. Stadler, A. J. Frey, H. Ott, and A. Hofmann, Helv.Chim. Acta 47, 1921 (1964). 23. P. Stiitz, P. A. Stadler, and A. Hofmann, Helv. Chim. Acta 53, 1278 (1970). 24. W. Schlientz, R. Brnnner, A. Riiegger. B. Berde, E. Stiirmer, and A. Hofmann, Ezperientia 23, 991 (1967); Pharm. Acta Helv. 43, 497 (1968). 25. A. Stoll and A. Hofmann, Helv. Chim. Acta 26, 1570 (1943). 26. P. A. Stadler, S. Guttmann, H. Hauth, R. L. Huguenin, E. Sandrin, G. Wersin, H. Willems, and A. Hofmann, Helv. Chim. Acta 52, 1549 (1969). 27. E. C. Kornfeld and N. J. Bach, Chem. Ind. (London) 1233 (1971). 28. E. C. Kornfeld, E. J. Fornefeld, G. B. Kline, M. J. Mann, R. G. Jones, and R. B. Woodward, J . Amer. Chem. SOC.76, 5256 (1954). 29. R. T. Anselmi, Diss. Abstr. 26, 1342 (1965). 30. M. Julia, F. Le Goffic, J. Igolen, and M. Baillarge, Tet. Lett. 1569 (1969). 31. BE 738,926; F R 2,052,237; Ger. Offen. 1,947,063 and 1,965,896. 32. Cf. Fr. Addn. Pat. 91,948 (1968) to FR 1,368,420. 33. Cf. FR 1,531,205; GB 1,158,380; GER 1,806,984; GER 1,909,216. 34. A. Hofmann, A. J. Frey, and H. Ott, Ezperientia 17, 206 (1961); A. Hofmann, H. Ott, R. Griot, P. A. Stadler, and A. J. Frey, Helv. Chim. Acta 46, 2306 (1963). B 377 (1966). 34a. A. T. McPhail, G. A. Sim, A. J. Frey, and H. Ott, J. Chem. SOC., 35. P. A. Stadler, A. J. Frey, H. Ott, and A. Hofmann, Helv. Chim. Acta 47, 1911 (1964). 36. P. A. Stadler and E. Sturmer, Chimia 26, 321 (1972). 37. G. Lucente, G. M. Lucente, F. Pantanella, and A. Romeo, Ann. Chim. Appl. 60, 259 (1970). 38. G. Lucente and A. Romeo, Chem. Commun. 1605 (1971). 39. S. Cerrini, W. Fedeli, and F. Mazza, Chem. Commun. 1607 (1971). 40. G. Lucente and P. Frattesi, Tet. Lett. 4283 (1972). 41. P. A. Stadler, A. J. Frey, F. Troxler, and A. Hofmann, Helv. Chim. Acta 47, 756 (1964). 41a. F. Arcamone, A. H. Glasser, A. Minghetti, and V. Nicolella, Boll. Chim. Furm. 110, 704 (1971). 42. F. Troxler, Helv. Chim. Acta 51, 1372 (1968). 43. F. TroxlerandP. A. Stadler, Helv. Chim. Acta 51, 1061 (1968); F R 1,439,953. (1964). 44. M. Semonsky and N. Kucharczyk, Collect. Czech. Chem. Commun. 33, 577 (1968). 44a. G. Franceschi, R. Mondelli, S. Redaelli, and F. Arcamone, Chim. Ind. (Milan) 47, 1334 (1965). 45. P. Stutz and P. A. Stadler, Helv. Chim. Acta 55, 75 (1972). 46. T. Fehr, P. A. Stadler, and A. Hofmann, Helv. Chim. Acta 53, 2197 (1970). 47. Y. Nakahara and T. Niwaguchi, Chem. Pharm. Bult. 19, 2337 (1971). 48. A. Stoll and TY. Schlientz, Helv. Chim. Acta 38, 585 (1955). 49. W. Barbieri, L. Bernardi, G. Bosisio, and A. Temperilli, Tetrahedron 25, 2401 (1969). 50. G . Cainelli, L. Caglioti, and W. Barbieri, Farmaco, Ed. Sci. 22, 456 (1967). 51. BE 775,145. 52. E. Campaigne and D. R. Knapp, J . Pharm. Sci. 60, 809 (1971).
38
P. A. STADLER AND P. STUTZ
Cf. F. Weygand and H. G. Floss, Angew. Chem., Int. Ed. EngZ. 2, 243 (1963). Cf. also E. Ramstad, Lloydia 31, 335 (1968). R. Voigt, Pharmazie 23, 285 (1968). R. Voigt, Pharmazie 23, 354 (1968). R. Voigt, Pharmazie 23, 419 (1968). Cf. S. Agurell, Acta Pharm. Suecica 3, 71 (1966). T. Fehr, W. Acklin, and D. Arigoni, Chem. Commun. 801 (1966); T. Fehr, Ph.-D. Thesis, Swiss Federal Institute of Technology, Zurich (1967). 60. D. Groger, D. Erge, and H. G. Floss, 2. Naturforsch. B 21, 827 (1966). 61. H. G. Floss, U. Hornemann, N. Schilling, D. Groger, and D. Erge, Chem. Commum. 105 (1967). 62. H. G. Floss, Chem. Commun. 804 (1967). 63. R. Voigt, M. Bornschein, and G. Rabitzsch, Pharmazie 22, 326 (1967). 64. J. E. Robbers and H. G. Floss, Arch. Biochem. Biophys. 126, 967 (1968). 65. H. G. Floss, U. Hornemann, N. Schilling, K. Kelley, D. Groger, and D. Erge, J . Amer. Chem. Soc. 90, 6500 (1968). 66. M. Seiler, W. Acklin, and D. Arigoni, Chem. Commun. 1394 (1970). 66a. C. I. Abou-Chaar, H. F. Gunther, M. F. Manuel, J. E. Robbers, and H. G. Floss, Lloydia 35, 272 (1972). 67. R. Bentley, “Molecular Asymmetry in Biology,” Vol. 2. Academic Press, New York, 1970. 68. H. G. Floss, H. Gunther, D. Groger, and D. Erge, J. Pharm. Sci. 56, 1675 (1967). 69. Cf. also S. Agurell, E. Ramstad, and J. Wolinsky, Sv. Farm. Tidski. 66, 741 (1962). 70. A. Jindra, E. Ramstad, and H. G. Floss, Lloydia 31, 190 (1968), and references cited therein. 71. E. 0. Ogunlana, B. J. Wilson, V. E. Tyler, and E. Ramstad, Chem. Commun. 775 (1970). 72. J . C. Hsu and J. A. Anderson, Chem. Commun. 1318 (1970); Biochim. Biophys. d.cta 230, 518 (1971). 73. B. J. Wilson, E. Ramstad, I. Jansson, and S. Orrenius, Biochim. Biophys. Acta 252, 348 (1971). 74. B. Naidoo, J. M. Cassady, G. E. Blair, and H. G. Floss, Chem. Commun. 471 (1970) 75. R. Voigt and P. Zier, Pharmazie 25, 272 (1970). 76. R. Voigt and P. Zier, Pharmazie 26, 494 (1971). 77. H. Plieninger, C. Wagner, and H. Immel, Ann. 743, 95 (1971). 78. U. Nelson and S. Agurell, Acta Chem. Scand. 23, 3393 (1969). 79. J. Majer, J. Kybal, and I. Komersova, B’oZia MicrobioZ. (Prague) 12, 489 (1967). 80. A. Minghetti and F. Arcamone, Experientia 25, 926 (1969). 81. G. P. Basmadjian, H. G. Floss, D. Groger, and D. Erge, Chem. Commun. 418 (1969). 82. H. G. Floss, G. P. Basmadjian, M. Tcheng, C. Spalla, and A. Minghetti, Lloydia 34, 442 (1971). 83. H. G. Floss, G. P. Basmadjian, D. GrBger, and D. Erge, Lloydia 35, 449 (1972). 84. S. Agurell, Acta Pharm. Suecica 3, 33 (1966). 85. E. Castagnoli, Jr. and A. Tonolo, Proc. Int. Congr. Microbiol. 9th, 1966 Symposia p 31 (1966). 86. E. Castagnoli, Jr., K. Corbett, E . B. Chain, and R. Thomas, Biochem. J . 117, 451 (1970). 87. D. Groger, D. Erge, and H. G. Floss, 2. Naturforsch. B 23, 177 (1968). 88. E. Ramstad, Lloydia 31, 327 (1968). 53. 54. 55. 56. 57. 58. 59.
1. THE ERGOT ALKALOIDS
39
89. M. Abe, T. Yamano, S. Yamatodani, Y. Kozu, M. Kusumoto, H. Komatsu, and S. Yamada, Bull. Aqr. Chem. SOC.J a p . 23, 246 (1959). 90. A. M. Amici, A. Minghetti, and C. Spalla, Biochim. Appl. 12, 50 (1966). 91. D. Groger and D. Erge, 2. Naturforsch. B 25, 196 (1970). 92. L. C. Vining, and W. A. Taber, Canad. J . Microbiol. 9, 291 (1963). 93. R. Voigt and M. Bornschein, Pharmazie 19, 772 (1964). 94. D. Griiger and S. Johne, Ezperientia 28, 241 (1972). 95. M. Abe, Abh. Deut. Akad. Wiss. Berlin 411 (1971). 96. H. G. Floss, G. P. Basmadjian, M. Tcheng, D. Groger, and D. Erge, Lloydia 34, 446 (1971). 97. T. Ohashi, H. Takahashi, and M. Abe, J . Agr. Chem. Soc. Jap. 46, 537 (1972). 98. W. Maier, D. Erge, and D. Groger, Biochem. Physiol. Pflanzen 161, 559 (1971). 99. A. Stoll, Helw. Chim. Acta 28, 1283 (1945). 100. W. Schlientz, R. Brunner, F. Thudium, and A. Hofmann, Ezperientia 17, 108 (1961). 101. W. Schlientz, R. Brunner, A. Hofmann, B. Berde, and E. Stiirmer, Pharm. Acta Helv. 36, 472 (1961). 102. P. A. Stadler and E . Stiirmer, Naunyn-Schmiedebergs Arch. Pharmakol. E x p . Pathol. 266, 457 (1970). 103. M. Semonsky, Pharmazie 32, 899 (1970). 104. L. Bernardi, Chim. Ind. (Milan) 51, 563 (1969). 105. V. Zikan and M. Semonsky, Collect. Czech. Chem. Commun. 25, 1922 (1960). 106. V. Zikan and M. Semonsky, Collect. Czech. Chem. Commun. 28, 1080, 1196 (1963). 107. Z. Votawa and J. Lamplova, Neuro-Psychopharmacol. 2, 68 (1961). 108. L. Bernardi, B. Camerino, P. Patelli, and S. Redaelli, Gazz. Chim. Ital. 94, 936 (1964). 109. G. B. Fregnan and A. H. Glasser, Experientia 24, 150 (1968). 110. G. Avvezzu and R. Giannone, Minerwa Ginecol. 21, 1483 (1969). 111. G. De Caro, Farmaco, Ed. Sci. 20, 781 (1965). 112. G. Arcari, L. Dorigotti, G. B. Fregnan, and A. H. Gliisser, Brit. J . Pharmacol. 34, 700 P (1968); G. Arcari, L. Bernardi, G. Bosisio, S. Coda, G. B. Fregnan, and A. H. Glasser, Experientia 28, 819 (1972). 113. Ger. Offen. 2,223, 681. 114. Ger. Offen. 1,901,750. 115. Swiss Appl. 5236/67. 116. A. Hofmann, Chim. Ther. 3, 367 (1968); A. Cerletti and B. Berde, in R. Smith, “Background t o Migraine” (R. Smith, ed.), p. 53. Heinemann, London, 1968. 117. BE 767,558. 118. M. C. Shelesnyak, Amer. 2. Physiol. 179, 301 (1954). 119. M. C. Shelesnyak, B. Lunenfeld, and B. Honig, L i f e Sci. 1, 73 (1963). 120. E. Fliickiger and H. R. Wagner, Ezperientia 24, 1130 (1968); E. Billeter and E. Fliickiger, ibid. 27, 464 (1971); E. Fliickiger, P. M. Lutterbeck, H. R. Wagner, and E. Billeter, ibid. 28, 924 (1972). 121. P. M. Lutterbeck, J. S. Pryor, L. Varga, and R. Wenner, Brit. Med. J., 228 (1971); L. Varga, P. M. Lutterbeck, J. S. Pryor, R. Wenner, and H. Erb, ibid. 743 (1972); Schweiz. Med. Wochemchr. 102, 1284 (1972). 122. K. Rezabek, M. Semonsky, and N. Kucharczyk, Nature (London)221, 666 (1969); Czech. 143,100; V. Zikan, M. Semonsky, K. Rezabek, M. Auskova, and M. Seda, Collect. Czech. Chem. Commun. 37, 2600 (1972).
40
P. A. STADLER AND P. STUTZ
123. H. G. Floss, J. M. Cassady, and J. E. Robbers, J . Pharm. Sci. 62, 699 (1973). 124. G . Stamm, Ph.D Thesis, Swiss Federal Institute of Technology, Zurich No. 4418, 53 (1969). 125. R. P. Gysi, Ph.D Thesis, Swiss Federal Institute of Technology, Zurich No. 4990, 23 (1973). 126. H. Tscherter and H. Hauth, Helv. Chim. Acta 57, 113 (1974). 127. P. Stutz and P. A. Stadler, T e t . Lett. 5095 (1973).
-CHAPTER
2-
THE DAPHNIPHYLLUM ALKALOIDS SHOSUKEYAMAMURA Faculty of Pharmacy. Meijo University. Showa.ku. Nagoya. J a p a n AND
YOSHIMASA HIRATA Chemical Institute. Nagoya University. Chikusa.ku. Nagoya. Japan
I. Introduction ....................................................... I1. Structural Elucidations .............................................. A. Daphniphylline-Type Alkaloids .................................... B . Secodaphniphylline and Methyl Homosecodephniphyllate . . . . . . . . . . . . . C . Daphnilactone-A ................................................ D . Daphnilactone-B ................................................ E . Yuzurimine-Type Alkaloids ....................................... F . Alkaloids of Undetermined Structure ............................... I11. Chemistry ......................................................... A. Zinc Reduction .................................................. B . Anti-Bredt’s Rule Imine .......................................... I V . Structural Relationship ............................................. V. Biosynthesis ....................................................... A. Daphniphylline and Codaphniphylline .............................. B . Daphnilactone-B ................................................ V I . Pharmacology ...................................................... VII . Addendum ........................................................ References .........................................................
41 43 43 53 55 57 58 64 64 64 67 70 72 72 77 77 78 80
.
I Introduction The plant Daphniphyllum macropodum Miquel is a lofty tree growing widely in Japan . It is interesting from the viewpoint of plant physiology that this plant puts forth new leaves in early summer before defoliation of the old leaves which fall gradually . Thus. the plant D. macropodum is called Yuzuriha in Japanese from such a phen0menon.l The decoction of the bark and leaves of this plant had been used for a long time as a remedy for vermicide and asthma . Pharmacological properties of the Daphniphyllum alkaloids are briefly described in Section V I . Yuzurabmeans “transfer from hand t o hand” and H a means “leaves.”
42
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
From a viewpoint of plant classification D . macropodum has been included in Euphorbiaceae, whereas Hutchinson (1)and Hegnauer ( 2 ) have suggested the new Daphniphyllaceae for this plant. Chemical constituents of the Daphniphyllaceae have been investigated and several new alkaloids have been isolated from D . calycium Benth ( 2 ) . However, structural studies have not been made although it is quite desirable from chemotaxonomical aspects to elucidate their structures. Three species are found in Japan, namely, D. macropodurn, D. teijsmanni Zollinger (Himeyuzuriha), and D . humile Maxim. (Ezoyuzuriha). I n 1909, Yagi (3) first isolated an amorphous powder (mp 75-84’; C2,H,,0,N)3 named daphnimacrine from D . macropodum. However, structural studies on these alkaloids had been delayed until 1966 and the structure of daphniphylline (1) which was determined by means of an X-ray crystallographic analysis of the corresponding hydrobromide (a),appeared in this series (Vol. X, p. 556). I n addition, several Daphniphyllum alkaloids were further cited in Yolume XI1 (p. 472), where they were included in the chapter “Alkaloids Unclassified and of Unknown Structure.” Recently, further notable investigations on the Daphniphyllum alkaloids have been carried out including the absolute configuration ( 5 , 6 ) , and many new alkaloi+ have also been isolated as summarized in Table I. Most of those cited in Table I have been isolated from the bark and leaves of D . macropodum. To date, however, methyl homodaphniphyllate (23) and daphnilactoneB (36) have been obtained only from the fruits of all three species ( 7 ) . From a biogenetic point of view, the former is the C,, alkaloid corresponding to codaphniphylline (2), one of the C,, alkaloids. Daphnilactone-B, a main alkaloid of the fruits, is regarded as one of the important intermediates between two main groups represented by daphniphylline (1) and yuzurimine (43). Furthermore, the structures of these alkaloids have been elucidated on the basis of the spectral and chemical evidence. In particular, the successful application of X-ray crystallographic analyses has been invaluable not only in the structural elucidations of the novel alkaloids but also in the biogenetic consideration. From a structural viewpoint, these alkaloids are mainly divided into five types of nitrogen heterocyclic skeletons represented by daphniphylline ( l ) ,secodaphniphylline (28), daphnilactone-A (34), daphnilactone-B (36),and yuzurimine (43).In this chapter, all of these alkaloids will be described including their spectral and chemical properties. Biogenesis of these bases with complex structure is quite interesting The authors adopt the latter classification in this chapter. Daphnimacrine as described by Yagi (3) seems to be a mixture of more than two alkaloids. 2
3
2.
THE DAPHNIPHYLLUM ALKALOIDS
43
TABLE I
THEALKALOIDS OF DAPHNIPRYLLUM MACROPODUM Empirical formula
Name
Melting point ("C)
Ref.
~~~
Daphniphylline (daphniphyllamine) Codaphniphylline Daphniphyllidine Daphnimacropine Daphmacrine Daphmacropodine Methyl homodaphniphyllate Secodaphniphylline Methyl homosecodaphniphyllate Daphnilactone-A Daphnilactone-B Yuzurimine (macrodaphnidine) Macrodaphnine Y uzurimine-A Macrodaphniphyllamine Y uzurimine-B Macrodaphniphyllidine Yuzurimine-C Neodaphniphylline Alkaloid A, Alkaloid Az Neoyuzurimine Yuzurimine-D
C32H4905N
C30H470SN
C30H484N C3OH*,O,N C32H4904N C32H5104N
CZ3H3,OzN C3oH4703N Cz3H3,0zN C23H3502N
C22H3102N
Cz,H3,0,N Cz'&9O,N Cz5H3505N C23H3304N
C23H3303N C25H3504N
Cz3HzsO5N C23H3303N C24H3'704N
C24H3105N
238-240 (B.HC1)
4, 8
266-267 (B.HC1) 263-264 (B.MeI) 306-307 (B.MeI) > 300 (B.HBr) 214 233-234 (B.HC1) 129-130 102.5-103 194.5-195.5 92-94 150-152 180-181.5 249-252 (B.HC1) 152-153 282-284.5 (B.HC1) 305-306 (B .HBr) 186-187 242-244 (B ,HCl) 225-226 (B.MeI) 229-230 (B.MeI) 195-198 (B.picrate) 194-195
8. 9 13 15 5 , 17 16, 18 19 6, 21 6 , 21 21, 22 7, 23 24, 26 16, 25 26, 27 16 26, 27 16 14 28 14, 21 14, 21 9 14, 21
and puzzling. The radioactive tracer studies have revealed that they are biosynthesized from six molecules of mevalonic acid via a squalenelike intermediate (Section V).
11. Structural Elucidations
A. DAPHNIPHYLLINE-TYPE ALKALOIDS
Of seven structurally known daphniphylline-type alkaloids, the structure of daphniphylline (1) was first elucidated by an X-ray crystallographic analysis of the corresponding hydrobromide (4). Further X-ray crystallographic studies on daphmacrine methiodide revealed it to have the absolute configuration depicted as 18 (5). Methyl homosecodaphniphyllate (29) has also been proved to have the same absolute configuration as that of daphmacrine (6).Therefore, the
44
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
above-mentioned absolute stereochemistry must be adopted for all of the other related alkaloids. From a biogenetic point of view it is noteworthy that remarkable variations in the remaining partial structure except for the main nitrogen heterocyclic skeleton are found in this group. 1. Daphniphylline
Daphniphylline [l; [aID +43.7" (in CHCl,;)] is one of the main alkaloids isolated from the bark and leaves of D. mucropodum (see Vol. X, p. 556), the structure of which was deduced by the X-ray crystallographic analysis of the hydrobromide ( 4 ) as mentioned earlier. The structure 1 of daphniphylline thus obtained is in good agreement with its spectral and chemical properties. I n particular, the
1
R:Ketal moiety
mje 272
or
mle 286 SCHEME I. Principal fragmentation path for daphniphylline.
2.
45
THE DAPHNIF'HYLLUM ALKALOIDS
mass spectra of daphniphylline (1) and its derivatives have a pair of the prominent peaks a t mle 272 and 286 corresponding to two cleavages (Scheme I) which play an important role in structural elucidations of the daphniphylline group of alkaloids (8). The structure 1 of daphniphylline consists of two main moieties (a nitrogen heterocyclic skeleton and a ketal), which are connected through the straight chain of three carbon atoms containing an a-acetoxy keto group. Thus, two main moieties are expected t o be readily cleaved a t this position. On hydrolysis with 0.6 N NaOH in aqueous MeOH daphniphylline was converted into deacetyldaphniphylline (2) which was then oxidized with NaIO, to a ketal acid (3, mp 122-123'; C9HI4O4)and an unstable aldehyde (4). The latter was subsequently reduced with NaBH, followed by acetylation with Ac,O-pyridine to give daphnialcohol acetate [5, mp 268-270" (as hydrochloride); C,,H,,O,NI (8, 9).
OHC 7
( I ) NalJH,
5
Fig. 1
From a biogenetic point of view (Section V) the ketal moiety must be constructed by the intramolecular ketal formation of a plausible dihydroxy-diketone (6a). When treated with 6 N HC1 a t 80' for 45 min, daphniphylline as well as the corresponding alcohol was converted into deacetylisodaphniphylline (7a) in quantitative yields which was
46
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
then acetylated with Ac,O-pyridine to an isomer of daphniphylline [8, mp 197-198.5' (as hydrochloride); C,,H,,O,N; m/e 527 (M+), 286, 272; vmaX (KBr) 1756, 1744, and 1709 cm-l] (8, 1 0 ) . I n the course of the acid isomerization recyclization of the intermediate (6b) must give rise to two possible compounds (7a and 7b). I n comparison of the NMR spectra between deacetylisodaphniphylline and isodaphniphylline an AB quartet at 63.49 in the former was shifted to 63.99(2H, J = 11 Hz) in the latter indicating the presence of a HO-CHAHB-C-
I
grouping in deacetylisodaphniphylline. Accordingly, the structure 8 can be assigned to isodaphniphylline. On the other hand, codaphniphylline (9), whose structure will be discussed below (Section 11,A, 2), is quite stable and recovered even under more vigorous conditions as compared with that of daphniphylline ( l ) ,suggesting that the intramolecular ketal formation of the dihydroxy-diketone (6a) can take place under such acidic conditions quite easily. Thus, the ketal acid 3
I
HO
GRR * eM
\
7b
bH
~H,OH 6b Fig. 2.
has been synthesized from the known ketal 10 of levulinic acid (11) in several steps as shown in Scheme I1 (12). Treatment of 10 with oxalyl chloride (50-60°, 3 hr) followed by condensation with methyl diethyl malonate in the presence of NaH (room temperature, 6 hr, and then under reflux, 1 hr) afforded a condensation product [11, bp 148-151" (2.0 mm Hg), C,,H,,O,] in 53% yield. The compound 11 was further treated with LAH (under reflux, 3 hr), and then with 6 N HC1 (room temperature, 24 hr) to give
2.
47
THE DAPHNIPHYLLUM ALKALOIDS
10
I MI3
11
12
3
SCHEME 11. Synthesis of the ketal acid (3).
a hydroxy ketal[12, bp 111-112" (2.2 mm Hg); C9H,,0,] in 42y0 yield which was readily converted into d,l-ketal acid 3 (mp 144-145') in 77yoyield. 2. Codaphniphylline
Codaphniphylline (9) is the second daphniphylline-type alkaloid whose structure can be deduced by exhaustive comparison of its spectral data with those of daphniphylline (1) (8). Daphniphylline has an or-acetoxy keto group as a partial structure which can be supported 1742, 1714, and 1233 cm-l) and NMR spectra [62.05 by its IR (v,, (3H, s)] and 5.52[1H, q, J = 12, 3 Hz)]. On the other hand, the I R spectrum of codaphniphylline indicates the presence of a carbonyl group (v,, 1707 cm-l) and no ester group. I n addition, the multiplet at 62.90 (2H), which can be assigned to two methylene protons adjacent to the carbonyl group, is observed only in the NMR spectrum of the latter. The mass spectrum of codaphniphylline also has two prominent peaks a t 272 and 286, indicating that it has the same nitrogen heterocyclic moiety as that of daphniphylline (1). From these data codaphniphylline (9) can be regarded as deacetoxydaphniphylline. I n fact, chemical transformation of the base 1to codaphniphylline was successfully carried out.
48
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
At first zinc reduction of daphniphylline (1)was attempted without success. Therefore, deacetyldaphniphylline (2) was converted with MsC1-pyridine into the corresponding methane sulfonate (13, mp 162-164"; C,,H,,O,NS) which has a better leaving group than an acetoxyl group in 1. This compound as a hydrochloride was readily reduced with zinc powder in MeOH to codaphniphylline (9).
9
la
(X = H) (X = OMS) Fig. 3.
3. Daphniphyllidine Daphniphyllidine (14)4 is an isomer of deacetyldaphniphylline (2). The IR absorption bands at 1710 and 3430 br. cm-l indicate the presence of a carbonyl group and a hydroxyl group, respectively. Furthermore, this alkaloid has the NMR signals [60.73 (3H, s), 1.51 (3H, s), 3.45 (IH, d, J = 12 Hz), 4.00 (lH, q, J = 12, 2 Hz), and 4.20 (lH, m)] corresponding to those of the ketal acid (3), and methyl signals due to each isopropyl and tertiary methyl group, both of which must be attached to the same amine moiety as that of daphniphylline (1) as suggested by finding two characteristic peaks at rnle 272 and 286 in the mass spectrum of daphniphyllidine. Therefore, the chain connecting the two moieties in daphniphyllidine seems to be different from that of 2. In the NMR spectrum of the corresponding acetate 15, an acetylation product of daphniphyllidine, a sharp singlet was observed a t 65.63 (1H) indicating that this alkaloid was an isomer of deacetyldaphniphylline (2) at the carbonyl position. I n fact, the compound 2 was successfully converted with hot MeONa-MeOH to daphniphyllidine (14) in ca. 50y0 yield (13). Biogenetically, the structure of daphniphyllidine is of interest because of a different carbonyl position from those of daphniphylline (1) and codaphniphylline (9). This alkaloid is 4 Daphniphyllidine has been cited as the alkaloid D isolated from the bark and leaves of the plant Duphniphyllum rnucropodum Miquel [see Toda et al. (Irl)].
2.
14 15
49
THE DAPHNIPHYLLUM ALKALOIDS
(X = OH) ( X = OAc)
16
Fig. 4.
probably formed from deacetyldaphniphylline (2) via an endiol (16) or direct 1,2-hydride shift a t the position of the a-hydroxyketone in 2 (Section V). 4. Daphnimacropine
Daphnimacropine (17) has been isolated from the bark of D. macropodum and characterized as the corresponding methiodide, the
structure of which has been reported by Nakano, Osaki, and their coworkers on the basis of an X-ray crystallographic analysis of the methiodide (15).Although the structure 17a thus obtained is of interest from a biogenetic point of view it is questionable on the basis of the following reasons : 1. The approximate formula (C,,H,,O,NI) from chemical analysis is not in good agreement with the molecular formula (C,,H,,O,NI) calculated from the result of the X-ray crystallographic analysis. 2. As reported by Nakano and Saeki (16, p. 4795), the mass spectrum of daphnimacropine shows two fragment peaks at mle 272 and 286 which are characteristic of the amine moiety of daphniphylline (1) as well as of the corresponding methiodide (8). This finding cannot be explained by the structure 17a containing a hydroxyl group attached to the amine moiety. 3. It seems to be quite difficult t o explain the partial structure of a n oxabicyclo[3.2.l]octane system in 17a in the light of biosynthetic studies on daphniphylline (1) and codaphniphylline (9) (Section V). Another possibility cannot be ruled out in which the oxygen heterocyclic skeleton of daphnimacropine is identical with that of daphniphylline (1).Quite recently, further refinement of the X-ray crystallographic analysis5 of this methiodide has revealed it to have another Private communication from Dr. K. Osaki (Kyoto University): The molecular formula of this methiodide should be revised to C3,H,,0,NI.
50
SHOSUKE YAMAMURA A N D YOSHIMASA HIRATA
17a
17b
Fig. 5.
structure (17b). However, it seems to be quite difficult to rationalize the mass spectral data of daphnimacropine. Further chemical and spectral data of daphnimacropine have not yet been reported in detail. 5. Daphmacrine
The IR,NMR,and mass spectra of daphmacrine (18) suggest that it has a nitrogen heterocyclic skeleton similar to that of daphniphylline (I) but differs in the oxygen-containing moiety. The IR spectrum of this alkaloid showed two carbonyl bands a t 1770 and 1730 cm-l resulting from a five-membered lactone and an ester group, respectively. The N M R spectrum showed the presence of two tertiary methyl H
Fig. 6 .
I
groups r61.24 (3H, s) and 1.50 (3H, s ) ] and a -CH-OAc grouping rS2.12 (3H, s) and 4.89 ( l H , m, J,x+Bx = 8 Hz)], in addition to one isopropyl [SO.% and 1.17 (each 3H, d, J = 6 Hz)] and one tertiary methyl [61.13 (3H, s ) ] group, both of which must be attached t o the same amine moiety as that of daphniphylline (1) as suggested by the mass spectrum having two prominent peaks a t mle 272 and 286.
2.
51
THE DAPHNIPHYLLUM ALKALOIDS
Finally, the structure and absolute configuration of daphmacrine (18) was deduced by an X-ray crystallographic analysis of the corresponding methiodide ( 5 , 17). From a biogenetic point of view, the most important point is that the oxygen heterocyclic moiety in 18 consists of a six-membered ring in the chair form bridged by carbon and oxygen atoms to form a five-membered lactone with methyl groups substituted a t each bridgehead as compared with the ketal moiety of daphniphylline (1) (Section V).
6. Daphmacropodine
+
4.9" Daphmacropodine [19; mp 215-218' (as hydrobromide); [.ID (in CHC1,); m/e 513, 286, and 2721 has also been isolated from the bark of D. macropodurn together with daphmacrine (18). This alkaloid has an acetoxyl group (v,,, 1740 and 1240 em-') but any IR absorption band resulting from a five-membered lactone, which can be found in the case of the alkaloid 18, is not observed. The NMR spectra of both alkaloids are quite similar except for the appearance of a singlet a t 64.78 in daphmacropodine which can be assigned t o the one proton of
I
a hemiacetal grouping (HO-Cg-O-). Furthermore, the mass spectrum of daphmacropodine has two prominent peaks a t 272 and 286 as found in that of daphmacrine (18). However, a dehydration peak (M+ - 18) is found only in the former. From these spectral data and the following chemical evidence the structure of daphmacropodine was established as 19 (16, 18). Hydrolysis of daphmacropodine with 1 N methanolic NaOH gave the corresponding alcohol (20, mp 130-135') in almost quantitative yields which was further oxidized with Jones reagent (O", 10 min) t o a keto lactone [21, mp 179-180" (as hydrochloride); vmax 1766 and 1716 cm -I]. Finally, chemical corelation between daphmacrine (18) and daphmacropodine was carried out. Lithium aluminum hydride (LAH) reduction of both alkaloids gave a mixture of the same two compounds [22, mp 238.5-239" (C,,H,,O,N); an anomer of 20, mp 204-205" (C,,H,,O,N)]. The IR spectrum of the latter proved to be different from that of the deacetyl derivative 20 obtained by alkaline hydrolysis of daphmacropodine (19). Probably, they are anomers which differ in the configuration a t the hemiacetal carbon atom. Thus, daphmacropodine was converted into daphmacrine hydrobromide (18, mp > 300") by Jones oxidation followed by the formation of the
52
SHOSUXE YAMAMURA A N D YOSHIMASA HIRATA
H
19 $0
(R = Ac) (R = H)
21
H
Y
22
Fig. 7.
hydrobromide. The stereochemistry at the hemiacetal carbon atom remains undetermined. 7. Methyl Homodaphniphyllate
The carbon skeletons of the Daphniphyllum alkaloids consist of thirty or twenty-two carbon atoms. Probably the CZ2 alkaloids are formed by oxidative cleavage of eight carbon atoms from the C,, compounds. Methyl homodaphniphyllate [23, m/e 359(M+), 286, and 2721, one of the representative Czz alkaloids, was isolated from the fruits of D. macropodum (19) but not from the bark and leaves of the same plant. The structure of this alkaloid (23) was deduced by chemical transformation from daphniphylline (1)which had already been carried out in several steps. Oxidation of deacetyldaphniphylline (2) with NaIO, followed by reduction with NBH afforded daphnialcohol [24, mp 239-241.5" (as hydrochloride); C,,H,,ON], which was further converted via the corresponding tosylate (25, mp 107.5') and nitrile (26, mp 156') t o homodaphniphyllic acid (27),which was directly treated with 20% methanolic HC1 to afford methyl homodaphniphyllate (23). This alkaloid was also obtained in 2001, yield by Beckmann
2.
T H E DAPHNIPHYLLUM ALKALOIDS
53
25 (X = OTS) 26 ( X = CN) 27 ( X = C O O H )
Fig. 8.
rearrangement of codaphniphylline (9) followed by esterification with 6 N methanolic HC1 (20). Biogenetically, methyl homodaphniphyllate (23) must be produced from codaphniphylline (9),which belongs t o a group of the C,, alkaloids, by oxidative removal of the oxygen heterocyclic moiety.
B. SECODAPHNIPHYLLINE AND METHYLHOMOSECODAPHNIPHYLLATE Secodaphniphylline (28) and methyl homosecodaphniphyllate (29) are isomers of codaphniphylline (9) and methyl homodaphniphyllate (23), respectively. The difference is that 28 and 29 both have an NH group which can be acetylated with Ac,O-pyridine whereas 9 and 23 are tertiary amines. The absolute stereostructure of methyl homosecodaphniphyllate (29) was determined by an X-ray crystallographic analysis of the corresponding N-bromoacetyl derivative (30, mp 117-118.5'; C,,H,,O,NBr) which was produced by treatment of methyl homosecodaphniphyllate with bromoacetyl bromide and K,CO, in dry benzene (6, 21). The structure of secodaphniphylline was established as 28 by comparison of the NMR and mass spectra with those of 28 and 29 coupled with chemical evidence (21). The former has a NMR signal corresponding t o protons of the ketal acid 3, a degradation product of daphniphylline (1) (8), whereas these signals are not found in the alkaloid 29. The remaining signals are nearly identical in both compounds except for a methyl singlet a t 63.67 in 29 (Table 11). I n addition, the difference of molecular weights (110) as well as the appearance of a characteristic peak a t mle 286 arising from a fragment ion 31 indicates 6 A s expected, 8 prominent peak a t m/e 272, which can be observed in the mass spectra of daphniphylline (1) and its derivatives, is not observed in this case.
54
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
C~OH,,O~N-CZ~H~~O~N C7H,,0 = 110
that secodaphniphylline can be formally constructed from methyl homosecodaphniphyllate (29) and the ketal acid 3. I n fact, the N acetylsecodaphniphylline (32), an acetylation product of 28, was converted into methyl N-acetylhomosecodaphniphyllate (33, mp 105-106"; C25H3903N)by Beckmann rearrangement followed by methanolysis (Scheme 111). 0
29
28
MeOOC
1-= 32
33
(a)AczO-pyridine, a t room temperature, overnight. (b) NH,OH.HCI-pyridine, a t go", 24 hr. (c) MsC1-pyridine, at 80", 24 hr. (d) 6 N HCI--MeOH, under reflux, 24 hr.
SCHEME 111. Chemical corelation between secodaphniphylline and methyl homosecodaphniphyllate.
2. THE DAPHNIPHYLLUM ALKALOIDS
30
(R = COCH,Br)
55
31
Fig. 9.
TABLE I1
NMR SPECTRA O F SECODOPHNIPRYLLINE AND METHYLHOMOSECODAI’HNIPHYLLATE 3
28
3.63 (lH, d, J = 12 Hz) 4.30 (lH, d,d, J = 12,2 H z ) 4.77 ( l H , m)
0.77 (3H, 8 ) 0.89 (3H, s) 0.89 (3H, d, J = 6 H z ) 0.90 (3H, d, J = 6 H z ) 1.42 (3H, s) 2.51 (lH, d, J = 4.2 H z ) 2.6-2.9 (2H, m) 3.01 ( l H , br. s) 3.49 (IH, d, J = 12 Hz) 4.23 (lH, d,d, J = 12,2 H z ) 4.62 ( l H , m)
1.03 (3H, s)
1.50 (3H, s)
29
0.79 (3H, s) 0.89 (6H, d, J = 6 H z )
2.53 (lH, d, J = 4.2 H z ) 2.1-2.5 (2H, m) 2.98 ( l H , br. s)
3.67 (3H,
8)
C. DAPHNILACTONE-A Daphnilactone-A (34)7 is a minor component of the alkaloids isolated from the bark and leaves of D. macropodum (yield, ca. 0.00001%) (21). Its spectral data indicate the presence of an isopropyl group [S0.91 and 0.93 (each 3H, d, J = 6 Hz)], a tertiary methyl group [Sl.OS (3H, s)], and a lactone or ester group (Y,,, 1737 cm-l). However, a signal resulting from a methoxyl group was not observed in the NMR spectrum. Accordingly, one more carbon atom must be included in such a carbon skeleton as that of methyl homodaphniphyllate (2%).Finally, the structure of daphnilactone-A was established as 34 by an X-ray crystallographic analysis of the free base (22). Daphnilectone-A has been reported as the alkaloid C (14, 21).
56 56
r I
I'
SHOSUKE YAMAMURA YAMAMURA AND AND YOSHIMASA YOSHIMASA HIRATA HIRATA SHOSUKE
u0 0
xo
m
'r
R 0 0
: u
r
m Y) t-
% E
d
m
2.
57
THE DAPHNIPHYLLUM ALKALOIDS
Biogenetically, daphnilactone-A (34)is considered to be formed from a squalene-like intermediate (Section V) via a plausible intermediate 35 (Scheme IV). D. DAPHNILACTONE-B Daphnilactone-B (36)is a major component of several alkaloids isolated from the fruits of three kinds of plant growing in Japan (2'). Its NMR spectrum indicates the presence of a secondary methyl group [Sl.OO (3H, d, J = 6.0 Hz)] and an olefinic proton r65.67 (lH, br.s, Wh = 5.5 Hz)]. The presence of a lactone grouping [A] is confirmed by the spectral data [v,,, 1726 cm-l, 63.63 and 4.73 (each lH, d, J = 13 Hz)] coupled with chemical evidence. Action of MeONaMeOH on daphnilactone-B converted it to the corresponding methyl ester 37 which was gradually recyclized to the original lactone. In the mass spectrum of the ester 37 two prominent peaks were observed at m/e 300 and 286 indicating the presence of a -CH,CH,COOMe grouping. In addition, in the light of co-occurrence of methyl homodaphniphyllate (23)and yuzurimine-B (52)(see Section 11, E, 5 ) , a tentative structure (36)of daphnilactone-B can be deduced from the common intermediate 35. This was confirmed by an X-ray crystallographic analysis of the free base of daphnilactone-B (23).
O
\
'.J
pH
'I'
q
&: :M e
%,
'.U H r
I
1
O=C-O-CH~-C--, CH,CH,----------,' I
1-41 36
37 Fig. 10.
Biogenetically, daphnilactone-B (36) is regarded as a plausible intermediate between daphniphylline-type and yuzurimine-type alkaloids. Thus, daphnilactone-B (36)was converted to a daphniphyllinetype compound (38,mp 166-168"; C2,H3,O2N) via a bromocyanamide [39,mp (dec) 210'1 and a debromocyanamide (40, mp 208-212"), as shown in Scheme V. The structure of this daphniphylline-type compound 38 was confirmed by its mass, IR, and NMR spectra coupled with von Braun degradation of 38 leading to the formation of a new
j
58
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
36
-
BrCN-K,C03
Br 40
39
I Hr(:N--X.C03
'N-CN
41
. "H
c- O -%-
in benzene
38
7'
90% HCOOH undpr reflux overnight
42
SCHEMEV. Chemical transformation of daphnilaotone-B t o daphniphylline-type compound (38).
cyanamide, an isomer of the compound 40 (41, mp 233-235"), having a trisubstituted double bond [65.72 (lH, br.m, Wh = 15 Hz)]. I n the course of acid isomerization from 40 to 38 a secondary amine 42 may be an intermediate from which the daphniphylline-type compound 38 can be formed by protonation a t the tetra-substituted double bond followed by simultaneous participation of the secondary amino group as shown in Scheme V.
E. YUZURIMINE-TYPE ALKALOIDS Of seven structurally known alkaloids belonging to the yuzurimine group of alkaloids the structure of yuzurimine (43) was first determined by an X-ray crystallographic analysis of the corresponding hydrobromide 24. The others were based on their exhaustive spectral analyses together with chemical evidence. A tentative structure of macrodaphnine had also been reported as dihydromacrodaphnidine (50) on the basis of a combination of its spectral and elemental analyses (16). However, an X-ray crystallographic analysis of the hydrobromide gave it the interesting N-oxide structure 51 (25). 1. Yuzurimine
Yuzurimine [43; [a], + 8.3" (in CHCI,)] is one of the major alkaloids isolated from the bark and leaves of D . macropodum. The spectral data
2. THE
DAPHNIPHYLLUM ALKALOIDS
59
of this alkaloid are quite different from those of daphniphylline (l),one of the main alkaloids. Thus, yuzurimine hydrobromide [mp 251-253'; [a],, +7.9" (in CRCl,)] was subjected to an X-ray crystallographic analysis, elucidating an unusual structure (43), which was in good agreement with its spectral data [Azlo .,(EtOH) E , 7400 (end absorption); vmax 3490, 1744, 1735, and 1722 cm-l; NMR signals are cited in Table 1111 ( 2 4 ) . Chemical properties of yuzurimine are also fully consistent with the structure 43 (26). Action of methanolic NaOH or 15% methanolic HCI on yuzurimine converted it to deacetylyuzurimine (44, mp 174-176'), which was further treated with SOC1,-pyridine to afford a sulfite (45, mp 237-239"; C23H3106NS),indicating that both TABLE I11
NMR SPECTRA OF YUZURIMINE AND RELATED ALKALOIDS ~~
Yuzurimine (43)a 1.11 (3H, d, J = 7 Hz) 1.98 (6H, s) 3.53 (3H, s) 4.32 (2H, q, JAB= 11 Hz) 5.36 (lH, q, J = 7,12 Hz) 6.66 (IH, s) a
Yuzurimine-A (48)" 1.07 1.17 2.01 3.55
Yuzuriminc-B (52)b 1.22 (3H, d, J = 6 Hz)
(3H, d, J = Hz) (3H, s) (3H, s) (3H, s)
3.72 (3H, s) 3.92 (2H, q, JAB= 11.5 Hz)
4.89 (lH, q, J = 7,12 Hz)
6.66 ( l H , s)
CDC1,.
D,O.
primary and secondary hydroxyl groups are sterically close t o each
I I
other. Furthermore, the presence of HO-C-N-
grouping in 43 is
also supported, as follows. Yuzurimine methiodide (mp 180-182"; Cz,H,oO,NI) was readily converted to a keto amine (46, mp 136-138"; C2,H3,0,N) only by contact with aqueous alkaline solution. Similarly, treatment of the methiodide with methanolic NaOH gave a deacetyl keto amine (47, mp 208-209"; Cz,H3,0,N). I n their IR spectra, extraordinarily low CO frequencies [vmaX(CC1,) 1633 cm-l in 46; vmax (CHC1,) 1 6 0 0 ~ r n in - ~471 must result from proximity of the nitrogen atom with a lone pair of electrons. 2. Yuzurimine-A
Yuzurimine-A (48), which has been isolated from the bark and leaves of D.macropodum, is a minor alkaloid crystallized in the form of the
60
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
43 44 45
(R = Ac) (R = H)
("R.
=
46 47
(R = Ac) (R = H)
so) Fig. 1 1
hydrochloride whose I R spectrum is quite similar to that of yuzurimine hydrochloride (43) (26, 27). This alkaloid can be regarded as deacetoxyyuzurimine (48) on the basis of comparison of the NMR spectra of these two alkaloids (see Table 111) coupled with the difference of mass number (C,H,O, = 58). I n particular, the NMR spectrum of yuzurimine-A has no signals due to the acetoxymethyl group which is found in the case of yuzurimine (43) but instead a methyl singlet a t 61.17.
MeOOC
48 49
(R = Ac) (R= H)
Fig. 12.
3. Macrodaphniphyllamine
Macrodaphniphyllamine [49; [a]= - 51.7" (in CHCl,)] has an ester carbonyl absorption band a t 1730 cm-l and a hydroxyl band a t 3400 cm-l in its IR spectrum. The NMR spectrum of this alkaloid has the signals corresponding to a secondary methyl group (61.03, d, J = 7 Hz)
2. THE DAPHNIPHYLLUM ALKALOIDS
61
and Me0 group (63.63) as found in that of yuzurimine (43). However, an NMR signal resulting from an acetoxyl group was not observed but instead a methyl singlet was found a t somewhat low field of 61.23. From these spectral data, together with co-occurrence of yuzurimine, the structure of macrodaphniphyllamine was established as 49 (16).Clearly, this alkaloid is deacetylyuzurimine-A. I n fact, action of 10% HCIMeOH (under reflux, 17 hr) on yuzurimine-A (48) converted it t o macrodaphniphyllamine hydrochloride (49, mp 251-254") (26). 4. Macrodaphnine
The structure of macrodaphnine [[a],,- 18.4" (in MeOH)] was first proposed to be dihydromacrodaphnidine (50) on the basis of the erroneous illustration of mass fragment peaks, which appeared by two mass units higher than the corresponding peaks in yuzurimine (as), together with observation of uncertain IR absorption band at 3350 cm-l which should be assigned to a hydroxyl group (16). However, X-ray crystallographic analysis of the corresponding hydrobromide (mp 249-252"; C,,H,,O,N. HBr) disclosed the interesting Noxide structure 51 which was consistent with the NMR spectrum having the prominent signals corresponding t o those of yuzurimine (42) (25). Thus, the revised structure (51) required a reexamination of the mass spectrometric fragmentation of this alkaloid and these fragment peaks a t mle 471, 470, and 469 may result from the formation of the fragment ions A, B, and C, respectively, as illustrated in Scheme VI, in which macrodaphnine (51) with the N-oxide structure loses an atom of oxygen as well as a hydroxyl radical on electron impact. MeOOC
AcO
; 50
Fig. 13.
51
5. Yuzurimine-B
Yuzurimine-B (52) is a minor alkaloid crystallized as the hydrochloride which has a secondary methyl group 161.22 (3H, d, J = 6.0
62
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
SCHEME VI. Mass fragmentation of macrodaphnine.
Hz)] and a carbomethoxyl group [63.72 (3H, s); vm,, 1735 as found in yuzurimine (43) (see Table 111). The presence of a tertiary hydroxymethyl group in the former can be confirmed by its NMR spectrum having an AB quartet centered a t 63.94 (2H, q, JAB= 11.5 Hz) which is shifted t o 64.47 on acetylation yielding an acetate (macrodaphniphyllidine. HC1, 53,mp 266-267.5'). These spectral data, together with the difference of molecular weight (C,H,O, = 116) between yuzurimine and yuzurimine-B, suggested the structure 52 for the latter (27),which was finally confirmed by chemical transformation of yuzurimine (43) to yuzurimine-B mesylate [54, mp 225-227" (as hydrochloride); C,,H,,O,NS . HCl] as follows (26). Reduction of yuzurimine (43)with active zinc powder in AcOH (9095', 2 hr) or with NBH gave deoxyyuzurimine (55, mp 132-134").
52 53 54
(R = H) (R = Ac) (R = Ms)
55 57
58
(R = Ac) (R = H) (R = Ms)
Fig. 14.
56
63
2 . THE DAPHNIPHYLLUM ALKALOIDS
Further hydrolysis of the compound 55 with 7 7 , HC1-MeOH followed by treatment with MsC1-pyridine and then with LiCl in dimethylformamide (DMF) (90-100", 18 hr) afforded a monomesylate [56, mp 253-254" (as hydrochloride)] via deacetyldeoxyyuzurimine (57) and dimesylate (58). I n the NMR spectrum of 56, a broad singlet resulting from two olefinic protons was observed a t 65.93. Finally, catalytic hydrogenation of this compound over PtO, gave yuzurimine-B mesylate (54) which was directly obtained from yuzurimine-B on mesylation with MsC1-pyridine. 6. Macrodaphniphyllidine
Macrodaphniphyllidine (53) was also isolated from the bark of macropodum and crystallized as the hydrobromide [[a],,
+ 3.9"
D.
(in MeOH)]. I n the light of co-occurrence of yuzurimine (43), the structure of macrodaphniphyllidine (53) was estimated on the basis of comparison of the NMR spectra between macrodaphniphyllidine and yuzurimine, in which the former lacked a signal due to a secondary acetoxyl group in 43 coupled with the mass spectrum indicating the presence of a carbomethoxyl group [m/e 354 (M+ -59)] and an acetoxymethyl group [m/e 340 (M+ -73)] (16). As mentioned earlier macrodaphniphyllidine is identical with yuzurimine-B acetate (53) which has already been correlated to the structurally known yuzurimine. 7. Yuzurimine-C
Yuzurimine-C (59) is a minor alkaloid which has a secondary methyl group [61.04 (3H, d, J = 6 Hz)] and a carbomethoxyl group [v,, (KBr) 1736 cm-l and 63.58 (3H, s)] analogous to those of yuzurimine (43). The I R spectrum indicates the presence of two different carbonyl groups [vmax (KBr) 1736 and 1723 cm-l], one of which can result from an aldehyde group [v,,, 1723 cm-l and 69.99 (lH, s)] instead of a tertiary acetoxymethyl group in yuzurimine. I n addition, two sharp doublets a t 65.61 (lH, d, J = 10 Hz) and a t 66.20 ( l H , d, J = 10 Hz) in the NMR spectrum are assigned to two olefinic protons
iH\c=c /
\
. On the basis of these spectral data, together with
co-occurrence of yuzurimine (43)) the tentative structure 59 has been given to yuzurimine-C. However, further chemical evidence has not been obtained ( 1 4 ) .
64
SHOSWE YAMAMURA AND YOSHIMASA HIRATA
59
Fig. 15.
F. ALKALOIDS OF UNDETERMINED STRUCTURE
A list of the Daphniphyllum alkaloids is given in Table I. In addition to two alkaloids of undetermined structure, neodaphniphylline (28) and neoyuzurimine, both of which have been isolated in very small quantities (Vol. X , p. 556, and Vol. XII, p. 472), three more structurally unknown alkaloids (alkaloids A, and A,, and yuzurimine-D) have been obtained from the bark and leaves of D. macropodum (14, 21). In particular, the carbon skeletons of the alkaloids A, and A, seem to be considerably different from those of the other alkaloids cited in parts A-E, on the basis of their spectral data. 111. Chemistry
I n this section, zinc reductions, which have been found in the course of chemical studies on isodaphniphylline (8), and isolable and nonisolable anti-Bredt's rule imines are described.
A. ZINC REDUCTION As mentioned in Section 11,A, action of 6 N HCl on daphniphylline (1) followed by acetylation converted it to isodaphniphylline (8). Further treatment of 8 with active zinc powder under various conditions did not cleave an a-ether oxygen-carbon bond leading to the formation of the desirable ketone 6a, which was expected to be spontaneously converted into codaphniphylline (9) (see Section 11, A), but instead afforded deoxyisodaphniphylline [60,mp 212-214" (as
2.
65
THE DAPHNIPHYLLUM ALKALOIDS
TABLE IV
ZINC REDUCTIONS IN COMMON ORGANICSOLVENTSSATURATED WITH HC1 GAS Yield Solvent
Product
(7%)
AczO Et,O Tetrahydrofuran Benzene
Cholestane Cholestane Cholestane Cholestane 3-Chlorocholestane Cholestane 3-Chlorooholestane Androstane 178-Acetoxyandrostane Androstane
87a 8gb 44b 64b 21 57b 8 66= 26 75b
Ketone Choleston-3-0110
n-Hexane Androstan-3,l'ii-dione
Ao,O EtzO
a
At 0" for 2 hr. At 0" for 1 hr. At 0" for 6 hr.
-
hydrochloride); C3,H,,0,N HCl], in which the sterically hindered five-membered ring ketone has remained (8, 10). Thus, modified Clemmensen reduction, which can be done in common organic solvents (Table IV), has provided a simple method of reducing a variety of ketones to the corresponding deoxy compounds in high yields under much milder condition ( O O , 1-2 hr) than those normally used in Clemmensen reduction (29, 30). Furthermore, this reduction method also permits the selective deoxygenation of the ketones having polyfunctional groups such as cyano, amido, acetoxy, and carboalkoxy which are stable under the milder conditions (29).
0 8 R : Amine moiety
60
Fig. 16.
In view of the high reactivity of these reduction systems [Zn-HC1 gas-Ac,O (or Et,O)], zinc reductions of a-substituted, a,/?-unsaturated, and aryl ketones have also been studied, as summarized in Table V in which considerably different results have been obtained depending
66
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
TABLE V ZINC REDUCTIONS OF a-SUBSTITUTED,a,p-UNSATURATED,A N D ARYLKETONES Yield Ketone 2a-Bromocholestan-3-one
Cholestane 3-Acetoxycholest-2-ene a-Acetoxycholestan-3-onec Cholestane Enol acetates 3/3,5a-Diacetoxy-7a-bromocholestan-6-one 38-Acetoxycholestane 3~,17a-Diacctoxypregn-5-en-20-one 38-Acetoxypregn-5-ene Cholestane Cholest- 1 -en-3-one 3-Acetoxycholest-2-ene Cholestan-3-one Cholest-4-en-3-one Cholestane Coprostane Methyl 8-benzoyl propionate Methyl y-phenyl butyrate Indanone Indane a
(70)
Product
86a, 8Fib 8"
go", 7 9 b 2a.d
73e 6Ze
30-32a, 8Sb 24-10" 30-40a 4Sb 40b 4 P , 41b 22a, 42b
I n acetic anhydride saturated with HCl (On, 2 hr). I n diethyl ether saturated with HCl (0", 1 hr). A mixture of 2a- and 4a-acetoxycholestan-3-ones( 1 : l ) . A mixture of 3-acetoxycholest-2 and 3-enes. In acetic anhydride saturated with HC1 (Oo,6 hr).
on two different reduct,ion systems, particularly in the case of a$unsaturated ketones (30). On zinc reduction in Ac,O saturated with HCl gas, cholest-1-en-%one (61) afforded a mixture of three reduction products [cholestane (62) (32-30y0), 3-acetoxycholest-2-ene (63) (24-1007,), and cholestan-%one (64) (30-40%)], as shown in Scheme VII.
+ 64
H
iAc+
H
63
SCHEME VII. Reduction mechanism of cholest-1-en-3-onewith Zn-HC1-Ac,O.
2.
67
T H E DAPHNIPHYLLUM ALKALOIDS
Further developments have been made in this field by using ZnHC1-Ac,O as the reducing agent, providing a convenient method t o synthesize mono- and diacetoxycyclopropanes. Zinc reductions of the a$-unsaturated ketones (65 and 66) in Ac20HCI both afforded a mixture of two cyclopropanol acetates (67 and 68) in different ratios (67j68 = 3 in 65; 67/68 > 100 in 66) ( 3 1 ) .
QPh 0
+/L---Ji; +--e
65
Zn-Ac,O-HCI
aPh 66
4
-
H
H
OAc
OAc
67
68
0
F1g. 1 7 .
Generally, zinc reductions of P-diketones under Clemmensen conditions have been known to afford a complex mixture. However, when treated with Zn-Ac,O-HC1 gas ( O O , 2 hr), l-acetyl-l-methylcyclohexanone (69) was readily converted into the diacetoxycyclopropane 70 in more than 80% yields, as shown below ( 3 2 ) . OAc
70
69
Fig. 18.
B. ANTI-BREDT’S RULEIMINE Generally, bicyclic compounds (71) containing a bridgehead double bond and with S 5 7 may be regarded as an anti-Bredt’s rule compound, which is quite unstable because of high ring strain energy (3 3 ). In 1967, two American groups first succeeded in the synthesis of bicyclo[3.3.l]non-l-ene,an anti-Bredt’s rule olefin (72) ( 3 4 ) . Since then several isolable anti-Bredt’s rule olefins with S = 7 have been prepared (35). The heterocyclic anti-Bredt’s rule compound was first produced
68
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA h
S = a + b + c (a, b, c # 0) Fig. 19.
in the course of chemical studies on the Duphniphyllum alkaloids (22, 36). When treated with Pb(OAc), in dry benzene (room temperature, 1 hr), methyl homosecodaphniphyllate (29) was converted into a ,v (KBr) 1739 and dehydro compound [mp 96-98'; C,,H,,O,N; 1589 em-'] in high yields, which was quantitatively reconverted into the original alkaloid with NBH (room temperature, 1 hr) or by catalytic hydrogenation over PtO, in MeOH (room temperature, 1 hr), indicating that this oxidation product was an imine with the original carbon skeleton. Of the two possible imines 73 and 74, the latter seems sterically impossible. As expected from a 2-azabicyclo-[3.3.llnon- 1-ene system in an anti-Bredt's rule imine 73, the IR absorption band a t 1589 em-l assigned to the C=N stretching vibration indicates that it has much single bond character because of increase of the strain energy. Action of excess NaCN in DMF (90-looo, 3 hr) on the imine 73 converted it to a cyano compound [75; m/e 384 (M+); vmax (CHCl,) 2240 em -I]. Surprisingly however, treatment of 75 with Ac,O-pyridine (room temperature, overnight) did not give the corresponding N-aeetyl derivative but the anti-Bredt's rule imine 73. The facile formation of the anti-Bredt's rule imine seems t o result from the stable boat conformation of its 2-azabicyclo[3.3.l]non-l-enesystem, which is fixed by a part of the 2-azabicyclo[2.2.2]octanesystem, as well as t o some steric relief from steric repulsion between the cyano group and the other substituents in the cyano compound 75.
Fig. 20.
2.
69
THE DAPHNIPHYLLUM ALKALOIDS
Further investigations on nonisolable anti-Bredt’s rule imines have been made by using 3-oxo-2-azabicyclo[3.3.l]nonane(76) and 3-0x0-2azabicyclo[3.2.lloctane (77) (37). Oxidation of the compound 76 with Pb(OAc), in dry benzene (120°, overnight) gave an acetoxy-lactam 78 in 30y0 yield via an anti-Bredt’s rule imine 79 as a plausible intermediate. On reduction with NBH this acetate was readily reconverted into the original compound as found in the case of 73. Furthermore, some substitution reactions a t C, position were carried out. Treatment of 78 with HC1-MeOH (room temperature, 3 hr) or MeONa-MeOH (OO, 5 hr) gave a methoxy-Iactam 80 in high yields. Similarly, action of KCN in aq. tetrahydrofuran (room temperature, overnight) on 78 converted it to the corresponding cyano derivative 81 in high yields. I n the above reactions, 3-0~0-2-azabicyclo[3.3. llnon-l-ene is also regarded as a plausible intermediate. Under similar conditions, oxidation of 3-0x02-azabicyclo[3.2.l]octane (77) with Pb(OAc), in dry benzene afforded the expected acetoxy-lactam 82 via an anti-Bredt’s rule imine 83 although the yield was poor (ca. Zoj,).
0 76 78 80 81
0
(X = H) (X = OAc) (X = OMe) (X = CN)
77 82
(X = H) (X = OAc)
83
79
Fig. 21.
Reed and Lwowski (38) have done the photolysis of l-azidonorbornane (84) in MeOH and obtained two amines (85 and 86) in 54 and 2407, yields, respectively. I n the course of intramolecular nitrene rearrangements, an anti-Bredt’s rule imine, 2-azabicyclo[3.2.l]oct-lene (87), can be regarded as a plausible intermediate from which the amine 85 is produced. On the other hand, a biradical 88 has been
70
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
87
88
89
Fig. 22.
suggested as a plausible intermediate in the case of the latter (38) because LAH reduction of 85 in ether (under reflux, 4 hr, and then room temperature, overnight) gave 2-azabicyclo[3.2.lloctane in 40y0 yield via the anti-Bredt’s rule imine 87, whereas the starting material was only recovered in the case of 86. However, it seems to be that 2 azabicyclo-[2.2.2]oct-l-ene(89),as a quite unstable intermediate, is not necessarily ruled out.
IV. Structural Relationship Daphniphyllum macropodum contains a great variety of related alkaloids that are structurally divided into five types of nitrogen heterocyclic skeleton. However, all these bases possess in common the 2-azabicyclo[3.3. I Inonane system [A]. Furthermore, one may classify these alkaloids into two groups, C,, and C,, alkaloids, by the number of carbon atoms constituting their carbon skeletons, but this classification is not necessarily suitable because the latter must be biogenetically produced from the corresponding C,, alkaloids by oxidative removal of eight carbon atoms. Formally, these Daphniphyllum alkaloids are related to one another by bond formation or fission, as shown in Scheme VIII, in which such compounds as B and C are plausible key intermediates between two main groups represented by daphniphylline (1) and yuzurimine (43).These secondary amines have not been isolated from the plant nor synthesized to date, but may be in the plant. I n addition, such a plausible alkaloid as 90 also has not been isolated from the plant but chemically transformed from deoxyyuzuriniine (55) in three or four steps ( 2 6 ) . Von Braun degradation of 55 with BrCN in benzene followed by NBH reduction in dimethyl sulfoxide (DMSO) afforded a cyanamide
0 MeOOC
MeOOC
AcO
+
: ;
3
90
(R = Ac or H)
SCHEME VIII. Structural relationships among the Daphniphyllurn Alkaloids.
34
71
36
m
r, 29
28
THE DAPHNIPHYLLUM ALKALOIDS
R
x
8
F
MeOOC
43
2.
/
\
23
9
t
AcO
\
72
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
91 92
(R = CN, X (R = CN, X
= H) = Br)
93 (R = CONH,, X = H)
Fig. 23.
(91,mp 208-210') via a bromocyanamide (92,mp 188-190"). Further hydrolysis of the compound 91 with AcOH saturated with HC1 gas (under reflux, 46 hr) gave a mixture of urea (93)and secondary amine [go,(R = OAc)] in 19 and 49% yields, respectively. The latter was further hydrolyzed with methanolic NaOH to give a fine crystalline dihydroxy compound [90, (R = OH), mp 212-214'1. V. Biosynthesis
Daphniphyllum macropodum contains a great variety of related alkaloids whose structures are quite complex and novel (Section 11). It is structurally evident that these alkaloids with an isopropyl or a potential isopropyl group are regarded as a terpene alkaloid. Biogenetically, these Daphniphyllum alkaloids, particularly C,, alkaloids, have been proposed to be derived from four molecules of mevalonic acid (MVA) and one acetate unit (15, 39). However, the recent tracer experiments showed that these alkaloids could be biosynthesized from six MVA molecules through a squalene-like intermediate. Accordingly, they should be included in a group of triterpene alkaloid. A. DAPHNIPHYLLINE AND CODAPHNIPHYLLINE Daphniphylline (1)and codaphniphylline (9),both of which are the C,, alkaloids, constitute one of the two main groups of the alkaloids isolated from the bark and leaves of D. macropodum. Of course these alkaloidal components as well as the amounts varied with the season,
2.
73
THE DAPHNIPHYLLUM ALKALOIDS
and the highest incorporation of labeled MVA in these two alkaloids was recorded in June and July (total incorporation: 1, 0.14%; 9, O.13yo) ( 4 0 ) . Further degradation studies on the labeled deacetyldaphniphylline ( Z ) , the hydrolysis product of 1, proved that daphniphylline (1)was constructed from six MVA molecules (Scheme I X and Table VI). *#--
'.
2
C* from [2-I4C]MVA C* from [5-'*C]MVA
24
SCHEME IX. Degradation of the 14C- labeled deacetyldaphniphyllie.
Furthermore, when (3R,4R and ~S,~AS)-[~-~H]MVA (100 pCi) and DL-[Z-~~C]MVA (50 pCi) were fed to the plant, doubly labeled deacetyldaphniphylline was obtained in which the relative value of 2 x 14C/3Hwas ca. 1.27, indicating that five 3H atoms must be incorporated into daphniphylline (1). In addition, further radioactive tracer experiments using 14C-labeled squalene, which was incorporated into ), daphniphylline and codaphniphylline (total incorporation, 0.0087, TABLE V I OH' THE 14C-LABELEDCOMPOUNDS SPECIFIC ACTIVITIES
DL-[~-~~C]MVA DL-[~-~~C]MVA
2 (dpm/mM)
3 (dpm/mW
24 (dpm/mM)
24/3
1.95 x 105 4.37 x 104
0.65 x 105 0.69 x 104
1.30 x lo5 3.52 x 104
2.0 5.1
74
Squalene
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
Squalene-2,3-oxide
H
R:Amine moiety or polyene
SCHEME X. Biogenesis of the oxygen heterocyclic skeletons of the daphniphyllinetype alkaloids.
indicated that the C,, Daphniphyllum alkaloids represented by daphniphylline (1) must be biosynthesized from six MVA molecules via a squalene-like intermediate. As shown in the Section 11, A, daphniphylline (1) and daphmacrine (18), whose stereostructures have been unambiguously determined, have the same amine moiety but differ in the oxygen heterocyclic skeleton. Thus, it is quite reasonable to suppose that two different moieties must be constructed from such a common precursor as A which can be derived from squalene via squalene-2,3-oxide, and from a monocyclic olefin (Scheme X).
75
2. T H E DAFHNIPHYLLUM ALKALOIDS Enz
28
I
-
R
Daphniphylline (1)
* R:Ketal moiety
2
SCHEME XI. Riosynthetic pathway from [2-i4C]MVA t o daphniphylline.
On the other hand, the amine moiety of daphniphylline (1) is complicated. However, in connection with the co-occurrence of secodaphniphylline (28), whose stereostructure has also been established, the heterocyclic skeleton of the amine moiety seems to be constructed as shown in Scheme XI in which the distributions of 14C-labeledcarbon atcrns are based on the squalene biosynthesis from six [2-14C]MVA molecules.
[s.a.: 4.27 x lo4 dpm/mM]
36
NaOI
CHI, [s.a.: 1.09
x lo4 dpm/mM]
N
P P 2
u
*
$
9 z
F
[s.a.: 4.20 x lo4 dprn/mM]
+
HCHO [
0 dpm/mM]
SCHEME XII. Degradation reactions of ''C-labelled daphnilectone-B.
2.
77
THE DAPHNIF’HYLLUM ALKALOIDS
B. DAPHNILACTONE-B Daphnilactone-B (36))one of the Czz alkaloids, has been isolated as a major product from the fruits (7). I n the radioactive tracer experiwas ments using the fruits of the plant D. teijsmanni, DL-[Z-~~C]MVA totally incorporated to daphnilactone-B (36)in O . O l ~ o( 4 1 ) .As expected degradation studies on this labeled alkaloid revealed that four 14C atoms were included in 36 and one-fourth of the total radioactivity was located a t the secondary methyl group (see Scheme XII). On the basis of the above results, coupled with the stereostructures of daphnilactone-B (36) and methyl homosecodaphniphyllate (29), the former can be derived from the latter (29) (Scheme XIII).
* 36
29
SCHEME XIII. Possible pathway from methyl homosecodaphniphyllate t o daphnilactone-B.
In conclusion, the biosynthetic pathway from a squalene-like intermediate to the Daphniphyllum alkaloids must be acceptable (Schemes X, XI, and XIII) although the specific degradation studies have not been completed.
VI. Pharmacology An amorphous powder, named daphnimacrine, was first isolated from the bark of D. macropodum and also subjected to pharmacological tests as follows ( 3 ) . A half of the minimum lethal dose of daphnimacrine (for frog Rana nigromaculata) operates directly on the central nervous system resulting in depression of voluntary movement as well as of respiratory function. In addition, this material acts on peripheral parts leading t o myocardial anesthesia. The minimum lethal dose of daphnimacrine is as follows: ca. 0.8 mg/lO g (injection to alymphatic bursa) for frog R.nigromaculata;
78
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
14 mg/kg (hypodermic injection) and 3 mg/kg (venous injection) for rabbit Oryctolagus cuniculus. Quite recently, yuzurimine (43), one of the main Daphniphyllum alkaloids, was subjected to general pharmacological tests (for mouse) ( 4 2 ) 8 ;for example, injection of a small quantity of yuzurimine (10 mg/kg intraperitoneal) led t o a slight depression of the righting reflex as well as of righting. With much larger quantities (50 mg/kg intraperitoneal), one can observe such phenomena as depression of righting reflex, abnormal gait, body sagging, and ptosis. I n addition, one-third of the mice used for this test were dead in 3 days. As reported by Yagi ( 3 ) a small amount of yuzurimine (43) acts as a weak depressant for the central nervous system. With larger quantities i t was proved that this alkaloid had an efficient effect on muscle relaxation and sedation.
VII. Addendum Quite recently, three new alkaloids were isolated as minor components from the fruits of the plant Daphniphyllum teijsmanni Zollinger and their structures also determined on the basis of their physical , ~ of and chemical data (43).I n addition, the structure of y u ~ u r i n e one the alkaloids of undetermined structure (see Section 11, F), was also elucidated by means of an X-ray crystallographic analysis of its methiodide (44). 1. Daphniteijsmine
Daphniteijsmine (94; mp 187-188"; C,,H,,O,N) is one of the minor components having the same molecular formula as that of daphniphylline (1).However, the mass spectrum of the former has a prominent peak only a t m/e 286, as found in the case of secodaphniphylline (28) (see Section 11,B). I n addition, daphniteijsmine was readily acetylated with Ac,O-pyridine t o give the N-acetyl derivative (95). From these data coupled with an exhaustive comparison of the NMR spectra between daphniteijsmine and secodaphniphylline, the former can be regarded as acetoxysecodaphniphylline (94) : The multiplets a t 82.62.9, which can be assigned t o the methylene protons adjacent to the carbonyl group, are observed in 28, whereas the former has the signal
* The authors wish to thank Dr. M. Sawai and Dr. S. Nakamura, Teikoku Zoki Co. Ltd., for pharmacological tests. This alkaloid has been cited as alkaloid A, ( 2 1 ) .
2.
THE DAPHNIPHYLLUM ALKALOIDS
79
at 65.77 (lH, dd, J = 12, 2.5 H z ) due t o O=C-C€€(OAc) as found in the case of daphniphylline (1) [65.52(1H, dd, J = 12, 3 Hz)]. The remaining signals are nearly identical with each other.
94 95
R = H R = Ac
Fig. I .'
2. Daphnijsmine and Deacetyldaphnijsmine
and deacetyldaphniDaphnijsmine (96; mp 205-207"; C,,H,,O,N) are minor alkaloids of the jsmine (97; mp (dec.) ca. 200"; C&&O,N) fruits. The only different point is that the former has an acetoxy(Nujol) 1745 em-l; G(CDC1,) 2.06 (3H, s), 3.92 methyl group [v,,, (IH, d, J = 12 Hz), and 4.16 (1H, d, J = 12 Hz)], whereas a hydroxymethyl group is present in 97. The presence of an amine oxide in both alkaloids can be detected by their mass spectra having three fragment peaks (M+ - 16, M + - 17, and M + - 18), as found in that of macrodaphnine (51). Furthermore, both alkaloids have a secondary methyl group as well as a carbomethoxyl group which must be conjugated with two double bonds [96; vmax 1680 br., 1650 and 1628 cm-l; G(CDC1,) (MeOH) 300 nm (E, 16300). 97; vmax 1690 br., 1650 3.73 (3H, s ), ;, ,A and 1625 crn-l; 3.72 (3H, s); vmax (MeOH) 301 nm (E, 15000)].
RO
96
R
=
Ac
97 R = H Fig. 2.'
80
SHOSUKE YAMAMURA AND YOSHIMASA HIRATA
On the basis of these data coupled with co-occurrenceof yuzurimine-B (52), the structures of daphnijsmine and deacetyldaphnijsmine are represented by 96 and 97, respectively. 3. Yuzurine
Yuzurine is a colorless viscous liquid [C,,H,,O,N; vmax (KBr) 1740 cm-l; m/e 403 (M+); S(CDC1,) 0.85 (3H, t, J = 7.4 Hz), 2.17 (3H, s), 3.21 (3H, s), 3.64 (3H, s), and 3.93 (2H, s)] and has been characterized as the corresponding methiodide (mp 229-230”; C,,H,,O,NI), an X-ray crystallographic analysis of which has revealed it to have the novel stereostructure 98.
MeOOC
Me0
:--,
&
Me
Et 98
Fig. 3.
Biogenetically, yuzurine (98) may be derived from yuzurimine-B (52). REFERENCES 1. J. Hutchinson, “Evolution and Phylogeny of Flowering Plants,” p. 141. Academic Press, New York, 1969. 2. R. Hegnauer, “Chemotaxonomie der Pflanzen,” Vol. 4, pp. 9-11, and references cited therein. Birkhaeuser, Bwel, 1966. 3. S. Yagi, Kyoto Igaku Zasshi 6 , 208 (1909). 4. N. Sakabe and Y. Hirata, Tet. Lett. 965 (1966). 5. C. S. Gibbons and J. Trotter, J. Chem. Soc., B 840 (1969). 6. K. Sasaki and Y. Hirata, J. Chem. SOC.,B 1565 (1971). 7. H. Niwa, M. Toda, Y. Hirata, and S. Yamamura, Tet. Lett. 2697 (1972); M. Toda, H. Niwa, H. Irikawa, Y. Hirata, and S. Yamamura, Tetrahedron30, 2683 (1974). 8. H. Irikawa, N. Sakabe, S. Yamamura, and Y. Hirata, Tetrahedron24, 5691 (1968). 9. H. Irikawa, H. Sakurai, N. Sakabe, and Y. Hirata, Tet. Lett. 5363 (1966). 10. S. Yamamura, H. Irikawa, and Y. Hirata, Tet. Lett. 3361 (1967). 11. C. K. Warren and B. C. L. Weedon, J. Chem. Soc., London 3972 (1958).
2 . THE DAPHNIPHYLLUM ALKALOIDS
81
12. H. Irikawa, Doctoral Thesis, Nagoya University (1972). 13. M. Toda, H. Niwa, Y. Hirata, and S. Yamamura, Tet. Lett. 797 (1973). 14. M. Toda, H. Irikawa, S. Yamamura, and Y. Hirata, N i p p o n Kagaku Zasshi 91, 103 (1970); C A 73, 22137j (1970). 15. N. Kamijo, T. Nakano, Y. Terao, and K. Osaki, Tet. Lett. 2889 (1966). 16. T. Nakano and Y. Saeki, Tet. Lett. 4791 (1967). 17. T. Nakano, Y. Saeki, C. S. Gibbons, and J. Trotter, Chem. Commun. 600 (1968). 18. T. Nakano, M. Hasegawa, and Y. Saeki, J . Org. Chem. 38, 2404 (1973). 19. M. Toda, S. Yamamura, and Y. Hirata, Tet. Lett. 2585 (1969). 20. H. Irikawa, M. Toda, S. Yamamura, and Y. Hirata, Tet. Lett. 1821 (1969). 21. M. Toda, Y. Hirata, and S. Yamamura, Tetrahedron 28, 1477 (1972). 22. K. Sasaki and Y. Hirata, J . Chem. SOC., Perkin Trans. 2, 1411 (1972). 23. K. Sasaki and Y. Hirata, Tet. Lett. 1891 (1972). 24. H. Sakurai, N. Sakabe, and Y. Hirata, Tet. Lett. 6309 (1966). 25. T. Nakano and B. Nilsson, Tet. Lett. 2883 (1969). 26. H. Irikawa, S. Yamamura, and Y. Hirata, Tetrahedron 28, 3727 (1972). 27. H. Sakurai, H. Irikawa, S. Yamamura, and Y. Hirata, Tet. Lett. 2883 (1967). 28. N. Sakabe, H. Irikawa, H. Sakurai, and Y. Hira*a, Tet. Lett. 963 (1966). 29. S. Yamamura, S. Ueda, and Y. Hirata, Chern. Commun. 1049 (1967); S . Yamamura and Y. Hirata, J . Chem. Soc., London 2887 (1968). 30. S. Yamamura, Chem. Cornmun. 1494 (1968); M. Toda, M. Hayashi, Y. Hirata, and S. Yamamura, Bull. Chem. SOC.J a p . 45, 264 (1972); S. Yamamura, M. Toda, and Y. Hirata, Org. Syn. 53, 86 (1973). 31. M. I. Elphimoff-Felkin and P. Sardrs, Tet. Lett. 3045 (1969). 32. T. J. Curphey, C. W. Amelotti, T. P. Layloff, R. L. McCartney, and J. H. Williams, J. Amer. Chem. Sac. 91, 2817 (1969); M. Iguchi, M. Niwa, and S. Yamamura, unpublished. 33. G. Kobrich, Angew. Chem., Int. Ed. Engl. 12, 464 (1973), and references cited therein. 34. J. A. Marshall and H. Fauble, J . Amer. Chem. SOC.89, 5965 (1967); 92, 948 (1970); J. R. Wiseman, ibid. 89, 5966 (1967); J. R. Wiseman and W. A. Pletcher, ibid. 92, 956 (1970). 35. J. R. Wiseman et. al., J . Amer. Chern. SOC.91, 2812 (1969); 94, 8627 (1972); 95, 1342, 6120 (1973); W. Caruthers, Chem. Commun. 832 (1969). 36. M. Toda, Y. Hirata, and S. Yamamura, Chem. Commun. 1597 (1970). 37. M. Toda, H. Niwa, K. Ienaga, Y. Hirata, and S. Yamamura, Tet. Lett. 335 (1972). 38. J. 0. Reed and W. Lwowski, J . Org. Chern. 36, 2864 (1971). 39. 0. E . Edwards, in “The Alkaloids” (J.E. Saxton ed.), Vol. 1 (Specialist Periodical Reports), p. 375. Chemical Society, London, 1971. 40. K. T. Suzuki, S. Okuda, H. Niwa, M. Toda, Y. Hirata, and S. Yamamura, Tet. Lett. 799 (1973). 41. H. Niwa, Y. Hirata, K. T. Suzuki, and S. Yamamura, Tet. Lett. 2129 (1973). 42. S. Yamamura and Y. Hirata, unpublished. 43. S. Yamamura and Y. Hirata, Tet. Lett. 2849 (1974). 44. S. Yamamura, K. Sasaki, M. Toda, and Y. Hirata, Tet. Lett. 2023 (1974).
This Page Intentionally Left Blank
CHAPTER3-
THE AMARYLLIDACEAE ALKALOIDS CLAUDIOPUGANTI Istituto d i Chimica del Politecnico 20133 M i l a n , I t a l y
.. . . . . . . . . . . . .. .. . . .. ...
.. ..
........................ .................................................. ............ Ungminoridine .................................................
A. Lycorine B. Caranine
D. 111. Lycorenine-Type Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Galanthusine ............................. B. Clivonine ................................
IV.
V.
............................................... ......................... ................... E. Miniatine.. . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . ............................. Galanthamine-Type Alkaloids . . . . . . . A. Habranthine ................................................... B. Chlidanthine ........................... C. Galanthamine .................................................. D. Lycoramine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... Crinine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . ...............
A. 6-Hydroxybuphanidrine and 6-Hydroxypowelline . . . . . . . . . . . . . . . . . . . B. 11-Epihaemanthamine . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . .. C. Haemanthidine, Pretazettine, and Tazottine . . . . . . . . . . . . . . . . . . . . . . . VI. Montanine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
....................................................
83 88 89 102 103 104 104 106 106 109 110 111 111 114 117 121 121 124 124 137 139
VIII. Narciclasine. . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . IX. Biosynthesis .......................................... A. The Norpluviine Series ...... . . . . . . . . . . . . . . 146 B. The Galanthamine Series . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 C. Narciclasine .................................................... 154 D. Haemanthamine ................................................ 158 References ........................................................ 160
I. Introduction and Occurrence A limited number of new plants of the Amaryllidaceae have been examined over the past few years for alkaloids and, in general, the few new compounds actually characterized have been obtained from plants
84
CLAUD10 FUGANTI
which had already been investigated. A revival of interest in Gulunthus and Ungerniu spp. has been shown on the part of Russian workers who have turned their attention t o the physical and chemical behavior of the major basic constituents. Structurally, the most relevant innovations are represented by the isolation from Crinum spp. of cherylline (332))possessing a new C,, skeleton, and by the observation that tazettine (240) and related alkaloids are extraction artifacts arising from base-catalyzed isomerization of the corresponding [2]benzopyrano[3,4-~]indole derivatives. The uncertainties relating t o most of the alkaloids reported in Volume XI, p. 384, still remain. Elegant syntheses of representative members of this family of alkaloids have been completed. However, in spite of numerous efforts, lycorine (1) has resisted all synthetic approaches. Physical investigations on Amaryllidaceae metabolites include the X-ray analysis of selected derivatives which proved to be of crucial importance in solving structural and stereochemical problems (13, 14, 20, 45, 46, 72, 88). The I3C spectra in natural abundance of typical alkaloids of this group have been studied. It appears from the results that the main advantage of the 13C spectrum is the much higher separation of signals which facilitates interpretation in cases where the proton spectrum would be too complex t o be useful. I n the first paper the spectra have been recorded a t 15.8 MHz in continuous waves. The assignments of individual carbons were obtained with the aid of proton decoupling both with broad band modulation and with single frequency. I n some cases a correlation with the shifts which occur on the formation.of specific derivatives have also been helpful (86~). Subsequently, the 13C spectrum of narciclasine tetraacetate obtained a t 22.6 MHz was used in order to confirm the revised structure of the lactam (85). More recently, a further group of alkaloids has been examined with the 13C NMR spectroscopy. The assignments were obtained from peak multiplicity, single frequency decoupling, and the use of lanthanide shift reagents and empirical calculations of chemical shifts based on additivity (86). The advantages of chemical ionization mass spectrometry over the electron impact mass spectrometric determination have been illustrated using natural compounds including Amaryllidaceae alkaloids ( 7 0 4 . The antimitotic activity of several Amaryllidaceae metabolites has been emphasized (790, 79b), although, in the case of narciclasine (376), the considerable degree of toxicity seemed t o prevent its clinical use. Biosynthetically, a definite picture of several of the metabolic
3. THE AMARYLLIDACEAE ALKALOIDS
85
operations of the biological processes leading from the C,, precursor 0-methylnorbelladine (343)to the various alkaloids has been provided through feeding experiments with specifically labeled precursors. It has also been recognized that the CI3 metabolites narciclasine (376) and ismine (402) represent the final degradation product of C1, intermediates possessing the crinane skeleton. Table I gives the botanical distribution. TABLE I
BOTANICAL DISTRIBUTION Plant
Chlidanthus fragrans Herb Clivia miniata Regel
Grinum de$xum Ker. C. ervbescens Ait.
C. latifolium L. C. longifolium Roxb. C. powellii var. Hort. album
C. pratense Herb. C. unidentified Cooperanthes (hybr. Cooperia x Zephyranthes) Cyrthanthus mackenii Hook. f. Galanthus caucasicus Baker (G. nivalis h.)
G. krasnovii Khokhr.
Alkaloida 0-Methylgalanthamine Cliviasine Clividine Miniatine Lycorine N-Demethylmacronine N-Demethylcarboethoxymacronine Crinine Coranicine Macronine Powelline Buphanidrine Flexinine Crinamidine Nerbowdine Deacetylbowdensine Lycorine Lycorine Cherylline Precriwelline Lycorine 6-Hydroxybuphanidrine 6-Hydroxypowelline Lycorine Lycorine Lycorine Galanthamine Tazettine Galanthine base mp 214" Demethylhomolycorine Galanthusine Lycorine
Percent
Ref. (304 27 28 26 112 51 51
0.004
51 51 51 51 51 51 51 51 51 112 112 71 51 112 47 47 113 113 114 114 114 114 115 116 117
86
CLAUD10 FUGANTI
TABLE I-continued Plant G . nivalis L.
woronovii Losinsk.
cf.
(Habranthus brachyandrus Baker/Scaly ) (Hippeastrum brachiandrurn Baker) Haemanthus katherinae Baker Hippeastrum equense Ait.
H . johnsonii
Hymenocallis concinna Baker Ismene calathana Herb Leucojum vernum
Narcissus folli
.
N kristalli
N . tazetta L.
N . pseudonarcissus L. King Alfred Narcissus hybd. Texas Nerine bowdenii W.Wats. Pancratium maritimum L.
Alkaloid Galanthamine Nivalidine Hippeastrine Narwedine Lycorine Tazettine Galanthine Galanthidine Galanthamine Habranthine
Epihaemanthamine Ly corin e Pseudolycorine Tazettine Lycorine Tazettine Pseudolycorine Tazettine Haemanthidine Pretazzetine Lycorine Galanthamine Tazettine Lycorine Tazettine ( & )-Namedine ( )-Narwedine Lycorine Tazettine Galanthamine Lycorine Tazettine Pancratine Oduline
+
Norpluviine 6-Hydroxybuphanidrine 6-Hydroxypowelline Norpluviine Pseudolycorine Tyramine N-Methyltyramine Haemanthamine Dihydrolycorine
Percent
Ref.
0.06b.c 0.05b 0.06c 0.06b 0.03b9C 0.02b.C 0.03c
118, 119 118 118 718 118 118, 119 120 120 120 29
0.002 0.003 0.04
0.1
0.009 0.032 0.011 0.007 0.13b 0.52c 0.011b O . l l c O.OO1b*c
0.018
48 121 121 121 122 122 122 123 123 51 124 124 124 125 125 125 125 125 125 125 125 125 125 108 94 47 47 126 126 126 126 126 126
3.
87
THE AMARYLLIDACEAE ALKALOIDS
TABLE I-continued Plant
Rhodophiala bifida (Herb.) Traub
Sprekelia formosiesirna L. Sternbergia lutea (L.) Roem. and Schult. Sternbergia sicula Tineo (8.Zutea Ker. Gawl.)
Ungernia minor Vved. U. sewertzowii (Regel). B. Fedtsch. U . spiralis
U . trisphaera Bunge
Vallotta speciosa L'Herb. Zephyranthes robusta Baker
Z. sulfurea
Alkaloid
Percent
Ref.
11-Hydroxyvittatine
70
Haemanthidine Pancracine Tazettine Coranicine Lycorine Haemanthamine Montanine Vittatine Pretazettine 3-Epimacronine L ycorine Tazettine Pancratine Lycorine Galanthamine Hippeastrine Tazettine Ungminoridine Lycorine
70 70 70 70 70 70 70 70 51 51 127 127 127 128 128 128 128 17 129
Lycorine Galanthamine Ungeremine Hippeastrine Tazettine Hippeastrine L ycorine Tazettine Hordenine Pancratine Pseudolycorine Lycorine Haemanthamine Basemp 252" Tazettine Haemanthidine Base mp 252'
1 . w 0.21c 0.0~52~
0.1V 0.028
0.04-0.45
0.116 0.75 0.3 0.2 0.15
127 127 127 127 127 130 130 130 130 130 131 132 132 132 133 133 133
a The following Narcissus plants contain the lactams narciclasine and lycoricidine, Narcissus pseudonarcissus L., King Alfred, Flower Carpet, Rembrandt, Mount Hood, President Lebrun, Golden Harvest. Narczssus incomparabilis Mill. Tunis, Helios, Sempre Avanti, Mercato, Walt Disney, Mrs. R. 0. Backhouse, Scarlet Elegance, Carabiniere, Oranje Bruid. Narcissus triandrus L. Thalia, Tresamble N . jonquilla L. Trevithian (Footnote continued on p. 88.)
88
CLAUD10 FUGANTI
11. Lycorine-Type Alkaloids Evidence in favor of structures 1-15 for the alkaloids in this group has been furnished in Volume XI, Chapter 10, Section 11.The uncertainty relating to the structure of the alkaloids nerispine, parkamine, niflexine, and amaryllidine, however, still remains. The structures of narcissidine (Volume X I , p. 331) and of the related alkaloids parkacine (p. 332) and ungiminorine (p. 333) have, on the other hand, been revised by means of X-ray analysis. Work has been devoted t o the study of the physical properties of the alkaloids in this group in an attempt tQ establish a general relationship between structure and behavior as well as t o the study of the correlation of same with other classes of alkaloids and t o the investigation of the chemical reactivity of representative members.
1 2
3 4
5 6
7 8
R' R1
= R2 = R6 = H ; R3,R4 = OCH,O; R5 = OH = 8 2 = R5 = R6 = H ; R3,R4 = OCH,O R' = Ac; R2 = Re = H ; R3,R4 = OCHzO; R5 = OH R' = R2 = R6 = H; R3,R4 = OCH,O; R5 = OAC R' = R5 = R6 = H ; RZ = OMe; R3,R4 = OCH,O R' = R2 = R6 = H; R3,R4 = OH, OMe; R5 = OMe R' = R2 = Re = H;R3,R4 = OH, OMe; R5 = OH R' = R2 = Re = H ; R3,R4 = OCH,O; R5 = OMe
Lycorine Caranine Poetaminine Aulamine Falcatine Goleptine Golceptine Hippamine
Footnote (continued from TABLE I) N . poeticus L. Actea, Cheerfulness N . tazetta L. typica, Geranium N . cyclamineus D.C. typica N . odorus L. rugulosus N . canaliculatus Guss. typica N . serotinus L. typica Texas, Verger, Totus Albus, Celebrity, Clamor, Carlton. Narciclasine has been detected along with traces of lycoricidine in Galanthus nivalis L. 0. elwesii Hook., Haemanthus puniceus L., Leucojum aestivum L. var. pulchellurn Salisb., L. vernum L., Pancratium maritimum L., Sprekelia formosissima Herb., Sternbergia Zutea (L.) Ker-Gawl., and Vallotta speciosa L'Herb. Hymenocallis hybr. var. Advance contains only lycoricidine (101). Nearly equal amounts of narciclasine and lycoricidine have been detected in Lycoris radiata Herb. (78). Leaves. Bulbs. Dry leaves.
3. 9 10
R'
R'
=
RZ R2 R2 R2 R2
= = = = =
THE AMARYLLIDACEAE ALKALOIDS
H; R3, R4 = O C H 2 0 ; R5, R6 = 0 R5 = Re = H; R3 = OMe; R4 = O H R5 = R6 = H; R3 = R4 = ()Me Re = H; R3 = R4 = OMe; R5 = OH Re = H; R3 = R4 = R5 = OMe
11 12 13
= R1 = R' = R1 =
14 15
R' = R3 = H; R2 = O H R' = Ac; R2 = H; R3 = OAc
89
Jonquilline Norpluviine Pluviine Methylpseudolycorine Galanthine
Zephyranthine Nartazine
A. LYCORINE The conversion of lycorine (1) into the [Z]benzopyrano[3,4-g]indole alkaloid hippeastrine (101) was completed according t o the criteria previously developed during the transformation of caranine (2) t o lycorenine (102) (Vol. XI, p. 342). Thus cyanogen bromide reacted AcO I
16
R' R' R' 20 R' 2 1 R' 17 18 19
= CN; R2 = R3 = R4 = H = C ( N H ) O E t ; R2 = R3 = R 4 = H = R2 = R3 = R4 = H = Me; R2 = R3 = R4 = H = Me; R2 = R3 = H; R 4 = Ac
OH
OEt 22
90
CLAUD10 FUGANTI
with 0,O-diacetyllycorine (16) to give two products which were directly converted, upon treatment with ethanolic KOH, into a mixture of 17, 18, and 22. Compounds 17 and 18, derived from the desired B ring cleavage, were hydrolyzed t o 19 which is N-methylated t o deoxyhippeastrine (20). Hippeastrine (101) is obtained from 20 by means of acetylation to 21, oxidation, and final hydrolysis therefore confirming the previously established stereochemistry and absolute configuration of the lactonic alkaloid (Vol. XI, p. 341). A similar correlation has been completed on the dihydro series ( 1 ) . An extended study of the optical behavior of this class of products has been performed in connection with investigations on the conformations of lycorine (1) and related compounds. An empirical rule, similar t o the octant rule, which allows the prediction of both the sign and magnitude of the Cotton effect a t 290 nm from the steric orientation of the atoms about the aromatic chromophore, has been deduced from considerations on the ORD and CD curves of lycorine (1) and derivatives. When the benzene ring is viewed along the - z --f + z axis (the coordinates are fixed on the aromatic ring as depicted in Fig. l), four back octants are defined which contribute, with the signs indicated, t o the Cotton effect. Although the applicability of this approach did not appear to be general (13) the results obtained within the examined series are selfconsistent (2). Lycorine (1) and its diacetyl derivative (16) give two diastereoisomeric series of methiodides with methyl iodide, named the a series and the ,B series, 23 and 24, and 25 and 26, respectively, being the product ratio of a- and 8-methiodides which increases with the decrease of the reaction temperature. Furthermore, 23 and 25 can be converted into 24 and 26 on acetylation. The a-methiodides of lycorine (1) and diacetyllycorine (16) exhibit, in the UV spectra, absorption maxima a t only approximately 290 nm, whereas the ,B-methiodides show characteristic inflections a t approximately 250 nm in addition to slight hypsochromic shifts at a bands a t approximately 290 nm, and the optical rotatory values of a-methiodides are more levorotatory than those of the ,B-methiodides. Diacetyldihydrolycorine gives a single product (28) with methyl iodide which is identical with the acetylation product of dihydrolycorine methiodide (27). Both derivatives, from analysis of the UV spectra, are assigned t o the B series. This statement was further strengthened by the fact that 27 is also obtained from 25 by means of hydrogenation on Adam’s catalyst. Lycorine-a-methiodide, under the same conditions but over a much longer period of time, gave a different product converted, through methochloride and vacuum
-Y I I
I
I I
I I
I
I I
I 1
+Y
(A)
+X I
+
I
I
I I
-
I
I 1
+
-X
(B)
+X I
+
I
I I
I
OH
tC)
I
I I I I -X
FIQ.1. (A) Coordinates fixed on aromatic ring; (B) Lycorine 8-methiodide; (C) Lycorine a-methiodide.
91
92
CLAUD10 FUCANTI
pyrolysis, into dihydrolycorine (15, OH instead of OAc). The hydrogenation of 24 and 26 failed.
23 24
R' = R' = H R' = R2 = AC
25 26
R' = R2 = H R' = R2 = Ac
OR2
27 28
R' = R2 = H R' = R2 = AC
The reasons why the quaternization of lycorine (1) affords two diastereoisomeric methiodides, whereas dihydrolycorine gives a single product, were identified in the differences of the conformations in both lycorine (I) and dihydrolycorine. If lycorine (1) in solution is fixed in the A form (Fig. 2), having the half-chair B ring, on quaternarization, methyl iodide will be accessible to the molecule with the same probability on both sides. The entry of the reagent from the rear face should generate a conformational change of the B ring from half-chair to twisted boat, a change that occurs without noticeably affecting the conformations of the other rings, and the transition state derived from the B form will be less stable than that of the half-chair from the A form. It follows that the formation of the a-methiodide from the A form would seem t o be more probable than the j3 form from the B conformation. This is supported by the above-mentioned increase in the a form at the expense of the j3 upon decrease of the reaction temperature. Dihydrolycorine, as shown unequivocally by the X-ray analysis of its hydrobromide, is fixed in the D conformation with a much easier approach of the reacting species from the rear side of the molecule.
3.
OH
THE AMARYLLIDACEAE ALKALOIDS
OH (C)
93
(D)
Fig. 2. Conformations of Lycorine and Dihydrolycorine; (A); Lycorine, form A: (B) Lycorine, form B; (C) Dihydrolycorine, form C; (D) Dihydolycorine, form D.
In the event of an attack from the upper side of the molecule, dihydrolycorine would evolve t o the conformation C with remarkable conformational changes in rings C, D, and B. For the said reasons dihydrolycorine would afford only the methiodide from the D form therefore bearing the N-methyl group in the CL (steroid notation) configuration. The absolute configuration a for the methiodides of the ,8 series and ,8 for those of the a series, respectively, thus far established by chemical reasoning, is in agreement with the optical rotatory values which are predictable from the octant rule (Fig. 1) for the following reasons. The two methiodides 23 and 25 give rise to (-), and (+)-anhydrolycorine methiodides (29) and (30) respectively, which differ on the basis of the absolute configuration of the quaternary nitrogen atom. The ORD and CD curves of ( + )-anhydrolycorine a-methiodide (30) in aqueous solution showed a high-intensity positive Cotton effect a t 240 nm while the curves of ( - )-anhydrolycorine /3-methiodide (29) are of the mirror image type. Since previous work on the aporphine alkaloids had shown that the absolute configuration may be determined from the sign of their highamplitude Cotton effect centered a t 235-245 nm and that the positive Cotton effect corresponds to ( S ) configuration of a twisted diphenyl system, the coincidence of the CD curves of ( - )-anhydrolycorine methiodide and ( + )-anhydrolycorine methiodide a t 240 nm with those
94
CLAUD10 E’UGANTI
of nuciferine (31) ( R configuration) and nanteine (32)(8configuration), respectively, indicates the stereostructures 29 and 30 for the two
p x
Me
Me 30
29
Me0
Me0
j H
\
,--
/
0 L 31
/ O
32
products. This is in agreement with the absolute configuration already established for the parent lycorine a- and /3-methiodides. Similar reasoning holds for the determination of the absolute configuration of the a- and /3-methiodides obtained from pluviine (11) and caranine (2) (3, 4). Several approaches to the synthesis of lycorine (1)have been reported over the past few years. The two entries experimentally explored by Hendrickson’s group involved the functionalization of ring C of the pyrrolo[d,e]-phenanthridine skeleton late in the sequence since its instability toward aromatization is a well-established feature of this alkaloid, therefore representing its weak aspect from a chemical point of view. I n the first atjtempt the tetracyclic intermediate (33) was prepared from 3,4-methylenedioxy-w-nitrostyrene upon Diels-Alder addition of butadiene followed by zinc and hydrochloric acid reduction to an amine eventually converted into 33 by formaldehyde and hydrochloric acid. All other experiments, designed to anticipate the addition of a C, diene (in order to introduce a t once also the C, carbon unit for ring D formation) or of a four-carbon diene with different functionality, failed. The structure of 33 is based on spectroscopic data, on considerations on the accepted stereochemical courses of this type of
3.
T H E AMARYLLIDACEAE ALKALOIDS
95
reaction, and on chemical reactions. The amides 34, 35, and 36 were prepared from 33 in the hope of constructing ring D by cyclization t o the enol of a ketone a t position 3 which, in turn, ought t o be formed by means of oxidative functionalization of the double bond. The goal was to convert one of the amides 34,35, or 36 into an a-hydroxyketone, which would be in tautomeric equilibrium between the two isomers thus providing activation for the required cyclization.
R = H R = COCHCl, R = COCOOEt 38 J3 = COCH(OMe), 33
34 35
The diol 37 was obtained, but its further oxidation failed. The bromohydrins 38 and 39 were prepared from the corresponding amides 34 and 35 upon treatment with N-bromosuccinimide in wet dimethyl sulfoxide (DMSO). Oxidation led to the corresponding bromo ketones, which could be converted into acetoxy ketones. But, even under oxygenfree conditions, hydrolysis and methanolysis gave the acid 43 from 40 or 41, whose structure rests on IR spectrum, percentage composition, neutralization equivalent. I n the oxalamide series 39 a crystalline ketoacetate 42 was obtained though in low yield. The latter with NaOMe in methanol gave am enolic product which was converted into the crystalline diacetate 44. Owing t o the low yields of the synthetic sequence this route was abandoned. The second approach was one of a biogenetically patterned nature. Starting from the CI5 amide 45, it was expected that under Pschorr conditions it would form via path a the lycorine skeleton or via path b the crinine system. Conjugate addition of the nitrogen onto the intermediate ring C diene would complete the sequence as assumed in the biosynthesis. The amine 46 was therefore prepared by standard methods and converted into the fluoborate 47. The sole product which could be obtained from 47 was the benztriazinone 48 which resisted all attempted chemical changes. It seemed therefore necessary t o operate with a fully substituted nitrogen and to invert the order of the operations in the above-mentioned synthetic strategy.
96
CLAUD10 FUGANTI
R'
37 38 39 40 41 42
R' R' R' R'
OH; Rz = OH; R3 = CHCl, OH; Rz = Br; R3 = CHCl, OH; Rz = Br; R3 = COOEt 0; R2 = OH; R3 = CHC1, R' = 0; R2 = OAc; R3 = CHC1, R' = 0; Rz = OAc: R3 = COOEt = = = =
0 44
43
NH
O 0 45 46 47
R
= NOz
N 0 48
R = NH, R=N$BF;
The synthesis of the tetracyclic intermediate 49 was therefore studied in the hope that it might further cyclize to the desired lycorine skeleton. Birch reduction of o,p-dimethoxyphenethylamineled to the amine 50 which was converted into 51, giving rise in turn upon hydrolysis t o 49. Its structure rests on physical data. Ordinary methods for nitro group reduction seemed to also destroy the 289-nm chromophore, but hydrogen transfer (a-phellandrene and Pd/C) gave a product which analyzed for the product of nitro reduction t o amine in 49, the mass spectrometric data also being in agreement. The product was, however, not affected by diazotization, and, on the basis of spectral data, was
3.
97
THE AMARYLLIDACEAE ALKALOIDS
assigned structure 52. Its formation was mechanistically explained in terms of conjugate addition of the aromatic amino group to the enone system followed by an irreversible retro-aldol reaction thus frustrating also this synthetic approach to lycorine (1) ( 5 ) .
49
Me0
50
OM
51
52
Later, it seemed possible to obtain the intermediate 55 by cycloaddition of 3,4-methylenedioxy-P-nitrostyrene(53) and a-pyrone (54).
0 53
54
55
This intermediate contained the correct stereochemistry and functionalization for further conversion into the lycorine-type alkaloids. However, 53 did react in the expected manner with a series of cyclic and open-chain dienes, but the reaction failed with 54 ( 6 ) . The tricyclic intermediate 58 was subsequently used to construct the pentacyclic nucleus of lycorine (1) by base-catalyzed Michael addition and aldol condensation. The key intermediate (58) was obtained from 3-pyrrolidone ethylene ketal with one equivalent of 4,5-methylenedioxyphtalicanhydride followed by LiAlH, reduction,
98
CLAUD10 PUGANTI
oxidation t o the aldehyde (56), and addition onto the latter of a C, unit to form 57. Compound 57 was hydrolyxed and isomerized t o 58. 0
II
56
57
R =CHO R = CH(OH)CH,C=CH
58
The tricyclic intermediate 58 was transformed on K,CO, treatment into 59 cleanly dehydrated to the enone 60. The latter proved, however, t o be a stereoiosomer of Kotera’s 1-deoxy-2-lycorinone. Degradation of the synthetic material 60 gave y-lycorane (87) therefore demonstrating the B/C cis-ring juncture and the high stereochemical control in the cyclization stage. Attempts to equilibrate the B/C fusion of 60 failed 0
59
60
because it was destroyed under basic conditions and was recovered unchanged from boiling trifluoroacetic acid ( 7 ) . The tetracyclic intermediate 61, possessing the correct functionalization for the further introduction of a C, unit to form the ring C of lycorine, was the synthetic goal in a subsequent approach to this alkaloid. Model compounds showed indeed the possibility of addition of aldehydes onto position 4 of 1,2-dihydroisoquinoline (63 and 64 were obtained from compound 62). However, the synthesis of the required intermediate 61 starting from 65 was not completed owing t o the discouraging yields observed in the dehydrogenation. Furthermore, an enamine obtained from the model compound 66, seemed not to react with pyruvic aldehyde in the desired manner. Finally, the unexpected product 68 was obtained from 67 with ethyl-P-aniinopropionate. This product, on acid hydrolysis followed by NaOEt treatment, gave the tricyclic compound 69, again in discouraging yields (8).
3.
THE AMARYLLIDACEAE ALKALOIDS
99
<mm:eooE 0
62
61
63
R = 3,4-CH20,C,H3 R = 3,4-(MeO),C,H3
64
R = 3,4-CH202CsH3
R It
= 3,4-(MeO),C,H3 = COOH R = COMe
R
0
65
66
67
68
0 R = H R = COOEt
69
Anhydrolycorine (73) was prepared by photolytic dehydrobromination of the amide 70, which gave the lactam 72 as first cyclization product. Reduction (LiAIH,) of 72 led t o 73 in a good overall yield. Attempts to induce photocyclization of the amide 71 t o 73, failed, the photo-Fries product 74 being the only relevant reaction result (9). A total synthesis of dihydrolycorine (85), y-lycorane (87) and 8-lycorane (92),has been achieved starting from the indanone carboxylic acid 77. This, in turn, was obtained, like the tetralone ester 76, from the known anhydride (75) via Friedel-Crafts cyclization of the monomethyl esters obtained from 75 by treatment with 1 mole of methanol. Reduction of the methyl ester of 77 (LiAlH,), followed by MnO, oxidation,
100
CLAUD10 FUGANTI
70 71
R = Br R = H
72 73
R’,RZ= 0 R’,R2 = H
74
gave the ketol alcohol (78) which, subjected t o the Schmidt reaction with sodium azide in trichloroacetic acid, yielded two products after hydrolysis. While one of these products remained unidentified, the other was assigned the expected structure 79. Compound 79 was converted into the carboxylic acid 80 by standard methods. Upon treatment with I,-KI in aqueous NaHCO, 80 yielded the unstable iodolactone 81, readily converted into the iodoacetyl imide 82. The inversion of the stereochemistry a t position l l a as well as the introduction of the axial hydroxy group a t position 2 of the lycorane skeleton were performed as follows. Dehydrohalogenation of 82
75
77 78
R’, R2 = 0; R3 = COOH R’,R2 = 0; R3 = C H 2 0 H
76
79 80
R = O H =COOH
R
3.
THE AMARYLLIDACEAE ALKALOIDS
do
81
B
101
0
0
0 84
83
OH
[LiCl in dimethylformamide (DMF)] led to the olefin 83, converted by means of m-chloroperbenzoic acid into the a-oxide 84. Its structure is based on spectral data, since the NMR showed the signal of the hydrogen at position 1 as a singlet, thus indicating that the dihedral angle between the protons a t positions 1 and 2 is approximately 90". The final conversion of 84 into the required racemic 85 (mp 248-250") proceeded at only 5% yield using LiAlH, in the presence of ZnC1, as the reducing agent (10). The compound 77 proved to be a key intermediate for further synthesis in this field. Indeed, ( rf: )-y-lycorane (87) was obtained from 77 through the acid lactam 80. The latter, on treatment with acetic anhydride, gave the imide 86 readily converted upon LiAlH, reduction and hydrogenation into 87 (10). The fourth possible stereoisomeric lycorane, namely, 6-lycorane (92) was obtained from 77 by hydrogenation to 88 which, with sodium
102
CLAUD10 FUGANTI
87
86
methoxide in methanol, furnished in 85% yield the epimerized products 89 and 90. The latter mixture was converted into the imide 91 in a way similar to that used previously in the transformation of 77 into 86. Racemic 6-lycorane (92) was obtained from 91 by LAH reduction. It was identical with an authentic sample of 6-lycorane derived from caranine (2) (11).
R1 = COOH; Ra = H R' = H; R 2 = COOH 90 R1 = H; R2 = COOMe 88
89
91 92
R1 = R2 = 0 R' = H,; R 2 = H,
B. CARANINE An elegant additional proof of the already established absolute configuration of caranine (2) and related alkaloids through the determination of biphenyl asymmetry has been produced. Inspection of the models of caranine anhydromethine (94), obtained by Hofmann degradation of caranine methiodide (93), showed that the anhydromethine might be able t o exist in enantiomeric forms owing to the difficulties involved in twisting as a result of the presence of the 2'hydrogen. This observation suggested that only one of the two possible atropoisomers would be formed because elimination of nitrogen under Hofmann conditions would take place from one side of ring C in the methiodide (93). Hofmann degradation of caranine a-and P-methiodide (93) (potassium t-butoxide in dry DMSO, room temperature) gave, in fact, optically active caranine anhydromethine (94) [mp 82-83';
3.
THE AMARYLLIDACEAE ALKALOIDS
103
[ ~ t ] ~ ~ - (c 2 71.45, ~ CHCl,)] thus bringing about the conversion of a compound with four asymmetric atoms into an asymmetric biphenyl which is devoid of asymmetric atoms. However, the absolute configuration of 94 can be related to the absolute stereochemistry of parent 2 only providing that the configuration of the nitrogen atom a t the instant of the elimination is known. Although degradation experiments with 0.5 mole of base/mole of 93 in deuteriated solvent showed the pickup of 0.4 mole of deuterium a t position I l c in the recovered 93, the lack of a decrease in its optical activity and the presence in the reaction product (94) of 25y0 nondeuteriated species suggested that epimerization a t position l l c is an unlikely event. Consequently, the stereochemistry of the biphenyl 94 rests on the known configuration of the nitrogen atom in caranine j?-methiodide. Confirmation in favor of the proposed stereochemistry of 94 arose from the negative sign of the Cotton effect a t 260 nm in ORD and CD measurements if it was possible t o extend the generalization established by Mislow for simple twisted biphenyls t o biphenyl systems like 94 (12).
Me
194
93
C. NARCISSIDINE The problem of the structure of narcissidine (Vol. XI, p. 331) has finally been settled by means of X-ray analysis. It has been deduced from the analysis of the hydrobromide and, independently, of the methiodide (13, l a ) , that narcissidine must be represented by the stereostructure 95. Two other alkaloids, parkacine (Vol. XI, p. 332) and ungiminorine (Vol. XI, p. 333) (15))which had been related t o narcissidine, should now be depicted as 96 and 97, respectively (13).Recent feeding experiments have shown that narcissidine (95) biosynthetically derives from galanthine 13, having lost a pro-X hydrogen from position 4 of (13) at some stage of the biosynthesis (16).It might well be that narcissidine
104
CLAUD10 FUGANTI
(95)arises from galanthine (13)by hydroxylation /3 to the nitrogen atom followed by rearrangement. OR^
D. UNCIMINORIDINE An optically inactive alkaloid (mp 193-194', from MeOH) named ungminoridine has been isolated from Ungernia minor. On the basis of spectral data it has been assigned the structure of racemic zephyranthine (14)(17). 111. Lycorenine-Type Alkaloids Structures 98-112 (the stereochemistry a t position 7 of compounds 99,102,104,105,109,and 112 was unsettled) were reported in Volume XI, p. 334,for the alkaloids possessing the [2]benzopyrano[3,4-g]indole nucleus. Since that time experimental support for the in vivo derivation of this class of compounds from the lycorine-type alkaloids by benzylic oxidation and cleavage of the C-7-N bond has been presented (18, 19) thus strengthening the stereochemical relationships between the two groups of natural products. The X-ray analysis of lycorenine methiodide has established the a (steroid notation) configuration of the hydroxy group at position 7. From considerations of the specific and molecular rotations of analogous hemiacetal and lactonic alkaloids it has been inferred that oduline (log),nerinine (99),krigeine (105),unsevine (112), and krigmamine (104)all possess an a-hydroxy group at position 7 (20). In an extended study the mass spectra of several alkaloids of this class have been examined. The spectra seem quite characteristic, but owing to the homolytic nature of the cleavages, steric differences among the various samples were not revealed. In this chapter adihydrocandimine is displayed with an axial hydroxy group a t position
3.
THE AMARYLLIDACEAE ALKALOIDS
105
n 98 99 100
101 102 103 104 105 106 107 108 109
110 111 112
XI, p. 337, the parent unsaturated alkaloid had an equatorial substituent in the same position (21). The structural revision resulted from a more detailed investigations on the chemical and spectroscopic behavior of the alkaloid and of its hydrogenation product (2%). The uncertainties relating to the structural assignments reported in Volume XI for compounds of this class still remain. 5 whereas in Volume
106
CLAUD10 FUGANTI
A. GALANTHUSINE Structure 113 has been assigned by physical methods to galanthusine isolated from Galanthus caucasicus (22).
&
P
O CH,OH M
e
113
B. CLIVONINE Clivonine (114)(Vol. XI,p. 338) is unique among the Amaryllidaceae alkaloids because, although a metabolite of O-methylnorbelladine (343),it would seem not to derive from norpluviine (10)by benzylic hydroxylation as do the other lycorenine-type alkaloids (23).This is to be expected owing to the unusual stereochemistry of the hydroxy group at position 5a which indicates a biological derivation from the not yet isolated 2-epinorpluviine. I n the full paper on the experiments which led to the structure determination further points regarding the chemistry of this alkaloid have been clarified. Von Braun degradation of clivonine (114)and of the relative derivatives 115 and 116 led to the products 117,1l!8,and 119,respectively, as shown by physical methods. Any attempt to convert any of these into the cyclic ether 120 proved unsuccessful, compound 121 being the only product obtained from 118 upon alcoholic potassium hydroxide treatment. Reaction of clivonine (114)with POC1, led to 122 (the inversion of stereochemistry at C-5 is supported by NMR data) which, upon subsequent treatment with dilute alcoholic KOH, 2 N H,SOc, and aqueous ammonia, led to the known lactone 123 bearing an axial oxygen substituent a t position 5a as in the “normal” series. The mechanism which is proposed for this conversion involves the opening of the lactone ring followed by formation of the 5,5a-a-epoxidefavored by the trans-diaxal relationship between C1 and OH which is finally opened to 123 with inversion of configuration at position 5 . Purthermore, the trio1 obtained from 114 by LiAlH, reduction has been converted into 124 (mp 301-303”), which is formally l-epi-dihydro-
3. THE
AMARYLLIDACEAE ALKALOIDS
107
H
114 115 116
R', R2 = 0 ; R3 = H R' = R2 = R3 = H R' = R2 = H; R3 = Ac
120
117 118 119
R', R2 = 0; R3 = H R' = R2 = R3 = H R' = RS = H; R3 = Ao
121
lycorine methiodide. A proposal was made to describe the compounds having the [2]benzopyrano[3,4-g]indole nucleus derived from the two basic systems 125 and 126, homolycorane and masanane, respectively, with the functionalizations indicated for them according to the normal notations (24). The total syntheses of clivonine (114) and clividine (138) have been achieved from the anhydride 75 already used in the syntheses of dihydrolycorine (85), y-lycorane (87), and 6-lycorane (92). Treatment of 75 with MeOH mainly gave the half ester 127 which was converted into the urethane 131 via the acid chloride 128, the azide 129, and the isocyanate 130. The desired methyl ester 132 was obtained from 131 through the corresponding chloride and diazoketone. The
MeN
12 2
123
108
CLAUD10 FUGANTI
product was then hydrolyzed to an acid which cyclized with Ac,O to the oxindole 133. The acetate 134, prepared from 133 (chloromethyl
h e 1125
124
126
127 128 129 130 131 132
R1 = COOH; R2 = COOMe R' = COCl: R2 = COOMe; R' = CON,: Ra = COOMe R' = NCO; R2 = COOMR R1 = NHCOOMe: R2 = COOH R1 = NHCOOMe: R 2 = CH,COOMe
133 R1 = H; R2 = COOMe: R3 = 0 134 R1 = CH20Ac: R2 = COOMe: R3 = 0 135 R' = CH20H: R 2 = Me: R3 = H2
3. THE AMARYLLIDACEAE ALKALOIDS
109
ether in CH,COOH in the presence of ZnCl,, followed by CH,COOAg in Ac,O/AcOH), gave the amino alcohol 135 upon reduction. This, in turn, with osmium tetroxide gave the stereoisomeric triols 136 and 137. The two latter products 136 and 137, separated by chromatography, were oxidized (M"0,) to ( + ) - clivonine (114) and ( _+ ) - clividine (138) respectively (25)
C. CLIVIDINE Clividine [C,,H,,NO,; mp 195-197"; - 75" (CHCl,)], isolated from Clivia miniata, has been assigned structure 138 on the basis of spectral and chemical evidence. Its similarity to dihydrohippeastrine (123)appeared from spectral data. The difference in the stereochemistry of the substituents at position 5 and 5a was checked in the following way. Clividine (138) when reduced with LiAlH, under controlled conditions gave the hemiacetal (139) which was oxidized with HIO, at a much greater speed than the corresponding compound 140 obtained from hippeastrine (143) which bears the two oxygen substituents at positions 5 and 5a in a trans relationship. The relative and absolute stereochemistry of 138 was confirmed by converting hippeastrine (143) into the ketone 144 which, in turn, was reduced with LiAlH, and hydrogenated to a triol. The latter, upon acid treatment, yielded the compound 142 identical with the product obtained from 138 upon
138 139 140 141 142
R', Ra = 0;R3 = OH;R4 = H R1 = H; R2 = OH; R3 = OH; R4 = H R1 = R3 = H;RZ = R4 = OH R', Ra = 0;R3 = H;R4 = O H R1,RZ = 0;R3 = OH; R4 = H
143 144
R' = OH;R2 = H R1,Ra = 0
LiAlH, reduction and acid cyclization. NMR studies further defined the stereochemistry a t C-3a (26).
110
CLAUD10 FUGANTI
D. CLIVIASINE Related to the above-mentioned alkaloids clivonine (114)and clividine (138), a third lactonic alkaloid cliviasine (mp 195-197') has been isolated from Clivia miniata. By means of spectroscopic investigations its identity has been shown to be a-dihydrohippeastrine (141) (27).
E. MINIATINE
A sparingly soluble base (C,,H,,N,OI,; mp 206') named miniatine has been isolated from Clivia miniata. Saponification experiments have indicated the presence in miniatine of clivonine (114) and of the acid 145. By acid treatment miniatine gave clivinine (Vol. XI, p. 338), whereas by LiAlH, reduction the acid corresponding to the lactonic alkaloid clivonine (114) and tetrahydroclivonine (136) was obtained.
Hoocnco Me
N
Me
145
I n the mass spectra the molecular peak was absent, but under differing conditions the peak a t mle 793, corresponding to clivimine, appeared whereas titrimetric analysis indicated the equivalent weight of 811. From these observations it is inferred that miniatine is represented by 146. It is however likely that miniatine is an extraction artifact since clivimine by column chromatography gives 146 (28).
i'I 0 o*& .& .).
Me
N
0 146
Me
- ooc
\
3.
T H E AMARYLLIDACEAE ALKALOIDS
111
IV. Galanthamine-Type Alkaloids I n Volume XI, p. 348, the following alkaloids were described: (-)galanthamine (147), ( - )-epigalanthamine (last,( - )-narwedine (149), chlidanthine (152) (without stereochemical assignments) in addition to bodamine coincident with racemic galanthamine, narcissamine which is a mixture of ( - )N-demethylgalanthamine (150) and ( + )dihydrogalanthamine, and lycoramine (153) which is dihydrogalanthamine. Nivalidine (162),6-0-methylapogalanthamine, was also reported but i t seemed to be an extraction artifact derived from galanthamine (147) or its epi derivative (148) by acid treatment.
147 148 149 150 151 152
R' = OH; R2 = H; R3 = R4 = Me R1 = H; R2 = OH; R3 = R4 = Me R1,R2 = 0 ; R3 = R4 = Me R' = OH; R2 = R3 = H; R4 = Me R' = OMe; R2 = H; R3 = R4 = Me R' = OMe; R2 = R4 = H; R3 = Me
-
( )-Galanthamine ( )-Epigalanthamine ( )-Narwedine ( - ) -N-Demethylgalanthamine
The structures and the absolute configuration of these alkaloids have been firmly established by chemical and physical methods since t h a t time. The work which has been carried out in this field led t o the structural assignment of a new alkaloid, habranthine (155),to the definition of the stereochemistry of chlidanthine (152),and to the synthesis of galanthamine-type derivatives through several approaches. A. HABRANTHINE Prom Habranthus brachyandrus habranthine (155) (mp 198-199'; - 320") has been isolated in 0.00670 yield. Its gross structure has been initially determined by converting (155) via hydrogenation, thionyl chloride treatment, and LiAlH, reduction into deoxylycoramine (154).The NMR spectra of the alkaloid and of its 0,O-diacetate pointed to the structure 155 with a hydroxy group to the nitrogen atom in the tyramine-derived moiety of the molecule. Indeed, the protons a t C-3 and (2-12 appeared as triplets a t 4.10 and 3.43 ppm in the spectrum of the base and a t 5.30 and 4.88 ppm in that of the diacetyl derivative. [a]?5,,
112
CLAUD10 FUGANTI
On irradiation of the 3.05 signals, attributed to the C-11 protons, the triplet representing the C-12 hydrogen collapsed to a singlet. I n the spectrum of 155 the two protons at position 4 showed signals at 2.0 and 2.7 ppm with JAB= 16 Hz, whereas the C-4a proton appeared as a triplet at 5.33 ppm. In the diacetyl derivative the latter triplet shifted upfield to 4.70 ppm, which is closely coincident with the 4.58 ppm found in galanthamine (147), therefore suggesting that the unusually low chemical shift of the C-4a proton of habranthine (155) has to be attributed to an anisotropic deshielding effect of the C-12 hydroxy group which is absent in the diacetate.
Me0
Me0
BorH /
N**’
Me 158 154
R = OH R =H
155
Further confirmation in favor of structure 155 arose from mass spectrometric studies on habranthine and on the alkaloids of this class. An ion at mle 230 is the base peak in the spectrum. It is formed directly from the molecular ion and it corresponds to the loss of the C-12-C-11-N fragment, including any attached substituent. In the I R spectrum (diluted CHCl, solution) habranthine showed two intramolecularly hydrogen-bonded hydroxy groups (3570 and 3457 cm-I). The C-12 hydroxy group seems to be strongly bonded with the nitrogen lone pair since addition of a trace of mineral acid changed its absorption from 3457 cm-1 to 3623 cm-I which is characteristic of a free hydroxy group. The 3570 cm-l band remained unchanged. ORD and CD measurements indicated the stereochemistry at C-3. Since habranthine exhibited similarity in its optical behavior with galanthamine (147) and not with epigalanthamine (148) it must bear an axial hydroxy group a t C-3. Structurally, habranthine remains unique among this class owing to the presence of the hydroxy group /3 to the nitrogen (29).
B . CHLIDANTHINE Evidence has been produced indicating for chlidanthine the stereostructure 152 and its catabolic derivation from galanthamine (147). Since spectral data, though strongly supporting the similarity between
3. THE AMARYLLIDACEAE ALKALOIDS
113
chlidanthine (152)and galanthamine (147),were not probative, a direct conversion of both alkaloids into the same derivative was considered necessary. This conversion was explored first on the model compounds 156 and 157 which presented spectral features quite similar to those of galanthamine and epigalanthamine (148).Compound 156 thus showed, in the NMR spectrum, an intramolecularly hydrogenbonded hydroxy group. The alcohol 157 was converted into the epimeric 0-methyl ether (159) as follows. Treatment of 157 with thionyl chloride in benzene or chloroform, in the presence or in the absence of pyridine, gave an oily chloro compound identified as 158 and produced with retention of configuration. The latter with NaOMe in methanol yielded the methyl ether 159 and nearly 10% of a compound tentatively identified as the epimeric derivative 160. Reacting the alcohol 156 with trisdimethylaminophosphine and CCl,, under conditions which ensured inversion of configuration, the chloro derivative 158 was obtained. It seemed therefore possible to indirectly methylate galanthamine since direct methylation was unsuccessful because of solubility problems of the intermediates.
p /
Me 156 R' = OH; Ra = H 157 R' = H; R2 = OH 158 R' = H; R2 = C1 159 R1 = OMe; Ra = H 160 R' = H; R" = OMe
Galanthamine was epimerized under acidic conditions and the resulting 148 was treated with thionyl chloride. The resulting chloro derivative was converted with NaOMe in methanol into two compounds. An elimination product and galanthamine-0-methyl ether (151), were obtained. On treatment with Me1 in methanol a crystalline methiodide (mp 259") was obtained. It was identical with the product prepared from chlidanthine (152)by methylation with dimethyl sulfate and alkali followed by K I addition (30). 0-Methylgalanthamine has been isolated in minute amount from Chlidanthus frqrans Herb. (30a).
114
CLAUD10 FUGANTI
C . GALANTHAMINE
Structure 161 has been assigned to the byproduct (mp 190-200") which accompanies narwedine (149) in the chromic acid oxidation of galanthamine (147). The same compound can be obtained in the MnO, oxidation. I t s formation was explained by assuming a benzylic hydroxylation which is followed by the opening of the carbinolamine to an amino aldehyde whose amino group adds onto the double bond of the previously formed enone system finally yielding the required 161 (31).
161
During studies designed t o synthesize compounds with the galanthamine-type skeleton but with a free phenolic hydroxy group for potential pharmacological applications a conversion of galanthamine (147) into nivalidine (162) under nonacidic conditions has been carried out. Heating galanthamine a t 200" with KOH and hydrazine hydrate in diethyleneglycol, conditions which were previously used to achieve de-0-methylation in the thebaine series, led t o several products. They were separated by chromatography and identified as anhydrogalanthamine (163), nivalidine (162), anhydro-0-demethylgalanthamine (164), and, finally, compound 165, presumably arising from 164 by isomerization. Experiments were performed which suggest that the
162
168 164
HO
Me 165
R = Me R =H
3.
115
THE AMARYLLIDACEAE ALKALOIDS
observed isomerizations have to be attributed to the alkaline reagents and not to the elevated temperature (32). Since the successful biogenetically patterned synthesis of the galanthamine skeleton from 0,N-dimethylnorbelladine (397) by oxidative coupling performed by Barton and Kirby several attempts have been carried out along these lines. However, several norbelladine derivatives were used in the hope that a decrease in the nitrogen lone pair availability might increase the yields in the oxidation phase. Using the N-mesyl derivative 166 and alkaline potassium ferricyanide as oxidizing agent, an 81% yield of a coupled product has been reported, without however definite structural assignment (33). From the same product 166 with MnO, in diluted CHC1, solution at room temperature, other authors obtained 10-1307, yields of the paracoupled product 168, whereas with MnO, mixed with 3-5 parts of Kieselgel the yield increased to 30y0.From the hydroxy derivative 167 in a two-phase system using CHC1, and a 5 times excess of aqueous FeC1, solution, the desired galanthamine-type compound 169 was obtained in 46% yield. The dienone 168 was rearranged in a galanthamine-nivalidine type of interconversion with acetic anhydride/H,SO, to the compound 170. On the other hand, with NaBH, 168 yielded
166 167
R =H R = OH h
Ma0m
O
M
168
.o
OAc
e
169
Ma0 /
170
OM'
OH
HO \ S0,Ma 171
S0,Me 172
116
CLAUD10 FUGANTI
171 which, in turn, under the above-mentioned conditions, was isomerized to 172. The advantages presented by the use of N-mesyl derivatives along with the disadvantage of their hydrolysis were discussed (34). Since the galanthamine-type derivative 169 was actually obtained by para-para coupling the bromo amide 173 has been used as starting material in a biosynthetic-like synthesis of ( f )-galanthamine (147). Compound 173 was oxidized in a two-phase system of CHCI, and aqueous K, [Fe(CN),] in the presence of NaHCO, a t 60" t o the enone 176 in 40y0 yield. By LiAlH, reduction from 176 a mixture of (-t )galanthamine and ( k )-epigalanthamine (148) in 50 and 40% yields, respectively, was obtained. Also, in addition to the enone 176, a small amount of the dienone 185 was isolated (35). Attempts to obtain N-demethylgalanthamine (179) starting from the amide 174 were unsuccessful in the first instance (36). I n later experiments a 0.7% yield of the enone 177 was achieved on oxidation of the amide 174. I n the usual way, ( k )-norgalanthamine (179) was prepared from 177 (37). Oxidation of 175 yielded, although in a small amount, the enone 178. Upon LiAlH, reduction only 180 was isolated which gives, upon treatment with MeI, a methiodide. The latter proved t o be identical with the compound obtained from ( f )-galanthamine with benzyliodide. Furthermore, from the isomeric amide 181 the enone 182 was prepared in the usual manner yielding, as before upon reduction, a mixture of ( k )-galanthamine and ( f )-epigalanthamine (36).
\ e
M
O
NR e
o
MeoqNR Br
173 174 175
R = Me 0 R =H R = CH2CeH5
176 R = Me 0 177 R = H 178 R = CH,CBH5
179 R = H 180 R = CHZCBH5
3.
THE AMARYLLIDACEAE ALKALOIDS
117
Meo&qo Meo@q; /
\
N
Me
Br
Me
Br
181
182
By phenolic oxidation of the amide 183 using K,[Te(CN),] the two coupling products 184 and 185 in 5 and 10% yields, respectively, were obtained. Conversion of 184 into 147 and 148 proceeded in the usual manner (38). The important intermediate 184 was also prepared from the bromoamide 186 by photochemical cyclization (39).
fie Meoa 184
183
MHo e0 / \
NMe
\
N Me
0 185
0 186
D. LYCORAMINE Two syntheses of ( )-lycoramine (153)have been reported from the same group. The first approach required the construction of rings A and B, then of the seven-membered ring C, followed by the formation of the dihydropyran ring. Thus, the starting material was aldehyde 187, which was converted by standard procedures into the cyanide 188. The latter, with methylacrylate, using Triton B as a catalyst, was transformed into the methylpimelate 189 yielding, on Dieckmann cyclization, the ketoester 190. Upon acid treatment 190 gave the keto nitrile 191. Reduction (LiAIH,) of 191 led, in poor yield, to the hydroxyaldehyde 192. A two carbon unit was added to the aldehydic
118
CLAUD10 FUGANTI
group of 193 via a modified Witting reaction to give 194, easily reduced over Adam's catalyst t o 195. From 195, by saponification and reacetylation, the acetoxy acid 196 was prepared. The latter, via the chloride, yielded with SnC1, the tricyclic intermediate 197 as well as smaller quantities of 198. The naphthalenone 197 under Schmidt conditions (NaN, in CC1,COOH) furnished a mixture of the isomeric lactams 199 and 200 ( 3 : 2 ) . The acetoxy lactam 200, separated by SiOz chromatography, gave the N-methyl derivative 201 which was saponified and oxidized to the keto lactam 202 but in extremely low yield. Therefore, 202, necessary for the further completion of the synthetic route, was prepared from oxolycoraminone (204), available in turn from natural lycoramine (153). The overall conversion, 153 --f 202 proceeded in several steps. Starting from larger quantities of 202, ( 5 )-lycoramine was obtained as follows: bromination of 202 gave a monobromo derivative 203, (which was dehydrobrominated to 206), C ,OOMe
EtooHo @: @' . ' O t 188 Y C N
187
189
EtO \
EtO /
190 191
R = COOMe R =H
EtO /
192 193 194 195 196
R1 = O H ; Ra = H; R3 = C H O = OAC; R a = H; R3 = CHO = OAc; Ra = H; R3 = CH=CHCOOEt
R' R' R' R'
a0
= OAC; Ra = H; R3 = CH,CH,COOEt = OAc; R2 = H; R3 = CH,CH,COOH
EtO /
EtO /
0 197
R1 = OAC; R Z = H
198
199
g o
3. THE
200 201 202 203
~
4
R1 = R1 = R1 = R1 =
Et; RZ Et; RZ Et; R2 Et; R2
= = = =
Me; R3 = R3 = Me; R3 = Me; R3 = Me;
R5 = R6 = H; R4 = Ac R4 = OAc; R6 = Re = H R4, R5 = 0; R6 = H R4, R6 = 0 ;R6 = R r
BR'/ 0
\
204 205
119
AMARYLLIDACEAE ALKALOIDS
R2
NMe
R3 R ' , R 2 = 0 ; R3 = 0; R4 = Me R', R2 = 0; R3 = 0; R4 = H
@'
EtO /'
\
NMe
0 206
yielding with BBr, ( & )-demethyloxolycoraminone (205)in 5% based on 202. Methylation of the phenolic hydroxy group and reduction (LiAlH,) led from 205 to the required ( & )-lycoramine ( 4 0 ) . The second approach to 153 started from 2,3-dimethoxybenzaldehyde (207)which was converted into 2,3-dimethoxyphenylacetone(209)via 1 -(2,3-dimethoxyphenyl)2-nitropropene (208).Michael addition of 209 to acrylonitrile gave the pimelonitrile 210.From the latter, via 211 the cyclized compound (212)was prepared through the use of conventional reactions. The carbonyl group at position 4 was selectively acetalyzed with an excess of 2-ethyl-2-methyl-l,3-dioxolan and BF, to 213 and finally reduced (LiAIH,) to 214. The latter compound, on treatment with oxalic acid in methanol, gave a compound whose physical characteristics pointed to the structure 215. When 215 was subjected to hydroiodic acid in acetic anhydride the phenolic hexahydrodibenzofuran 216 was obtained. Its stereochemistry is based on NMR data. Methylation of 216 and treatment with silver acetate followed by boiling in ethanol with toluene-p-sulfonic acid led to the alcohol 217. Oxidation of 217 (Cr03 in acetone/H,SO,) gave the ketoacid 218 which was finally reduced with NaBH, to the hydroxy acid 219. The stereochemistry of the hydroxy group is mainly based on analogy. Since '
120
CLAUD10 FUGANTI
lycoraminone under these conditions gives 153, an analogous reaction was expected t o take place in the case of 218. The acetoxynaphthalenone 220 was prepared from 219 as before. It yielded two isomeric lactams in the Schmidt reaction. The desired isomer 221 was converted into racemic 153 by reduction in 0.67y0 overall yield from 207 (41).
207 208 209 210 211
R R R R R
MeooR
= CHO = CH=CMeN02
212 213
R =0
R = OCH2CH20
= CH,COCH, = C(COCH,)(CH,CH,CN), = C(COCH,)(CH2CH2COOEt),
do
Me0 /
\
& .-OH 214
216 217
R =H; X = I R = Me; X = OH
215
218 219
R1,R 2 = 0 R' = O H ; R2 = H
M e 0 @OR'
0 220
221
0 R' = Ac; R2 = H
3.
THE AMARYLLIDACEAE ALKALOIDS
121
V. Crinine-Type Alkaloids In 1966 (Vol. XI, p. 352) over thirty alkaloids possessing the 5,lObethanophenanthridine nucleus were reported. The absolute configuration relied, first, on the interconversions of those alkaloids which permitted correlation with tazettine (240) whose absolute stereochemistry seemed firmly established through degradation to ( + )-(B)-2methoxyadipic acid and, second, on empirical reasonings based on the application of Mill's rule. Subsequently, the application of a quadrant rule developed for compounds bearing an asymmetric center adjacent t o the aromatic ckromophore by means of considerations of the CD and ORD spectra of products of established absolute configuration t o the alkaloids of the 5, lob-ethanophenanthridineseries led t o conclusions on their absolute stereochemistry a t variance with those mentioned above (42). The method was indeed useful for inter- and intra-system identifications among alkaloids of several groups; for example, the O R D and CD curves of maritidine (277) could be compared in shape and intensity with those of vittatine (284) and haemanthamine (318) although the suggestions of a a configuration for the C-3 hydroxy group, as deduced from the amplitude of the ORD curve a t 250m, proved t o be incorrect (43, 44). The problem of the absolute configuration of these alkaloids was finally solved by means of X-ray analysis of haemanthamine p bromobenzoate (319) which confirmed the correctness of the earlier assignment (45). A crystallographic study of 6-hydroxycrinamine (Vol. XI, p. 370) confirmed the stereostructure deduced for the alkaloid by chemical methods. Furthermore, it showed that in the solid state the C-6 hydroxy group is fixed in a trans position with respect to the pyrrolidine nucleus with the molecules appearing in the crystals as dimers through hydrogen bonding. I n solution, as shown previously, 6-hydroxycrinamine (249) and haemanthidine (248) exist as mixtures of C-6 epimers (46). Tazettine (240) is dealt with in this section because recent knowledge as to its origin showed it to be derived from pretazettine (242) which, under certain conditions, exists in the 5,lObethanophenanthridine form.
A. 6-HYDROXYBUPHANIDRINE AND 6-HYDROXYPOWELLINE A new alkaloid, 6-hydroxybuphanidrine (222) (mp 95-96"; been isolated by thin layer chromatography (TLC) from the
- 64", has
122
CLAUD10 FUGANTI
extract of Nerine bowdenii bulbs. Spectral data indicated the presence of an aromatic methylenedioxy-methoxy chromophore, of hydroxy group in addition t o two olefinic protons, of an aromatic proton, and an aliphatic methoxy group. Upon treatment with thionyl chloride followed by LiAlH, reduction 222 gave buphanidrine 223, thus establishing the basic nucleus of the alkaloid, its absolute configuration, the stereochemistry of the aliphatic methoxy group a t (3-3, along with the location of the double bond. NMR and IR studies showed the removed hydroxy group to be assigned to position 6. MnO, oxidation yielded a minute amount of the lactam 224 (IR:1690 cm-l, UV: 231, 287, and 320 nm) whose NMR spectrum did not show benzylic hydrogens. The low yield in the oxidation and the likely existence of a single epimer a t C-6 were attributed to the presence of a peri aromatic methoxy group since the corresponding unsubstituted derivatives were easily oxidized and were shown t o exist in solution as a mixture of epimeric forms at (2-6. The chemical behavior of 222 appears unique. Indeed, 6-0-acetylbuphanidrine (225) is hydrolyzed with cleavage of the alkyl oxygen bond as shown from the generation of 226 by methanolysis. This fact is to be attributed t o conjugative electron release by the benzene ring containing both ortho and para electrons releasing substituents which
favor the devehgneub of ' a ~ i ~ , ~G lUi~cO ~ ~ Uion, ID The a configuration of the C-6 hydroxy group was established by chemical means and through crystallographic X-ray analysis of the methiodide (45, 4 7 ) . 6-Hydroxypowelline (227) (mp 233-235"; [a]2$ - 36") has been isolated from the same plants and formerly from an unidentified Crinum species. Its NMR spectrum was quite similar to that of 222. Furthermore, 227 gave on acetylation a diacetyl derivative which was
222
R1 = H; R2 = OH; R3 = Me = Ra = H; R3 = Me R2 = 0; R3 = Me = H; R2 = OAc; R3 = Me = H; R3 = OMe; R3 = Me = R3 = H; R2 = O H = H; R2 = O H ; R3 = Ac = R2 = R3 = H
223 R' 224 R', 225 R' 226 R' 227 R' 228 R' 229 R'
3.
THE AMARYLLIDACEAE ALKALOIDS
123
partially hydrolyzed to 228 yielding powelline (229) through the above-mentioned sequence, thus indicating the structure 227 for the new alkaloid. It has been pointed out that 6-hydroxybuphanidrine (222) and 6hydroxypowelline (227) could exist in solution as a mixture of tautomeric carbinolamine and open chain amino aldehyde, but investigation using physical methods did not reveal aldehydic forms. However, both alkaloids, upon treatment with NaNO, in diluted acetic acid, were converted into N-nitroso aldehyde derivatives 230 and 231 which seems to suggest the existence in solution of an amino aldehyde form.
0 230 R = Me 231 R = H
Furthermore, 6-hydroxybuphanidrine (222) reacted with NH,OH HC1 in refluxing ethanol to give the isoxazoline 233, probably through the intermediacy of the oxime 232, whereas 6-hydroxycrinamine (249) and haemanthidine (248) did not react. I n order t o verify the above-mentioned mechanism 6-hydroxyundulatine (234) was prepared and treated under the same conditions to give the oxime 237 along with a small but significant amount of 6-ethoxyundulatine (235) which would suggest the possible intermediacy of a carbonium ion a t C-6. The carbonium ion 238 could react with hydroxylamine to give 236 undergoing, in turn, acid-catalyzed isomerization to the oxime 237. This mechanism seems likely when it is considered that, in sodium acetate buffer, 6-hydroxybuphanidrine (222) did not react with hydroxylamine, whereas 6-hydroxyundulatine (234) gave a quantitative yield of the oxime using the polar DMSO as solvent (47).
232
233
124
CLAUD10 FUGANTI
\ 234 235 236
R = OH R = OEt R=NHOH
OH
237
OMe
+
238
B. 11-EPIHAEMANTHAIIIINE 1l-Epihaemanthamine (239) has been isolated along with haemanthamine (318), which is the major alkaloid, from Haemanthus katherinae. Its identification was based on physical and chemical methods (48).
239
C.
HAEMANTHIDINE,
PRETAZETTINE, AND TAZETTINE
I n Volume XI, p. 378, evidence in favor of stereostructures 240 and 241 for tazettine and criwelline, respectively, was reported. It has been shown that the two above-mentioned alkaloids are extraction artifacts arising from pretazettine (242) and precriwelline (243) by rearrangement. During large-scale extractions of Xprelcelia formosissima and Ismene calathina, two well-known sources of tazettine (240), it has been
3.
125
THE AMARYLLIDACEAE ALKALOIDS
observed that, avoiding basic conditions, tazettine was absent, an amorphous alkaloid, pretazettine being isolated instead. The latter, under very mild basic conditions (the free base itself is converted into tazettine within 1 hr on heating in water at 7 0 ° ) , gives tazettine, although in the presence of acids it appears to be stable. R.l
NMe
OH 240 241
R' = OMe; R" = H R' = H; R" = OMe
242 243
R' = OMe; R" = H R' = H ;R" = OM0
The chemical and physical characteristics of pretazettine (242) are in agreement with those previously reported by Proskurnina for isotazettine (49). The more significant difference between pretazettine and tazettine was in their NMR spectrum. The AB pattern a t 4.72 ppm (benzylic protons) present in 240 was substituted in pretazettine (242) by a one-proton singlet at 6.06 ppm. Upon MnO, oxidation pretazettine gave a mixture of 244 and 246 whose structural assignment relied on physical data and chemical interconversions. Furthermore, 244 and 246 were easily interconvertible by chemical means. The desired relationship between pretazettine (242) and haemanthidine (248) was achieved when 248 was oxidized to 250, converted, in turn, with sodium acetate-acetic acid buffer a t reflux to 244, thus establishing a structural and stereochemical link between 242 and 248. A t C-11 haemanthidine bears a hydroxy group directed toward the C-1-C-2 unsaturation, and since it seemed mechanistically
244 R' = OMe; Ra = R3 = H 246 R' = R3 = H; R" = OMe 248 R1 = OMe; Ra = H; R3 = Me 247 R' = H; R1 = OMe; R3 = Me
248 R' = 249 R' = 250 R' = 261 R' =
OMe; Ra = R3 = H; R' = OH R3 = H; Ra = OMe; R' = OH OMe; Ra = H ;R3, R' = 0 H; R2 = OMe; R3, R' = 0
126
CLAUDIO FUGANTI
inexplicable that the configuration a t C-11 be altered during the reaction it appears that the configuration of the C-6a hydrogen of 244 and 250 is p (steroid notation) and that the B-D ring fusion is trans, as maintains for pretazettine. Methylation experiments using acidic methanol converted pretazettine into a mixture of a- and p-0-methylpretazettine (252) having slightly different R, on (TLC) but showing a single signal for benzylic proton in the NMR. It was concluded that pretazettine exists in solution as a mixture of C-8 epimers although the protons of the C-8 epimers must have equivalent chemical shifts. Pretazettine (242) has a trans B-D ring juncture and seems a fairly strained molecule whereas tazettine (240) bears a cis B-D fusion allowing more flexibility, and the driving force for the B-ring opening is attributed to the relief of this internal strain. The reaction would be completed by an intramolecular crossed Cannizzaro reaction followed by hemiketal formation yielding the cis B-D fusion present in 242.
Similarly, from Crinum powellii, avoiding basic treatment, criwelline (241) was not obtained but the amorphous precriwelline (243) whose hydrochloride melted a t 199-201' was isolated. The sequence leading from 243 t o 245 and 247, the known alkaloid macronine (Vol. XI,
p. 381), and its synthetic N-demethyl derivative, respectively, established structure 243. The compound 247 was isolated from Crinum erubescens along with the carbamate 253 which probably arose from 247 during the extraction by the action of chloroform and ethanol. Epimacronine (246), another lactonic alkaloid of this series, was obtained in small amounts from S. formosissima (50, 51). Independently, the structure of isotazettine, which had identical properties with Wildman's pretazettine, was investigated. On the basis of physical and chemical means structure 254 has been assigned to the compound (52). Structures 242 and 254 differ in the configuration of the C-6a hydrogen which in 254 is in the a configuration.
3.
THE AMARYLLIDACEAE ALKALOIDS
127
boMe
% H OH
NMe
OH 254
Subsequently, the partial synthesis of pretazettine (242) from the metho salt of haemanthidine has been realized. The reaction proceeded by dissolving haemanthidine methiodide in diluted hydrochloric acid at room temperature and extracting pretazettine with chloroform after basification to pH 10. By elegant physical methods i t has been shown that the conversion is caused by the basic conditions required in the isolation and by the greater solubility of the tertiary amine 242 in chloroform since pretazettine hydrochloride seems to exist in solution as the 5, lob-ethanophenanthridinederivative 257. 6-Hydroxycrinaminemethiodide (258) and precriwelline (243) undergo this same type of interconversion. The existence of two isomeric forms for pretazettine (242) and precriwelline (243) is attributed to the presence of an N-methyl group and of hydroxy group, each capable of nucleophilic attack on the carbonyl of the intermediate amino aldehydes 255 and 256, respectively. I n the light of the complete reversibility of the isomerization of pretazettine to the metho salt of haemanthidine (257), the inversion of the C-6a hydrogen of pretazettine, as required by structure 254 which should be revised to 242, would seem to be mechanistically inexplicable. Furthermore, haemanthidine (248) itself, could be transformed into the [2]benzopyrano[3,4-~]indolederivative 242 by methylation with formaldehyde and formic acid, reactions whereby primary and secondary amines are methylated to tertiary bases. Clearly, a secondary amino group must have been present in sufficient concentration t o allow methylation. Furthermore, 6-hydroxycrinamine (249) gave the N-nitroso derivative 259 which is obtainable only from a secondary amine. The two latter reactions indicated the presence of a secondary amine although its precise nature remained unknown. It later seemed possible to identify it in acidic media in the hemiacetal forms 242 and 243 (without N-methyl) since O-methyl-N-demethylpretazettine was obtained from haemanthidine on refluxing in acidic methanol. However, ORD and CD spectra of haemanthidine (248) and haemanthamine (318) indicated that between pH 2 and 12 in methanol 248 exists
128
CLAUD10 FUBANTI
256 268
R' = OMe; R" = H R' = H; R ' = OMe
267 258
R1 = OMe; Ra = H R' = H; Ra = OMe
269
predominantly with 5, lob-ethanophenanthridine nucleus, being therefore N-demethylpretazettine formed reversibly, but with a very short lifetime. Upon hydrogenation, from pretazettine (242) the dihydro derivative 260 was obtained which is in equilibrium with the metho salt of dihydrohaemanthidine (261). Furthermore, dihydrohaemanthidine seems to exist in methanol between pH 2 and 12 in the 5,lOb-ethanophenanthridine form.
& Me0
--H
<$
( 01
NM0
OH 280
OH 281
At this point the synthesis of the pretazettine nucleus with the inverted (cis) B-D ring fusion seemed possible starting from ll-epihaemanthidine (262). Indeed, 262 easily undergoes rearrangement to N-demethyl-6a-epipretazettine (263) which cannot be converted back to the 5, lob-ethanophenanthridine form. Since 6a-epipretazettine
3.
THE AMARYLLIDACEAE ALKALOIDS
129
(264) has the cis B-D ring juncture present in tazettine (240) its conversion into 244 still takes place but under more forced conditions. It follows that the ring strain present in the pretazettine nucleus is responsible for the ring opening to the intermediate aminoaldehyde 255. Once this strain is reduced (as in 264) the ring opening still occurs but more slowly and the ring-opened intermediates undergo hydride shift to form tazettine (53).
I
OH 262
OH 268 264
R =H R=Me
I n the detailed paper on the degradation work leading from tazettine to ( + )-2-methoxyadipic acid, unequivocal proof employing deuteriated intermediates has been produced in favor of the expected course of the Hofmann reaction giving rise to the key intermediate 265 which, on exhaustive ozonolysis, yielded the above-mentioned acid. The product 267 is formed from 265 which, in principle, could be degraded to 268. The relevant difference between 267 and 268 is represented by the fact that in 267 the double bond is formed between the atoms C-4a and C-12b of the original alkaloid (240), whereas in 268 the double bond appears at atoms C-12b and C-1. The consequence of this second course would be an absolute configuration opposite to that assigned considering the first reaction path. Therefore, 266, prepared by regiospecific catalytic deuteriation, was converted in two ways to the products 269 and 270 whose deuterium content is in favor of path one and excludes path two. Comparison of the optical behavior of several pairs of interrelated epimeric alkaloids substantiates the applicability of Mill’s rule for this group of natural products (54, 55). The absolute configuration of tazettine has been determined also through X-ray analysis of tazettine methoiodide ( 5 5 ~ ) . Several biogenetic-type syntheses of 5,lOb-ethanophenanthridine derivatives have been realized. The model compound 273 (R2= OMe) in a two-phase oxidation in CHCI,/l N FeCI, (1:l) yielded 12% of the dienone 271 which, under basic conditions, gave the product 272 (56).
130
CLAUD10 FUGANTI
R
265 266
M
X
R =H R =D
267
R = COCH,NMe,
I
path 2
JIT--H OMe
i
0
0
CHzOR
R = COCH,NMe,
288
M
HO
e
271
269
O
'
OMe
d
R
Ho \
R = COCF,
272 R2
N R' 273
R1 = COCF,; R2
=H
3.
THE AMARYLLIDACEAE ALKALOIDS
131
A simple synthesis of the racemic form of maritidine (277) through a procedure involving as its key step phenol coupling of the O-methylnorbelladine derivative 273 has been achieved with VOCI, as the oxidizing agent in diluted ethereal solution. The success of the oxidation stage is ascribed to the intramolecular complex which is formed between VOCI, and the substrate 273. The conversion of the intermediate enone 274 to 277 proceeded by means of hydrolysis to 275, reduction (NaBH,), methylation to ( & )-epimaritidine (276),and partial acid-catalyzed epimerization to the desired product (57). More recently, the same group synthesized racemic oxocrinine (275) (methylenedioxy instead of methoxy-hydroxy) starting from 273 (substituted as above) using thallium (111)trifluoracetate as the two-electron oxidizing agent and proceeding from the intermediate dienone as before t o oxocrinine (58). d R ; - R 2
do
Me0 /
Me0 /
HO \ 274
~
R R = COCF,
275 276 277
3
\ 0
R', R2 = 0; R3 = H R1 = H; R2 = OH; R3 = Me R' = OH; R2 = H; R 3 = Me
Photolytic cyclization of the phenolic bromo compounds 278 and 279 led t o ( _+ )-oxocrinine (275) (methylenedioxy instead of methoxyhydroxy) and ( & )-oxomaritidine (275),known intermediates t o crinine and maritidine (277) (59, 60).Oxocrinine was also obtained by photolysis of the isomeric bromophenol 280 (61).
278 279 280
R', Ra = OCH20; R3 = H; R4 = Br R1 = OMe; Ra = OH; R 3 = H; R4 = Br R', R2 = OCH20; R3 = Br; R4 = H
More recently, the yields from the oxidation of the 0-methyl derivative 273 t o 274 have been greatly increased (ca. 35y0)using 10 molar excess of the complex [Fe(DMF),Cl,][FeCl,] in a two-phase system of ether and water (62).
132
CLaUDIO BUGANTI
A total synthesis of ( k)-crinine (284) has been completed from the intermediate ( 2 )-l-oxocrinane (281) (Vol. XI, p. 368) by bromination to an a-bromoketone which was dehydrobrominated (LiC1 in boiling DMF, 77'7" yield) to 282. The latter was reduced to 283 which, once transformed into the toluene-p-sulfonyl ester, gave by solvolysis the expected ( f )-crinine (284) as well as dehydration products (63).
281
282 288
R', Ra = 0 R', R2 = H, OH
284
The rare alkaloid 3-epielwestine (285) was prepared in racemic form from piperonylcyanide (286) in eight stages through a scheme involving as its relevant reactions the acid-catalyzed thermally induced rearrangement of the cyclopropylimine (287) to the pyrroline 288 followed by the acid-catalyzed addition onto 288 of methylvinylketone to give the octahydroindole (289) with the desired cis anellation. From 289, by NaBH, reduction, hydrogenolytic removal of the protecting benzyl group, and Pictet-Spengler ring closure ( & )-3-epielwestine (285) was obtained (64).
285
0
288
286
287
R = CH2C8HB
R R = CHaC8H6
289
R = CHaCgH,
( f )-Crinane (293) has been obtained from the tricyclic intermediate 291 bearing the required B/C trans ring juncture. This compound, in turn, was prepared in 15y0 yield from the N-piperonyloylenamine (290) synthesized in two stages from 2-allylcyclohexanone by stereo-
133
3. THE AMARYLLIDACEAE ALKALOIDS
selective photocyclization. The stereochemical assignment is mainly based on theoretical grounds and on the identity with natural crinane of the final product. From 291, the ring D was constructed by ozonolysis, LiAIH, reduction to 292, debenzylation, and SOCI, treatment in dioxane giving directly ( )-crinane (293). Alternatively, from 292 by iodide treatment of the toluene-p-sulfonyl derivative, a quaternary salt was prepared yielding upon hydrogenolysis ( i )-crinane (293) (65).
(&
NR
H$ ( 0 0
0 290 R = CH2CeH,
292
R = CH&eHB
291
R = CH2CeH,
293
The first total synthesis of haemanthidine (248) and tazettine (240) has been completed starting from the lactam acid 294 previously transformed into substituted crinane (Vol. XI, p. 368). The compound 294 has the required trans B/C ring juncture besides the axial carbonyl required to direct the steric course of the functionalization in ring C as well as the ring D formation to the nitrogen atom. The first goal was reached in several stages through conversion into the iodolactone 295 (KI, in NaHCO,), basic treatment to the cis-2,3-epoxy acid, followed by its opening (BF,-MeOH) to the methoxy lactone (296). The latter was transformed into the acid derivative 297 by basic treatment, displacement in phenacylbromide by the carboxylate anion and mesylation. The homologation of 297 to the crinane derivative 298 was brought about by saponification to acid, SOCI, and CH,N, treatment, and ring closure to nitrogen with dry HC1 of the intermediate diazoketone. Reduction of 298 with NaBH, in the cold gives the carbinolamine 299 in agreement with the expected behavior of a carbonyl near a bridgehead nitrogen. However, when 299 was reduced with NaBH, in boiling isopropanol, followed by basic elimination of the mesylate group which directed the right approach of the reducing agent,
134
CLAUD10 FUCANTI
nortazettine and hence tazettine (240) was obtained, with the familiar internal Cannizzaro hydride shift as a consequence of the alkaline conditions. Therefore, 299 was reduced under acidic conditions [refluxing disiamylborane in tetrahydrofuran (THF)] to give a diol which was acetylated and subjected to mesylate elimination (hot 1,5-diazabicyclo[3.4.O]nonane-5). Deacetylation (LiAlH,) finally gave racemic haemanthidine (248) (66).
295 296
294
R =1 R = OMe
(&gOMe
&**oMe
Q0 I R1
0 297
R’ = OCH2COCeHs Ra = OS0,Me
298 299
R2
R’ = Ra = 0; R3 = OSOzMe R’, R2 = OH, H; R3 = OSOzMe
(y3
\ Me0 /
COOH
M e 0 f i o
300
301
302
303
H
3.
135
THE AMARYLLIDACEAE ALKALOIDS
The crinine-type skeleton has been obtained starting from the cyclohexanone derivative 300 which, with NH,, gave the cyclic enamine 301, hydrogenated (Pd/C) in turn t o the cis-octahydroindole derivative 302. The conversion of 302 into the tetracyclic 5,lObethanophenanthridine 303 proceeds by standard methods (67). Tsuda’s approach t o the total synthesis of the haemanthamine (318), haemanthidine (248), tazettine (240) series of alkaloids involved as its key intermediate the tricyclic tetrahydroindole 306, which is susceptible to further functionalization and which has the required cis fusion, The latter was prepared by cycloaddition of butadiene (HCONMe, or DMSO) to 3(3,4-methylenedioxyphenyl)-A2-pyrroline-4,5-dione (305) prepared from 3,4-methylenedioxybenzylcyanideand ethyl oxalate via the pyruvate (304),followed by hydrogenation (ether containing a trace of ethanol). The methoxy group a t C-3 of the crinane skeleton was introduced by converting 306 into a mixture of the bromoacetal307 and of the bromohydrin 308 ( 2 : l ratio). However, when both were kept in MeOH containing 5% NaOMe the epoxy ketone 309 was obtained. The latter upon treatment with BF,-etherate in methanol, led almost exclusively to 310 reduced (LiAlH,) to the diol 311. Its stereochemistry rests on the results of experiments with a model compound and on its conversion into the racemic haemanthamine (318).Compound 311 under Pictet-Spengler conditions (CH,O-MeOH, followed by acetic acid) gave the ethanophenanthridine 314 (50%) and the N-methyl derivative 312 (4079.The monotoluene-p-sulfonyl derivative of 314 upon heating with 1,5-diazabicyclo[5.4.0]undec-5-ene(DBU) in DMSO gave racemic haemanthamine (318) (68).
304
R = COOEt
305
R = Et 0
306
307
R = Br
CLAUD10 FUOANTI
136
309
308
310
From the intermediate 311 haemanthidine (248) and tazettine (240) were obtained as follows. The 0-acetyl-N-formyl derivative 313 obtained from 311 by formylation, hydrolysis, and acetylation, gives rise, when heated with POC1, in xylene followed by methanol treatment, to the methoxy compound 315.The latter was hydrolyzed with NaOH, tosylated, and treated with DBU in DMSO to yield methylhaemanthidine (317).From 317,haemanthidine (248) was prepared by hot 50% acetic acid treatment. When the compound 313 was treated with POC1, in xylene followed by aqueous base the hydroxy derivative 316 was obtained instead. Its methiodide rearranges to 320. Tosylation and detosylation in the above-mentioned way gave ( f )-tazettine (240) (69).
OR3 a16 816
R' = R1 = Ac;R3 = Me R' = R2 = Ac; R3 = Me
3.
THE AMARYLJJDACEAE ALKALOIDS
OM0 317
137
318 R = H 319 R = p-BrCsH4C0
OMe
320
VI. Montanine-Type Alkaloids In addition to montanine (321), coccinine (322), and manthidine (323) (Vol. XI, p. 377), a fourth alkaloid, pancracine (mp 272-273") (Vol. XI, p. 318), has been assigned to the 5,llb-methanomorphanthridine class. Pancracine (324) is present in a modest amount in Rhodophiala bifida along with a relatively large quantity of montanine (321). The IR spectrum indicated a methylenedioxy group and one or more hydroxy groups, but no carbonyl absorption. A study of the NMR spectrum of pancracine diacetate (325) and of montanine (321) indicated a montanine-type skeleton for the new alkaloid. Indeed, signals were observed in the spectrum of 325 at 6.53 and 6.47 ppm (two aromatic protons), at 5.88 ppm (9, ZH,methylenedioxy), at 5.47 ppm (m, lH, olefinic proton), and at 5.02 and 5.12 ppm (m, 1H each, corresponding to the C-3 and C-2 protons); on irradiation the olefinic proton appeared coupled to the C-2 proton but not with the C-3 hydrogen. An AB pattern centered at 4.05 pprn (J = 17 Hz) was assigned to the two benzylic protons. A peak a t 3.28 ppm, weakly coupled with the C-10 aromatic proton, was assigned to C-11 hydrogen whereas the multiplet a t 3.28 ppm (lH), coupled with the two C-4 hydrogens (broad multiplet between 1.4 and 2.4 ppm) and with the olefinic proton at C-1, was attributed to the C-4a hydrogen. There were
138
CLAUD10 FUGANTI
also signals a t 3.02 ppm (s, 1H) corresponding to the C-11 proton and a t 2.0 and 2.05 ppm (s, 3H each) (the two methyls of acetates). The C-4 protons were coupled with the C-3 hydrogen but not with the C-2 proton. The montanine-type skeleton of pancracine was further indicated from its generation from montanine (321) on HBr hydrolysis. On partial hydrolysis pancracine diacetate (325) gave two isomeric monoesters 326 and 327. The isomer 327 was not affected by MnO,, whereas 326 gave an a-,P-unsaturated ketone 328 identical with 2-oxo-3-0-acetyliso-1l-hydroxyvittatine. As expected, this defines the identity of configuration of the acetoxy groups in the two compounds, provided no racemization occurred, because of the absence of alkaline treatment. The configuration of the C-2 hydroxy group in 324 was assigned on the basis of hydrogen bond studies in the IR spectrum.
( O m R3 R a
/
=N--
H 321 322 323 324 325 826 327 328
R1 = OMe; R2 = R4 = H; R3 = OH R' = R' = H; Ra = OMe; R3 = O H R' = OMe; Ra = R3 = H; R' = O H R' = OH; Ra = R' = H; R3 = OH R' = R3 = OAc; R2 = R4 = H R' = OH; Ra = R4 = H; R3 = OAC R' = OAC;R2 = R' = H; R3 = OH R', Ra = 0 ; R3 = OAc; R' = H
Diacetyl pancracine (325), upon hydrogenation (Pd/C in glacial acetic acid), gave 329, 330, and 331. The mass spectra of pancracine (324) and of several derivatives of alkaloids with the montanine-type skeleton have been examined with the relevant observation that the EI fragmentation of these molecules strongly depends on the nature of the substituents (OH or OCH,) at C-2 and C-3, thus allowing a correlation between the fragmentation patterns and the structural variables a t C-2 and C-3. However, there is an ion of m/e 175 in the dihydro series which seems diagnostic of this skeletal type and which appears
329
331
3.
THE AMARYLLIDACEAE ALKALOIDS
139
in the spectra of all these compounds irrespective of the substitution pattern a t C-2 and C-3 (YO). The chemical ionization mass spectrometry of other Amaryllidaceae alkaloids has been reported ( 7 0 4 .
VII. Cherylline A phenolic alkaloid, cherylline (mp 217-218'; - 69' MeOH; C1,Hl,NO, by mass spectrometry and analysis) has been isolated in 0.00470 yield from several Crinum species. On the basis of spectroscopic and chemical considerations, cherylline has been assigned structure 332 thus representing a new C,, skeletal type among the basic metabolites isolated from Amaryllidaceae plants. The NMR spectrum showed signals characteristic of a 174-disubstituted aromatic ring and of a para-oriented aromatic proton on a second aromatic nucleus in addition to OMe and NMe and other not well-defined signals. On the basis of the S values and on the extent of the upfield shift occurring in the signals of the aromatic protons on addition of NaOD t o the sample in heavy water, the OMe group was assigned a t C-6 and the OH a t C-7, respectively, in the ring A. The UV spectrum showed maxima at 285 and 280 nm undergoing a bathochromic shift t o 299 nm on basification. Diazomethane converted cherylline (332)into a di-O-methyl derivative (333)which exhibited chromatographic and spectroscopic behavior (IR in KBr disc of the hydrochloride) coincident with that of ( )6,7-dimethoxy-4 - (4'- methoxypheny1)-2 - methyl-1,2,3,4 - tetrahydroisoquinoline. By means of comparison of the ORD and CD curves of natural cherylline (332) and of the two enantiomeric di-0-methyl ethers obtained by synthesis, on the basis of the previous observations in the lignan series, the S absolute configuration a t C-4 was assigned.
332 333 334 335 336 337
R' R' R' R' R',
= p-HOCeHI;Ra = R3 = H; R4 = Me = p-MeOCeH4;Ra = H; R3 = R4 = Me = H; Ra = p-MeOCeH4;R3 = R ' = Me
= p-MeOCeH,;Ra = H; R3 = R4 = Me Ra = 0; R3 = Me; R4 = CH,C6Hs R', Ra = H, MeOCeH4;R3 = Me; R4 =CH,CeHS
The enantiomeric di-0-methyl ethers were prepared as follows. Addition of p-methoxyphenylmagnesium bromide onto 336 led t o a
140
CLAUD10 PUGANTI
carbinol which was dehydrated and reduced to 337. The latter, once debenzylated, was resolved via the dibenzoyl-D-tartrate and the Ltartrate from which, by N-methylation, the required enantiomeric amines were obtained. They showed mirror-shaped ORD and CD curves. The enantiomer 334 had a positive Cotton effect a t 294 nm and CD maximum at 288 nm, whereas 335 exhibited the opposite shape to that of cherylline (332)(72). Confirmation in favor of the assigned stereochemistry arose from X-ray analysis of cherylline-N-p-bromobenzoate (72). Several syntheses of cherylline have been developed. The benzophenone 338 was benzylated to 339, reduced (NaBH,) to an alcohol, which, via the chloride and cyanide displacement, followed by Raney cobalt hydrogenation, gave the amine 340. The latter, with methyl formate gave the N-formyl derivative which was cyclized (BischlerNapieralsky) and debenzylated (conc. HC1) to 341. Selective de-0methylation (48% HBr) led to 342 which was quaternized with Me1 and reduced (NaBH,) to ( & )-cherylline (332)(73).Subsequently, the racemic phenylethylamine 340 was resolved into the two enantiomers via the ( - )-diacetone-2-keto-~-gulonic acid and the ( - )-di-O-ptoluoyl-D-tartaric acid salts. The two enantiomers gave, as before, the natural and the unnatural forms of cherylline (74).
838 R' = H; R", R3 = 0 339 R' = CHaC6H&; R3, R' = 0 840 R' = CH1C6H6;R', R3 = H , CHzNHl
341 R = M e 342 R = H
Biogenetically, cherylline could represent an anabolic or a catabolic metabolite of the C,, aminophenol 0-methylnorbelladine (343). Thus, it might arise from 343 by cyclization either after hydroxylation /?to the nitrogen atom took place through the intermediacy of 344 or possibly through oxidation to the quinone methide 345 or catabolically from a mantanine-type intermediate 346,arising in turn from 343 by phenol coupling and rearrangement of the 5,lOb-ethanophenanthridine skeleton.
141
3. THE AMARYLLIDACEAE ALKALOIDS 0
OR'
a43 344
R' = = R3 = H R' = H; R" = OH; R3 = H or Me
345
a46
Experimentally, it- has been shown that 344 (R3= Me) cyclizes readily on basic treatment to racemic cherylline and under a variety of conditions (75).
VIII. Narciclasine The evidence which permitted structural assignment to two nonbasic substances, narciclasine and narciprimine, extracted from daffodil bulbs has been briefly summarized in Volume XI, p. 383. The detailed paper (76) reported the reasoning which pointed to structure 347 for the lactam narciclasine and the formula 355 for the phenanthridone narciprimine, respectively. The mass spectrum of narciclasine showed a molecular ion at m/e 307 and important peaks at m/e 289 and 271. I n the UV spectrum the maxima were a t 329, 302, and 252 nm, changing in 0.01 N NaOH to 355, 320, 249, and 219 nm. The NMR spectrum, taken in DMSO d,, presented signals at 13.23 (8, lH), 7.85 (8, lH), 6.87 (s, IH), 6.18 (broad, lH), 6.12 (s, 2H), 4.4-5.5 (broad, 3H), and 3.7-4.2 6 (broad, 4H). The signals a t 13.2, 7.85, and 4.4-5.5 6 disappeared on addition of D,O. The phenolic hydroxy group was slowly methylated by alcoholic diazomethane to a mono-0-methyl ether which is readily oxidized with HIO, to narciclasic aldehyde (372) whose structure was based on spectral data. The generation of
142
CLAUD10 FUGANTI
narciclasic aldehyde 372 by periodic acid oxidation indicated that the three hydroxy groups were adjacent and seemed to suggest that positions 1, 2, and 3 of the tetrahydrophenanthridine skeleton bear the hydroxy groups. Indeed, the product expected from the periodate cleavage of O-methylnarciclasine (348) must needs be a vinilogue of rnalondialdehyde which was known to be further cleaved by periodate. Furthermore, extended NMR investigation on O-methyltriacetylnarciclasine (349) supported this assignment also defining, through double resonance experiments, the relative stereochemistry displayed in 347.
Kuhn methylation of narciclasine led to the pentamethyl derivative 350 as well as a smaller amount of the aromatized product 357 whereas,
upon acid treatment, narciclasine was transformed into a phenanthridone which is identical with narciprimine. Structure 355 was assigned to narciprimine rather than the isomeric 356, equally acceptable on the basis of the three adjacent protons of the NMR spectrum, but because of its derivation from narciclasine which had assigned a structure bearing the three hydroxy group at positions 1, 2, and 3. From the mother liquors of narciclasine another lactam has been isolated in trace amount. On the basis of chemical and spectroscopic evidence the new compound, named margetine, was indicated as 7deoxynarciclasine 77. Independently, lycoricidine and lycoricidinol, two lactams which presented physical and chemical properties identical with those of margetine and narciclasine, respectively, were isolated from Lycoris radiata. A different interpretation of the physical and chemical data
355 356 357 358 359 360 361 362 363
3.
THE AMARYLLIDACEAE ALKALOIDS
R' R' R' R' R' R' R' R' R'
= R5 = = R2 = = R3 = = R2 = = R2 = = R2 = = R2 = = R2 = = R3 =
143
OH; R2 = R3 = R4 = H R4 = H; R3 = R5 = OH H; R2 = R5 = OMe; R' = Me R5 = H; R3 = OMe; R4 = CH,C,H, H; R3 = R5 = OMe; R4 = Me R4 = H; R3 = OCH,C6H5; R5 = OH R4 = R5 = H; R3 = OCH2C,H5 R3 = R5 = H; R4 = Me H: Ra = R5 = NO,; R4 = Me
permitted lycoricidine and lycoricidinol to be assigned structures 365 and 364, respectively, without however stereochemical definition. The assigned structures were further strengthened from the synthesis of the arolycoricidine derivative 358 from the N-benzylamide 366 via Pschorr cyclization, thus establishing an implicit revision of the structures of narciclasine, narciprimine, and margetine (78). The two series of compounds proved t o be identical since a direct comparison has been performed between the Italian narciclasine and the Japanese lycoricidinol in Professor Battersby's laboratory in England. Later, in Germany, Professor Mondon also proposed using the terms narciclasine and narciprimine to indicate the natural phenanthridone derivatives bearing a hydroxy group a t C-7 and lycoricidine and arolycoricidine for the 7-deoxy analogs instead of lycoricidinol, arolycoricidinol, and margetine, respectively (79). It must also be pointed out that narciprimine certainly is an extraction artifact since, avoiding acid treatment during the daffodil extraction, it seemed completely absent (79, 80). Several syntheses of phenanthridone derivatives related t o the aromatization products of narciclasine and lycoricidine and apparently designed t o further support the structural revision have been completed. I n a photochemical synthesis starting from 368 the compound 360 was obtained yielding on debenzylation narciprimine (356))whereas from 369 in an analogous way arolycoricidine (361) was prepared. Also, starting from the amide 370 through photocyclization t o 362 via 363 a compound identical with natural permethylisonarciprimine (357) was obtained (81).
144
CLAUD10 FUGANTI
do:
(00
' R
NH
a
0
R' 5 NH,; R" = R5 = H; R" x OMe; R4 = CH,CBH, 367 R' = NH,; RS x H; R3 = Rs = OMe; R' = Me 368 R1 = Br; Ra = R4 = H; R3 = R5 = OCHpCeH, 369 R' = Br; Ra = R' = R5 = H; R3 = OCHaC8H5 370 R' = R" =; R3 = R5 = H; R' = Me 371 R1 = NH,; Ra = Rs = OMe; R3 = H; R4 x Me
364 R = O H 366 R = H
386
Along the lines followed for the synthesis of the arolycoricidine derivative 358 starting from 367, permethylnarciprimine (359)was obtained (82).Similarly,permethylisonarciprimine (357)was synthetized from 371 (83).An elegant synthesis of the phenanthridone 355 possessing the structure initially assigned to narciprimine has been performed starting from 3,4-methylenedioxy-6-bromobenzoicacid and cyclohexane-1,3-dione through the key intermediates 373 and 374 (84).
a72
373 874
x =0 X = NH
With the gross structure of narciclasine firmly established through the above-mentioned syntheses of the isomeric phenanthridone derivatives 355, 356, 357, and 359, a reinterpretation of the previously reported spectral data and considerations on the chemical behavior of the natural lactam permitted the assignment of stereostructure 375 or its mirror image (84).Furthermore NMR spectroscopy indicated that only the gross structure 364 is in agreement with the observed number of carbon multiplicities revealed in the narciclasine tetraacetate spectrum, which was fully assigned (85), although more recently one of the earlier assignments was revised (86).The structural information obtained for narciclasine through the I3C-NMR spectroscopy further support the previously established (86u) usefulness of the technique.
3. T H E
AMARYLLIDACEAE ALKALOIDS
145
However, the problem of the stereochemistry and of the absolute configuration of narciclasine has been solved through X-ray analysis and biosynthetic investigations. Thus, the biological derivation of narciclasine from vittatine 284 and the X-ray data obtained on a single crystal of narciclasine tetraacetate pointed to the stereostructure 376 for the antimitotic lactam (87, 88). Subsequently, Mondon and Krohn revised their structure 375 to the correct 376 by chemical means. The acetonide 377 was obtained from 376 and oxidized to an a,p-unsaturated ketone which was reduced back (NaBH,) to a mixture of the epimeric alcohols 377 and 378. NMR data permitted full assignment for the relative stereochemistry a t positions 3,4,and 4a of 377. The full stereochemical problem was however solved through the attainment, during catalytic hydrogenation of narciclasine, of the unsaturated product 351. Indeed, comparison of the NMR spectra of 352 with those of the model compounds 353 and 354 of known stereochemistry permitted the choice of stereostructure 376 for narciclasine (89).
375 376 377 378
R' = OH: R2 = R3 = R4 = H R' = R3 = R4 = H; R2 = O H R' = H; R2 = OH; R3,R 4 = CH(Me), R' = OH; RZ = H; R3, R 4 = CH(Me),
More recently, a detailed paper discussed the synthetic problems presented by the syntheses of the substituted phenanthridones of the narciprimine-isonarciprimine series along with the synthesis of permethylisonarciprimine 357 (79).The potential pharmacological interest of narciclasine and other Amaryllidaceae metabolites has been suggested (79a, 79b).
IX. Biosynthesis As summarized in Volume XI, p. 387, the aromatic amino acids phenylalanine and tyrosine provide, through independent ways, the C - 6 4 - 1 and the C-6-C-2-N units, respectively, of the important inter-
146
CLAUD10 FUGANTI
mediate norbelladine (399) which, once suitably protected by methylation, gives rise by phenol coupling to the different C,, skeletons found among the Amaryllidaceae alkaloids. The development of sophisticated methods for tritium labeling made possible experiments which allow a rather precise description of the operations of the biosynthetic process leading (a) from the abovementioned amino acids to the C,, intermediate O-methylnorbelladine (343); (b) from the latter to the tetracyclic intermediates norpluviine (lo), noroxomaritidine (275), and narwedine (149); and (c) from the three latter alkaloids to the products of their metabolism. A description of the alkaloids of this family resulted in terms of an experimentally supported biosynthetic derivation from the abovementioned advanced precursors through a limited number of metabolic operations, involving hydroxylation Q to the nitrogen atom, at benzylic position, f l to the nitrogen atom, at saturated carbon atoms, and at allylic position, as more relevant steps of the oxidative catabolic processes in accordance with known biosynthetic schemes (90-92). Furthermore, the precise timing of the single process is defined through feeding experiments with precursors strictly related on the sequence.
A. THENORPLUVIINE SERIES A definite picture of the biosynthesis of norpluviine (lo), the key intermediate to the pyrrolophenanthridine, and the lycorenine-type alkaloids was derived from two sets of feeding experiments. In the first the mode of incorporation of the amino phenol O-methylnorbelladine 343 into 10 was examined. Thus, tritium labels were inserted ortho and para to the phenolic hydroxy groups of 343 by basecatalyzed exchange with tritiated water under conditions ensuring equal labeling in all exchangeable positions. Norpluviine biosynthetized from multiply labeled 343 in Texas daffodil was selectively degraded to locate the tritium labels. Only two of the tritium atoms present in the fed precursor were retained in radioactive 10- those at positions 2 and 8. The unexpected loss of the 3H from position 1 l b of norpluviine require some comments. The primary proposal of Barton and Cohen (90) on the oxidative cyclization of O-methylnorbelladine (343) suggested the intermediacy of the bisdienone 379 which then aromatizes to the diphenyl380 giving later, in a few stages, norpluviine. A subsequent scheme (93) involved more economically the biosynthetic route leading from 379 to 10, the ketone 381 which, by reduction, would give the required product
3. THE AMARYLLIDACEAE ALKALOIDS
147
10. In the first case, the 3H at C-1 in 379 must be lost, in the second it can survive, unless it is lost from C-1 of 381 by a selective enolization of the C-2 ketone. This would be required in order to allow epimerization at C-11 to convert a more readily formed cis B/C fused ketone 381 into the transfused skeleton of norpluviine (94). Furthermore, in an attempt to explain the low incorporation (0.00370)of 343 into galanthine (13) as compared with the 1.2y0 incorporation found for 10, a possible more advanced intermediate was tested. The choice compound was the diphenol 382 which, labeled with 14C in the skeleton, was fed to King Alfred daffodil. There was no incorporation into galanthine (13)) whereas norpluviine, carrying 3H labels a t (2-8, ortho to the phenolic hydroxy group, was incorporated although a t a low extent (0.00670). These results mean that the introduction of the fourth oxygen function takes place late in the sequence, once the pyrrolophenanthridine nucleus has been constructed (91),as already shown through the conversion of [3H]norpluviine into lycorine (1) in Twink and Deanna Durbin plants (Vol. XI, p. 399).
343
-
N H
H 379
380
OMe
HO
H 881
382
During the incorporation of 343 into 10 protonation takes place a t some stage in the sequence to form the allylic methylene a t C-2. The stereochemical course of this process has been estabiished in the following way. Tyrosine, labeled with 3H ortho to the phenolic hydroxy group and with 14C at position 2 in the side chain was incorporated (Twink and Deanna Durbin daffodil) into norpluviine and into lycorine (1))with the loss of half of the 3H labeling, the L and D forms of the amino acid being incorporated with the same efficiency. An analogous result was obtained using [3’,5’-3H2;14C-O-methyl]O-methylnorbelladine
148
CLAUD10 FUGANTI
as precursor. The 3H atom retained in lycorine was located a t C-2 by conversion into acetyllycorine-2-one (385) which was devoid of 3H activity. It follows that in the biological conversion of norpluviine into lycorine all the 3H a t C-2 of norpluviine is retained in the derived ( l ) ,thus suggesting a stereospecific course in both protonation to form the allylic methylene of 10 and hydroxylation to (1) (95). The site of the protonation was determined degrading norpluviine biosynthetized from [3’,5’-3H,; 14C-O-methyl]0-methylnorbelladine to the amine 384 through 383 with sodium ethoxide. The reaction followed secondorder kinetics and proceeded with almost complete 3H loss. Since the configuration a t C-1 Ic of norpluviine and the stereochemistry of the 1,4-conjugate, E2 elimination are both known, it was concluded that the 3H atom a t C-2 in radioactive norpluviine has the /3 configuration. It follows that (a) protonation a t C-2 of the intermediate leading from the aromatic precursor 343 t o norpluviine takes place from the a side of the molecule, and (b) hydroxylation a t C-2 of norpluviine to form lycorine occurs with an inversion mechanism (96).
383 R = CH2C,H5
384
R = CH,C,H,
385
An inversion mechanism had been previously observed in the hydroxylation of caranine (2) t o lycorine by Wildman and Heimer. They observed 77, incorporation of [2/3-3H]caranine into lycorine in Zephyranthes candida Herb., the 3H being retained a t C-2 of 1 as shown by the conversion into the inactive 385. The stereospecifically labeled precursor was obtained through LiAPH, reduction of lycorine1,2-a-epoxide prepared from lycorine via its cis-chlorohydrin and chromatography on Florisil. The structure of the a-epoxide rests on physical and chemical grounds, whereas the stereochemistry of the
3.
149
THE AMARYLLIDACEAE ALKALOIDS
introduced isotopic hydrogen is based on mass spectrometric studies in the deuteriated series. Thus the mass spectrum of acetyl [2/3-2H] caranine showed the loss of acetic acid (m/e254) with a metastable ion at 205.5. From the analogies with the known fragmentations in acetylated 3-amino steroids and peracetylated sugars it is deduced that the lack of increase in the intensity of the M-61 ion a t m/e 253 in the spectrum of acetyl [213-2H)caranine is in favor of the ,B (steroid notation) configuration of the isotopic hydrogen. The lack of an internal standard against which t o measure the 3H loss limitated the biosynthetic significance of these experiments. However, they excluded the intermediacy of a 2-keto derivative and the direct insertion of oxygen into the 213-CH bond. I n the same feeding experiments zephyranthine (14), bearing at C-2 an a-hydroxy group, isolated by dilution with inactive material was devoid of tritium (97). The unusual stereochemical course of the hydroxylation a t allylic position during the biosynthesis of lycorine in daffodil and Zephyranthes candida has been tentatively explained with the intermediacy of an epoxide like 386, undergoing stereoselective ring opening t o 387 followed by allylic isomerization t o (1) (95)or, alternatively, of an allylic carbonium ion at C-2 or of the related 1,2-a-epoxide (97).
386
387
388
The stereochemical course of the allylic hydroxylation, occurring in the biosynthesis of lycorine, was further investigated in Clivia miniata plants where lycorine is present as a minor component along with large amounts of clivimine which contains clivonine (lla), an alkaloid unique among the Amaryllidaceae metabolites because of its equatorial hydroxy group a t C-5a. I n Clivia miniata, O-methylnorbelladine (343) carrying 3H labels ortho to the phenolic hydroxy group of the tyramine-derived part and reference labels elsewhere is incorporated into lycorine and clivonine with the loss of both the 3H atoms. To explain this result, which contrasts with the previous one in daffodils (95), feeding experiments with [2/3-3H;5-14C]norpluviine (10)and [2w3H; 5-14C]caranine (2) were devised. The first precursor was isolated from daffodil in separate
150
CLAUD10 FUGANTI
incorporation experiments with [3'5'-3H2]- and [1-14C]O-methylnorbelladine (343). [2~-~H]Caranine was synthetized along the scheme used by Wildman for the synthesis of the [2p-3H] isomer (97). Thus, NaB3H, reduction of 385gave a separable mixture of [2-3H]2-epilycorine and [2-3H]lycorine (1). The latter, through the lycorine-1,2-a-epoxide and LiAlH, reduction, was converted into the required [2a-3H]caranine which was mixed with the [5-I4C] sample isolated in the abovementioned experiments in daffodils. In Clivia miniata [2w3H; 5J4C]caranine was efficiently incorporated into lycorine with ca. 92y0 3H retention, being retained at C-2, as shown from specific degradation. Instead, [Z/il-3H;5-14C]norpluviinelost ca. 80% of the 3H activity in the same conversion into lycorine. Clivonine (114) isolated in these experiments was inactive. Therefore in Clivia miniata in the biosynthesis of lycorine from 0-methylnorbelladine (343) protonation at C-2 of the intermediate leading to caranine via norpluviine (10) takes place from the a face of the molecule, as in daffodil, whereas allylic hydroxylation to form lycorine proceeds with retention of configuration, which represents the common stereochemical course of the hydroxylation at saturated carbon atoms (23). The second aspect of the biosynthesis of norpluviine which has been studied is the mechanism whereby phenylalanine is incorporated into the C-643-1 aromatic unit of the alkaloid. This takes place via cinnamic acid, hydroxylated cinnamic acids, and protocatechualdehyde (389).
889
In connection with studies on the mechanism of the 1,2 migration of hydrogen to neighboring carbon during biological hydroxylation of aromatic substrates (NIH shift) the incorporation of [3,5-2H,; 4-3H; /il-14C]cinnamicacid, of the [3-3H;/3-14C] and [4-3H;/il-14C] isomers into the aromatic C-6-C-1 unit of norpluviine and capsaicine has been studied. Since the augmented 3H retentions observed in previous work on the conversion of phenylalanine into tyrosine and of cinnamic acid into p-coumaric acid had been explained through the operation of a kinetic tritium isotope effect the work was designed to measure accurately this effect using intact plants. Incorporation of [4-3H; /l-14C]cinnamicacid into norpluviine caused 507, 3H loss, and the same loss was observed in the incorporation of the [3,EG2H2; 4-3H; /3J4C] isomer, in agreement with para-hydroxylation
3.
THE AMARYLLIDACEAE ALKALOIDS
151
involving complete migration and retention of tritium and a second hydroxylation at one of the two equivalent positions causing loss, without migration, of half the remaining tritium. The 3H atom which is retained is a t position 11 of 10. Since in the para-hydroxylation process an intermediate like 388 is invoked, tritium loss without enzymic control would show in the first experiment an H/T isotopic effect and in the second experiment a much smaller D/T isotopic effect. The identity of the 3H values for the two experiments is in favor of an enzymic control in the elimination without isotope effect. Confirmation of these results arose from feeding experiments using [3-3H; /?-14C]cinnamicacid which was incorporated with ca. 75y0 3H loss, thus indicating para-hydroxylation with migration and retention of hydrogen to carbon bearing either tritium or hydrogen with loss of half the 3H, followed by introduction of the second hydroxy group with loss of half the remainder. The evidence therefore suggested that if an arene oxide is involved in the para-hydroxylation its isomerization to a phenol occurs with retention of the migrating hydrogen and loss of the hydrogen from carbon ortho to the point of attack. It follows that if intermediates like 388 are involved hydrogen removal therefore is enzymically controlled and hence stereospecific (98). The next intermediate following hydroxylated cinnamic acids on the biosynthetic route from phenylalanine to the C-6-C-1 unit of the Amaryllidaceae alkaloids is protocatechualdehyde (389). The stereochemistry of the protonation taking place in the incorporation of 389 into the aromatic C-642-1unit of norpluviine and haemanthamine (318) has been determined along with the stereochemical course of the hydrogen removal occurring in the hydroxylation a to the nitrogen atom in the conversion of 10 and 318 into lycorenine (102) and haemanthidine (248), respectively. In the first instance [formyl-3H]protocatechualdehyde was incorporated into norpluviine and haemanthamine (Twink and Texas daffodil). The latter 3H-labeled materials were mixed with identical compounds obtained through feeding experiments with [1-l4C]0methylnorbelladine (343) to furnish [7-3H; 5-14C]norpluviine and [6-3H; 12-14C]haemanthamine. Doubly labeled norpluviine was incorporated (Tresamble and Inglescombe daffodil) into pluviine (11) and lycorenine without significant 3H loss, the retained 3H atom being at C-7 of 102 as shown by its degradation to 103 which was devoid of 3H. Doubly labeled haemanthamine (318) was converted in X. formosissima into haemanthidine (248) again without 3H loss. In the same two plants [l’-3H; l-14C]0-methylnorbelladine(343), randomly labeled with 3H at benzylic position, was incorporated into pluviine
152
CLAUD10 FUGANTI
(11) without loss and into lycorenine with the loss of half the 3H, whereas 318 retained an unchanged 3H/14C ratio with respect to the fed precursor 343 and haemanthidine a 50% drop in the 3Hactivity. This evidence indicated that in the incorporation of 389 into the C-6-4 1 unit of the Amaryllidaceae alkaloids both the protonation taking place to form the benzylic methylene of 343 and hence of 10 and 318 and the subsequent hydroxylation of the latter two t o 102 and 248 respectively, are stereospecific processes, the hydrogen introduced being that removed in the oxidation (19). The absolute stereochemistry of the two processes was determined through feeding experiments using stereospecifically labeled precursors. Enzymic reduction (liver alcohol dehydrogenase and NADH,) of [formyl-3H]3-benzyloxy-4-methoxybenzaldehyde yielded the alcohol 390 converted, through the chloride 391 (SOC1, in dry ether), into the azide 392 (NaN, in hexamethylphosforicacidtriamide. The amine 393 was obtained by LiAlH, reduction. The conversion of the amine 393 in the desired 0-methylnorbelladine (343) was performed through the amide 394, LiAlH, reduction and debenzylation, conditions not affecting the chiral center. Therefore, the optical purity and the absolute configuration of the final product can be safely considered coincident with those of the amine 393. This information was gained in the deuteriated series, degrading 393 (R2 = 2H)to [2-2H]glycine which was shown by ORD and mass spectrometric measurements t o contain ca. 75y0of the 2R isomer (395).( l'R)-[l'-,H; l-14C]-0-Methylnorbelladine (396)was incorporated (Texas daffodil) into norpluviine without tritium loss. The latter doubly labeled alkaloid was later incorporated (Inglescombe and Tresamble daffodil) into pluviine (11) without loss and into lycorenine (102) with ca. 82% loss, thus showing that in the oxidation of 11 to 102 a pro-R hydrogen from C-7 is removed. These results, compared with those mentioned above, establish that in the incorporation of protocatechualdehyde into the aromatic C-6-C-1unit of the Amaryllidaceae alkaloids protonation takes place from the re-face of the molecule and that the oxidation of the rigid amine 11 proceeds C6H,CH,0 "'OQX 390 391 392 393 394
R' = 3H; R2 = R1 = 3H; RZ = R' = 'H; R2 = R' = H; R2 = R' = H; R 2 =
R'
R2
H; X = OH H; X = C1 3H; X = N3 3H; X = NH, 3H; X = NHCOCH&,H,OCH,C,H,(p)
HoocxN H
395
2H
3. THE AMARYLLIDACEAE
ALKALOIDS
153
with the stereospecific removal of an a: hydrogen from benzylic position (99).
B. THE GALANTHAMINE SERIES I n daffodil plants, galanthamine (147) is biosynthesized from the aminophenols 397, 398, and 399 but not from 343 which is, however, in the same plants a good precursor of haemanthamine (318) and lycorine (1) (Vol. XI, p. 397). These experimental results were interpreted as proving the existence of a definite order of methylation of norbelladine (399) during the biosynthesis of 147. Thus, methylation takes place in the first instance a t nitrogen to give 398, later converted into 397.
396 397 398 a99
R' = Me; RZ = H R' = R2 = M e R' = H; R2 = Me R' = ~2 = H
I n feeding experiments in Leucojum aestivum L. it has been observed that [3',5'-3H,; 14C-O-methyl]O-methylnorbelladine (343) is a good precursor of 147 which retains the same 3H/14Cratio of the fed precursor. As expected lycorine showed ca. 50% 3H loss. The 3H labels in radioactive 147 were located a t positions 2 and 4 because its oxidation t o narwedine (149) followed by alumina chromatography and crystallization from MeOH, conditions which cause exchange of the hydrogen atoms ortho to the carbonyl, determined complete loss of the 3H activity. This means that in the biosynthesis the addition of the phenolic hydroxy group onto the intermediate enone 400 is not reversible or, if so, under enzymic control (100).
400
154
CLAUD10 FUGANTI
( k )-[3H]Narwedine and from the latter ( & )-[3H]galanthamine (147) and ( f )-[3H]epigalanthamine(148) were prepared from narwedine
and tritiated methanol. The three labeled alkaloids were used to show that in Chlidanthus fragrans Herb. chlidanthine (152) arises from galanthamine through demethylation and methylation, not necessarily in this order. The incorporation values decreased from the 1 .08% after 2 days from the feeding to 0.081% a t the seventh day. The biosynthetic catabolic derivation of chlidanthine from 147 thus established confrmed the stereochemical relationship based on chemical interconversions (30).
C . NARCICLASINE The antimitotic lactam narciclasine (376) is widely distributed in Amaryllidaceae plants. It seems, however, nonassociated apparently with any particular alkaloid, the only chemotaxonomic peculiarity being its absence in plants usually containing alkaloids possessing the
(- )-crinaneskeleton (101). Lycorine and haemanthamine, which more frequently accompany narciclasine (3761, are biologically derived from O-methylnorbelladine (343) by phenol coupling along path a or path b, and it seemed possible that 376 might arise by a variant of the same biosynthetic process involving late degradation of the C,, skeleton formed by either way (Scheme I). Feeding experiments with several specifically labeled precursors support this view and further define some of the metabolic operations which follow path b. [3’,5’-3H,; 14C-0-methyl]0-Methylnorbelladinewas synthetized from tyramine labeled with 3H ortho to the phenolic hydroxy group and [l*C]benzylisovanilline according to well-established methods. The [2’, 6’-3H,; 14C-O-methyl]isomer was similarly prepared from tyramine carrying 3H labels meta to the phenolic hydroxy group. The latter, in turn, was obtained as follows. Tritium atoms were inserted ortho to the phenolic hydroxy group of mono-0-benzylhydroquinone by base-catalyzed exchange with tritiated water. The activating hydroxy group was reductively removed to give [3,5-3H,]phenol, converted into meta-labeled tyramine in unexceptional ways. The first, ortho-labeled precursor O-methylnorbelladine, was incorporated in Twink and Deanna Durbin daffodils into lycorine (ca. 5007, 3H retention), haemanthamine (ca. 10070 3H retention), and narciclasine (ca. 7507, 3H retention). The 75y0 3H retention observed
3. THE AMARYLLIDACEAE ALKALOIDS
155 OH
343 path b
I
343
I H
OH
401
0 378
I
t
402 403
R =H R = Br 9H
404
405
408
SCHEME I
in 376 compared with the expected 50y0 retention shown by lycorine pointed t o a derivation of the lactam from 343 along path b. This was further strengthened by the location of the 3H labels in radioactive narciclasine and haemanthamine. Indeed, narciclasine, when it was aromatized t o narciprimine in acidified heavy water, lost ca. 30Ya of the 3H activity without pick up of deuterium from the solvent. Since in this conversion the hydrogen atoms a t positions 4 and 4a of 376 are removed, the tritium which is lost must be located a t one or both of the above-mentioned positions. However, because of the inactivity of narciclasic aldehyde which retains the 4a hydrogen, the removed 3H atom was assigned at position 4. Haemanthamine was converted into the ketone 321 (R1, R2 = 0; R3 = OMe; R4 = H) with the loss of half the 3H a t the last step of the sequence when the hydrogen originally at position 2 was removed. Confirmation in favor of this metabolic pathway arose from the second experiment using the meta-labeled
156
CLAUD10 FUGANTI
precursor. This was incorporated into narciclasine and haemanthamine without significant 3H loss and into norpluviine with ca. 15% 3H loss. The 3H labels were assigned a t positions 1 and 4a of 376 because narciclasic aldehyde 372 retained all the 3H activity and because narciprimine, formed with 50y0 3H loss, resulted free of 3H activity when the hydrogens ortho and para to the phenolic hydroxy group of ring C were substituted for deuterium by base-catalyzed exchange on a suitable derivative. Narciclasine is therefore biosynthetized from 0-methylnorbelladine by para-para coupling, three of the 3H atoms present in the corresponding position in the fed precursor being retained completely a t positions 2,1, and 4a of 376. Half of the 3H activity originally present in one of the two positions ortho t o the phenolic hydroxy group in the precursor is lost from position 4 of 376.Furthermore, [3H]oxocrininewas specifically incorporated into narciclasine and haemanthamine (102). Subsequent feeding experiments defined the nature of the intermediates between 343 and 376.Thus, noroxomaritidine (275),carrying 3H labels a t positions 1 and 4a, was obtained chemically from 343. The tetracyclic labeled compound 275 was reduced (NaB3H,) to give [1,3,4a-3H3]epinormaritidine,partially converted upon acid treatment into [ 1,3,4a-3H3]normaritidine(404). The labeling pattern of the above-mentioned compounds was determined by specific degradation. Similarly, from synthetic oxocrinine [3-3H]epicrinine and [3-3H]crinine were synthesized. Daffodil plants incorporated racemic noroxomaritidine (275),normaritidine (404),and crinine but not epinormaritidine and epicrinine into narciclasine and haemanthamine. Again, specific degradation of radioactive 376 obtained from the multiply labeled precursors showed that no 3H loss took place during the biosynthesis. It must therefore be concluded that narciclasine biologically derives from 343 through its first coupling product noroxomaritidine, the successive intermediates bearing a pseudoaxial hydroxy group a t position 3 of the 5, lob-ethanophenanthridineskeleton. Furthermore, hydrogen removal from position 3 during the biosynthesis does not occur and, finally, the methylenedioxy group of the crinine skeleton is formed irrespective of the oxidation level a t C-3 (103). The availability of the enantiomeric alkaloids vittatine (284)and crinine in labeled form through separate feeding experiments with labeled 343 in Pancratium maritimum L. and Nerine bowdenii, respectively, provided experiments which indicated the absolute configuration of narciclasine. Thus, the two alkaloids were obtained from [3,'5'-3H,]0-methylnorbelladine. Experiments with multiply labeled 343 have previously shown that no 3H loss takes place during the biosynthesis,
3.
THE AMARYLLIDACEAE ALKALOIDS
157
the 3H atoms a t positions 2 and 4 being retained as indicated by specific degradation. Vittatine was incorporated in P. maritimum into narciclasine and haemanthidine, whereas crinine in Texas and Twink daffodil was not. I n a parallel experiment using racemic material 2.1 yo incorporation was observed. The ratio of the 3H labels between positions 2 and 4 of 376 was ca. 2: 1 because radioactive narciclasine was degraded t o narciprimine with ca. 35y0 3H loss. This indicated that in the conversion of vittatine into narciclasine, the process whereby the methylene a t position 4 of 284 is hydroxylated, involves 50% 3H loss (87). The latter observation pointed to the question of the stereochemistry of the 3H atoms present a t position 4 of vittatine biosynthesized from ortho-labeled 3H 343. Previous work on haemanthamine (318) had shown that the degradations of oxohaemanthamine (407) and oxohaemanthamine methiodide (408) prepared from 318 biosynthesized from [3’,5’-3H,; 14C-O-methyl]0-methylnorbelladine leading t o the diphenyl derivatives (409) and (410) possibly through the intermediacy of 407a and 40% proceeded with different 3H retentions: 74 and 93y0, respectively. It seemed therefore that the protonation taking place in the conversion of the dienone (401) into noroxomaritidine (275) proceeded in a nonstereospecific fashion although further work is needed t o settle the question completely (104).
407
408
407a
408a
409
410
158
CLAUD10 FUQANTI
Ismine (402), which possesses a C,, skeleton as does narciclasine, is present in trace amount in a few Amaryllidaceae plants. Feeding experiments in Sprekelia formosissima have shown its derivation from oxocrinine through late elimination of the ethano bridge. Thus [2,43H]oxocrinine was incorporated into ismine, the 3H label(s) at both or one of positions 2 and 4 being retained as shown from the inactivity of the dibromo derivative (403) (105).More recently, it has been shown that the biological conversion of the 5,lOb-ethanophenanthridine intermediate noroxomaritidine into ismine involves the stereospecific hydrogen removal of a pro-R hydrogen from the benzylic position a to the tertiary nitrogen followed by hydrogen addition. Furthermore, the carbon atom at position 1 in 343 is not retained in 402 as N-methyl group. The stereochemical course of the oxidation in the biosynthesis of ismine is identical with that observed in the conversion of haemanthamine into haemanthidine, therefore strengthening a possible biogenetic relationship between the haemanthamine-haemanthidinepretaeettine-tazettine series and ismine (206). These results in the biosynthesis of narciclasine and ismine prompted the search for the next intermediate which might undergo C-C cleavage in a mechanistically acceptable manner to account for the loss of the two carbon units represented by the “ethano” bridge as well as the 3H retention observed so far. The choice compound seemed 11-hydroxyvittatine (405) which might undergo a retro-Prins reaction as indicated in the scheme to give an intermediate like 406 which in a few oxidative steps could give the required lactam 376. Indeed, 3H-labeled 405 obtained in feeding experiments in P. maritimum, seems to be a precursor of narciclasine in daffodil (107).
D. HAEMANTHAMINE In the biosynthesis of haemanthamine (318) hydroxylation at the methylene a t position 11, /3 to the nitrogen atom, takes place late in the sequence once the 5 , lob-ethanophenanthridine skeleton had been constructed from 0-methylnorbelladine (102). The stereochemical course of the hydroxylation process has been studied independently by two groups. Two specimens of 0-methylnorbelladine carrying stereospecific 3H labels a t position 2 were synthesized from the alcohol 412 obtained by enzymic reduction of the [f~rmyl-~Hlaldehyde 411. Conversion of 412 into 415 and 416 proceeded through malonate displacement of the chlorides 413 and 414, respectively. The chloride 413 was obtained by the
3. THE AMARYLLIDACEAE ALKALOIDS
159
action of thionyl chloride on 412, whereas compound 414 was formed upon treatment of 412 with triphenylphosphine and CCl,. The two acids 415 and 416 were transformed into the enantiomeric O-methylnorbelladine (417) and (418) through a procedure not affecting the chiral center. Therefore, the optical purity and the absolute configuration of the precursors must be the same for the propionic acids 415 and 416. These, in the deuteriated series, were degraded to [2-2H]succinic acids whose configuration and optical purity were determined by ORD and mass spectrometric measurements.
RYo *H
411
R = p-CBHSCH20CBH4
418 416
R' = 'H; R" = 3H R' = 3H; Ra = 'H
H *H
*H H 412 413
417 418
X = OH X = C1
414
X = C1
HB= 3H; H, = 'H H, = 'H; H, = 3H
The two enantiomeric precursors, when mixed with identical 14Clabeled samples, were fed to King Alfred daffodil. High 3H retention (ca. 660jb) was observed in haemanthamine with the (28) isomer 417, whereas 30y0 was detected for the (222) isomer 418. Oduline (109) completely retains the 3H labels in both feedings. Furthermore, O-methylnorbelladine labeled with 3H and 14C at position 1 was incorporated without 3H loss in both 318 and 109. It follows that the 3H loss from the position p to the nitrogen atom in 318 takes place during the hydroxylation which, since the absolute stereochemistry of 318 is known, proceeds with retention of configuration (108). The alternative approach to the determination of the stereochemistry of hydroxylation /3 to the nitrogen occurring in the biosynthesis of haemanthamine involved the synthesis of stereospecifically labeled tyrosine. Catalytic hydrogenation of suitable acylaminocinnamic acids labeled with isotopic hydrogen in i3 position proceeds stereoselectively to furnish an equimolecular mixture of ~-#?R-~H]-and ~-[%%~H]tyrosine (419) and (420). Enzymic resolution of the racemic amino acid yielded the L and D isomers. The two optically active forms of tyrosine were
160
CLAUD10 PUGANTI
epimerized at the Q center to give ~ ~ - [ P R - ~ H ] t y r o sand i n e DL-[PS-~H]tyrosine. The optical purity of the labeled materials was determined, in the deuteriated series, by oxidative cleavage of the mixture of 419 and 420 (2Hinstead of 3H) to DL-deuteroaspartic acid, shown by NMR studies to be the threo isomer. Feeding experiments with optically active doubly labeled tyrosine carrying 3H label showed that in Texas daffodil hydroxylation t o the nitrogen to form haemanthamine proceeds with retention of configuration. The 3H atom which survives in haemanthamine (318) is in position 11 because the ketone 407 obtained from radioactive 318 was devoid of tritium activity (109).
420
419
A third synthesis of C-6-C-3 phenylpropanoid precursors stereospecifically labeled with isotopic hydrogen a t benzylic position has been reported. This involves, as a relevant step, the stereospecific ring opening of isotopically labeled optically active oxazines to form amides (110). According to this procedure, the two isomeric O-methylnorbelladines (417) and (418) were prepared. The materials were used to show that in Haemanthus coccineus the conversion of O-methylnorbelladine into the montanine-type alkaloids a pro-S hydrogen is removed from the methylene p to the nitrogen. Chemically, haemanthamine derivatives are converted by solvolysis into montanine-type derivatives. The stereochemical course observed so far in the biological conversion of O-methylnorbelladine into montanine (321) is opposite t o that shown in the hydroxylation leading to haemanthamine (318). The work therefore indicates that if a haemanthamine-like intermediate is involved in the biosynthesis of the montanine-type alkaloids from 343 in these plants hydroxylation takes place with opposite stereochemistry (111). REFERENCES
1. K. Kotera, Y. Hamada, and R. Nakane, Tetrahedron 24, 759 (1968). 2. K. Kuriyama, T. Iwata, M. Moriyama, K. Kotera, Y. Hamada, R. Mitsui, and K. Takeda, J . Chem. Soc., B 46 (1967). 3. K. Kotera, Y. Hamada, and R. Mitsui, T e t . Lett. 6273 (1966). 4. K. Kotera, Y. Hamada, and R. Mitsui, Tetrahedron 24, 2463 (1968). 5. J. B. Hendrickson, R. W. Alder, D. R. Dalton, and D. G . Hey, J . Org. Ghem. 34, 2667 (1969).
3.
THE AMARYLLIDACEAE ALKALOIDS
161
6. V. A. Landeryou, E. J. J. Grabowski, and R. L. Autrey, Tetrahedron 25, 4307 (1969). 7. B. Ganem, Tet. Lett. 4105 (1971). 8. S. F. Dyke, M. Sainsbury, and J. R. Evans, Tetrahedron 29, 213 (1973). 9. H. Hare, 0. Hoshino, and B. Umezawa, Tet. Lett. 5031 (1972). 10. H. Irie, Y. Nishitani, M. Sugita, and S. Uyeo, Chem. Commun. 1313 (1970). 11. H. Irie, Y. Nishitani, M. Sugita, K. Tamoto, and S. Uyeo, J. Chem. Soc., Perkin Trans. 1, 588 (1972). 12. E. W. Warnhoff and S. Valverde Lopez, Tet. Lett. 2733 (1967). 13. J. C. Clardy, W. C. Wildman, and F. M. Hauser, J. Amer. Chem. SOC.92, 1781 (1970). 14. A. Immirzi and C. Fuganti, J. Chem. SOC.,B 1218 (1971). 15. M. R. Yagudaev, K. A. Abduazimov, and S. Yu. Yunusov, Khim. Prir. Soedin. 99 (1969). 16. C. Fuganti, unpublished observations, (1973). 17. K. A. Abduazimov and S. Yu. Yunusov, Khim. Prir. Soedin. 4, 263 (1968). 18. R. J. Suhadolnik, Abh. Deut. Akad. Berlin, K1. Chem., Geol. Biol. 369 (1966). 19. C. Fuganti and M. Mama, Chem. Commun. 1196 (1971). 20. J. C. Clardy, J. A. Chan, and W. C. Wildman, J. Org. Chem. 87, 49 (1972). 21. H. K. Schoens, D. H. Smith, A. L. Burlingame, P. W. Jeffs, and W. Doepke, Tetrahedron 24, 2825 (1968). 218. J. F. Hansen, Ph.D. thesis, Duke University (1968). 22. D. M. Tsakadze, A. Abdusamatov, R. Razakov, and S. Yu. Yunusov, Khim. Prir. Soedin. 6 , 773 (1970); CA 74, 100246 (1970). 23. C. Fuganti and M. Mama, J. Chem. Soc., Chem. Commun. 936 (1972). 24. P. W. Jeffs, J. F. Hauser, W. Doepke, and M. Bienert, Tetrahedron 27,5065 (1971). 26. H. Irie, Y. Nagai, K. Tamoto, and H. Tanaka, J. Chem. ~ o c . ,Chem. Commun. 820 (1973). 26. W. Doepke and M. Bienert, Tet. Lett. 3245 (1970). 27. W. Doepke and M. Bienert, P h m a z i e 25, 700 (1970). 28. W. Doepke and M. Bienert, Tet. Lett. 745 (1970). 29. W. C. Wildman and C. L. Brown, Tet. Lett. 4673 (1968). 30. J. C. Bhandarkar and G. W. Kirby, J. Chem. SOC.,C 1224 (1970). 30a. C. Nogueiras, W. Doepke, and G. Lehman, Tet. Lett. 3249 (1971). 31. J. C. Bhandarkar end G. W. Kirby, J. Chem. Soc., C 592 (1970). 32. T. Kametani, K. Yamaki, S. Shibuya, K. Fukumoto, K. Kigesawa, F. Satoh, M. Hiiragi, and T. Hayasaka, J. Chem. SOC.,C 590 (1971). 33. R. A. Abramovitch and S. Takahashi, Chem. I d . (London) 1039 (1963). 34. B. Frank, H. J. Lubs, and G. Dunkelmann, Angew. Chem., Int. Ed. Engl. 6 , 969 (1967); B. Frank and H. J. Lubs, Ann. 720, 131 (1968). 36. T. Kametani, K. Yamaki, H. Yagi, and K. Fukumoto, Chem. Commun. 425 (1969). 36. T. Kametani, C. Seino, K. Yamaki, S. Shibuya, K. Fukumoto, K. Kigasawa, F. Satoh, M. Hiiragi, and T. Hayasaka, J. Chem. Soc., C 1043 (1971). 37. T. Kametani, K. Yamaki, and T. Terui, J . Heterocycl. Chem. 10, 35 (1973). 38. T. Kametani, K. Shishido, E. Hayashi, C. Seino, T. Kohno, S. S. Shibuya, and K. Fukumoto, J. Org. Chem. 86, 1295 (1971). 39. T. Krtmetani et al., Symp. Pap. Natur. Prod., 15th, 1971 p. 123 (1971). 40. N. Hazama, H. Irk, T. Mizutani, T. Shingu, M. Takada, S. Uyeo, and A. Yoshitake, J . Chem. SOC.,C 2947 (1968). 41. Y. Misaka, T. Mizutani, M. Sekido, and S. Uyeo, Chem. Commwn. 1258 (1967); J. Chem. Soc., C 2954 (1968).
162
CLAUD10 FUGANTI
G. G. De Angelis and W. C. Wildman, Tetrahedron 25, 5099 (1969). G. G. De Angelis and W. C. Wildman, Tet. Lett. 729 (1969). M. A. Schwartz and R. A. Holton, J . Amer. Chem. Soe. 92, 1090 (1970). J. Clardy, F. M. Hauser, D. Dahm, R. A. Jacobson, and W. C. Wildman, J. Amer. Chem. Soc. 92, 6337 (1970). 46. J. Karle, J. A. Estlin, and I. L. Karle, J . Amer. Chem. Soc. 89, 6510 (1967). 47. M. R. Slabaugh and W. C. Wildman, J . Org. Chem. 36, 3202 (1971). 48. C. Nogueiras, W. Doepke, E. Grundemann, and G. Lehmann, Tet. Lett. 2743 (1971). 49. N. F. Proskurnina, Zh. Obshch. Khim. 23, 3365 (1957). 50. W. C. Wildman and D. T. Bailey, J. Amer. Chem. Soc. 89, 5514 (1967). 51. W. C. Wildman and D. T. Bailey, J. Org. Chem. 33, 3749 (1968). 52. W. Doepke and P. W. Jeffs, Tet. Lett. 1307 (1968). 53. W. C. Wildman and D. T. Bailey, J. Amer. Chem. SOC.91, 150 (1969). 54. R. J. Highet, J. C. N. Ma, and P. F. Highet, J. OTg. Chem. 33, 3096 (1968). 66. R. J. Highet and P. F. Highet, J. Org. Chem. 33, 3105 (1968). 55a. T. Sato, and H. Koyama, J . Chem. Soc., B 1070 (1971). 56. B. Frank and H. J. Lubs, Ang. Chem. 80, 238 (1968). 57. M. A. Schwartz and R. A. Holton, J . Amer. Chem. SOC.92, 1090 (1970). 58. M. A. Schwartz, B. F. Rose, and B. Vishnuvajjala, J. Amer. Chem. Soe. 95, 612 (1973). 59. T. Kametani and T. Kohno, Tet. Lett. 3155 (1971). 60. T. Kametani, T. Kohno, S. Shibuya, and K. Fukumoto, Chem. Commun. 774 (1971). 61. T. Kametani, T. Kohno, and R. Charubala, Chem. Pharm. Bull. 20, 1488 (1972). 62. E. Kotani, N. Takeuchi, and S. Tobinaga, Tet. Lett. 2735 (1973). 63. H. W. Whitlock, Jr. and G. L. Smith, J. Amer. Chem. SOC.89, 3600 (1967). 64. R. V. Stevens and L. E. Du Pree, Jr., Chem. Commun. 1586 (1970). 65. I. Ninomiya, T. Naito, and T. Kiguchi, Chem. Commun. 1669 (1970). 66. J. B. Hendrickson, T. L. Bogard, and M. E. Fisch, J . Amer. Chem. SOC.92, 5538 (1970). 67. M. Lauglois, C. Guillonneau, J. Meingan, and J. Maillard, Tetrahedron 27, 5641 (1971). 68. Y. Tsuda and K. Isobe, Chem. Commun. 1555 (1971). 69. Y. Tsuda, A. Ukai, and K. Isobe, Tet. Lett. 3153 (1972). 70. W. C. Wildman and C. L. Brown, J . Amer. Chem. Soc. 90, 6439 (1968). 70a. H. M. Fales, H. A. Lloyd, and G. W. A. Milne, J . Amet-. Chem. SOC. 92, 1590 (1970). 71. A. Brossi, G. Grethe, S. Teitel, W. C. Wildman, and D. T. Bailey, J . Org. Chem. 36, 1100 (1970). 72. V. Toome, J. F. Blount, G. Grethe, and M. Uskokovic, Tet. Lett. 49 (1970). 73. A. Brossi and S. Teitel, Tet. Lett. 417 (1970). 74. A. Brossi and S. Teitel, J . Org. Chem. 35, 3559 (1970). 75. M. A. Schwartz and S. W. Scott, J. Org. Chem. 36, 1827 (1971). 76. F. Piozzi, C. Fuganti, R. Mondelli, and G. Ceriotti, Tetrahedron 24, 1119 (1968). 77. C. Fuganti, A. Selva, and F. Piozzi, Chim. Ind. (Milan) 49, 1196 (1967). 78. T. Okamoto, Y. Torii, and Y . Isogai, Chem. Pharm. Bull. 16, 1860 (1968). 79. A. Mondon and K. Krohn, Ber. 105, 3726 (1972). 79a. G. Ceriotti, Nature (London) 213, 595 (1967). Exp. 33601. 79b. E. Furusawa, S. Furusawa, S. Morimoto, and W. Cutting, Proc. SOC. Med. 136, 1168 (1971). 80. C. Fuganti, unpublished observations (1968). 81. A. Mondon and K. Krohn, Tet. Lett. 2123 (1970). 42. 43. 44. 45.
3.
T H E AMARYLLIDACEAE ALKALOIDS
163
82. G. Savona, F. Piozzi, and M. L. Marino, Chem. Commun. 1006 (1970). 83. G. Savona and F. Piozzi, Chem. Ind. (London) 1627 (1970); J. Heterocycl. Chem. 8, 681 (1971). 84. A. Mondon and K. Krohn, Ber. 103, 2729 (1970). 85. L. Zetta, G. Gatti, and C. Fuganti, Tet. Lett. 4447 (1971). 86. L. Zetta, G. Gatti, and C. Fuganti, J. Chem. Soc., Perkin Trans. 2, 1180 (1973). 86a. W. 0. Crain, W. C. Wildman, and J. D. Roberts,J. Amer. Chem.Soc. 93,990 (1971). 87. C. Fuganti and M. Mazza, J . Chem. Soc., Chem. Commun. 239 (1972). 88. A. Immirzi and C. Fuganti, J . Chem. Soc., Chem. Commun. 240 (1972). 89. A. Mondon and K. Krohn, Tet. Lett. 2085 (1972). 90. D. H. R. Barton and T. Cohen, Festschr. Prof. Dr. Arthur Stoll Siebzigsten Qeburtstag 1957 p. 117 (1957). 91. A. R. Battersby, i n “Oxidative Coupling of Phenols” (W. I. Taylor and A. R. Battersby, eds.), p. 119 Arnold, London, 1967. 92. K. Mothes and H. R. Schiitte, “Biosynthese der Alkaloide,” VEB Deut. Verlag Wiss., Berlin, 1969. 93. D. H. R. Barton, Hugo Muller Lecture, Proc. Chem. Soc., London 293 (1963). 94. G. W. Kirby and H. P. Tiwsri, J . Chem. SOC.,C 676 (1966). 95. I. T. Bruce and G . W. Kirby, Chem. Commun. 207 (1968). 96. I. T. Bruce and G. W. Kirby, Chimia 22, 314 (1968). 97. W. C. Wildman and N. E. Heimer, J . Amer. Chem. SOC.89, 5265 (1967). 98. W. R. Bowman, I. T. Bruce, and G. W. Kirby, Chem. Commun. 1075 (1969). 99. C. Fuganti and M. Mazza, J . Chem. Soc., Perkin Trans. 1, 954 (1973). 100. C. Fuganti, Chim. Ind. (Milan) 51, 1254 (1969). 101. F. Piozzi, M. L. Marino, C. Fuganti, and A. Di Martino, Phytochemistry 8, 1745 (1969). 102. C. Fuganti, J. Staunton, and A. R. Battersby, Chem. Commun. 1154 (1971). 103. C. Fuganti and M. Mazza, Chem. Commun. 1388 (1971). 104. C. Fuganti, Chim. Ind. (MiZan) 51, 1254 (1969). 105. C. Fuganti and M. Mazza, Chem. Commun. 1466 (1970). 106. C. Fuganti, Tet. Lett. 1785 (1973). 107. C. Fuganti, unpublished results. 108. A. R. Battersby, J. E. Kelsey, and J. Staunton, Chem. Commun. 183 (1971); A. R. Battersby, J. E. Kelsey, J. Staunton, and K. F. Suckling, J . Chem. SOC., Perkin Trans. 1, 1609 (1973). 109. G. W. Kirby and J. Michael, Chem. Commun. 187 (1971); J. Chem. SOC.,Perkin Trans. 1, 115 (1973). 110. C. Fuganti, D. Ghiringhelli, and P. Grasselli, J . Chem. SOC.,Chem. Commun. 1152 (1972). 111. C. Fuganti, D. Ghiringhelli, and P. Grasselli, J . Chem. SOC.,Chem. Commun. 430 (1973). 112. S. Rangaswami, Colloq. Int. Cent. Nat. Rech. Sci. 144, 89 (1966); C A 67, 79632 (1967). 113. R. V. K. Rao, Curr. Sci. 39, 134 (1970). 114. D. M. Tsakadze, D. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. Soedin. 5 , 331 (1969); C A 7 2 , 51804 (1970). 115. D. M. Tsakadze, N. T. Kiparenko, N. S. Tsitsishvili, A. Abdusamatov, and S. Yu. Yunusov, Soobshch. Akad. Nauk Gruz. SSR 56, 305 (1969); C A 72, 107840 (1970). 116. S. Yu Yunusov, T. N. Kiparenko, R. Razakov, A. Abdusamatov, and D. M. Tsakadze, Soobshch. Akad. Nauk Qruz. SSR 65, 333 (1972); C A 77, 45496 (1972).
164
CLAUD10 FUGANTI
E. Z. Asvenaand E. N. Vergeichik, Nauch. Dokl. Vy'yssh.Shk., Biol.Nauki 98 (1967). L. D. Kalashnikov, Khim. Prir. Soedin. 6, 380 (1970); C A 73, 127734 (1970). I. Leifertova and V. Brazdova, Cesk. Farm. 16, 352 (1967). N. S. Tsitsishvili, T. N. Kiparenko, G. I. Tsitsishvili, and D. M. Tsakadze, Tr. Tbilis. Qos. Univ. 137, 171 (1971). 121. R. V. Rao and R. Vimaladevi, Planta Med. 42, 142 (1972). 122. R. V. Rao, A. Nazar, and M. Vimaladevi, Indian J. Pharm. 33, 56 (1971). 123. E. V. Rao, V. Devi, and R. V. Rao, Cum. Sci. 38, 341 (1969). 124. L. D. Kalashnikov and M. V. Savicheva, Farmatsiya (Moscow) 19, 26 (1970); CA 73, 38477f (1970). 125. Kh. A. Abduazimov and S. Yu. Yunusov, Khim. Prir. Soedin. 3,64 (1976); C A 67, 220573 (1969). 126. F. Sandberg and K. H. Michel, Acta Pharm. Suecica 5 , 61 (1968). 127. Kh. Allayarov, A. Abdusamatov, and S. Yu. Yunusov, Khim. Prir. floedin. 6 , 143 (1970); C A 73, 68771 (1970). 128. G. Phokas, Pharm. Acta. Helv. 44, 257 (1969). 129. T. Sadikov and T. T. Sakirov, Khim. Prir. Soedin. 8, 134 (1972). 130. Kh. Allayarov and Kh. Abduazimov, Probl. Osvoeniga Pustyn 1, 83 (1970); CA 75, 1484883 (1971). 131. R. V. K. Rao and R. V. Devi, Cum. Sci. 39,374 (1970). 132. R. V. Rao, IndianJ. Pharm. 31, 62 (1969). 133. R. V. K. Rao, Indian J. Pharm. 31, 86 (1969). 117. 118. 119. 120.
-CHAPTER
4---
THE CYCLOPEPTIDE ALKALOIDS" R . TSCHESCHE AND E . U . KAUBMANN Irastitut fur Organische und Biochemie der Universitat Bonn. B R D . Germany
I. Introduction ...................................................... I1. Occurrence and Isolation ........................................... I11 Properties ........................................................
.
A. General Properties .............................................. B. Identification .................................................. C. Classification .................................................. I V . Types of Cyclopeptide Alkaloids ..................................... A Frangulanine Type ............................................. B . Integerrine Type ............................................... C. Amphibine-B Type ............................................. D Zizyphine-AType .............................................. E. Mucronine-AType .............................................. F Other Peptide Alkaloids ......................................... V UV and I R Spectra and Circular Dichroism ............................ VI NMR Spectra ..................................................... A. General ....................................................... B Stereochemistry of the Aryl Ether Group .......................... C StyrylamineGroup ............................................. V I I Mass Spectra ...................................................... A. Frangulanine and Integerrine Types .............................. B . Amphibine-B Type ............................................. C Zizyphine-AType .............................................. D Mucronine-A Type .............................................. VIII Biochemistry and Pharmacology..................................... References ........................................................
.
.
. .
.
.
.
.
.
. .
165 166 168 168 169 169 179 179 182 183 183 184 186 188
189 189 189 190 191 191 193 196 200 203 204
.
I Introduction The term peptide alkaloid was first proposed by Goutarel and coworkers. However. since these alkaloids. with one known exception. are cyclic ones the term cyclopeptide alkaloids seems to be more appropriate; the lone exception (lesiodine-A) could in fact arise by secondary opening of the cyclic system . I n this review only those alkaloids are treated which incorporate a hydroxystyrylamino group
* Translated from the German of the authors by the editor. R . H. Manske.
166
R. TSCHESCHE AND E. U. KAUQMANN
as such or in a modified form. Consequently, lunarine (Lunaria biennis Moenchi Cruciferae) and homaline (Homalia spp. ; Flacourtiaceae), which do not incorporate such a nucleus, are excluded. Also excluded are the ergot alkaloids conveniently known as peptide alkaloids, for which the term “peptide type alkaloids” now was proposed ( I ) , and peptides isolated from Amanita species by Wieland and co-workers (2). Since two previous reviews of the subject under discussion (3, a), which brought it up to 1970, some thirty new alkaloids of this type have been described. Their study has revealed a definite chemotaxonomic relationship ( 5 ) , and the preliminary stages in their syntheses have been recorded (6). The first discovery of the cyclopeptide alkaloids was made by Goutarel and Pais (7), working a t Gif-sur-Yvette, France, who isolated adouetines X, Y, and Z from Waltheria americana without however proposing a complete structure. Nevertheless, some earlier work in this field had been reported (8, 9); Clinch (lo),in 1884, noted the presence of alkaloids in Ceanothus americanus, a plant which found use in folk medicine; it was Bertho (11) who succeeded in 1933 in isolating pure ceanothine-B from the mixture of alkaloids and determined the correct empirical formula (C,,H,,O,N,), even though no structural detail was suggested. The similar chemical and physical properties of these alkaloids rendered their separation and study extremely tedious by the methods then available. In 1963 a group of Swiss authors (12) isolated zizyphine from Zixyphus oenoplia and recognized isoleucine and proline as components. Two years later Zbiral et al. (13)proposed a complete structure which was later revised (14).Pais et al. (15)in an earlier “preliminary report” suggested the structure of pandamine which had been isolated from Panda oleosa. This was confirmed in 1966, and the structure of the similarly constituted pandamine was reported (17). Shortly thereafter Tschesche and co-workers (18)reported the structure of an alkaloid of this type; scutianine-A from Scutia buxifolia. Since then the number of cyclopeptide alkaloids of known structure has risen to more than sixty, a figure which Klein and Rapoport had envisioned in 1968 (20). The workers at Gif-sur-Yvette and a t Bonn have been in the forefront of these researches but others have made important contributions (19-26).
11. Occurrence and Isolation Cyclopeptide alkaloids are particularly common in plants of the Rhamnaceae family (fourteen species thus far), but they have also
4. THE CYCLOPEPTIDE ALKALOIDS
167
been found in plants of Sterculiaceae,Pandaceae, Rubiaceae, Urticaceae, Hymenocardiaceae, and Celastraceae. As a result of recent work it appears probable that they will be found in plants of other families (5) (cf. Section VIII). They occur in the leaves, bark, and presumably in other parts but often in small amounts difficult to capture. Furthermore, the isolated alkaloid mixture is a complex one frequently consisting of as many as twenty constituents, and, finally, the relative abundance of the various constituents may depend upon the relative maturity and even the region of growth of the plant as noted in recent examinations of Zizyphus species. Consequently, records of main and subsidiary alkaloids may not necessarily be confirmable. The yield of total base mixture from dried plant material varies from 0.01 to 1.0% and depends not only upon the plant source but also upon the method of isolation. The winning of the alkaloids is generally achieved by the usual procedures modified to suit the plant source and the properties of the bases. Pais et al. ( I 7 ) , when working with Panda oleosa, moistened the dried and ground plant material with 10% aqueous ammonia and 1% aqueous sodium carbonate followed by extraction with ether. The concentrated extract was shaken with aqueous amidosulfonic acid and the bases regenerated from the aqueous phase by ammonia. An ether solution of the liberated bases frequently yields crystals upon standing but these are virtually always a mixture of bases. Scutianine-A was obtained from a methanol extract of the ground plant. The somewhat concentrated extract was diluted with water, basified with ammonia to pH 8, and exhausted with benzene. The alkaloids were removed from the benzene extract by means of 5% aqueous citric acid. The bases, regenerated from the aqueous phase, were recovered with chloroform or methylene chloride (18). This procedure is recommended when large amounts of plant material are available. A further simplification has been reported (27) in which the dried plant material is extracted with three times its volume of a mixture of benzene, concentrated aqueous ammonia, and methanol in the ratio 100:1 :1, respectively. Some five successive extractions appear to be adequate. The bases are separated from the combined benzene extract by shaking with 5y0 aqueous citric acid. The troublesome emulsions that are encountered in other procedures are largely avoided by this method. The further purification and the separation of individual bases is conveniently achieved by chromatographic methods. The alkaloids isolated from an individual plant often differ only from the lipophyllic side chain of the amino acids, or, as recently observed in studies of
168
R. TSCHESCHE AND E. U. KAUDMANN
Zizyphus abyssinica and Z. rnucronata, from the degree of methylation of the basic nitrogen (28). The base mixture is conveniently eluted through a silica gel column with chloroformlmethanol, the fractions being detected by means of a UV light source. Preliminary mass spectrographic examination of the separated fractions is utilized to determine the identity, whether known or new, and the structural type (Section VII). The isolation of pure bases by repeated chromatography with varied solvent systems is often tedious and sometimes not possible; for example, zizyphine-B and zizyphine-C showed identical Rfvalues in a dozen different solvent systems. The isolation of pure zizyphine-C was only achieved when the contaminant zizyphine-B was acetylated (29). Similarly, the sensitive mucronine-G and mucronine-H were only obtained pure as acetyl derivatives (28). Presumably, the problem of the separation of these alkaloids could be rendered more facile by the high pressure liquid chromatographic technique.
III. Properties A. GENERALPROPERTIES The pure alkaloids generally crystallize easily; the amphibines and the mauritines have only been obtained in the amorphous state. The melting points, with a few exceptions as noted in Tables I-VI, are mostly over 200". The reduced bases generally melt 20-80" higher. Most of the alkaloids are levorotatory ( - 200 to - 400" in chloroform or alcohols) but aralionine-A ( + 82", methanol) and lasiodine-A ( + 38", chloroform) are dextrorotatory. The dihydro derivatives show an increase in the positive direction. The dependence of the optical activity on the solvent and on the degree of methylation of the amino group in the 15-member cyclopeptide alkaloids is worthy of note (Table V). Such alkaloids are sparingly soluble in water but readily so in alcohols, chloroform, and some other organic solvents, but subsequent to adequate recrystallization their solubility may decrease considerably. A number of salts are appreciably soluble in nonpolar solvents. Their pK values, measured in Methyl Cellosolve, sometimes with the addition of 2 0 7 , water, range between 5.39 for adoubtine-Z to 6.55 for zizyphine -A. Hence, the basicity is minimal and frequently the free bases crystallize in part from aqueous solutions of weak acids. A study involving ion exchange resins in efforts to isolate and purify these bases has indicated that they form relatively stable complexes with appropriate components (27).
4. THE CYCLOPEPTIDE ALKALOIDS
169
B. IDENTIFICATION The identification and characterization of peptide alkaloids is primarily the prerogative of spectral studies-UV, IR, NMR, and mass spectrum in which the latter is particularly informative. Acid hydrolysis reveals the nature of the component building units. Typical bands for NH, N-methyl, phenol ether, and amide functions in the I R spectrum relegate a base to the cyclopeptides and the -C=G double bond (1625 cm-l) is easily recognized (Section V). The mass spectrum generally reveals a molecular peak and the kind and intensities of the secondary peaks give adequate information to relegate the base to a known subgroup (Section VII). Melting points and optical activity may differ in different preparations and are not reliable as criteria for identification (Tables I-VI). Preparations of constant melting points and apparent homogeneity in thin layer chromatography (TLC) have at times been shown to be composed of more than one constituent by mass spectra. The latter as well as elementary analyses have also shown that solvents of crystallization are so tenaciously retained by some of the alkaloids that their thermal elimination may result in deep-seated decomposition. Comparative chromatography with known cyclopeptide alkaloids should not be accepted as positive identity. C. CLASSIFICATION The following classification of cyclopeptide alkaloids into structural types is based upon the varied structural components. Since those alkaloids treated here, with the exception of lasiodine-A, are cyclic the first separation into classes is based upon the number of atoms in the ring; i.e., those containing 13, 14, and 15 members. The larger group containing 14 members is again separated via the contained P-hydroxyamino acids; namely, those with 8-hydroxyleucine (frangulanine type), with /3-hydroxyphenylalanine (integerrine type), and with trans-3-hydroxyproline (amphibine-B type). Only rarely do /3-hydroxyvaline (hymenocardine) or ,'3-hydroxyisoleucine (ceanothine-D) occur in the ring. A number of peptide alkaloids that do not readily lend themselves to tabular classification because of structural anomalies are separately described (pandamine, pandaminine, hymenocardine, and Iasiodine-A). Tables I-VI may indicate some chemotaxonomic relevance based upon the type of hydroxyamino acid, from which the ether bridge originates, and upon the size of the ring. Table VII gives addenda to Tables, I, IV, and V.
F
TABLE I FRANGULlLNINE
Name and S O U P C ~ ~ 1 Adodtine-X
2
3
4
5 6
(Ceanothamine-B) a, b Adoubtine-Y' (Myrianthine-B) a, c, d Americine b Ceanothine-B b Ceanothine-C b Discarine-A
TYPE-14-MEMBERED
Ring bond amino acid
Discarine-B e
RINGWITH ~HYDROXYSTYRYLAKIN UNIT AND ~~-HYDROXYLFUCINE
Intermediate amino acid
Basic end amino acid
Molecular formula
MW
ne
-
Dimethyl Leu
C2BH44N404 500
Ue
-
Dimethyl Phe
C31H42N404
TYP
-
Monomethyl Val
C31H3,N504 545
Methyl Pro
C2aH3GN404
Methyl Pro
C2eH3eN404
Dimethyl Typ
Phe
I
Leu or Ile
-
ne
-
e
7
4 0
Tm
mP
[ . I D b
Refs.c
r, 43 24, 25
277-279' 278-280' 279-280.5" 289-290' 302' (dec.)
-316' - 338" - 370" - 305' - 294'
504
135.5-137" and 142-182" 238.5-240.5'
- 198O m - 293'
19, 23, 25, 26
470
223-229"
- 368'
24, 26, 42
C33H43NS04 573
237-239'
- 310'
22
534
52 53 r, 23 20
m
Dimethyl Ile
C3&&50,
573
235-236'
- 172'
22
Franganine
8
Leu
Dimethyl Leu
500
248"
- 302"
Leu
Dimethyl Phe
534
244'
- 299"
Leu
Dimethyl Ileu
275-276' 276-279"
- 293"
Val
Dimethyl Leu
486
- 228'
d, f
Frangufolhe d, e,f, 9 10 Frangulanine b, f (Ceanothamine-A) 11 Myrianthine-C 9
294"
C
12 Lasiodine-B h 13 Scutianine-A i 14 Scutianine-B i 15 Scutianine-C i 16 Scutianine-D i 17 Scutianine-E
i Ceanothine-D b
18
a
-288'
Leu
Monomethyl Phe
617
221'
- 301"
Phe
Dimethyl Phe
665
186-187'
- 399"
Phe
Dimethyl Phe
568
248-250'
- 296'
Phe
Dimethyl Ile
534
267'
-231"
Phe Ser Dimethyl Phe 585 219-220" (threo, L) Phe Ser Dimethyl Phe 585 121' (threo, D 14-MemberedRing with p-Hydroxystyrylamine Unit and 8-Hydroxyisoleucine Leu Monomethyl Pro C2,H3,N404 470 227-229"
Plant sources (indicated by italic letters under name) are given in a list following Table VI. The solvents for [a]D have been chloroform except where noted, m being methanol c-m being chloroform methanol. Reference numbers in all the tables follow these in the text unless they are already in the text.
54 53 54 22, 36, 53 25,55
52
rp
1-3
33
E
- 198'
30
k-
- 22"
30
- 347"
24
E
F
s
TABLE ~ T E G E R R I N ETYPE-14-MEMBERED
II
RINU WITH ~HYDROXYSTYR-
UNIT A N D
,~-HYDROXYPH~NYLALANINE
?j
2
fL5
Ring bond Name and E O W C ~ 19 AdouBtine-Y a, b 20 AdouAtine-Z a
21 Arelionine-A j 22 Aralionine-B j 23. Ceanothine-E b 24 Centhiumine
amino acid
Ile
Intermediate amino acid
-
Integerrine Basic end Molecular amino acid formula Dimethyl Phe
CB4H4,N404
d
w
MW 568
[fflD
mP 292"
Phe
Pro
Dimethyl Phe
C42H45N505
699
140-145'
C-benzoyl-Gly
-
Dimethyl Ile
C34H38N406
582
165-167"
- 230" c-m - 184'
Ref. 7, 43 24 7, 43
ne
-
Monomethyl Phe
C33H38N404
554
103-105°
Leu
-
Dimethyl Phe
C34HION404
568
238-239"
Pro
-
Dimethyl Phe
C33H3eN404
552
232-233"
+ 82' - 73O m - 285" - 254O
TYP
-
Dimethyl Val
C35H39N504
593
258O
Not reported
34a
Leu
-
Dimethyl Ile
C31H4aN404
534
278"
- 228"
59
Phe
-
Dimethyl Val
C33H38N404
554
285" (dec.)
- 164'
59
Ile
-
Dimethyl Leu
CS1HaaN4O4
534
286"
- 263"
52
31
m
57 24
58
k: Integerrine 1 26 Integerrenine 1 27 Integerrissine 25
1
28
Myrianthine-A 0
@
8
u P ci
w
!+
9
29
Amphibine-B ~~
Name and 8ource
Ring bond amino acid
Intermediate amino acid
Basic end amino acid
Molecular formula
Mw
mP
[a]=
Phe
ne
Dimethyl Phe
C39H47N505
665
Amorphous
-181' m
Phe
ne
Dimethyl Leu
C38H49NS06
631
Amorphous
31 Amphibine-D 9, m
Ile
ne
Dimethyl Phe
C3eH4DN505
631
Amorphous
-2224" m -203"
32 Amphibine-E
Ile
Amphibine-B 5m 30 Amphibine-C
$9
m
g9
m
m
33 Amphibine-F g9 m
Phe
TYP
-
Dimethyl Leu
C38H50Ne05
670
Amorphous
-175" m
Monomethyl He
C29H3eN404
604
Amorphous
- 171'
Ref. 60 62 60 60 36 60, 36 62
27 62
-i
TABLE III-ntinued ~~~
Ring bond Name and soume 34
Amphibine-G
amino acid
~
~
Intermediate amino acid
Basic end acid
amino
Molecular formula
Mw
mP
Leu
-
Dimethyl Typ
C32H3nN504
557
182-185"
Phe
Val
Dimethyl Ala
C32H41N505
575
104'
D I . [
Ref.
-218"
27
-315'
36 47 36
m
35
Mauritine-A
m
9, m, n
36 Mauritine-B
Phe
9
37 Mauritine-C 9 38 Mauritine-D 9 39 Mauritine-E 9 40 Mauritine-F 9
Phe
Val
-
Dimethyl Ile
C35HdTN505
617
Amorphous
- 151"
m Monomethyl Val
C28H34N404
490
Amorphous
- 224"
62
m
Ile
Leu
Dimethyl Ile
C33H51N505
597
Amorphous
Phe,
Val
Dimethyl Ala
C32H41N506
591
Amorphous
Phe
Val
Monomethyl Ala
C31H38NS05
561
222-225"
-
259" m - 243" m - 285' m
62
62 62
tl
Ring bond Name and source 41
Amphibine-H na
42 Mucronine-D
Basic end amino acid
M
amino acid
Intermediate amino acid
Phe
Val
Dimethyl Ala
C33H43N506
ne
Leu
Dimethyl Phe
Pro
Ile
Pro Pro
Mw
mP
[a],
Refs.
2k-
605
202" (dec.)
-570"
27
b
C~THS~N~O ~ 661
Amorphous
-487'
38
m
Dimethyl Ile
C33H49N506
611
121' (dec.)
-411'
14, 13, 44
Ile
Monomethyl Phe
C35H,5N,06
361
Amorphous
-457'
1 4 , 3 7 , 44
Ile
Dimethyl Phe
C ~ ~ H ~ T N E O645 ~
Amorphous
-331'
29
Molecular formula
8
0
43 Zizyphine-A
P 44
Zizyphine-B
P 45
Zizyphine-C
P
I-
-3
or
cH30aR
H,C, ,N-HCH2C
H3C
I co
CH=CH
I
NH
I
I
NH~H-CO-NH-CH-do
I I
I
H,C-CH
w
CH2
I
C8H5
c2H5
49 Mucronine-A (R = H\
Amino wid
Basic end methylation degree
H
Leu
Monomethylated
C25H,8N404
458
236-239"
H
Ile
Monomethylated
C2sH38N404
458
237-239"
H
ne
No methylation
CarHssN404
444
229-330"
H
Phe
Dimethylated
CaeHmN404
506
235"
- 15"m - 28.3"
H
Phe
Monomethylated
C28H38N404
492
222-224"
+ 175"
R
Name and source 46 Abyssenine-A
Molecular formula
Mw
mP
P, q 47
Abyasenine-B
P. Q 48 Abyssenine-C ?!
49 Mucronine-A 0 9
q
50 Mucronine-B 0 9 P 51 Mucronine-C
H
Leu
Dimethylated
CasH40N404
472
257"
OCH,
Leu
Monomethylated
C28H40N405
488
232-234'
A ID
+ 160" + 151' + 144'
- 58'm
- 39.4O
Ref. 28 29 28
29 28
39 28
39 28
39
0
52 Mucronine-E 53 Mucronine-F
OCH,
Leu
No methylation
C25HseN40,
474
208-213"
OCH,
Ile
No methylation
C ~ S H ~ ~ N ~ O 474 S
€ I
Phe
N o methylation
C
Amo~hous
0
56
Mucronine-H 0
28
f
17.4'
28
m
0
54 Mucronine-G
- 890 m
0
Z
~
L
~
~478O
~
Amorphous
-50' m
+ b0
m
28 28
177
4. THE CYCLOPEPTIDE ALKALOIDS TABLE V I OTHERPEPTIDE ALKALOIDS
NMe, 56 R = -CH(CH3)C1H,
59
58
57 R = -CH(CH3)9
Name and source" ~
Molecular formula
MW
mP
ID
Ref.
C31H44N405
562
266"
-103"
15,17
CaoH*aNaOs
638
272'
-117'
17
C37H,oN,0,
674
261"
-124"
32,40
C38HlON10,
699
196"
+
33
~~
Pandamine
66
T
Pandaminine r 58 Hymenocardine a 69 Lasiodine-A h
57
a
Plant sources: a Waltherica amricana L. (Sterculiaceae) b Ceanothus ammicanus L. (Rhamnaceae) C Myrianthus arborem P. Beauv. (Urticaceae) d Melochia corchorqolia (Sterculiaceae) e Discaria longiapina (Hk. et Am.) Miera (Rhamnaceae) f Rhamnus franqula L. (Rhamnaceae) 9 ziZyphU8 muritiana Lam. (Rhamnaceae) h Laaiodiscus mmnoratus C. H. Wright (Rhamnaceae) i ScZitia b m o l i a Reiss. (Rhamnaceae) j Araliorhamnus vaginatus Perrier (Rhamnaceae) k Centium e w y d e a Bull. (Rubiaceae) 1 Ceanothus integgerimus Hk. et Am. (Rhamnaceae) m Zizyphus amphibia A. Cheval (Rhamnaceae) n Zizyphus a p i n a Christ; (Rhamnaceae) 0 Zizyphus mucronata Willd. (Rhamnaceae) P Zizyphus oenoplia Mill. (Rhamnaceae) q Zizyphus abyssinica Hoechst. ex A. Rich. (Rhamnaceae) r Panda Ok08a Pierre (Pandaceae) 8 Hyinenocardia a d a Tul. (Hymenocardiaceae)
38"
TABLE V I I ADDENDA TO TULES I, IV, AND V
Name
Ring bond amino acid
Intermediate amino acid
Basic end amino acid
Molecular formula
Ile
-
-
Hovenine-A
Len
-
Monomethyl Ile
Texensine
TYP
-
Dimethyl Ile
Ile Phe Leu
Leu Val
-
1
Name Zizyphine-D Zizyphhe-E a
R H H
mp
[ a ] ~
Addendum to Table I: fiangulanine Type C33H.&I,04 573 237-239" -310"
Amphibine-A
Nummularine-A Nummularine-B Nummularine-C
MW
Ca7H4aN404 486
215"
C3BH49N508 647 C3aH4~N60e 591 C ~ I H ~ O N S O548 ~
235-240" 23&231° 278-280°
Isolatedfrom the plant
Plant family
Ref.a
MeOH
Zizyphus amphibia A. Cheval Hovenia dulcis Thunb. H.tOmenteUa Nakai Colubrilza ternmi8 Gray
Rhamnaceae
5
Rhamnaceae
1
Rhamnaceae
2
Rhamnaceae Rhamnaceae Rhamnaceae
3 4 4 4
F
-
-
-
(CHCL)
C3&&04 573 249-252' 144' Addendum to Table IV: Zizyphine-A Type
Monomethyl Phe Monomethyl Ala Dimethyl Phe
Solvent
- 397O -390' - 371°
(CHCI.) (CHCk) (CHCI.)
Zizyphus nummularia Zizgphugnummularia Zizyphus nummularia
0
Addendum to Table V: Mumnine-A Type
Amino acid
Basic end methylation degree
8-OH-Ile 8-OH-Ile
Dimethylated Monomethylated
Molecular formu
MW
474 Ca6H&i404 Ca4H3BN405 460
mp
195'
-
References indicated by numbers a8 follows: 1. M. Takai, Y.Ogihara, and S. Shibata, Phytoehem. 12,2985(1973). 2. M. C. Wani, H. L. Taylor, and M. E. Wall, Tet. Lett. 47,4675 (1973). 3. B. K.Cassels, G. Eckhardt, E. U. KauBmann, and R. Tschesche, Tet7ahedron 30,2461 (1974) 4. R. Tschesche, G. A. Miana, and G. Eckhardt, Ber, 107,3180 (1974) 5. R. Tschesche, E. U. KauOmann, and H. -W. FehIhaber, Tet. Lett. 865 (1972).
rn
8
M
'3 M
P w
tQlD
Solvent
Isolatedfrom the plant
Plant family
Ref.
$
+236' + 150'
(CHCI.) (CHC13
ZiwphusoenopliaMill. Zizgphus osnoplia Mill.
Rhamnaceae Rhamnaceae
3 3
5 !2
4. THE CYCLOPEPTIDE ALKALOIDS
179
IV. Types of Cyclopeptide Alkaloids A. FRANGIULANINE TYPE 1. General Structural Criteria
A 14-membered ring system and an aryl ether resulting from p hydroxystyrylamine and /3-hydroxyleucine are characteristic of this group of bases. The carboxyl of the hydroxyleucine is coupled in a peptide linkage with the amino of another amino acid (ring bond amino acid) whose carboxyl in turn is linked with the amino of the styrylamine in an amide linkage. The “side chain” arises in another peptide linkage of the amino of the hydroxyleucine with another amino acid whose nitrogen is generally bismethylated, rarely monomethylated (basic end amino acid). Occasionally an “intermediate ” amino acid is inserted between the hydroxy- and the basic end amino acid (scutianineA, lasiodine-B, and adouetine-Z). The types of amino acids in these bases as well as in the other peptide alkaloids are comparatively limited-mostly those with lipophyllic side chains such as leucine, isoleucine, and phenylalanine although tryptophan, proline, and valine also occur. Aralionine-A with C-benzoylglycine as “ring bond amino acid” is at present an exception as are scutianine-D and -E with phenylserine in this location. 2. Degradation
Hydrogenation of the double bond of the bases followed by complete hydrolysis with 6 N hydrogen chloride in a sealed tube at 120” The amino acids in the hydrolysate are identified by standard methodsamino acid analyzer or paper chromatography. The kind and configuration of the amino acids may also be determined even with milligram quantities (47). The hydrolysate is directly converted into the N-trifluoracetyl- or N,N-dimethylamino acid L-methyl esters and subjected to gas chromatography. By comparison with known diastereomers the identity and configuration can be defined. The hydrolysate also contains p-tyramine which originates from the reduced styrylamino moiety. In the structural elucidation of aralionine-A the tyramine was coupled with diazosulphanilic acid on the paper chromatogram and the resultant dye eluted and compared with similar derivatives of 0-, m-, and p-hydroxyphenethylamine by its UV spectrum (31). I n other examples the p substituent was ascertained by ozonolysis of the double bond and comparison of the UV spectra of the resultant aldehyde with that of p-methoxybenzaldehyde (18-20).
180
R. TSCHESCHE AND E. U. KAUBMANN
Partial hydrolysis can give important clues but seems to be difficult to reproduce and depends greatly on the nature of the alkaloid: Dihydroscutianine-A (60) when boiled with 6 N sulfuric acid liberates the amino acids of the side chain and leaves the ring system intact. Dihydroceanothine-B when subjected to the normal procedure of total hydrolysis lost only the “basic end amino acid” (26).Deoxopandamine (61); which structurally resembles the dihydro bases of the franguline type, was hydrolyzed in acetic acid-hydrochloric acid to liberate the ring bond amino acid to give the diaminoacid 62 (17). Attempted enzyme hydrolysis of scutianine-A failed.
V
60
61
62
In general, alkaline hydrolysis is mandatory for the chromatographic identification of tryptophan, but its identification and configuration have been achieved following acid hydrolysis (32).The hydroxyleucine resulting from the hydrolysis of the frangulanine-type alkaloids is separable only in traces. Along with it a-ketoisocaproicacid, glycine, and leucine can be identified, which originate via a transamination reaction (Fig. 1, 63-64) (17). 3. Stereochemistry
Not only those amino acids which occur in the frangulanine group but also those in cyclopeptide alkaloids generally occur in the L form as far as is presently known. Exceptions are lasiodine-A in which the
4. THE CYCLOPEPTIDE ALKALOIDS
181
I
,c=o
/C=O 63
6-t ) 8 4 % & b NHSI
N
‘7
R-C-H
I
c=o I
N
OOH
N
R -C
II ‘c=o I
64
FIG.1. Transamination Sequence 68 + 64.
“ring amino acid” is D-phenylserine (33), and Scutianine-E which contains D-threo-/3-phenylserineand D-erythro-p-hydroxyleucine(30). Ruveda and co-workers have shown that the /3-hydroxyleucine, of which the aryl ether function in frangulanine is constructed, is present in the erythro-L-form (21). Dihydrofrangulanine was reduced with lithium in methylamine to an enol ether of 8-hydroxyleucine which on hydrolysis generated the free amino acid. It was shown that the hydroxyleucine in the hydrolysate is degraded by snake venom Laminooxidase but not by pig kidney D-aminooxidase. Inasmuch as threo-hydroxyamino acids are attacked by neither enzyme it follows that the 8-hydroxyleucine, of hydrolytic origin, is the L-erythro form. In parallel experiments, in which dihydrofrangulanine was hydrolyzed the hydroxyleucine which survived the hydrolysis occurred entirely in the rearranged threo form. Marchand et at. degraded lasiodine-B (12)in a series of reactions via lasiodine-B aldehyde (65) to 8-(p-toly1oxy)leucine (72) and compared
182
R. TSCHESCHE AND E. U. KAUBMANN
this with synthetic stereospecific isomers showing that the hydroxyamino acid is the erythro form (6, 34). 4. Syntheses
The above mentioned synthesis of thep-tolyloxyleucine (6)is the first step in what is evidently a difficult synthesis of a peptide alkaloid. The reaction of a p-tosyloxyamino acid with a chosen phenol does not generate an aryl ether. A synthesis was achieved via leucinol. N carbobenzoxy-P-hydroxyleucinemethyl ester (66) was tosylated (67) and reduced to N-carbobenzoxy-P-tosyloxyleucinol (68) with lithiumborhydride. This in turn was condensed with sodium p-cresylate in hexamethylphosphoric triamide to the oxazolidone 69 which was hydrolyzed with sodium hydroxide in ethanol to /3-p-tolyloxyleucinol (70) whose N-benzoyl derivative (71)upon Jones oxidation and subsequent hydrolysis generated /3-p-tolyloxyleucine (72).
66
67
68
SOCH3 NH,
OH
OC-NH
70
69
I
C6HLi
OH
71
SQCH NH,
OH
72
B. INTE~ERRINE TYPE The cyclopeptide alkaloids of the integerrine type differ from those discussed in the previous section in that the j3-hydroxyleucinein the ring
4.
THE CYCLOPEPTIDE ALKALOIDS
183
system is replaced by phenylserine. However, the phenylserine is not available thus far via degradative processes. The acid hydrolysate contains phenylnaphthalene. The feasibility of structural determination by mass spectrometry was demonstrated with integerrine of which only 5.5 mg was available (34a). Aralionine-A (21)is included in Table I1 in that the benzoyl group is readily cleaved and the resultant debenzoylaralionine-A resembles the integerrine type with glycine as the ring amino acid. Only one alkaloid, adouktine-Z, carries an extended side chain in this group of bases.
C. AMPHIBINE-B TYPE The characteristic feature of the amphibine-B type is the trans-3hydroxyproline as a constituent of the I4-membered ring system. In addition most of the bases included in Table I11 have the side chain extended by an amino acid. These alkaloids represent the first known occurrence of 3-hydroxyproline in a peptide of plant origin; it has been recognized as a constituent of some antibiotics, of collagen, and of sponges and has been isolated in free form from Delonix regia Rafin. (Poinciana regia Boj.; Leguminosae) (35).It is not accessible from the acid hydrolysate of these alkaloids. The ether scission involves /3 elimination in the pyrrolidine ring and generates, via pyrroline carboxylic acid, small amounts of difficulty accessible A1-pyrroline (13). Its chromatographic identification was consequent upon drastic ozonolysis of the aromatic nucleus followed by hydrolysis of the oxalester function (formerly the aryl ether position). The hydroxyamino acid in mauritine-A (35),of which larger amounts were available, was isolated and identified as trans-~-3-hydroxyproline (36). The sequence of leucine and isoleucine in mauritine-D (38) is not determinable by mass spectrometry, but partial hydrolysis indicated the sequence shown. These alkaloids, as shown in Table 111, contain essentially the same amino acids that occur in other 14-membered cyclopeptides, although alanine constitutes the basic end amino acid in several mauritines.
D. ZIZYPHINE-A TYPE The zizyphine-A type alkaloids also contain trans-3-hydroxyproline but in a 13-membered ring which includes the unit of 8-(2-methoxy-
5-hydroxy )styrylamine.
184
R. TSCHESCHE AND E. U. KAUDMANN
The cyclic structure of mucronine-D (42) follows not only from its mass spectrum but also from the oxidative scission of the double bond with osmium tetroxide and sodium periodate to a N-formylaldehyde which is very easily hydrolyzed to the amidoaldehyde 73, whose identity was confirmed by its mass spectrum. Similar oxidation products obtained and identified from zizyphine-A together with its mass spectrum (cf. Section VII, C) provided the revised structure 43 for it (14).Zizyphine had been isolated from Zizyphus oenoplia in 1963 and on chemical evidence was given an open basic peptide structure (13). The structure of zizyphine-B (44), consequent upon that of zizyphine-A, is included as thus corrected in Table IV without direct proof (37). Acid hydrolysis of the dihydro alkaloid yielded, depending upon the conditions, the side chain of zizyphine-A as a dipeptide or the ring system 74 from mucronine-D. Hydrolysis of the latter indicated that isoleucine is in the ring and that leucine is in the side chain of mucronineD. Hydrolysis of the reduced bases of the present type with alkali generates good yields of ~-(2-methoxy-5-hydroxyphenyl)ethanol (75) thus establishing the position of the substituents on the aromatic nucleus (13). This is confirmed by the UV spectrum of the alkaloid aldehyde (e.g., 73) which resembles that of 2,5-dimethoxybenzaldehyde in either neutral or acid medium (14,38). &OCH3
75
E. MUCRONINE-A TYPE The peptide alkaloids of the mucronine-A type have a 15-membered ring system. Recently, ten representatives have been isolated from Zizyphus mmronata and from Z. abyssinica (28, 39) and recent re-
4. THE CYCLOPEPTIDE ALKALOIDS
185
examination of 2. oenoplia has shown the presence of these bases (29). Ring closure in this type does not occur by ether formation with the /?-carbon of the second amino acid but through a /?-carbon of a third amino acid directly combined with the aromatic nucleus. The principal characteristic of these bases, in addition to the 15-membered ring, is a 2-methoxy-5-(/3-aminovinyl)phenylalanine group, which may bear,an additional methoxyl, and isoleucine in peptide linkage to the carboxyl of the alanine (Table V). The bases of this group, which are not methylated on the basic nitrogen and which are only known here, are chemically labile, occur in minimal amounts, are difficult to isolate, and often are contaminated with unknown substances. Consequently, mucronines-F, -G, and -H, as well as abyssenine-B were studied chemically and by mass spectrometry as their acetyl derivatives (Section VII, D). Oxidative scission of the double bond in the mucronines and the abyssenines with osmium tetroxide-sodium periodate generates the respective N-formylaldehyde which during manipulation and chromatographic purification is converted into the aldehyde 76.I n those alkaloids in which the basic nitrogen is primary or secondary the respective N-acetyl derivatives are employed (R3 = H; R, = acetyl) since unwanted side reactions between these primary and secondary amino groups and the resultant carbonyl are not excluded. Partial hydrolysis of the amidoaldehyde 76 generates the dipeptide 77 which is not accessible by hydrolysis of the original alkaloids. Its N-methylation and subsequent hydrolysis results in an N,N-dimethylamino acid (78a) and an amino acid (78b)from which the sequence of these constituents in the alkaloid may be deduced. CH30
R4
I
R,-N-CH-H&
I co I
NHz
I
NH-CH-CO-NH-CH-CO
HZN-CH-CO-NH-CH-COOH
I
I
CH,-CH I CzH,
I
Rl
I
CH3-CH
Rl
I
CZHS
76
(CH3)ZN-CH-COOH CH 3-
I I
CH
H N
+
-1
CH-COOH Rl
CzHs 78%
78b
77
186
R. TSCHESCHE AND E. U. KAUBMANN
Complete acid hydrolysis of the catalytically reduced alkaloids followed by chromatographic studies serves to identify the two simple amino acids. It has, however, not been possible to capture the aromatic portion from the hydrolysate. The positions of the substituents in the aromatic nucleus were learned by a comparison of the UV and NMR spectra of the amidoaldehyde 76 from one of the alkaloids with the relevant dimethoxy- and methoxymethylbenzaldehydes (28). A number of alkaloids in this group differ from each other only in the number of methyl groups on the basic nitrogen. They were fully methylated where necessary by the formaldehyde-hydrogen catalytic reduction (Pd/C) and thus identified with the N,N-dimethyl bases, also reduced at the double bond. In this manner mucronine-B (50)and mucronine-H (55) yielded dihydromucronine-A while abyssenine-A gave dihydromucronine-C. abyssenine-B and -C as well as mucronine-E and -F provided identical N,N-dimethyldihydro derivatives.
F. OTHERPEPTIDE ALKALOIDS There are several peptide alkaloids which do not fit the above described classification, namely, pandamine (56),pandaminine (57), hymenocardine (58), and lasiodine-A (59).The determination of their structures has already been referred to (3, 4 ) and is briefly outlined here. It was largely consequent upon chemical degradation in part because the mass spectral fragmentation patterns had not been worked out and in part because such analyses of the alkaloids or their derivatives do not, or only partly, lend themselves to the study of such fragmentation schemes as are described in Section VII. Pandamine and pandaminine, isolated from Panda oleosa by Pais et al. (17,24), differ from most cyclopeptide alkaloids in that the styrylamine unit is replaced by a 2-hydroxy-2-phenethylamineunit. They yield O-acetyl derivatives and chromic oxidation generates a ketone in which the carbonyl is in the 01 position to an aromatic nucleus. The UV spectrum of the ketone exhibits a strong maximum at 268 nm whereas pandamine has two weak maxima at 230 and 277 nm in addition to aromatic end absorption. Alkaline hydrolysis (NaOH in MeOH) gives rise to N,N-dimethyl-L-isoleucinamide, DL-phenylalanine, DL-leucine, generated from hydroxyleucine (cf. Section IV, A), 2(p-hydroxyphenyl)-2-hydroxyethylamine (79a), and the methoxy derivative 79b of the latter as a by-product. Partial acid hydrolysis yields phenylalanine and a fragment (C2,H,,04N,) whose structure (80) was arrived at by NMR and mass spectroscopy. Worthy of note
4. THE
CYCLOPEPTIDE ALKALOIDS
187
is the fact that the acid hydrolysis not only split the peptide linkages but also the C-C bond to the aromatic nucleus. Acid hydrolysis of deoxypandamine (61,Section IV, A) under like conditions leads to the earlier mentioned amino acid 62.
HO-&X€-CH2NH2 OR NMe, 79a
b
R =H R=CH3
80
Hymenocardine (58), ( 3 2 , 4 0 )has a p-hydroxy-w-aminoacetophenone unit (81), instead of the usual styrylamine, in its cyclic system which can be recognized in addition to N,N-dimethylisoleucylvaline and tryptophan in its acid hydrolysate. Mild alkaline hydrolysis results in ring opening via /3 elimination on the hydroxyamino acid and severance of the phenolate to a tetrapeptide 82 whose structure was determined by mass spectrometry and further hydrolysis. It is the only peptide alkaloid in which P-hydroxyvaline is involved in the aryl ether bridge.
Horn
NHZ
81
82
Lasiodine-A (59) (33),though not a cyclic peptide, exhibits many of the structural features common to that class and could conceivably result from subsequent scission of a cyclic precursor (4).Spectral study identified an isopropylidene, a secondary hydroxyl, a phenolic hydroxyl, and an ester function. Mass spectra fail to reveal the molecular ion but a fragment of mass M-106 as known from some other peptide alkaloids containing phenylserine as “ring bond amino acid” (30,31,62). Catalytic hydrogenation generates N-methylvaline and a moiety (83) whose structure was deduced from spectral studies and from hydrolytic degradations. Reduction of the alkaloid with lithiumaluminiumhydride
188
R. TSCHESCHE AND E. U. KAUBMANN
gave a product (84) from whose acid hydrolysate it was possible to isolate D-threo-phenylserine, the first example of a D-amino acid in ;I peptide alkaloid.
U
82
84
V. LJV and IR Spectra and Circular Dichroism The UV spectra of ICmembered cyclopeptide alkaloids generally show no characteristic peak in spite of the double bond and the aromatic nucleus of the styrylamine portion, the reason for which is to be sought in the strained ring system which prevents the overlapping of the p-orbitals of the aryloxy and the enamino groups so that they absorb independently, a condition which is demonstrable with molecular models. A keto group in the ol position with respect to the aromatic nucleus as in hymenocardine provides a maximum a t 266 nm (E = 7400) indicating partial conjugation. The keto group of C-benzoylglycine as in aralionine-A is evidenced by absorption a t 270-290 nm (E = 10,600). The tryptophan moiety in the alkaloids is recognizable by UV absorption a t ca. 220, 270, and 290 nm. The UV spectra of the 13-membered alkaloids (zizyphine-A type) provide maxima at 268 (log E = 4.06) and 210 nm (log E = 3.76) equivalent in position and intensity to those of 2,5-dialkoxystyrylamine derivatives. Following hydrogenation these bases show absorption maxima a t 290 nm similar to that of ethers of hydroquinone. The less strained 15-membered ring bases (mucronine-A, -B, -C) provide a characteristic maximum, resulting from the styrylamine portion, at 273 nm similar to the N-styrylamides. The dihydro derivatives show maxima at 227, 276, and 283 nm, typical of p-alkylphenol ethers. The IR spectra show bands a t 3285-3400 for the NH oscillations, at ca. 2780-2790 for the N-methyl, a t 1230-1240 for the phenol ether, and a t ca. 1625 cm-l for the styryl double bond. Furthermore, the
4.
THE CYCLOPEPTIDE ALKALOIDS
189
oscillations at 1680-1690 and at 1630-1655 cm-l are diagnostic for the secondary amido group of the peptide linkage, a characteristic which has been useful in relegating suspected alkaloids to the class of cyclopeptides. These spectra are not obviously influenced by the size of the ring. The methoxy group which is present in some of the 13- and 15membered ring systems evidences itself by a band a t ca. 2830 cm-l. Circular dichroism (CP) measurements reveal a weak positive band with a maximum at 285 nm and a strong negative one at 237 nm. The CD spectra of the 13-membered ring bases differ considerably from those with 14 members. Strong negative maxima 324, 276, 254, and 218 nm and a weak positive band at 232 nm are evident.
VI. NMR Spectra A. GENERAL Exhaustive NMR spectral studies have been reported for ceanothineB(19, 24-26), for pandamine (I?'), for americine (20), for aralionine-A ( 3 4 , and their derivatives. The number and type of NMe and OMe groups can be learned as can the number and position of the amide NH protons even though .exchange with deuterium is not always straightforward. In examples in which mass spectra do not differentiate between leucine and isoleucine the NMR spectra sometimes can do so.
13. STEREOCHEMISTRY OF THE ARYLETHER GROUP Frequently the configuration of the hydroxyamino acid component of the peptide alkaloid could be deduced with the aid of NMR studies. The coupling constants, JnS,of several a-amino-/3-hydroxyaminoacids as well as their N,N-dimethyl derivatives and their methyl ethers were determined by Marchand et al. (34). They showed that only the N,Ndimethyl derivatives yielded J,, values of configurational significance and that the conversion of the hydroxyl to alkoxyl exerted virtually no influence. The J,, value of N,N-dimethyl-p(p-toly1oxy)leucinein the threo form was 8.5 Hz whereas that in the erythro form was 2.5 Hz. Wenkert et al. studied frangulanine (lo),discarine-A (6), and discarine-B (7) whose amide protons had been replaced by deuterium (22). The a- and p-methine signals of hydroxyleucine occurred at 64.40 and 4.77, respectively, as a doublet with J,, = 8 Hz and as a double
190
R. TSCHESCHE AND E. U. KAUBMANN
doublet with J,, = 8 Hz and J,, = 2 Hz, respectively. The coupling constant of 8 Hz can only be explained on an aH//3H angle of 0-20" or of 150-180" and only the latter, an erythro configuration, can fit into the strained 14-membered ring structure. At the same time proof of the configuration of the /3-hydroxyphenylalanine nucleus in two of the integerrine-type bases was given, but this did not determine for certain the case of desbenzoylaralionine-A since the quoted coupling constant, J,, = 7 . 5 Hz, was not measured (31). The NMR spectra of the amphibine-B type offer important evidence t o distinguish between 3- and 4-hydroxyproline. The coupling constant, J,, = ca. 5 Hz, of this amino acid indicates a cis configuration (41) but chemical degradation had indicated a trans configuration (Section IV, C). Evidently the inclusion of this amino acid in the strained ring system involves an alteration of its conformation which reverts to normal (Jag= ca. 1 Hz) following the oxidative opening of the ring at the double bond.
C. STYRYLAMINE GROUP The signals of the olefine protons of the styrylamino group, present in most of the cyclopeptide alkaloids, was located by comparison with their dihydro derivatives. The coupling constant (7.5-9 Hz) characterizes the cis configuration even in the open chain lasiodine-A (33). The positions of the substituents on the aromatic nucleus of mucronine-A aldehyde (85) were determined from its NMR spectrum (39).Similarly, the NMR spectrum of N-acetylmucronine-E aldehyde (86) showed signals which corresponded well with those of a model substance, namely, 2,4-dimethoxy-5-methylbenzaldehyde (87). The early structural studies of the peptide alkaloids by chemical methods were difficult and were interpreted in structures which in some cases required later revision (13, 25). However, when high resolution mass spectrometry became available it was possible to elucidate the structures of many of these bases. Following the fragmentation schemes which Fehlhaber outlined for the frangulanine and integerrine types it was possible to interpret fragments of other peptide alkaloids into feasible structures thus accelerating the study of these bases (42). The mass spectrum of even a mixture of bases, which may contain as many as three or more constituents and which is obtainable by preliminary chromatography of the crude alkaloid fraction, can give important information on the nature and even number of constituents.
4.
191
THE CYCLOPEPTIDE ALKALOIDS
NH2
CO
I
I
NH-CH-CO-NH-CH-CO
I I
H,CCH
I
CHZ
I
CeHs
C,H, 85
H3COyJ11 CH,-CO-N-CH-H2C
I
H,C
I co I NH-CH-CO-NH-CH-CO
CH 3-
I CH I
CzHrj
NHa
I
I CHz I CH (CH3)z
86
H3c H3C
CHO
87
It may be determined whether known or new peptide alkaloids are present and whether or not the laborious isolation of pure constituents is warranted. The mass spectrum is particularly useful for purposes of identification because the physical properties are sometimes indefinite and often similar and nearly identical Rf numbers in several solvent systems are becoming very common. On the other hand, mass spectra are specific and only rarely require further chemical studies (adoubtineY and frangufoline). Even the relative homogeneity of a peptide alkaloid may be ascertained from its mass spectrum. Impurities are often similar peptide alkaloids, which, when they differ in the end amino acid, are detectable in traces by their intense base peaks. VII. Mass Spectra A. FRAN~ULANINE AND INTE~ERRINE TYPES The structures of the bases of frangulanine and integerrine types, t o which the majority of known peptide alkaloids belong, can largely be determined by their mass spectra (42). However, the positions of the
192
R. TSCHESCHE AND E. U. KAUBMANN
HN
to ipL),
mle [57
+ Rl -Il.
/
d m/e [343
+ R' + R"]
m/e [I24
+ R']
H2N-(
J
M + , m/e 1343
+ R + R' + R"]
e
m/e [203
R"
f
+ R' + R"]
m/e[147
+ R']
p*]' -
NH,
i m/e 136
g m/e [287
h
+ R' + R"]
m/e [217
+ R"]
/--HNCO
R" j wale [244 + R'
+ R"]
k mle [I10 + R'
+ R"]
1
m/e [82
+ R' + R"]
m mle [64 -I R']
SCHEME I. Mass spectrometric fragmentation of frangulanine- and integerrine-type alkaloids
4. THE CYCLOPEPTIDE ALKALOIDS
193
substituents on the aromatic ring cannot be determined nor can leucine be distinguished from isoleucine (Scheme I).* The base peak of the mass spectrum is the ion a, of 40-60y0 of the total ion production, resulting from the facile splitting of the C-C bond adjacent to the basic amino group. The opposite fragment b decomposes thermally to c and d; stepwise degradation of the side chain leads to g. The ring may open via homolysis of the C-C bond adjacent to the ether linkage and following scission at the amide group lead to ions e and f. A second ring scission generates a phenol ion which, following further decomposition, gives ions h and i. The separate building units of the molecule are recognizable as follows: i represents the styrylamine unit, m that of the hydroxyamino acid, a that of the terminal amino acid, + m/e 29-R”)represents and the typical amino fragment (H,N=CH-R; the ring amino acid component. While it is not possible to differentiate between leucine and isoleucine as ring components because of the low intensities of the peaks consequent upon the secondary nature of their fragments it is possible to identify the end amino acid. Hence it is possible to delineate the ring system from the fragments f, h, and k (or 1) and from the ions c and d the connection between the end amino acid and the hydroxyamino acid is derived. Fragmentation of bases in which proline forms part of the ring (centhiumine,24) (58)or when it is the end amino acid (ceannothine-B, -C; 4, 5 ) brings about a variation shown in Scheme I. Bases in which the side chain is extended by another amino acid (adouhtine-Z, 20) (2’,43),(lasiodine-B,12) (33), (scutianine-A, 13) (18) do rarely generate fragments resulting from ring scission (e, k, 1) but fragments resulting from the stepwise degradation of the side chain and which constitute the major fraction of the ion yield. Even so, the mass spectra of the alkaloids, whose ring components carry extra oxygen functions (aralionine-A, 21; scutianine-D, -E, 16, 17), conform only in part to the outlined fragmentation scheme. B. AMPHIBINE-B TYPE In the examples given in Scheme I1 the effect of the electron impact on the scission of the alkaloids is also largely independent of the nature of the amino acid nuclei R, R’ and R”. The fragmentation patterns are essentially modified by the inclusion of the 3-hydroxyproline molecule ‘The reaction routes (as indicated in earlier publications) shall present a clear picture, although they are not proved completely by metastable ions.
194
R. TSCHESCHE AND E . U. KAUDMANN
R ~~
R'
~~
Amphibine-B Amphibine-C 31 Amphibine-D 35 Mauritine-A 37 Mauritine-B 29
30
R"
~
-CH,CeH, -CH&H(CH3), -CH,C& -CH3 -CH( CH,)CZHs
-CH(CH,)Cg H, -CH(CH3)C,H5 -CH(CH,)C,H, --CH(CH3), -CH( CH,),
Ion Structure M+ a (CH,),N+=CH
I
-CH&eHS -CH,C,H, -CH(CH3)CSH, -CH,C,H, -CH&H,
29
30
mle 31
665 148
631 114
631 148
35 575 72
37 617 114
574
574
540
560
560
377
377
343
377
377
358
324
358
268
310
R b
(CH,),N +=CH-CO-NH-CH-CO-X
I
R' i
CO-NH-CH-CO-NH
k
I
R"
H
(CH3)SN-CH-CO-NH-CH-CO-N+
RI
RI'
a
195
4. THE CYCLOPEPTIDE ALKALOIDS mle
Ion 1
Structure (CH3)SN-CH-CO-NH-CH-CrO
I
+
I
R
+
m (CH3)aN-CH-CO-NH=CH
I
R
29
30
31
35
37
289
255
289
199
241
261
227
261
171
213
209
209
(209)
235
235
235
221
221
243
243
(209) 243
243
215
215
181
215
215
229
229
229
229
229
203
203
203
203
203
186
186
186
186
186
308
308
274
308
308
R'
I
R'
n
I
R' o
OCN-CH-CO-N
I
R'
CO-NH-CH-CzO
P
I R"
H 9
'4 +o=c \
Q-+
CO-NH=CH
H
I
+
R"
OCN-CH-CO-NH
I
R"
SCHEME 11. The moat characteristic fragment ions of the amphibine-B type of alkaloids
196
R. TSCHESCHE AND E. U. KAUBMANN
the presence of which in the ring system prevents the normal homolysis of the C-C bond adjacent to the ether oxygen. The side chain, which is mostly extended by one amino acid residue, also reduces the often typical fragmentation to scarcely recognizable proportions. Even so high resolution mass spectrometry can give sufficient information to orient the components and therefore to write the structure. As anticipated the base peak is constituted from the terminal N-methyl- or N,N-dimethylamino acid (a). Complimentarily, the fragment ion b arises through radical scission of the residue R. A plethora of fragments occurs in the higher mass region as a result of successive degradation of the side chain. The ions k to o identify the amino acid sequence of the side chain as far as 3-hydroxyproline and the fragments p to u establish the structure of the ring system (i). The dihydro derivatives provide entirely analogous spectra except that the fragments which include the dihydro-p-hydroxystyrylamine nucleus and these occur at 2 mass units. Amino fragments and the ion m/e 135 (C,H,ON) give useful structural information; the ions v and w are ascribed to hydroxyproline.
+
V
W
The differentiation between leucine and isoleucine is again not possible so that the structures of alkaloids which contain both (mauritine-D, 62) must be elucidated by other methods-partial hydrolysis followed by examination of the residual ring system or by examination of the resultant dipeptide side chain.
C. ZIZYPHINE-ATYPE The zizyphine-A type are 13-membered cyclopeptides composed of /3-(2-methoxy-5-hydroxyphenyl)vinylamine,3-hydroxyproline, and another amino acid. The first known representative was described as zizyphine in 1965 and given an open chain structure (13). It was subsequently renamed zizyphine-A in view of a further examination of Zizyphus oenoplia which disclosed other peptide alkaloids (14). Their mass spectra are largely analogous to those of the amphibine and mauritine type so that the fragmentation scheme of amphibine-B can be relied upon as a guide to those of this group (Scheme 11). The ion u does not appear in the usual form in the spectra of zizyphine-A,
4. THE CYCLOPEPTIDE ALKALOIDS
197
-B, and -C which contain proline. Instead, a fragment u' is apparent as in the spectrum of centhiumine (24). The separate components derived from the amino acids as well as the ion x derived from the hydroxystyrylamine group are recognizable.
-
HO OCN-CH-CO-NH
CH,=CH-CH,
I
I
H a
U'
X
The mass spectrum of the molecular peak of the amino aldehydes available by the oxidative scission of the double bond in mucronine-D (38), zizyphine-A (88) (13, 14,), zizyphine-C (29), and amphibine-H (27) is increased by 4 mass units. The characteristic peaks of all of the amino acids that are given by the alkaloids are also revealed by the aldehydes. By a McLafferty rearrangement the fragment originating from the aromatic nucleus gives fragment y and a tetrapeptidione (z with zizyphine-A) resulting further fragmentation from the ring bond
198
x
R. TSCHESCHE AND E. U. X A U D M A N N
I
PI
El
I
-8
5
7- -2 P
4. THE CYCLOPEPTIDE ALKALOIDS
m
m
199
200
R. TSCHESCHE AND E. U. KAUBMANN
amino acid as well as from the N-terminal amino acid. (Scheme 11, ions k, 1, m.)
D. MUCRONINE-A TYPE Alkaloids of the mucronine-A type, and particularly those in which the basic nitrogen carries two methyl groups, are exceptionally stable to thermal and electron impact. Significant mass spectral studies of these bases were first reported by Fehlhaber (39). Those mucronines and abyssenines which did not carry a methyl on the nitrogen were examined as acetyl derivatives and as aldehydes following oxidative scission of the double bond (28). These 15-membered cyclic peptides reveal an intense molecular peak which often serves as the base peak. The primary fragmentation is an ct scission a t the basic nitrogen t o generate isocyanic acid and the radical ion a (Scheme 111).Further stepwise degradation of the peptide fraction leads to b, c , d, and e which permits the sequence of both ring amino acids to be written. By means of the defocusing technique it was shown that a loses a
/
0 R, CH2
1I I
CH3-C-N-CH
I
etnlx, HN-CH
CO
NH-CH R,
L.
,R2
g
R1 = CHgCH(CH3)2,-CH(CH,)C2HS, -CH2C,HS R2 = H, -0CHB R, = H, -CH3 SCHEME IV. Mass spectrometric fragmentation of Mucronine-A N-acetyl derivatives
4. THE CYCLOPEPTIDE ALKALOIDS
20 1
methyl and an ethyl radical in very characteristic secondary reactions. In this manner the sequence isoleucine-leucine was established in mucronine-G, -E, -F, and in abyssenine-A and then confirmed by chemical reactions (28). The fragmentation of the dihydro derivatives via e generates f, g, and h. A second ring scission was noted when the basic nitrogen is monomethylated (R3 = H; mucronine-B, mucronine-E, abyssenine-A, abyssenine-B). A McLafferty rearrangement, dependent upon the hydrogen of the secondary amino group, and originating a t the benzene nucleus results in ring opening. The splitting of the enamide function leads to k (relative intensity 70-10070) or to 1 (relative intensity 10070) with the dihydro bases. The mucronines and abyssenines which are not methylated or only monomethylated at the basic nitrogen (R3= H or Me; R, = H) are studied as their acetyl derivatives (Scheme IV). The ring scission then occurs exclusively in the region of the styrylamide nitrogen. With the aid of isotope labeling and the recognition of metastable ions by means of defocusing techniques two degradation courses can be identified. The amino acid sequence can be ascertained from the
cH30
H3C, N=CH-H,C /
R3
NH,
I
NH-CH-CO-NH-CH-CO
I
H,C-CH
I
I Ri
I
C2H5
b
M+
\
a
I
NH-CH-CO-NH-CH-co R1
= -CH,CH(CH,),,
Ra = H, -0CH3
-CH(CH3)C,HS, -CH,CBH,
R3 = H, -CH3
I
HaC-CH
I
I
Rl
I
C2HS 0
SCHEME V. Mass spectrometric fragmentation of mucronine-A aldehydes
202
R. TSCHESCHE AND E. U. KAUBMANN
H L C H
CH
f
HO-C
SCHEME VI. Mass spectrometric aldehydes
I II
R1 = -CHZCH(CH,)z, -CH(CHS)CpH,, -CH2CeH, Rz = H, -0CH3 R3 = H, -CH3
NH fragmentation of
mucronine-A N-acetylamino-
stepwise degradation of the peptide chain arising from the fragment M , generating the ions a to f beginning a t the first amino acid. However, it is not possible to distinguish between leucine and isoleucine because of the low intensity of the secondary fragments. A second degradation can ensue following the splitting of acetamide or N-methylacetamide (McLafferty rearrangement) to a’ followed by stepwise degradation to c‘. The structural elucidation of mucronine-A-aldehyde (85) (39) (Scheme V) relies upon the peaks a t m/e 510 ( 0 . 2 7 0 ) ,m/e 206 (loox), and m/e 361 (11Y0). The first named is the molecular ion and reveals the former cyclic structure of the alkaloid. a-Fragmentation a t the tertiary amine forms the fragments b and c which indicate a nuclear substituted N,N-dimethylphenylalanine unit in mucronine-A aldehyde. Same derivatives of a number of mucronines and abyssenines were not accessible (Section IV, E). Mass spectra of the substituted N acetylaminoaldehydes resemble those of the acetylated alkaloids even +
4.
THE CYCLOPEPTIDE ALKALOIDS
203
though the peaks of these are very weak (Scheme VI). I n most of the spectra the base peak is the ion e.
VIII. Biochemistry and Pharmacology Meager information is known about the biogenesis of the cyclopeptide alkaloids. I n any event, the specificity of the enzyme system responsible for their formation cannot be very rigid because of the many different bases that are copresent in any plant. Characteristic is the incorporation of a variety of acids with a lipophyllic side chain and the absence of acid, basic, or sulfur containing amino acids. Bishay and co-workers ( 5 ) postulated a possible correlation between cyclopeptide and tetrahydroisoquinoline alkaloids when they isolated R-( - )-armepavine as well as franguline-type bases from Euonymus europaeus. Pailer and Haslinger (45) isolated, in addition t o the known peptide alkaloids, the same armepavine during a renewed examination of Rhamnus frangula. Zixyphus amphibia contains small amounts of nuciferine in addition to the amphibines ( 4 7 ) . Discaria crenata (Clos.) Regal yielded armepavine, N-methylcoclaurine, and a peptide alkaloid which may be identical with scutianine-B (46). It is noteworthy that some of these alkaloids have antibiotic properties whose potency and structural significance are under study. They are active against some of the lower fungi, against gram-positive bacteria, but seldom against gram-negative bacteria. The 13-, 14-, and 15-membered representatives are of about equal activity. Worthy of comment is the observation that the desmethyl bases are active only against fungi and the antibacterial activity only follows methylation of the basic end amino acid ( 4 7 , 4 8 ) .Recently, Andreo and Vallejos (61) have shown that discarine-B is a specific inhibitor of energy transfer reactions in spinach chloroplasts, while discarine-A behaves as a mixedtype inhibitor. Further studies are needed t o clarify the distribution of this activity in the whole group of alkaloids. Plants containing these alkaloids have been often employed in folk medicine without however any knowledge as t o a definite activity. Even the observed effects, if any, are not definitely ascribable t o the cyclopeptides alone. It has been reported that Zixyphus mucronata is emplqyed by the natives of central and southern Africa in the treatment of diirrhea and dysentery. It is not impossible that such an effect may be ascribable t o the alkaloids in view of their now known antibiotic
204
R. TSCHESCHE AND E. U. KAUBMANN
activity, an effect attributed previously to the tannin content of the plant (11). The difficulty of obtaining considerable quantities of these alkaloids in a pure condition for pharmacological testing has delayed such studies. Adoudtine-Z seems to have been studied more thoroughly than most without revealing specific activity (49).Its LD50 for the mouse was 52.5 mg/kg. Mauritine-A showed no appreciable pharmacological activity (50). A mixture of the alkaloids from Ceanothus americanus showed a LD50 of 90 mg/kg on intravenous injection in the rat (51).
REFERENCES 1. Cf. B. M. Abe, I n t . Symp. Biochem. Physiol. Alkaloide, 4th, 1971 p. 411 (1972). 2. T. Wieland, Fortsclw. Chem. Org. Naturst. 25, 214 (1967). 3. M. Pais and F. X. Jarreau, i n (B. Winsteins, ed.), “Chemistry of Amino Acids, Peptides, and Proteins” Vol. 1, Chapter 5, p. 127, Dekker, New York, 1971. 4. E. W. Warnhoff, Fortschr. Chem. Org. Naturst. 28, 162 (1970). 5. D. W. Bishay, Z. Kowalewski, and 5.D. Phillipson, Phytochemistry 12, 693 (1973). 6. J. Marchand, F. Rocchiccioli, M. Pais, and F. X. Jari-eau, Bull. SOC.Chim. Fr. 4699 (1972). 7. M. Pais, J. Mainil, and R. Goutarel, Ann. Pharm. Fr. 21, 139 (1963). 8. A. H. Clark, Amer. J . Pharm. 98, 147 (1926). 9. A. H. Clark, Amer. J . Pharm. 100, 240 (1928). 10. J. H. M. Clinch, Amer. J . Pharm. 56, 131 (1884). 11. A. Bertho and W. S. Liang, Arch. Pharm. (Weinheim)271, 273 (1933). 12. E. L. MQnard, J. M. Muller, A. F. Thomas, S. S. Bhatnagar, and N. J. Dastoor, Helv. Chim. Acta 46, 1801 (1963). 13. E. Zbiral, E. L. Menard, and J. M. Muller, Helv. Chim. Acta 48, 404 (1965). 14. R. Tschesche, E. U. KauBmann, and G. Eckhardt, Tet. Lett. 2577 (1973). 15. M. Pais, X. Monseur, X. Lusinchi, and R. Goutarel, Bull. Soc. Chim. Fr. 817 (1964). 16. H. Wastl, Fed. Proc., Fed. Amer. Soc. Ezp. Biol. 7, 131 (1948). 17. M. Pais, F. X. Jarreau, X. Lusinchi, and R. Goutarel, Ann. Chim. (Paris) [13], 83 (1966). 18. R. Tschesche, R. Welters, and H. -W. Fehlhaber, Ber. 100, 323 (1967). 19. F. K. Klein and H. Rapoport,, J . Amer. Chem. SOC.90, 3576 (1968). 20. F. K. Klein and H. Rapoport, J . Amer. Chem. Soc. 90, 2398 (1968). 21. M. Gonzales Sierra, 0. A. Mascaretti, F. J. Diaz, A. Ruveda, C. J. Chang, E. W. Hagaman, and E. Wenkert, J . Chem. Soc., Chem. Commun. 915 (1972). 22. 0. A. Mascaretti, V. M. Merkuza, G. E. Ferrara, E. A. Ruveda, C.-J. Chang, and E. Wenkert, Phytochemistry 11, 1133 (1972). 23. R. E. Servis and A. I. Kosak, J . Amer. Chem. Soc. 90, 4179 (1968). 24. R. E. Servis, A. I. Kosak, R. Tschesche, E. Frohberg, and H.-W. Fehlhaber, J. Amer. Chem. SOC.91, 5619 (1969). 25. E. W. Warnhoff, S. K. Pradhan, and J. C. N. Ma,Can. J. Chem. 43, 2594 (1965). 26. E. W. Warnhoff, J. C. N. Ma, and P . Reinolds-Warnhoff, J. Amer. Chem. Soc. 87, 4198 (1965).
4.
THE CYCLOPEPTIDE ALKALOIDS
205
27. R. Tschesche, Ch. Spilles, and G. Eckhardt, Ber. 107, 686 (1974). 28. R. Tsohesche, 8. T. David, R. Zerbes, G. Eckhardt, and E. U. KauBmann, Ann. 1915 (1974). 29. B. K. Cassels, G. Eckhardt, E. U. KauOmann, and R. Tschesche, Tetrahedron 30, 2461 (1974). 30. R. Tschesche and R. Ammermann, Ber. 107, 2274 (1974). 31. R. Tsohesche, L. Behrendt, and H.-W. Fehlhaber, Ber. 102, 50 (1969). 32. M. Pais, J. Marchand, G. Ratle, and F. X. Jarreau, Bull. Soc. Chim. Fr. 2979 (1968). 33. J. Marchand, M. Pais, X. Monseur, and F. X. Jarreau, Tetrahedron 25, 937 (1969). 34. J. Marohand, M. Pais, and F. X. Jarreau, Bull. SOC.Chim. Fr. 3742 (1971). 34a. R. Tschesche, E. Frohberg, and H.-W. Fehlhaber, Tet. Lett. 1311 (1968). 35. M.-L. Sung and L. Fowden, Phytoehernistry 7 , 2061 (1968). 36. R. Tschesche, H. Wilhelm, and H.-W. Fehlhaber, Tet. Lett. 2609 (1972). 37. M. Pailer, E. Haslinger, and E. Zbiral, Monatsh. 100, 1608 (1969). 38. R. Tschesche, S. T. David, J. Uhlendorf, and H.-W. Fehlhaber, Ber. 105, 3106 (1972). 39. H..W. Fehlhaber, J. Uhlendorf, S. T. David, and R. Tschesche, Ann. 759, 195 (1972). 40. M. Pais, J. Marchand, X. Monseur, F. X. Jarreau, and R. Goutarel, C . R. Acad. Bci., Ser. C 264, 1409 (1967). 41. J. S. Wolff, J. D. Ogle, and M. A. Logan, J . Biol. Chem. 241, 1300 (1966). 42. H.-W. Fehlhaber, 2. Anal. Chern. 235, 91 (1968). 43. M. Pais, J. Marchand, F. X. Jarreau, and R. Goutarel, Bull. SOC.Chim. Fr. 1145 (1968). 44. E. L. Mbnard, J. M. Muller, A. F. Thomas, S. S. Bhatnagar, and N. J. Dastoor, Helw. Chim. Acta 46, 1801, (1963). 45. M. Pailer and E. Haslinger, Monatsh. 103, 1399 (1972). 46. P. Pacheco, S. M. Albonico, and M. Silva, Phytochemistry 12, 954 (1973). 47. R. Tschesohe and co-workers, unpublished. 48. F. Sohonbeck, Institute for Pflanzenkrankheiten, Bonn (private communication). 49. 0. Blanpin, M. Pais, and M. A. Quevauviller, Ann. Pharm. Fr. 21, 147 (1963). 50. M. Schorr, Farbwerke Hoechst (private communication). 51. A. A. Manian, Ph.D. Thesis, Purdue University, La Fayette, Indiana (1954). 52. J. Marchand, X. Monseur, and M. Pais, Ann. Pharm. Fr. 26, 771 (1968). 53. R. Tschesche and I. Reutel, Tet. Lett. 3817 (1968). 54. R. Tschesche and H. Last, Tet. Lett. 2993 (1968). 55. R. Tsohesche, H. Last, and H.-W. Fehlhaber, Ber. 100, 3937 (1967). 56. R. Tschesche, E. Ammermann, and H.-W. Fehlhaber, Tet. Lett. 4405 (1971). 57. R. Tschesche, E. Frohberg, and H.-W. Fehlhaber, Ber. 103, 2501 (1970). 58. G. Boulvin, R. Ottinger, M. Pais, and G. Chiurdoglu, Bull. SOC.Chim. Belg. 78, 583 (1969). 59. R. Tschesche, J. Rheingans, H.-W. Fehlhaber, and G. Legler, Ber. 100, 3924 (1967). 60. R. Tschesche, E. U. KauOmann, and H.-W. Fehlhaber, Ber. 105, 3094 (1972). 61. C. S. Andreo and R. H. Vallejos, FEBS Letters 33, 201 (1973). 62. R. Tschesche, H. Wilhelm, E. U. KauOmann, and G. Eckhardt, Ann. 1694 (1974).
This Page Intentionally Left Blank
-CHAPTER
5-
THE PHARMACOLOGY AND TOXICOLOGY OF THE PAPAVERACEAE ALKALOIDS V. PREININGER Institute of Chemistry, Medical Faculty, Palacki University, Olornouc, Czechoslovakia
I. Introduction ........................................................ 207 11. Structure, Pharmacological, and Toxicological Properties of the Papaveraceae Alkaloids ............................................................ 208 A. Isoquinoline and Tetrahydroisoquinoline Groups . . . . . . . . . . . . . . . 208 B. Benzylisoquinoline and Benzyltetrahydroisoquinoline Groups . . . . . . . . . . . 209 C. Proaporphine, Dihydroproaporphine, and Tetrahydroproaporphine .................................................... 224 up ..................... ....................... 226 E. Promorphinane Group . . . . . . . . . . . . . . . . . . . . . 229 F. Morphinane Group ................................................ 229 ........._ G. Cularine Group . . . . . . . . . . . . . . . . . . . 230 H. Pavine and Isopavine Groups.. . . . . . . . . . , . . . . . , . . . . . . . . . . . . . . . . . . . . . 230 I. Protoberberine, Pseudoprotoberberine, Tetrahydroprotoberberine, and Tetrahydropseudoprotoberberine Groups . . . . . . . . . . . . . . . , . . . . . . . . . . . . . 23 1 J. Protopine Group .................................................. 236 K. Phthalideisoquinoline Group. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238 L. Narceine Group. . ........................ 239 M. Rhoeadine and P a ........................ 240 N. Benzophenanthridine Group ........................................ 241 0. Spirobenzylisoquinoline Group. . . . ............................... 243 References .......................................................... 243
I. Introduction The isolation of morphine from opium and the recognition of the significance of its physiological effects by F. W. A. Sertiirner in 18031817 as well as the first definition of the term alkaloid by Meissner in 1819-1821 have led to a rapid progress in the research of alkaloids ( I ) . In the beginning of the past century, much attention was paid tQthe e r uhas ~ been used cultivated poppy plant Papaver ~ o ~ ~ ~L.,f which since time immemorial in popular medicine. Of the so-far known 41 opium alkaloids, only morphine, codeine, and papaverine have found
208
V. PREININGER
wider application in medicine. Some of the other alkaloids, e.g., thebaine and neopine (P-codeine), are used as crude material for the preparation of synthetic medicaments. Concerning many of the Papaveraceae alkaloids there are practically no pharmacological data available though recent work carried out in that respect has shown that some of them might be of importance in medical practice. The family of the Papaveraceae includes 31 genera and approximately 700 species ( 2 ) .The alkaloids contained therein are derivatives of the 1-benzyltetrahydroisoquinoline alkaloid reticuline ( 1 ) . For the classification and chemical data of the described alkaloids (3-5) as well as for the pharmacodynamic properties of morphine and codeine (6, 7) see reviews. Some pharmacological aspects have been dealt with by Shamma ( 5 ) and Krueger et al. ( 8 ) .
11. Structure, Pharmacological, and Toxicological Properties of the Papaveraceae Alkaloids A. ISOQUINOLINE AND TETRAHYDROISOQUINOLINE GROUPS
Q N + L R
R = H or CH, Isoquinoline type
Tetrahydroisoquinoline type
1. Dihydrocotarnine
Dihydrocotarnine was isolated from opium by Hesse (9). Falcke [see Starkenstein (S)] reported that the irritating and inhibiting effects of this alkaloid upon the central nervous system are similar to those of the morphinane alkaloids. 2 . Dihydrohydrastinine
Dihydrohydrastinine has an antitussic effect which resembles that of narcotine (10). 3. Other Isoquinoline, Dihydroisoquinoline, and
Tetrahydroisoquinoline Compounds Some other isoquinoline and tetrahydroisoquinoline compounds have been studied (11-34). Arai and Enomoto (12-14) investigated the
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
209
relationship between chemical structure and toxicity as well as the antitumorous effect of isoquinoline substances and found that they selectively inhibit the incorporation of [3H]thymidine into deoxyribonucleic acid. The inhibition of incorporation of [3Hjuridine into ribonucleic acid or of [14C]leucineinto proteins is less significant. Some tetrahydroisoquinoline compounds have bronchodilating effects on isolated tracheal muscles of guinea pigs and hypotonic peripheral vasodilating and positive inotropic and chromotropic effects on dogs, rats, and guinea pigs (15-20). I n frogs and mice, tetrahydroisoquinoline and its methyl, hydroxyl, methoxyl, and ethoxyl derivatives stimulate the sympathicus and cause depression, tremor, and convulsions (21). Fasset and Hjort (22) observed the effect of these compounds on blood pressure, heart rate, respiration, and the smooth muscles. The secondary amines exert a greater effect on blood pressure than the tertiary amines. This effect is increased by the presence of hydroxyl groups and decreased by the presence of methoxyl and ethoxyl groups. The most effective derivatives are those with hydroxyl groups a t (2-7 and C-8. The tertiary amines proved t o be the most active depressants. The heart rate is affected only slightly. The N-methyl derivatives stimulate respiration. The hydroxyl derivatives increase the tonus of the intestines and decrease the tonus of the smooth muscle of the trachea, The presence of the ethoxyl groups usually has a depressant effect on the smooth muscle. For the inhibitory effect of the isoquinoline derivatives famotine and memotine on the growth of the influenza virus A in tissue cultures and on the antiviral effect in respiratory diseases in man, see Hobson et al. (23),Williamson and Jackson (24), and Reed et al. (25). The local anesthetic effect of cotarnine derivatives has been studied by Eckhart and Varga (26). In the I n d e x Pharmacorum (27) hydrastinine and cotarnine are mentioned as hematostyptics. The tetrahydroisoquinoline derivatives might; also play a role in alcoholism (31-34); for details of this theory and the critical comments, see Shamma (5).
B. BENZYLISOQUINOLINE AND BENZYLTETRAHYDROISOQUINOLINE GROUPS 1. Papaverine
Papaverine (6,7,3’,4’-tetramethoxy-l-benzylisoquinoline) was isolated for the first time by Merck (35) from opium. I n 1914, Pal (36) demonstrated on animals in vivo that papaverine decreases the tonus of the smooth muscle without affecting its natural mobility. It is a
210
V. PREININGER
R = H or CH, Benzylisoquinoline type
Benzyltetrehydroisoquinoline type
very effective inhibitor of pathological spasms of the smooth muscle. The mechanism of the spasmolytic effect of papaverine was studied by several authors (37-54). Santi et al. (37, 38) compared the spasmolytic effect of papaverine and of some of its derivatives on oxidative phosphorylation. All those substances inhibited the tonic phase of contractions of the guinea pig ileum and the rabbit duodenum which were induced by acetylcholine, histamine, or barium chloride. This effect is similar t o that of enzymic inhibitors, e.g., cyanide. The abovementioned compounds have a strong inhibitory effect upon the uptake of oxygen by the r a t liver mitochondria which oxidize glutamate under phosphorylating conditions. This effect is not influenced by dinitrophenol. When succinate is used as a substrate these substances do not affect the uptake of oxygen. Luciani et al, (39) observed inhibition of oxidation of succinate in isolated rat liver mitochondria. The results obtained indicate that inhibition takes place during transfer of electrons between nicotinamide-adenine dinucleotide and cytochrome b. Hydrogenation of the isoquinoline ring is followed by inhibition of the oxidative phosphorylating processes and by a progressive decrease in the intensity of the spasmolytic effect (40).The effect of papaverine on oxidative phosphorylation in the heart muscle was studied by Chetverikova (41). After administration of papaverine to rabbits, she observed an increase in the oxygen uptake and the formation of creatine phosphate in the myocardial tissue during respiration. Kisin ( 4 2 )found that administration of papaverine was followed by a decrease in the level of creatine phosphate and in a significant decrease in oxidative phosphorylation. I n rabbits with experimentally induced stenosis of the aorta, papaverine injected i.v. caused a return of the decreased level of dehydrogenase of lactic acid t o normal values (43). Higher concentrations of papaverine had a significant inhibitory effect on the utilization of energy from adenosine-5’-triphosphate(ATP) in experiments on rat
5 . THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
211
liver mitochondria (44). I n all probability papaverine inhibits the activity of cyclic 3’,5’-nucleotide phosphodiesterase and increases the concentration of cyclic 3’,5’-AMP, which results in relaxation of isolated bovine coronary vessels (45). Cyclic AMP may decrease or abolish the coupling between excitation and contraction by increasing the Ca2+ uptake by the vascular smooth muscle membrane (51).By a similar mechanism, Levy (47) explained the positive inotropic effects of papaverine on isolated human atrial preparation. The metabolism of papaverine in the organism has been described in several papers (55-57). I n man, papaverine is completely absorbed in the gastrointestinal tract. A negligible amount is excreted unchanged in the urine, which indicates that papaverine is practically completely metabolized. The main site of its metabolism is the liver. With the help of an enzymic system in liver microsomes, papaverine is degraded to give 4’-hydroxypapaverine, and approximately 6OY0 of the administered papaverine is excreted in man and in the guinea pig in form of 4’-hydroxypapaverine glucuronate. The results obtained from a comparison of the toxic properties of some opium alkaloids, including papaverine, were reported by Drommond et al. (58) and Aurousseau and Navarro (59).Papaverine is rather toxic t o albino rats irrespective of age and sex and has a low toxicity t o some bacteria (58).Subcutaneously administered papaverine is less toxic than that given per 0s (59). a. Papaverine and Enzymic Activity. The anticholinesterase activity of papaverine has been studied (60-68). Papaverine in a concentration of M produced a greater inhibitory effect upon acetylcholinesterase (60, 62) than on pseudocholinesterase (61). The relationship between papaverine and creatine kinase was studied by Chetverikova (69-71) who observed an increase in the formation of phosphocreatine in the rat aorta in phosphate buffer in the presence of papaverine. Papaverine a t 1.5 mg/kg prevented inactivation of creatine kinase from rabbit bone muscles. Garcia-Blanco and Grisolia (72) reported that papaverine activated blood pseudoperoxidase and Raphanus sativus peroxidase. b. The Effect of Papaverine on Blood and Blood Elements. It was found that papaverine inhibits the immune hemolysis by inactivation of the complement (73).I n a concentration of M it inhibits the function of thrombin (74, 75), the liberation of serotonin, histamine, and adenosine-5’-triphosphatefrom rabbit blood platelets induced by thrombin as well as human platelet aggregation and the cyclic AMP phosphodiesterase activity of platelet lysates (76). Gerlach et al. (77)
212
V. PREININGER
studied the phosphate metabolism of human erythrocytes in relationship to papaverine. Ancel and Scheiner ( 7 8 ) reported the teratogenic effect of some alkaloids. He found that administration of papaverine affected blood formation without causing any other abnormality. Papaverine inhibits the binding of Ca2+ions to the isolated membrane of erythrocytes (79).
c. The Effect of Papaverine on Intermediary Metabolism. Administration of papaverine to rabbits produces a slight decrease in the basal metabolism (80).Isimaru (81)observed an increase in the level of blood sugar and in that of lactic acid after administration of papaverine and a slight decrease followed by an increase in the alkaline reserve. Bilateral splanchnicectomy decreases this effect on the blood sugar and lactic acid levels but it exerts practically no effect on the alkaline reserve. Similarly, an increase in blood sugar and lactic acid content and a decrease in the alkaline reserve caused by epinephrine or barium chloride is potentiated by papaverine. Frommel et al. (82) found that application of one dose of papaverine to guinea pigs resulted in a significant but temporary decrease in ascorbic acid in all the important tissues as a result of oxidation of ascorbic acid to dehydroascorbic acid. Longenecker et al. (83) observed an increased excretion of ascorbic acid in rats. Pykhtina and Martynycheva (84, 85) reported that papaverine (10 mg/kg, s.c.) decreased the level of ascorbic acid in the suprarenals, in the liver, and in the spleen of rat; its administration over a period of 10 days increased the level of ascorbic acid in the suprarenals and decreased its level in the liver and spleen. The effects of papaverine on the blood pH value, the total carbon dioxide, the acid-base equilibrium, and free carbonic acid were studied by R a (86). Papaverine (1 mg/kg, i.v.) decreased the total carbon dioxide and bicarbonate ion contents, and the pH and the base excess in the cerebrospinal fluid in cat. In the arterial blood papaverine decreased only the PO, and pH values (87). Utinokura (88) reported a decrease in the body temperature of rabbits after administration of papaverine. The relationship between the surface temperature and the different substances, including papaverine, was investigated by Wertheimer et al. (89). d. The Effect of Papaverine on the Central Nervous Xystern. Experiments carried out on cats in vivo have shown that papaverine readily penetrates the hematoencephalic barrier (90). At first, stimulation of respiration and an increase in the blood pressure take place followed by inhibition of respiration and a decrease in blood pressure. Intraperitoneal
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
213
administration had no effect upon vomiting induced by nicotine, pilocarpine, or digitoxin, but it affected vomiting induced by apomorphine (91).Several authors (92-101) studied the effect of papaverine on cerebral blood circulation. It produced vasodilatation of the cerebral vessels and a decrease in blood pressure (92). I n healthy subjects (95)a rapid transient vasodilatation was observed. I n persons with affected cerebral blood circulation (hypertension and arteriosclerosis), papaverine had a more severe spasmolytic effect on cerebral vessels than on the peripheral vessels and a subsequent greater blood supply of the brain than of the extremities (96, 97). This effect manifested itself within the first few minutes after administration and it persisted for 1-14 hr. Subarachnoid injection of papaverine into dogs was effective in combatting hemorrhagic spasm of the basilar artery induced by introducing blood into the cisterna magna. Intravenous infusion was not effective. Intraarterial injection produced significant transient vasodilatation and moderate hypotension (98). Parenteral or peroral administration of papaverine had an analgesic effect which, however, was much weaker than that of morphine (102). Given per 0s this effect persisted much longer. The sedative and analgesic effects were attributed to the inhibition of the formatio reticularis in the brainstem (103, 104). I n the “summer frog” N-methylpapaverinium salt inhibited the central nervous system whereas in the “winter frog” the effect was of the curare type (105).This effect was ascribed to a decrease in the secretion of the thyroid hormones in winter since these hormones given for a few days led to the summer frog type of reaction. I n rats, papaverine ( 5 mg/kg) prolonged the synchronized electroencephalogram (EEG) sleep and shortened the desynchronizing cycles. It had no effect upon the monoamine content in the brain. The authors (106-108) assumed that this is caused by the hypotensive and antinicotinic action of papaverine. e. The Local Effect of Papaverine. Allergy caused by opium and opium alkaloids was studied by Risti6 and Volkanovska (109).Such an allergy was found to develop only on prolonged contact with opium or its alkaloids. It manifested itself by skin lesions, less frequently by asthma. Positive tests were obtained in 27y0of the workers continually exposed to opium or opium alkaloids. Papaverine inhibited (110) the formation of blisters when injected in combination with urea. Quevauviller and Gareet (111) compared the local anesthetic effect of papaverine and of its dihydro derivative with that of cocaine. Papaverine had a statistically significant palliative effect on experimentally induced pruritus (112).
214
V. PREININGER
f. The Effect of Papaverine on Respiration and on the Cough Rejlex. Intravenous injection of papaverine to cats inhibits the cough reflex and stimulates respiration (113). According to Haas (114) papaverine and papaveraldine have no effect upon the cough reflex. Injected into the marginal vein of the rabbit ear (115) papaverine inhibited respiration. Some authors (116, 117) reported that stimulation of respiration was caused by direct effect on the respiratory center whereas other authors assumed (118) that stimulation of respiration is actuated by action on the carotid and the aortal bodies rather than by the direct effect on the respiratory center. Subcutaneous administration of papaverine to guinea pigs may prevent bronchospasms (119-130) induced by inhalation of an aerosol of acetylcholine or histamine probably because of the direct effect on the smooth muscle. Papaverinol has the same effect whereas papaveraldine is somewhat less effective (124).The bronchodilator activity of papaverine in cats was increased by alkalosis and decreased by acidosis (125). g . The Effect of Papaverine on Blood Circulation. Papaverine increases the blood flow in the coronary arteries and causes their dilation (131140). In experiments carried out on isolated cat heart (141, 142) papaverine increased the volume of coronary circulation, the uptake of oxygen, and the quantity of reduced oxyhemoglobin. Intracoronary injection of papaverine to dogs (143)resulted at first in an increase and, later on, simultaneously with the decrease of blood pressure, in a decrease in the blood flow in the coronary arteries. After i.v. administration the effect was obscured by a decrease in blood pressure. Melville and Lu (144) demonstrated on isolated perfused rabbit heart that proportionate doses of aminophylline, nitroglycerin, and papaverine induced coronary vasodilatation and thus an increase in the blood flow. Small doses of papaverine had only a slight effect on the rapidity or amplitude of heart contractions. However, higher doses resulted in acceleration of the heart rate and reduction in the amplitude of contractions. Koide (145)observed an increase in the amplitude of contractions on isolated auricles of guinea pigs. The effect of papaverine on the rapidity of coronary blood flow is probably independent of its action on the innervation of the coronary vessels (140). Hanna and Shutt (146)studied the relationship between the chemical structure and the coronary dilator action of papaverine analogs on anesthetized dogs. The 6-alkoxy-, 5,6-dialkoxy-, and 6,T-dialkoxyisoquinoline derivatives acted as dilators. The 6,7-dialkoxyisoquinoline derivatives were most effective. Optimum results were obtained when the isoquinoline nucleus was aromatic, but the 3,4-dihydro- and 1,2,3,4-
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
215
tetrahydro derivatives were also found to be active. The nitrogen should be secondary, it is best if it is tertiary, but it should not be primary or quaternary. The coronary vasodilating effect of various substances was compared (142, 147-149). Persch and Nitz (149) studied the therapeutic application of parakhelline for angina pectoris in dogs and cats. Papaverine brought about a maximum blood flow in the coronary arteries much more rapidly than that of khelline which was, however, of longer duration. Fekete and Borsy (150) studied the effect of phenothiazine derivatives and of papaverine on the dilation of coronary arteries. Papaverine dehydroepiandrosterone-3-monophosphate(151) had a much more rapid coronary vasodilator action on the isolated cat heart than papaverine; the effect of papaverine was, however, of longer duration. Both compounds inhibited histamine bronchospasms. The spasmolytic effect of papaverine dehydroepiandrosterone-3-monophosphate on histamine-induced contractions of the small intestine of guinea pigs was twice as strong as that of papaverine but less toxic than papaverine. The effect of papaverine on atherosclerosis has been reported (152157). The vasodilating effect of sodium nitrite and papaverine on coronary vessels is intensified in cholesterol atherosclerosis, particularly when no morphological changes are present. In the opposite case, papaverine, contrary to sodium nitrite, diminishes the tendency of coronary vessels to spasms (154).Papaverine, eupaverine, and trasentine decrease the cholesterol level in blood (155). The effect of these substances is probably based on the conversion of cholesterol to cholic acids. Papaverine also promotes the excretion of cholic acids into the digestive tract. In angina pectoris, papaverine has a beneficial effect but does not mitigate pain (158).Papaverine and other substances cause not only coronary dilation but also have a specific effect upon myocardial metabolism (159, 160). Under aerobe conditions and in the presence of creatine (161) doses producing coronary vasodilation in vivo are followed by an increase in the formation of creatine phosphate in rabbit heart homogenates. The effect of papaverine and of other substances on coronary circulation in insufficiency of the myocardium resulting from ligature of coronary vessels was studied by Markova (162) on cats and McEachern et al. (163) on dogs. Intravenous injection of papaverine decreased the mortality from 75 to 50%. Papaverine also partially regenerated the loss of sodium and potassium ions (164). In experimentally induced myocardial infarction in cats (caused by ligature of coronary arteries)
216
V. PREININGER
administration of papaverine over a period of 2 weeks did not significantly change the size of the infarction area (165).However, Mokotoff et al. (166) reported that in dogs the infarction area became smaller when papaverine was applied. Kisin (167)studied the effect of papaverine on the supply of the myocardium with blood during coronary spasms. He observed changes in the electrocardiogram caused by papaverine, which he attributed to vasodilatation around the ischemic area. Harris et al. (168) studied on dogs the effect of papaverine on ectopic ventricular tachycardia produced by myocardial infarction. Greiner and Garb (169) investigated the effect of papaverine and of other substances on the irritability and automatism of the cardiac muscle. They observed a decrease in the sensitivity to irritation of the isolated papillary muscle of the right heart ventricle in cat. Papaverine causes a decrease up to disappearance of the sensitivity of the dog heart auricles to faradization (170). Larger doses are followed by an atrio-ventricular and intraventricular block. It protracts the refractory phase both of the auricles and the ventricles. Toxic doses lead to death resulting from cessation of cardiac activity in the diastole (171). In addition to the strong coronary vasodilating effect, papaverine diminishes the tendency to the development of ventricular fibrillation (172-180). Papaverine given to dogs and simultaneously carried out friction of the heart restore the normal contraction of the fibrillating heart. Consequently, papaverine can be applied prophylactically and therapeutically to control ventricular fibrillation. Quevauviller and Choix (182) and other authors (182) studied the positive chronotropic, inotropic, and dromotropic effects of papaverine and its analogs. Derivatives with ethoxyl groups proved to be more effective than those with methoxyl groups (181). Darby et al. (183) investigated on dogs the positive inotropic effect before and after sympathetic blockade. A comparison of the coronary dilating effect of papaverine with that of ethaverine did not show any difference. The effect of ethaverine was somewhat protracted (184, 185). Vasoactive substances (186-189) act upon the saturation of blood with oxygen in the sinus coronarius. In dogs this effect was very pronounced (186,187). Carra et al. (190) described the effect of papaverine and of other substances upon the myokinase activity of (coronary arteries. In dogs and guinea pigs it decreased the lethal dose of strophantin (191) and prevented cardiotoxic impairment induced by digitalis (192). Mercier et al. (193) found an increased fixation of salicylates in the cardiac muscle of dogs after their intravenous administration together with papaverine.
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
217
Littauer and Wright (194)did not observe any peripheral vasodilating effect of papaverine in normal subjects or in those suffering from arteriosclerosis whereas other authors (195-213) provided confirmation of the peripheral vasodilating effect of papaverine. It has a marked vasodilating effect upon the vessels of the rabbit ear (196);the dilatation is more marked in atherosclerotic than in intact vessels. In all probability, papaverine acts directly or indirectly via the vasomotor nervous centers. Small doses of papaverine (202) had a greater vasodilating effect when the tension of the vessel walls was increased by the action of epinephrine. Chronic oral administration (204) of papaverine to 13 rheumatoid arthritics significantly increased digital circulation in 9. The vasodilating effects of papaverine were noted unequivocally in rheumatoid arthritics who had functional vasospasms. In dogs under pentobarbital anesthesia i.v. injection of papaverine brought about a decrease in arterial blood pressure for a period of 10-20 sec, whereupon it returned to approximately the initial value (214). The lower blood pressure appeared in association with a considerable increase in cardiac activity. Meier et al. (215, 216) found that the intensity of the hypotensive effect of papaverine is dose-dependent. In dogs small doses of papaverine increased the hypotensive effect when given prior administration of sympathicomimetic substances (epinephrine, ephedrine, and norephedrine) (217). After injection of cocaine or /3,/3-diphenoxyethylaminesmall doses of papaverine produced only a slight increase in the hypotensive effect. Atropine had a similar effect, and when followed by an injection of epinephrine or ephedrine caused a further decrease. The sympathicolytic substances, as, for example, yohimbine or piperidinemethylbenzodioxane, moderately increased the hypotensive effect of papaverine ; ephedrine caused a further decrease in contrast to epinephrine. The potentiation of the hypotensive effect of papaverine by epinephrine was studied (218, 219). In rabbits and cats simultaneous application of i.v. injections of papaverine and epinephrine was usually followed by a lower blood pressure than that observed after administration of only papaverine. Atropinization, curarization, or denervation of the pressopreceptors of the sinus caroticus and of the aorta abrogated this effect. Local application of epinephrine or norepinephrine to the area, of the sinus caroticus of dogs or cats was followed by a reflexive decrease in blood pressure; with papaverine the effect was the reverse (220).The depressant effect of papaverine was increased by a blockade of the receptors of the sinus caroticus with procaine (221). In sheep, papaverine produced a slight decrease in pressure in the vena cava caudalis (222). Roy0 (223) observed on dogs an increase in the pressure in the portal vein resulting
218
V. PREININGER
from the effect of papaverine. Numerous papers (224-239) discuss the hypotensive effect of papaverine. The effect of dihydro- and tetrahydropapaverine on blood pressure was reported by Ben-Ziv and Sulman (240). Alekperov (241) studied the diurnal variations of the cortical functions of suprarenals and the effect of papaverine in subjects with essential hypertension. I n healthy females a maximum excretion of 17-hydroxycorticosteroids and of 17-ketosteroids in the urine (24 hr) was observed in the morning whereas a minimum occurred at night. I n females with hypertension the effect was the reverse. Administration of papaverine over a period of a month brought about a significant decrease in the nocturnal maximum; the diurnal excretion remained unchanged as far as the 17-ketosteroids were concerned, whereas the excretion of 17-hydroxycorticosteroids was lower. The total excretion of 17-ketosteroids in females with hypertension did not differ from that of the control group; the excretion of 17-hydroxycorticosteroids was, however, decreased.
h. The Effect of Papaverine on Xmooth Mwscles. Papaverine has a spasmolytic effect on the intestine (242-264). It inhibits the involuntary movement, the tonus of the isolated intestines of rabbits (245))and it suppresses the tonus of the isolated intestine of rabbits and dogs induced by barium, heart glycosides, and copper ions (253-257'). Application of labeled calcium (258) increased the loss of calcium from the smooth intestinal muscles. Excess of calcium antagonized the effect of papaverine on the mechanical response but not on the electrical response of the guinea pig taenia coli (259). When the muscle was depolarized in a calcium-free solution, papaverine caused repolarization of the membrane and the electrical activity reappeared. This effect was similar to that of magnesium. Papaverine increased the rate of calcium uptake by sarcoplasmic vesicles isolated from rabbit white skeletal muscle. The degree of activity of these drugs was clearly affected by changes in muscle ATP, oxalate, and calcium concentrations (260). The antagonistic effect of papaverine and of all the substances which lower the tonus of the smooth intestinal muscles of guinea pigs induced by acetylcholine, pilocarpine, barium chloride, histidine, or nicotine was studied by Tachibana (261) and Schmiterlow (262). Papaverine was found (263) to be the only substance producing relaxation during tetanic spasms of the ileum and the stomach of the rabbit caused by high doses of urea. Brummer and Bundul (265) reported that X-ray examination did not reveal any effect of papaverine on gastric peristalsis, whereas
5. THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
219
according to Vodovota (266) i t had a stimulating effect upon gastric motility. This alkaloid stimulates the emptying of the stomach (267) but does not stimulate secretion. Bromster et al. (268) also studied the effect of papaverine on gastric secretion. Rhode (269) determined its minimum concentrations which still have an analgesic effect and spasmolytic action on frog stomachs and the small intestine of mice after prior administration of pilocarpine. In patients with gastric and duodenal ulcers papaverine decreased the bioelectrical potential of the stomach (270). In rats, papaverine had a choleretic effect (271).It caused relaxation of the duodenum, of the sphincter of Oddi, and of the muscles of the bile duct (272-277). It paralyzed the spasmogenic effect of morphine on these structures. Papaverine (0.36 g) in combination with 100 ml of 60% sorbitol, administered to man by means of a duodenal probe, showed a higher choleretic and a lower cholecystokinetic effect than a 30% solution of magnesium sulfate (277). On the human uterus as well as on the pregnant uterus papaverine has a strong spasmolytic effect, particularly on the corpus and the isthmus (278). In the gravid uterus it also increases the amplitude of contractions (279).It might prove useful during delivery in hypertonia (279). Lehmann (280) carried out experimental studies by using spasmolytic suppositories containing atropine (0.8 mg), papaverine (20 mg), and calcium benzyl phthalate. The effect of papaverine on the smooth muscles of the uterus has also been described (281-289). Vasopressin given i.v. to rabbits decreased the blood flow in the ovaries (289). Simultaneous administration of papaverine abolished the vasopressin effect and increased the circulation rate to greater than normal levels. Papaverine had a vasodepressive effect on the vessels of perfused human placenta (290) increasing the blood flow through the placenta. However, no significant changes in the placental volume could be detected (291).Papaverine also acts as a relaxant upon the umbilicus (292). McCall et al. (293) studied the effect of papaverine during toxemia of pregnancy. I n preeclampsia and hypertensive toxemia, papaverine had no effect. During toxemia of pregnancy (without convulsions) a significant decrease in arterial blood pressure, a significant increase in the blood supply of the brain tissue, and a significant increase in the uptake of oxygen by the brain were observed. The effect of papaverine on the vas deferens and epididymis was investigated by Martius et al. (294, 295). High doses of papaverine had an antiejaculatory effect (296). The vasodilating effect of papaverine and acetylcholine on the renal function has been described (297-301). Harsing et al. (297) found that
220
V. PREININGER
intraarterial infusions of papaverine to dogs under chloral anesthesia were followed by an increase in the excretion of sodium, by increased diuresis, and by a decreased excretion of p-aminohippuric acid and creatinine. The effect of papaverine on the function of the cells of the uriniferous tubules was studied by Malynsz (301).
i. Various Ejfects of Papaverine. Papaverine in doses of 20 mg/kg decreased the uptake of oxygen by the mice brain, liver, spleen, or kidney slices (302). The effect of papaverine on cardiac disorders induced by cerebrocortical stimulation was studied by Sinitsin (303). Pykhtina (304)studied the changes induced by papaverine, sinomenine, etc., in the bioelectrical activity of the cortex cerebri. Frank (305) applied papaverine to prevent anaphylactic shocks in guinea pigs. The effect of papaverine and other compounds on the spontaneous rhythm of isolated chicken amnion was reported by Kuschinsky et al. (306). Papaverine liberated histamine during perfusion of the cat m. gastrocnaemius (307). Brock and Druckrey (308) studied the uptake of oxygen by the cat salivary gland. They found that papaverine in 5 x M concentration had no effect upon stimulation of the metabolism. However, a t concentrations as high as 5 x l o d 5 M cellular damage already began to appear. Druckrey et al. (309)described the antimitotic properties of papaverine. Schmitz (310) investigated the uptake of oxygen by the cells of ascitic tumors in mice. They did not find any relationship between the antimitotic activity of papaverine or of other alkaloids and the cell metabolism. Hasegawa and Tanaka (311) did not observe any changes in the production of plasma cells and ribonucleic acid in rabbit lymph nodes. Tyo reported (312) that even lethal doses of 3 mg/l6 mg had no effect upon the Plasmodium malariae in finches (Fringilla kawarahiwa minor). Gineste ascribed (313)the expansion of melanocytes of the scales of Cyprinus carpi0 and Barbus conchinius as resulting from the effect of papaverine. Axelrod studied (314) the enzymic degradation of aromatic ethers by using various substrates including papaverine. Pykhtina (315) investigated the direct stimulating effect of papaverine upon the interoceptors of the spleen, the intestine, and the hind legs of cats. A transient decrease in the tension of the isolated bovine ductus thoracicus was reported by Iida (316).The effect of papaverine upon contractions of the frog skeletal muscle induced by potassium and caffeine was reported by Buttar (317). Bauer and capek (318, 319) found that papaverine had a myorelaxant effect upon myoneural synapses and that it potentiated the effect of d-tubocurarine. Papaverine derivatives had sympathicomimetic effects (320).The i.p. toxic dose of papaverine in mice was
5. T H E
BIOLOGY OF PAPAVERACEAE ALKALOIDS
221
175 mg/kg a t 760 meters above sea level and 93 mg/kg at 3,200 meters (321).At higher altitudes (760 and 3200 meters) papaverine given to rats was followed by a decrease in the glycogen level and an increase in the lactic acid level (%%).
j. Potentiation of the Papaverine Effect by Other Substances and vice versa. Sulfonamides potentiate the effect of papaverine (323-325), and thus it may happen that the therapeutic dose of papaverine proves to be lethal. This effect was not antagonized by atropine, p-aminobenzoic acid, or by barbiturates. Papaverine increases the inhibition of the oxygen uptake (326)which is the result of the presence of sulfonamides in liver and brain homogenates. This potentiation is diminished or inhibited by amino acids (phenylalanine, leucine, proline, histidine, or glycine) as well as by p-aminobenzoic acid (327)or by small doses of phenothiazine derivatives (328). The application of papaverine in combination with typhene, dibasole, and salsoline was studied by Pykhtina (329). The depressor effect of papaverine i.v. in doses of 1 mg/kg to anesthetized cats lasted for 3-14 min, in combination with dibasole (1-2 mg/kg) 2-5 min, with dibasole and typhene (1-2 mg/kg) 10-27 min; the effect of salsoline was similar to that of papaverine but less pronounced. Mercier et al. (330) administered i.v. infusions of sodium salicylate to dogs and determined the lethal dose to be 1 g/kg. Simultaneous administration of papaverine resulted in a slight increase in the toxicity. Lettr6 et al. (331) studied the synergism of mitotic poisons and found that papaverine intensified the mitotic effect of colchicine on the growth of fibroblasts in vitro. The spasmolytic effect of khelline was augmented by small doses of papaverine (332). Therapeutic doses of khelline did not produce a hypotensive effect upon dogs, but in combination with barbiturates and papaverine a hypotensive effect was observed. Administration of papaverine along with trichloroisobutyl alcohol and acetylbromodiethylacetylurea increases the effect of the latter two substances (333).I n mice, small doses of papaverine reduce the convulsive effect of procaine not however the lethal dose (334).Papaverine inhibits contractions of excised muscles induced by adenosine derivatives (335). /3-Phenylisopropylamine in relatively high concentration increases the tonus of the vascular musculature of the surviving isolated rabbit aorta. This effect was inhibited by papaverine (336).
The effect of papaverine on respiration, blood pressure in dogs and cats, on isolated vessels, on the intestine in situ and in vitro as well as its toxicity in rats was not affected by Nalorphine (337).Premedication
222
V. PREININGER
of mice or cats with small doses of ether, phenobarbital, or pentobarbital intensified their sensitivity to the effect of curare and to similar compounds (338), whereas with urethane, papaverine, or scopolamine there were no visible sensitizing effects. Remezzano and Caivano (339) drew attention to the incompatibility of papaverine with more than a 15% solution of magnesium sulfate. This could be avoided by adjustment of the p H value from 5 to 5.5. Miyazaki et al. (340) did not observe any signs of incompatibility of papaverine with operidine. The effect of various compounds, including papaverine, on pyrogenic reactions has been studied by Prey et al. (341).Nicotine in doses of 2 x M caused relaxation of the isolated tracheal muscle of guinea pigs, in some cases preceded by a slight contraction. Administration of nicotine did not intensify the relaxation of muscles induced by doses of 5 x M of papaverine. I n rabbits this relaxation was not affected by nicotine (342). I%. The Eflect of Analogs or of Derivatives of Papaverine. The intact benzylisoquinoline nucleus is of great importance for the characteristic effect of papaverine (343, 344). Contrary to papaverine, papaverinol had a somewhat greater spasmolytic effect on isolated intestine stimulated by acetylcholine or barium chloride (345). Papaveraldine was slightly less effective. The relative spasmolytic activity of papaveraldine and 6-bromopapaveraldine was smaller than that of papaverine (346) and larger than that of papaverinol, 6-bromopapaverine, and 6-bromopapaverinol. Quevauviller (347) compared the toxicity, the musculotropic, and the neurotropic activity of papaverine, dihydropapaverine, dihydrobromopapaverine, tetraethylhydroxybenzylisoquinoline (perparine), dihydroperparine, and dihydrobromoperparine. The effect of the musculotropic spasmolytic dihydroperparine is noticeable. The spasmolytic effect of some carboxyl derivatives of papaverine and dihydropapaverine was studied by Mercier et al. (348). 1- (3',4'-Dimethoxybenz yl) - 6,7-dimethoxyisoquinoline-3-carbonic acid and its 3,4-dihydro analogs had no spasmolytic effect either in form of a free acid or in that of a sodium salt. After conversion into the corresponding ethyl esters the spasmolytic effect was greater than that of the original compounds (349). David and Gyarmati (350) carried out a comparison between the spasmolytic effect of papaverine, perparine, dihydroisoperparine, and tetrahydroperparine upon contractions in rats induced by oxytocin. The most effective was dihydroisoperparine. The significance of the phenylisopropylamine group was studied by Leuschner et al. (351). They found that l-benzylisoquinoline, papaverine, and N-allyl-
5.
THE BIOLOGY OP PAPAVERACEAE ALKALOIDS
223
papaverine inhibited the motility of mice and that they were antagonists of pervitine. The pharmacological effect of some analogs of papaverine has also been studied (352-357). The new spasmolytic drugs which have a papaverine-like action were described by Biniecki and Rylski (358). Tetrahydropapaveroline may be formed in mammals by condensation of dopamine with acetaldehyde or 3,4-dihydroxyphenylacetaldehyde (359-361).Low doses (0.5-2 mg/kg, i.p.) showed antireserpine, antioxotremorine, and anticataleptic activity in mice and rats while high doses (128/mg/kg, i.p.) induced akinesia (361). The possible relationship between papaveroline and the antiparkinsonian effects of L-dopa was discussed, and the structure and pharmacological effects of papaveroline were compared with those of bulbocapnine and apomorphine. For the pharmacology of papaveroline, see Kabiv (362), Reed and Bynoe (363), and Cheng (364) and for the pharmacology of 6,7 -dihydroxy- 3’,4’,5’-trimethoxy- 1-benzyltetrahydroisoquinoline, see (365-368). Intravenous administration of therapeutic doses of 3,4dihydropapaverine (20-40 mg) did not induce bronchospasms in man (369). 2. Takatonine
Takatonine (5,6,7,4‘-tetramethoxy-l-benzylisoquinoline) had a weak atropine-like and papaverine-like effect (370).Its spasmolytic activity was determined on isolated smooth muscle preparations of guinea pig ileum and mouse small intestine. 3. Laudanosine
Laudanosine (6,7,3‘,4‘-tetramethoxy-1-benzyltetrahydroisoquinoline) was isolated for the first time by Hesse (371)from opium. Intravenous administration of this substance to rabbits reduced the intraocular pressure (372).The whole effect manifested itself by motor restlessness, convulsions, disorders in coordination of movements, salivation, etc., which indicated an involvement of the extrapyramidal system and the mesencephalon. The effect produced by synthetic racemic laudanosine on rabbits was similar to that of the ( + ) form, but it was more toxic (373). The pharmacological properties of laudanosine have also been described (374). 4. Laudanine Very small quantities of laudanine [ ( & )-6,7,4’-trimethoxy-3’hydroxy-1-benzyltetrahydroisoquinoline] were found present in opium
224
V. PREININGER
from where it was isolated for the first time by Hesse (375).I n frogs, its effect is similar to that of strychnine (376). It induced convulsions and larger doses caused paralysis. A similar effect was observed in pigeons. I n rabbits, dogs, and cats small doses brought about a great acceleration of respiration and larger doses induced tetany. The effect of laudanine on blood pressure was of the strychnine type. Doses not producing convulsions caused a sudden rise in blood pressure by irritation of the vasomotor center. 5 . Armepavine
Armepavine (6,7-dimethoxy-4’-hydroxy-1-benzyltetrahydroisoquinoline) was isolated for the first time by Konovalova et al. (377) from Papaver armeniacum (L.) D C . Administration of armepavine to white mice, rabbits, and cats causes irritation and tonicoclonic convulsions (378) and disorders in heart activity. It has no spasmolytic, parasympathicolytic, or anesthetic properties. 6. ( - )-Norarmepavine
In mice ( - )-normmepavine [( - )-N-demethylarmepavine] given per produced mydriasis, bradypnoe, and a slight decrease in the spontaneous motor activity (379); when given per 0s to rats it had a very slight analgesic effect. 0s
7. Veronamine
The glycosidic alkaloid veronamine [( - )-4a’-L-rhamnosidothalifendlerine] produces systemic hypotension and bradycardia and a reduction in pressure of the perfused hindlimb of anesthetized dogs (380). The systemic effects of veronamine are blocked by bilateral cervical vagotomy or pretreatment with atropine, indicating that these effects are mediated through cholinergic mechanisms. The effect of veronamine in the perfused hindlimb is not sensitive to atropine.
C. PROAPORPHINE, DIHYDROPROAPORPHINE, AND TETRAHYDROPROAPORPHINE GROUPS 1. ( - )-Mecambrine ( - )-Mecambrine[(- )- 1,2-methylenedioxyproaporphine]was isolated for the first time by Slavik (381) from plants of the genus Papaver.
p 5.
THE BIOLOGY OF PAPAVERACEAE ALKALOIDS
225
C I
X
x
R = H or CH3 X = 0 or H + OH Proaporphine type Dihydroproaporphine Tetrahydroproeporphine type type
Experiments carried out (382, 383) on isolated duodenum of guinea pigs, rats, and rabbits showed that rising concentrations of mecambrine increased the motility and higher doses even the tonus of the duodenum; under the same conditions, the tonus of the intestine, which had been raised by carbachol, was decreased. Mecambrine did not affect the acetylcholine-induced contractions in the rat duodenum ; however, it significantly antagonized the effect of histamine on isolated ileum of guinea pigs. Mecambrine increased the blood pressure in rabbits and rats, it slightly stimulated respiration, and produced bradycardia. Experiments on rats showed that mecambrine did not influence the effect of norepinephrine on blood pressure and that the effect of mecambrine could not be affected by thiametone. Mecambrine also had a favorable effect upon various forms of experimental inflammations. For white mice the LD,, amounted to 4.1 mg/kg. The animals under experiment expired from clonicotonic convulsions. 2. ( - )-Glaziovineand ( - )-Pronuciferine
The pharmacological properties of the alkaloids ( - )-glaziovine and (-)-pronuciferine, found in the plants of the section Miltantha (384), have not been studied; however, mention has been made in the literature of their enantiomers (385-387). For white mice the LD,, of pronuciferine is 120 mg/kg. It has a local anesthetic effect. I n the ileum of guinea pigs pronuciferine intensifies contractions induced by acetylcholine; in higher doses it nullifies the action of acetylcholine and nicotine. Glaziovine exhibits an antidepressant and anxiolytic effect. It also shows limited tumor inhibition. To our knowledge the biological effects of the alkaloids of dihydroand tetrahydroproaporphine types have not been studied.
226
V. PREININGER
D. APORPHINE GROUP
R = H or CH,
1. Aporheine
Aporheine ( I$-methylenedioxyaporphine) was isolated for the first time by Pavesi (388) from P . dubium L. In small doses it reduces and in high doses it increases arterial blood pressure (389-392). Sublethal or lethal doses produce convulsions which are strychnine-like. Conversion of tertiary nitrogen to quaternary nitrogen brings about a great change in the pharmacological properties; aporheinium methohydroxide inhibits neuromuscular transfer and produces effects of the curare type whose duration depends upon the dose, the form of application, and the animal species; the toxicity of quaternary salts is ca. 1.6-5.6 higher than that of the base. I n cold-blooded animals this effect is the reverse. 2. Mecambroline Slavik (380) was the first to isolate mecambroline (1,2-methylenedioxy-10-hydroxyaporphine) from Meconopsis cambrica. It has hypotensive effects upon mice and rabbits (393). The question of the structure-activity relationships between the pharmacological actions of this alkaloid and aporheine has been discussed (393). 3. Isothebaine
Isothebaine (2,l l-dimethoxy-1-hydroxyaporphine) was isolated for the first time by Gadamer and Klee (394) from P. orientale L. In isolated normal intestine of rabbits and rats and in that tonicized by enterotonine smaller doses of isothebaine brought about a rise of the muscle tonus whereas higher doses produced relaxation (395, 396). Experiments carried out on the rat uterus in situ showed that isothebaine amplified the tonus and contractions but it did not affect the action of oxytocin. It slowed down significantly the frequency of respiration and the pulse rate. In mice it decreased the motor activity
5.
THE BIOLOGY OF PAPAVERACEAE ALKALOIDS
227
significantly and had an analgesic effect. I n experiments on rats some antiinflammatory effect was also observed. For mice the LD,, of S.C. applied isothebaine was 26 mg/kg. The animals expired from tonicoclonic convulsions. 4. Glaucine
( - )-Glaucine (1,2,9,1O-tetramethoxyaporphine) was isolated by Go (397) and ( + )-glaucine by Probst (398). Intravenous application of glaucine to cats reduced the blood pressure and inhibited respiration (399-403). It also had adrenolytic and antitussive effects which resembled those of codeine but were of longer duration. Blood glucose decreased from 90 to 70 mg-% in rats and cats to which a Bulgarian glaucine preparation Glaovent was administered per 0s 12 mg/kg for 6 months daily (404).The results showed a dose-dependent increase in glycogen storage in hepatic cells but no toxic effect. 5 . Corydine
( + )-Corydine (2,10,1l-trimethoxy-l-hydroxyaporphine) was isolated for the first time by Gadamer (405) and (-)-corydine by Go (406). I n animals it acts as an irritant and depressor on the central nervous system (407). The hydrochloride destroys tumors induced in hybrid mice by intramuscular application of sarcoma 37. Corydine methiodide, isocorydine methiodide, thalicmidine methiodide, and O-methylisocorydine methiodide (0.5-1 mg/kg, i.v.) decrease the blood pressure in anesthetized dogs, block transmission of nerve impulses through the superior cervical ganglia of cats and, in large doses, they block neuromuscular transmission in frogs and rabbits (408).
6. Corytuberine Corytuberine (2,10-dimethoxy-l,1l-dihydroxyaporphine) was isolated for the first time by Dobbie and Lauder (409).In frogs, it increases the reflex excitability (401). It accelerates respiration, stimulates lacrimation and salivation, and retards the pulse rate by stimulation of the vagus. Schmitz (320) studied the effect of alkaloids on cells of ascitic tumors in mice and found that the minimum concentration required for minimum inhibition of oxygen uptake amounted to 70 pglml. I n vitro it did not act as a mitotic poison (410). Fakhrutdinov and Kamilov (411, 412) studied the pharmacological properties of corytuberinium methiodide and magnoflorine iodide which produced a lesser curare-like activity than that of aporheinium methohydroxide
228
V. PREININGER
and a lesser hypotensive action than that of O-methylisocorydinium methiodide. Acetylation of the hydroxyl groups increased the toxicity. 7. Bulbocapnine Bulbocapnine (1,2-rnethylenedioxy-l0-methoxy-l l-hydroxyaporphine) was isolated for the first time by Freund and Josephi (413). Bulbocapnine induces catalepsy in mice at high doses, it antagonizes the effects of apomorphine and ( + )-amphetamine in pharmacological tests, and exhibits sedative effects as shown by the decreased motor activity in mice and by the potentiation of hypnotics such as pentobarbital (414-417). In both anesthetized and spinal rats, bulbocapnine at doses far below those evoking catalepsy in intact animals depresses spinal motoneuron monosynaptic reflexes without markedly affecting the polysynaptic ones (418-420). In dogs, bulbocapnine injected i.v. was found (421)to produce changes in the myocardial ventricular force of constriction and in arterial pressure. 8. Isocorydine
Isocorydine (1,2,lO-trimethoxy-1l-hydroxyaporphine) was isolated for the first time by Maraiion (422) and Go (423).Reynolds et al. (401) reported that its effect resembled that of bulbocapnine. Administration of N-methylisocorydinium chloride, a quaternary base isolated from Fagaro coco, results in apnea and finally in cardiac failure (424-426). I n rabbits it causes an increase in excitability whereas in rats it causes a decrease. The effect of mesantoine and coramine is to some extent antagonistic, which is contrary to the effect of lobeline and of the barbiturates. I n rabbits and toads isocorydine diminishes the contractility and excitability of the skeletal muscles; however, a curarelike effect was not observed. After intraperitoneal application to rats the recorded LD,, was 10.9 mg/kg. The alkaloids corydine, bulbocapnine, and isocorydine have an adrenolytic effect (427, 428). All of them, including glaucine, act cholinergically (429, 430); this effect is, however, smaller than that of dehydrocholic acid. For the synthesis and pharmacology of aporphine, the pharmacology of ( - )-nornuciferineand of pukateine, see Kupchan, et al. (379),Weisbach et at?.(431),and Smith et al. (432, 433), Burkman and Cannon (434),and Fogg (435). 9. Liriodenine
Liriodenine ( 1,2-methylenedioxy-7-oxodibenzoquinoline)was found to act in vitro upon cells of human nasopharyngeal carcinoma (436, 437).
5.
229
THE BIOLOGY OF PAPAVERACEAE ALKALOIDS
10. O-Methylatheroline
O-Methylatheroline ( 1,2,9,1O-tetramethoxy-7-0xodibenzoquino1ine) had a limited inhibitory effect upon tumors (387).
E. PROMORPHINANE GROUP The term promorphinane compounds is used for bases without an ether bridge between the rings A and D of the morphinane skeleton. Some preliminary pharmacological results have been obtained for 8,14-dihydronorsalutaridineand 8,14-dihydrosalutaridine(438). 8,14Dihydronorsalutaridine has an antagonizing effect upon tetrabenazine which is a reserpine-like compound in its action on the central nervous system. 8,14-Dihydrosalutaridine (300 mg/kg) produces a moderate reduction of spontaneous motor activity in mice.
F. MORPHINANEGROUP
@,
0
N-CH,
N- -CH,
/ Morphine type
Neopine type
Thebaine type
The pharmacodynamic properties of morphine and codeine and their derivatives have been dealt with in many publications, the enumeration of which would surpass the scope of this chapter (summaries,-6,7). 1. Thebaine
Thebaine was isolated from opium in 1835 by Pelletier (439). The therapeutic applicability of thebaine was studied by Balint et al. (440). It was found to be more toxic than morphine. It is a more effective narcotic but a weaker analgesic than morphine. The analgesic effect of thebaine in doses of 0.01 g/kg is greater than that of amidopyrine; this effect persists, however, only over a period of 30 min. Dihydrothebaine is somewhat more effective but it is more toxic ( 4 4 4 . The number and the location of the double bonds in ring D of the morphinane skeleton is of importance for the analgesic effect. Teraoko
230
V. PREININGER
(442) studied the effect of thebaine upon different organs. For white mice the LD,, was found to be 20 mg/kg when applied intraperitoneally and 31 mg/kg when given subcutaneously. A comparison of the effect of morphine with that of thebaine on body temperature as well as on the level of catecholamine and serotonin in brain and heart was carried out by Sloan et al. (443). They noted a slight decrease in the catecholamine content in those organs. I n rabbits, thebaine at 2 mg/kg abolished inhibition of respiration induced by morphine at 5 mg/kg (444). Respiration was strongly stimulated by a mixture of narcotine (15 mg) and thebaine (1 mg/kg). I n rabbits, Eddy (445) did not find a relationship between toxicity and the spasmolytic effect. Malorny (446) studied the central stimulating effect in mice and did not observe any antagonistic effect of thebaine if compared with that of morphine. Thebaine had a similar effect upon the EEG and the behavior of rabbits and cats (447). Smaller doses acted as depressors whereas larger doses produced spasms and respiratory paralysis. Taormina (448, 449) found that electroshock treatment sensitized rabbits and frogs to the effect of thebaine. An electrophysiological analysis of the spasmolytic effect of morphine, codeine, and thebaine was carried out by Corrado and Longo (450). Thebaine was considerably effective in liberating histamine from tissues (451).Cannava and Atzori (452, 453) found that thebaine had an inhibitory effect upon human, guinea pig, and horse cholinesterase and demonstrated (454, 455) its inhibitory effect on procainesterase in human blood. Thebaine had no inhibitory effect on the dehydrogenase of lactic and citric acid and upon glucose dehydrogenase (456). An antagonism between phenobarbital and thebaine in rabbits was observed by Carbonaro (457). It increased the effect of caffeine (458). Pseudohyperfeminization of the chicken embryo by physical and chemical agents, including thebaine, was studied by Stoll (459). For the analgesic effects of the derivatives of thebaine, see (460-467). G. CULARINEGROUP To our knowledge the biological effects of the alkaloids of the cularine group have not been studied.
H. PAVINE AND ISOPAVINE GROUPS The synthetic, structurally related substances produce tranquilizing effects.
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
231
I. PROTOBERBERINE, PSEUDOPROTOBERBERINE, TETRAHYDROPROTOBERBERINE, AND TETRAHYDROPSEUDOPROTOBERBERINE
Protoberberine type
Tetrahydroprotoberberine type
GROUPS
Pseudoprotoberbe>ine type
Tetrahydropseudoprotoberberine type
Imaseki et al. (468) carried out experiments for comparison in order to study the relationship between the chemical structure and the effect of protoberberine alkaloids upon the intestine and the uterus of mice. The tetrahydro derivatives have a great effect which is similar to that of papaverine whereas the effect of quaternary salts and that of the dihydro derivatives is small. Both the quaternary salts and the dihydro derivatives produce a strong contraction of the uterus whereas the effect of the tetrahydro derivatives is transient. This effect is intensified when the dioxymethglene group is replaced by a methoxyl or hydroxyl group. Supek (469) also observed a marked stimulating effect upon the isolated uterus of guinea pigs and cats. This effect is similar and somewhat stronger than that of hydrastine. Furuya (470) observed a strong paralyzing effect of berberine on the uterine muscle of mice which was very marked in pregnant mice. Fukuda and Watanabe (471) studied the effect of the substituents in the position C-9 of the berberine skeleton of cardiovascular activity. 1. Berberine
Berberine was isolated for the first time from Berberis vulgaris L. (472). The pharmacological properties of berberine resemble those of
232
V. PREININGER
hydrastine; it is comparatively little toxic (473). On intraabdominal administration to mice the LD,, was determined (474) to be 0.275 mg/lO g; the main symptoms were loss of motility and diminished respiration. Intravenous administration to dogs and cats resulted in a temporary decrease in blood pressure and stimulation of respiration immediately after injection. The decrease in blood pressure had no specific relationship to the glomus caroticum. The increase in blood pressure induced by epinephrine was not affected by previous administration of berberine. This alkaloid blocked responses to acetylcholine in both the isolated guinea pig ileum and the frog musculus rectus abdominis (475,476).A t 60 pg/ml berberine completely abolished the response to histamine (0.1 pg/ml) in the guinea pig ileum. At 10 pg/ml berberine potentiated the pentobarbital hypnosis in mice, and at 1-5 mg/kg it produced a mild hypotensive effect of short duration in anesthetized dogs. In cats, Turova et al. (477) observed general depression, salivation, vomiting and, a t higher doses, exitus within 8 to 10 days. Intravenous administration resulted in an increase in the frequency of respiration and excitation following depression. Higher doses also produced acceleration of respiration, dyspnea, salivation, defecation, and micturition. Excitation was followed by general depression. Higher doses gave rise to convulsions ending in episthotonos. Chronic toxicity resulted in yellow coloration of the mucous and serous membranes and of the sphincters of the digestive tract and in serous-hemorrhagic inflammations of the small intestine and the colon. Berberine had a sedative effect when given i.p. to cats and mice or intraventricularly to cats. It potentiated the pentobarbital sleeping time (478, 479). It had, however, no analgesic and no tranquilizing effects. The extract from Berberis vulgaris as well as that of the alkaloids berberine, oxyacanthine, berbamine, jatrorrhizine, and columbamine stimulate secretion of the bile (480, 481). The strongest effect was produced by berberine, followed by berbamine and oxyacanthine. The choleretic effect of berberine was also studied by Vartazaryan (482). Turova et al. (483) examined the effect of berberine on 225 patients with chronic cholecystitis. Peroral doses of 5-20 mg three times daily before meals over a period of 24-48 hours caused disappearance of the clinical symptoms, decrease in the level of bilirubin, and increase in the bile volume in the gall bladder. Berberine also had a favorable effect in patients with toxic hepatitis induced by intoxication. No side effects were observed on the liver functions or the blood composition. The effect of berberine on the stimulation of bile secretion was also studied by Samaj et al. (484).
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
233
For the effect of berberine on the heart activity and circulation, see Sabir and Bhide (485), Suzuki (486), and Jang (487). Berberine causes a reversible dose-linked decrease in the blood pressure of anesthetized dogs, cats, rats, and frogs (485). In dogs the berberineinduced hypotension is not inhibited by atropine, bilateral vagotomy, or brain ablation and it is not the result of tissue histamine release. Berberine causes tachycardia in dog heart in situ. In rabbits berberine reduces the functional activity of the vagus and accelerates the heart rate (486).A t the same time it increases the amplitude of contractions. It also evokes contractions of blood vessels. Stimulation of the bronchial muscles causes contraction of the air passage and compression of the pulmonal vessels. This is followed by a decrease in the quantity of the blood flow into the left ventricle and into the aorta which again is followed by a decrease in the aortal pressure in spite of the fact that the heart rate is accelerated and the blood vessels are narrowed. Similarly, Chang Shaw Jang (487) observed a stimulating effect of berberine on the heart and an increase in the blood flow through the coronary arteries; high doses inhibited the cardiac activity. The cardio-inhibitory effect of acetylcholine can be increased by small doses of berberine and paralyzed by middle and large doses. Those doses which antagonize the effect of acetylcholine have the same effect on pilocarpine but not on potassium chloride. Furuya (488) reported that S.C.administration of berberine to rabbits did not produce any significant effect upon the ECG whereas intravenous administration resulted in acceleration of the heart activity. Berberine depresses arrhythmia produced by i.v. administration of epinephrine or norepinephrine and inhibits bradycardia induced by epinephrine probably because of the inhibitory effect via the vagus. Bradycardia induced by acetylcholine is potentiated by administration of berberine. It has no inff uence upon the effect of histamine. Berberine also causes constriction of the peripheral vessels of the ear, decrease in blood pressure, and increase in the tonus of the isolated rabbit intestine (489). It inhibits the paralyzing effect of pilocarpine on the isolated intestine but it does not antagonize the effect produced by barium chloride (490). On the basis of fluorescence studies Nardi and Seipel (491) assumed that i.v. injections of berberine, palmatine, and columbamine result in selective localization of these substances in the pancreatic tissue. According to Schatz et al. (492), who analyzed different rat tissues, berberine was not selectively localized in the pancreas though it produced yellow fluorescence in that organ. This problem has been studied in detail (493, 494). The quantitative results showed that shortly after administration, berberine was deposited mainly in the
234
V. PREININQER
heart, the pancreas, the liver, and in the omental fatty tissue, relatively little in the kidneys, the lungs, the brain, and the spleen. After 24 hr only a minute quantity of berberine in the pancreas and in the fatty tissue could be detected. The distribution of berberine in the different organs varied according to the mode of administration: On peroral administration it was absorbed very little from the intestine, and in the organs only traces were found. Ogakurayama (495) drew attention to the ineffectiveness of berberine and of other alkaloids when administered perorally along with animal charcoal or dialuminum monosilicate. Nagakawa and Sad0 (496, 497) did not observe any local changes after S.C.administration to mice except clear hyperaemia of the kidneys. Berberine inhibits oxidative decarboxylation of yeast pyruvic acid (310);the same dose has, however, no effect upon aerobic glycolysis, Warburg’s respiratory enzymes, indophenol oxidase, etc. Berberine and tetrahydroberberine have an inhibitory effect on oxidation of ( )-alanine in rat kidney homogenates (498).Berberine and palmatine show a specific inhibitory effect upon cholinesterase in rabbit spleen and on pseudocholinesterase in horse serum (499). Berberine inhibits cellular respiration in ascitic tumors and even in tissue cultures (500502). The specific toxic effect of berberine on the respiration of cells of ascitic tumors in mice was described (310). The glycolysis was not found to be affected, but the uptake of oxygen was smaller. Fluorescence was used in order to demonstrate berberine in cellular granules. Hirsch (503) assumed that respiration is inhibited by the effect of berberine on the yellow respiratory enzymes. Since the tumorous tissue contains a smaller number of yellow respiratory enzymes than normal tissue i t is more readily affected by berberine. Subcutaneous injections of berberine, palmatine, or tetrahydropalmatine significantly reduce the content of ascorbic acid in the suprarenals, which is not affected by hypophysectomy (504). Inhibition of immune hemolysis by berberine was described by Tanaka (505). Subcutaneous or intravenous injections of berberine either in single doses or repeatedly did not affect the number of erythrocytes, leukocytes, and the hemoglobin level of intact rabbits (506). I n rabbits, with anemia induced by phenylhydrazine and toluenediamine, berberine had an antianemic effect. Hasegawa and Tanaka (50’7) did not observe any effect of berberine on the production of plasma cells. It decreased the anticoagulant action of heparin in dog and human blood in vitro (508).Morthland (509) carried out a spectrophotometric study of the interaction of nucleic acids with aminoacridine or with other basic stains including berberine.
5. THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
235
Numerous papers (510-533) deal with the investigation of the effect of berberine and its derivatives on bacteria. The effect of berberine upon Shigella dysenterieae and Neisseria gonorrhoeae appears to be greater than that of sulfathiazole (514). There was also observed a tripanocidal (515, 516) and tuberculostatic effect (517, 518). Berberine produced a strong antibacterial and bacteriostatic effect upon gonococci in vitro (519). Homma et al. (521) administered berberine to children in daily doses amounting to 30 mg over a period of 10 days. They observed insignificant changes in the intestinal microbial flora for which the disappearance of staphylococci was characteristic. By addition of berberine to a culture of Phymatotrichum omnivorum the growth of fungi was inhibited (528).Administration of berberine had a mutagenic effect (533) upon Allium cepa represented by chromatinic and chromosomal fragments. For the antiblastic properties of berberine and its derivatives, see also Shvarev and Tsetlin (534),Turkevich et al. (535), and Gheorghiu et al. (536). Administration of berberine to mice shortly before and after irradiation with gamma rays led to a decrease in the mortality rate (537, 538). With regard to pharmacology, the plants containing alkaloids of the berberine type have been studied (539-542). 2. Palmatine
Palmatine was found (543, 544) to produce antiarrhythmic, positive inotropic, adrenocorticotropic, anticholinesterase, analgesic, and bactericidal effects. 3. Coptisine
Coptisine had greater antimicrobial effects on Saccharomyces curbbergensis than berberine, palmatine, or jatrorrhizine (545). 4. Tetrahydroberberine (Canadine)
Tetrahydroberberine increased the antimitotic effect of colchicine on the growth of fibroblasts in vivo (331, 546). Intravenous administration to rabbits had an analgesic effect (547-551). Its intraperitoneal application to mice decreafled the spontaneous activity and potentiated significantly hexobarbital narcosis. ( - )-N-Methylcanadinium chloride produced hypotension (552). The LD,, was 84 mg/kg. Doses in the lethal range resulted in convulsions and potentiation of the contractile response of the isolated rat vas deferens to cumulative doses of norepinephrine. It caused a significant fall in blood pressure in intact anesthetized cats and dogs and a ganglion-blocking activity.
236
V. PREININCER
5. Tetrahydropalmatine
Tetrahydropalmatine has strong analgesic, sedative, and hypnotic effects (544, 553-563). They are produced by the ( - ) type but not by the ( + ) type. I n rabbits the analgesic effect was weaker than that of morphine, but the tolerance for this drug developed a t a far slower rate practically without any side effects. I n experiments on patients tetrahydropalmatine had a weaker analgesic effect but a stronger hypnotic effect than morphine. Application of doses of 10 mg/kg of tetrahydropalmatine to white mice led to disappearance of the conditioned reflexes whereas the unconditioned reflexes were maintained. For the influence of ( )-tetrahydropalmatine and other alkaloids on gastric ulcers in experimental animals, see Soji et al. (564).Variously substituted tetrahydroberberine and tetrahydropseudoberberine derivatives act as tranquilizers (565-569). 6. Xylopinine
Xylopinine (1-norcoralydine)inhibits the activity of the atria of the heart of guinea pigs without having any effect upon their contractions (570). In the early phase of the atrial depression, it acts upon the chronotropic effect of epinephrine whereas later on the same effect is potentiated. Coralynium chloride has antileukemic properties ( 5 7 4 , and tetrahydrocoralydine is considered to be an antipeptic ulcer ingredient (572).
J. PROTOPINE GROUP A
Protopine type
13-Oxoprotopinetype
13-Methylprotopinetype
Thus far the pharmacologically investigated alkaloids of this group (protopine, cryptopine, and a-allocryptopine) affect the heart activity. They are active dilators of the coronary vessels (573). After i.v. administration to rabbits and guinea pigs, a slight increase in blood pressure and a greater tendency to the development of cardiac arrhythmia induced by epinephrine are observed.
5. THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
237
1. a-Allocryptopine
a-Allocryptopine was isolated for the first time by Selle (574) from Chelidonium majus L. It is more effective than quinidine in preventing and treating aconitine-induced arrhythmia in rats (575), and it has a local anesthetic effect (576). A 1% solution of raw alkaloids from Mackaya cordata (Wild.) R.Br. (major alkaloid a-allocryptopine) has a stronger local anesthetic effect than procaine of similar concentration (577).Aizenman et al. (578) studied the antitumorous effect of various alkaloids and of allocryptopine. 2. Cryptopine
Cryptopine was isolated by Smiles (579) from opium in 1867. Its effect (580) is in many respects similar to that of papaverine and berberine. In dogs it produces hypotension, inhibition of cardiac activity, stimulation of respiration, inhibition of faradization of the vagus, and decrease in the oculocardiac reflex; in rabbits, it produces relaxation of the skeletal muscle (581).For guinea pigs the LDIooS.C. was found to be 160 mg/kg (582).Mercier et al. (583, 584) reported the effect of cryptopine on the intestine, the nervous system, blood pressure, cardiac activity, and respiration to range between that of papaverine and berberine. 3. Protopine
Protopine was isolated for the first time by Hesse (585) from opium, and later on its presence was demonstrated in practically all the plants of the Papaveraceae. The water-soluble fraction of ethanolic extracts of Fumaria indica were reported (586) to have relaxant and nonspecific antispasmodic effects on isolated intestines and uteri and moderate but prolonged hydrocholeretic effects in vivo which are attributed to the protopine contained therein. As a smooth muscle relaxant protopine was slightly weaker than papaverine. Small doses retarded the heart activity, decreased the blood pressure, and had a sedative effect (587, 588). Larger doses produced excitation and convulsions in the animals under experiment. It had an inhibitory effect on the isolated frog heart and muscle and a stimulating effect upon the intestine of guinea pigs. Stickel (589)observed a strong bactericidal effect on gram-positive bacteria, particularly on B . anthracis and the staphylococci. Bersch and Dopp (517) reported a negligible tuberculostatic effect. Lett& (590) studied the relationship between protopine
238
V. PREININGER
and carcinogenic substances. Sokolov et al. (591) described an insignificant inhibitory effect on tumors (mouse sarcoma 180 and Ehrlich carcinoma) in mice after application of protopine and chelidonine. The cytotoxic effect of these two substances was considerable. To our knowledge the biological effects of the alkaloids of 13-0x0and 13-methylprotopine types have not been studied.
K. PHTHALIDEISOQUINOLINE GROUP
1. Narcotine Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine ( 5 9 6 5 9 7 ) . LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. /3-Narcotine proved to be much more effective than a-narcotine (600); the effect of the N-oxides of the two isomers was more marked than that of the base. /?-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per 0s for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). Albricht (614) found that in cats a combination of morphine with narcotine was a more effective and less toxic analgesic than morphine. In mice (615)the analgesic effect of narcotine was smaller than that of morphine but its toxicity was greater. Bloch et al. (616) administered i.v. a mixture of scopolamine, morphine, and narcotine as an additional analgesic in local anesthesia. For the sedative and analgesic effects of narcotine, see Oelkers and Fiedler (103),Jeske et al. (617),and Krissig (618). Narcotine potentiates the effect of colchicine during inhibition of mitoses (619-622) ; narcotine itself is no mitotic poison. Administration
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
239
of narcotine to a 10-day-old chicken embryo produced various malformations (623). It inhibits the cholinesterase of horse serum (62) and histidine decarboxylase (624). A slight decrease in the basal metabolism in rabbits was observed by Tin (80) after administration of narcotine to rabbits. The relationship of narcotine to scurvy is noticeable (83,625,626).Many organic substances, including narcotine, induced (83) an increase in the excretion of vitamin C. 2. Hydrastine
Hydrastine has been employed (627) in the form of a hydrochloride for uterine and other hemorrhagias in doses of 25 mg 4-5 times daily. Higher doses produce an increase in blood pressure. 3. Bicuculline
Bicuculline was first isolated by Manske (628). It increases the arterial pressure, the amplitude of cardiac contractions, and the frequency of respiration in anesthetized cats. After administration of bicuculline the uterine tonus increases and the tonus of the intestinal musculature in vitro decreases (629). Subcutaneous administration of doses of 5 mg/kg produces convulsions and a decrease in the spinal cord acetylcholine content (630).In recent years, numerous papers have been concerned with the antagonism of bicuculline and y -aminobutyric acid (GABA) (631-661). GABA, which arises on decarboxylation of glutamic acid, is an inhibiting transmitter in the cortex, in Deiter’s nucleus of the prolonged spinal cord, and perhaps even in the other parts of the central nervous system (CNS). The mechanism of its effects is probably based on the increase in the permeability of the membrane of the cells for chloride ions. The liberation of GABA in the cortex increases during sleep and particularly during the evoked inhibition of the cortex. Since bicuculline antagonizes the inhibitory action of GABA, the inhibitory basket-type cells of the cerebellar and cerebral cortices may release GABA as a neural transmitter. The methochloride of bicuculline, which is a hundred times more soluble in water, is more effective in the antagonistic effect on the CNS of the cat than the hydrochloride.
L. NARCEINE GROUP 1. Narceine
Narceine (R = CH,) was isolated from opium by Pelletier (662) in 1832. Its i.v. administration (663)to rabbits stimulates the respiratory
240
V. PREININGER
R = H or CH,
center, it accelerates the frequency and increases the volume of respiration. It has an antitussic effect similar to that of codeine but no analgesic effect. It strongly depresses blood pressure and stimulates intestinal peristalsis. For mice, rabbits, and cats, LD,, ranges between 1.8 and 2.2 g/kg. A survey on the effect of various substances including narceine on mutation has been given by Oehlkers (664).A biological investigation of nornarceine (R = H) has not been reported.
M. RHOEADINE AND PAPAVERRUBINE GROUPS 0
R = H or CH,
1. Rhoeadine
Rhoeadine (R = CH,) was isolated for the first time by Hesse (665) in 1865. It has always been considered to be ineffective physiologically as well as poisonous. In children, the sedative and slightly expectorant effect of the syrup prepared from the flowers of P . rhoeas L. (where rhoeadine is the major alkaloid) could not be explained, nor can it be explained why cattle avoid P . rhoem (666). Hakim (667) observed, after administration of seed oil and extracts from poppy heads of P . rhoeas, an increase in intraocular pressure in rabbits. Lieb and Scherf (372) administered rhoeadine to rabbits and found a significant decrease in intraocular pressure, mydriasis, and a slight stimulation of respiration. For details refer to Section 11, N on the benzophenanthridine alkaloids. The increase in intraocular pressure is apparently not caused by rhoeadine. Awe (668) observed spasms after administration
5.
THE BIOLOGY OF PAPAVERACEAE ALKALOIDS
241
of rhoeadine. Schmitz (310) reported a slight inhibitory effect of rhoeadine on the uptake of oxygen by the cells of ascitic tumors in mice.
N. BENZOPHENANTHRIDINE GROUP
Sanguinarine type (Z = H) Senguilutine type (Z = OCH3)
Dihydrosanguinarine type
(X = Ha) Oxysenguinerine type
(X = 0)
R = H or CH, Chelidonine type (X = Ha, Y = H) Corynoline type (X = Hz. Y = CH3)
1. Chelidonine
Chelidonine exerts a spasmolytic effect (473, 669, 670) which is greater than that of papaverine. Administration of chelidonine brings about relaxation of spasms of the gastrointestinal tract and of the bronchi, and it decreases the tonus of the smooth muscle of the urinary bladder, the ureter, and of the uterus and vessels. It also lowers blood pressure and retards the activity of the heart by irritation of the vagus. Furthermore, it has a cholagogue and a choleretic effect (473). Therefore, it has been recommended as an analgesic and spasmolytic for spasms of the gastrointestinal tract instead of papaverine. Because of its analgesic, spasmolytic, cholagogue, and choleretic effects, it proves beneficial in cholecystitis and hepatitis. For its bactericidal effect, it is also used as an antisepticum for the bile duct. Lenfeld (671) found
242
V. PREININGER
that its spasmolytic effect on the rabbit intestine is approximately half that of papaverine. Even though it is no mitotic poison it increases the inhibitory effect of colchicine upon mitoses (622) and has a marked stathmokinetic effect (672). Peroral application of drops or lozenges containing chelidonine and a-allocryptopine against exanthemas in infants and children produces euphoria and, immediately after administration of the first dose, marked regression of the symptoms (673). 2. Homochelidonine
The effect of homochelidonine is similar to that of chelidonine (674). 3. Chelerythrine
Chelerythrine causes (675) a temporary blood pressure increase in mice, rabbits, and cats. When given at 15 min intervals it produces hypotension in 40-60 min. In 3-10 mg/kg doses i t has an analgesic effect and potentiates the pain relieving action of morphine. It also prolongs sleep induced in experimental animals by application of sodium thiopental or chloral hydrate. 4. Sanguinarine
Sanguinarine has been incorporated into expectorant mixtures (676).It inhibits oxidative decarboxylation of pyruvic acid by inactivation of sulfhydryl groups of enzymes (677).Sanguinarine has a similar effect upon tumorous growth as chelidonine (310, 622) and furthermore it has adrenolytic, sympathicolytic, and local anesthetic effects (678). I n vitro the spectrum of antimicrobial activity (589, 679) of sanguinarine is very large. It has a strong bactericidal effect upon grampositive bacteria (including those resistant to penicillin), particularly upon Bacillus anthracis and staphylococci and a slight tuberculostatic effect (680). A 0.1% solution of sanguinarine inhibits and finally kills Trichomonas vaginalis (681).For the effect of sanguinarine on bacteria, see (682-685). Nikolskaya (686) observed an inhibition of the cholinesterase activity as a result of the effect of sanguinarine and stimulation of the peristalsis in cats and dogs. For mice the LD,, was 19.4 mg/kg* The possible relationship of sanguinarine to glaucoma in epidemic tropical hydropsy which is frequent in India has been referred to (666, 677, 687). The oil from Argemona mexicana L., whose seeds
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
243
contain sanguinarine and dihydrosanguinarine, is sometimes added to mustard oil which is used in the food industry in India. Sarker (688) found that the oil from A . mexicana produces glaucoma in epidemic hydropsy. Later on this finding was confirmed by Hakim on rabbits and monkeys. Papaver alkaloids injected i.v. into rabbits (372)produce a decrease in intraocular pressure. Administration of sanguinarine (689) was followed by temporary changes in intraocular pressure. Hakim et al. (667, 687) discussed the comparatively large distribution of sanguinarine in the Papaveraceae and the relationship between the consuming of poppy -seeds and the possible development of glaucoma. In 1966, Kabelfk (676) carried out a critical evaluation of the relationship between glaucoma and sanguinarine. He assumed that the frequent incidence of glaucoma in epidemic tropical hydropsy is the result of the action of mustard oil contaminated with the oil from the seeds of A . mexicana containing sanguinarine. Sanguinarine is active only indirectly by causing s disorder in the carbohydrate metabolism when rice is eaten exclusively. This might be one of the many ways to explain the pathogenesis of glaucoma. For the anticancerous effect of benzophenanthridine alkaloids, see Tin-Wa et al. (690, 691).
0.SPIROBENZYLISOQTJINOLINE GROTJF To our knowledge the biological effects of the alkaloids of the ochotensimine group have not been studied.
REFERENCIW 1. K. Mothes and H. R. Schutte, “Biosynthese der Alkaloide,” p. 2. VEB Deut. Verlag Wiss., Berlin, 1969. 2. F. Fedde, in “Das Pflanzenreich” (A. Engler, ed.), Part IV, No. 40, p. 288. Engelmann, Leipzig, 1909. 3. F. Gantavf, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 12, p. 333. Academic Press, New York, 1970. 4. H.-G. Boit, “Ergebnisse der Alkaloid-Chemie bis 1960,” pp. 210-369, 944-949. Akademie-Verlag, Berlin, 1961. 5. M. Shamma, “The Isoquinoline Alkaloids.” Academic Press, New York, 1972. 6. E. Starkenstein, in Handbuch der experimentellen Pharmakologie,” Vol. 2, Part I1 p. 81-5. Springer-Verlag,Berlin and New York, 1924. 7. 0. Schaumann, in, “ Handbuch der experimentellen Pharmakologie,” Vol. 12, p. 1. Springer-Verlag,Berlin and New York, 1957.
244
V. PREININGER
8. H. Krueger, N. B. Eddy, and M. Sumvalt, U.S., Pub. Health Serv., Suppl. 165, 1-811 (1941); 813-1448 (1943); C A 38, 2738 (1944). 9. 0 . Hesse, Ann., Suppl. 8 , 261 (1872). 10. B. Kelentei, Acta Pharm. Hung. 39, 247 (1969). 11. G. P. Leszkowszky and D. Korbonits, Pharmazie 22, 448 (1967). 12. Y. Arai and K. Enomoto, Yakugaku Zasshi 88, 44, 55, 1197 (1968). 13. Y. Arai and K. Enomoto, Yakugaku Zasshi 89, 392 (1969). 14. Y. Arai and K. Enomoto, J . Pharm. SOC.Jap. 89, 947 (1969). 15. Y. Ywasawa and A. Kiyomoto, Jap. J . Pharmacol. 17, 143 (1967). 16. M. Sato, I. Yamaguchi, and A. Kiyomoto, Jap. J . Pharmacol. 17, 153 (1967). 17. Y. Ywasawa and A. Kiyomoto, Nippon Yakurigaku Zasshi 63, 28 (1967); C A 68, 10902 (1968). 18. M. Sato, Y. Ywasawa, and A. Kiyomoto, Nippon Yakurigaku Zasahi 64, 268 (1968). 19. A. Kiyomoto, M. Sato, T. Nagao, and H. Nakajima, Eur. J . PhurmacoZ. 5, 303 (1969). 20. A. Kiyomoto, Y. Ywasawa, and S. Harigaya, Arzneim.-Forsch. 20, 46 (1970). 21. A. M. Hjort, E. J. De Beer, and D. W. Fassett, J . Pharmacol. 62, 165 (19381; CA 32, 3023 (1938). 22. D. W. Fassett and A. M. Hjort, J . Pharmacol. 63, 253 (1938); C A 32, 6742 (1938). 23. D. Hobson, H. I. Flockton, and M. G. Gregory, Brit. J . Exp. Pathol. 50, 494 (1969). 24. G. M. Williamson and D. Jackson, BUZZ. W.H.O. 41, 665 (1969). 25. S. E. Reed, A. S. Beare, M. J. Bynoe, and D. A. J. Tyrrell, Ann. N.Y. Acad. Sci. 173, 760 (1970). 26. E. Eckhart and J. Varga, Magy. Kem. Foly. 67, 509 (1961); CA 56, 15557 (1962). 27. H. Ippen, “Index Pharmacorum.” Thieme, Stuttgart, 1970. 28. F. Markwardt, W. Barthel, G. Faust, W. Fiedler, and A. Hoffmann, Acta Biol. Med. Uer. 23, 295 (1969). 29. B. Kelentei, E. Stenszky, and F. Czollner, Pharmazie 15, 111 (1960). 30. P. Bouvier and C. Viel, Chim. The?. 6, 462 (1971). 31. R. Heikkila, G. Cohen, and D. Dembiec, J . Pharmacol. Exp. Ther. 179, 250 (1971). 32. V. E. Davis, M. J. Walsh, and Y. Yamanaka, J . Pharmacol. Exp. Ther. 174, 401 (1970). 33. G. Cohen, Biochem. Pharmacol. 20, 1757 (1971). 34. A. Goldstein and B. A. Judson, Science 172, 291 (1971). 35. G. Merck, Ann. 66, 125 (1848). 36. J. Pal, Deut. Med. Wochemchr. 40, 164 (1914). 37. R. Santi, M. Ferrari, and A. R. Contessa, Biochem. Pharmawl. 13, 153 (1964). 38. R. Santi, A. R. Contessa, and M. Ferrari, Biochem. Biophys. Res. Commun. 11, 156 (1963). 39. S. Luciani, A. R. Contessa, and C. Bortignon, Boll. SOC.Ital. Biol. Sper. 43, 409 (1967); C A 67, 8400 (1967). 40. C. E. Toth, M. Ferrari, A. R. Contessa, and R. Santi, Arch. Int. Pharmacodyn. Ther. 162, 123 (1966). 41. E. P. Chetverikova, Uch. Zap., I m t . Farmakol. Khimioter., Akad. Med. Nauk SSSR 2, 212 (1960); CA 57, 5273 (1962). 42. I. E. Kisin, Famaakol. Tokaikol. (Moscow) 26, 197 (1963). 43. 0. V. Alekseev and M. F. Vyalyhk, Mitokhondrii, Biolchim. Morfol., Mater. Simp., Znd, 1966 116 (1967); C A 68, 3686 (1968).
5. THE
BIOLOGY O F PAPAVERACEAE ALKALOIDS
245
44. S. Luciani, C. Bortignon, and R. Santi, Boll. SOC.Ital. Biol. Sper. 48, 410 (1967). 45. W. R. Kukovetz, Naunyn-Schmiedebergs Arch. Exp. PathoE. Pharmakol. 264, 262 (1969). 46. G. Poch and W. R. Kukovetz, f i f e Sci. 10, 133 (1971). 47. J. V. Levy, Res. Commun. Chem., Pathol., Pharmacol. 4, 261 (1972). 48. G. C. Toson and F. Carpenedo, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 273, 168 (1972). 49. 0. Rufeger, B. Tellhelm, and M. Frimmer, Naunyn-Sehmedebergs Arch. E x p . Pathol. Pharmakol. 270, 428 (1971). 50. W. R. Kukovetz and G. Poch, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 267, 189 (1970). 51. F. Demesy and J. C. Stoclet, J. Pharm. Pharmacol. 23, 712 (1971). 52. M. Veda, S. Matsumura, S. Kimoto, S. Matsuda, and T. Mineshita, Shionogi Kenkyusho Nempo 10, 31 (1960); C A 54, 25274 (1960). 53. A. A. Pykhtina, Farmakol. Toksikol. (Moacow) 17, 33 (1954). 54. A. A. Goldberg and M. Shapero, J. Pharm. Pharmacol. 6, 171 (1954). 55. J. Axelrod, R. Shafer, J. K. Inscoe, W. M. King, and A. Sjoerdsma, J . Pharmacol. Exp. Ther. 124, 9 (1958). 56. J. LBvy, Bull. SOC. Chim. Biol. 27, 578 (1945). 57. S. R. Elek and H. C. Bergman, J. Appl. Physiol. 6, 168 (1953). 58. F. G. Drommond, C. C. Johnson, and C. F. Poe, Acta Pharmacol. Tom’col. 6, 235 (1950). 59. M. Aurousseau and J. Navarro, Ann. Pharm. Fr. 15, 640 (1957). 60. S. Katsch, J . Appl. Phyaiol. 8, 215 (1955). 61. A. Denys and J. LBvy, C.R. Soe. Biol. 141, 653 (1947). 62. D. Vincent and P. Beaujard, Ann. Pharm. Fr. 3, 22 (1945); C A 40, 5204 (1946). 63. L. Parteni, M. Corneanu, and C. Papescu, Commun. Acad. Rep. Pop. Rom. 4, 161 (1954); CA 50, 10265 (1956). 64. A. A. Pykhtine, Parmakol. Toksikol. (Moacow)28, 719 (1965). 65. K. Takagi and I. Takayanagi, Pharm. Bull. 5, 580 (1957). 66. G. Dastugue and A. Bresson, Bull. Sci. Pharmacol. 47, 25 (1940); C A 34, 4153 (1940). 67. M. Y. Mikhelson, Byull. Eksp. Biol. N e d . 11, 230 (1941); C A 41, 6339 (1947). 68. E. Frommel and C. Fleury, C. R. SOC.Biol. 153, 18 (1959). 69. E. P. Chetverikova, Byull. Eksp. Biol. Med. 58, 45 (1964); C A 62, 9639 (1965). 70. E. P. Chetverikova, Dokl. Akad. Nauk SSSR 164, 696 (1965). 71. E. P. Chetverikova, Byull. Eksp. Biol. Med. 59, 71 (1965); C A 63, 12158 (1965). 72. J. Garcia-Blanco and S. Grisolia, Trab. Inst. Nac. Cienc. Med., Madrid 5, 165 (1944); C A 40, 6523 (1946). 73. N. Tanaka, Jap. J. E z p . Med. 22, 87 (1952). 74. F. Markwardt, W. Barthel, E. Glusa, and A. Hoffmann, Experientia 22, 578 (1966). 75. F. Markwardt, W. Barthel, E. Glusa, and A. Hoffmann, Naunyn-Schmiedebergs Arch. Pharmakol. Exp. Pathol. 257, 420 (1967). 76. F. Markwardt and A. Hoffmann, Biochem. Pharmacol. 19, 2519 (1970). 77. E. Gerlach, B. Deuticke, and J. Duhm, Pjluegers Arch. aesamte Phyaiol. Menschen Tiere 280, 243 (1964). 78. P. Ancel and H. Scheiner, Arch. Anat., Histol. Embryol. 34, 19 (1952); C A 49, 13510 (1955). 79. F. Carpenedo, Acta Isotop. 6, 51 (1966). 80. K. Tin, Folia Pharmacol. Jap. 29, 1 (1940); CA 34, 8054 (1940).
246
V. PREININGER
81. S. Isimaru, Jap. J. Pharmacol. 12, Abstracts, 29 (1939); C A 34, 7432 (1940). 82. I. E. Frommel, J. Piquet, C. L. Cubnod, M. Loutti, and J. Aron, Helv. PhysioE. Pharmacol. Acta 3, 83 (1945). 83. H . E. Longenecker, H. H. Fricke, and C. G. King, J . Biol. Chem. 135, 497 (1940). 84. A. A. Pykhtina and A. V. Martynycheva, Farmakol. Tok8iko2. (Moscow) 31, 700 (1968). 85. A. A. Pykhtina, Nekot. Aktual. Vop. Biol. Med. 38 (1968). 86. H. Ra, FoZk PharmacoZ. Jap. 32, 276 (1941); CA 36, 1095 (1942). 87. E. A. Amroyan, Dokl. Akad. Nauk Arm. SSR 53, 58 (1971). 88. T. Utinokura, Zikken Yakhbutugaku Zasshi 17, 223 (1940); C A 38, 6385 (1944). 89. L. Wertheimer, W. Redisch, K. Hirschhorn, and J. M. Steele, Circulation 11, 110 (1955). 90. G. S. Gvishiani, Farmakol. TOkSikOl. (Moscow) 10, 42 (1947). 91. W. Busse and L. Lendle, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 218, 169 (1953). 92. F . SchnellbiLcher, Deut. Med. Wochenschr. 80, 1646 (1955). 93. U. Gottstein, W. Niedermayer, and A. Bernsmeier, 2. aeaamte Exp. Med. 131, 430 (1959). 94. H . W. J a p e , P. Scheinberg, M. Rich, M. S. Belle, and I. Blackburn, J. Clin. Invest. 31, 111 (1952). 95. D. Hadjiev and A. Tzenov, Paychiat. Neurol. Med. Psychol. (Leipzig) 16, 242 (1964). 96. H. A. Shenkin, J. AppZ. Phy8iol. 3, 465 (1951). 97. E. N. Kozlova, Klin. N e d . 44, 48 (1966). 98. A. Kuwayama, N. T. Zerrasa, A. Shintani, and K. S. Pickren, Stroke 3, 27 (1972). 99. H. I. Russek and B. L. Zohman, N . Y . State J. Med. 49, 1411 (1949); C A 47, 12658 (1953). 100. A. S. Saratikov, L. A. Usov, and L. I. Gold, Farmakol. Toksikol. (Moscow) 32, 152 (1969). 101. P. Mucci and E. Sternieri, Boll. SOC.Ital. Biol. Sper. 44, 965 (1968). 102. F. Mercier, P. Marinacce, and L. Richaud, C.R.SOC.Bid. 146, 1757 (1952). 103. H. A. Oelkers and H. Fiedler, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 197, 636 (1941); C A 37, 3828 (1943). 104. A. A. Pykhtina, Farmakol. Toksikol. (Moscow)28, 524 (1965). 105. T. Takase and S. Suzuki, T o h u k u J . E x p . Med. 35,57 (1939); C A 33, 4682 (1939). 106. V. Bauer and R. N. Sur, PsychopharmacoEog~a26, 263 (1972). 107. V. Bauer and 0. KadlecovB, Psychopharmacologia 26, 275 (1972). 108. V. Bauer, Ezperientia 28, 928 (1972). 109. V. Risti6 and A. Volkanovska, Boll. Chim. Farm. 94, 3 (1955); CA 49, 9227 (1955). 110. 0. Rajka, Magy. Tud. Aknd. Bzol. Ow. Tud. Oszt. Xozlem. 12, 419 (1961); CA 57, 5214 (1962). 111. A. Quevauviller and S. Gareet, C.R.SOC.Biol. 144, 165 (1950). 112. S. G. Macris, G. M. Smith, and H. K. Beecher, J . Pharmacol. Exp. Ther. 123, 220 (1958). 113. A. Enders and L. Schmidt, Arch. Int. Pharmacodyn. Ther. 114, 446 (1958). 114. H. Haas, Nuunyn-Schmiedebergs Arch. Ezp. Pathol. Pharmakol. 225, 442 (1955). 115. A. A. Dzhugeli and V. K. Eliozishvili, G%sto-OematicheskieBar’ery, T r . Soveshch., 115 (1961); C A 57, 10446 (1962). 116. A. Enders and L. Schmidt, Arch. Int. Pharmacodyn. Ther. 91, 157 (1952). 117. A. Enders and L. Schmidt, Arzneim.-Forsch. 2, 221 (1952).
5.
THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
247
118. R. G. Nims, J. W. Severinghaus, and J. H . Comroe, Jr., J . Pharmacol. Exp. Ther. 109, 58 (1953). 119. A. A. Goldberg and M. Shapero, J . Pharm. Pharmacol. 6, 236 (1954). 120. J. C. Castillo and E. J. De Beer, J . Pharmacol. 90, 104 (1947). 121. F. Mercier, J. Mercier, and J. Colin, C.R. SOC.Biol. 144, 1187 (1950). 122. J. B. Farmer and E. A. Chick, J . Pharm. Pharmacol. 19, 124 (1967). 123. E. R. Loew, M. E. Kaiser, and V. Moore, J . Pharmacol. 86, 1 (1946). 124. F. Mercier, M. R. Sestier, and L. Richaud, C.R. SOC.Biol. 146, 1359 (1952). 125. A. Baisset, P. Montastruc, and M. A. Tran, Therapie 26, 755 (1971). 126. M. Herxheimer, Arch. Int. Pharmacodyn. Ther. 106, 371 (1956). 127. 0. Schauman, Med. Chem. (Leverkusen, Ger.) 4, 229 (1942); C A 38, 6377 (1944). 128. M. Yamaguchi, Nippon Yakurigaku Zasshi 60, 588 (1964); CA 62, 12191 (1965). 129. B. Issekuta and P. Genersich. Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol 202, 201 (1943); C A 38, 1796 (1944). 130. H. Imafuku, Nagasaki Igakkai Zasshi 33, 422 (1958); CA 52, 13118 (1958). 131. B. Nuki and N . Takeya, J . Philipp. Med. Ass. 32, 313 (1956); C A 50, 17150 (1956). 132. M. Litter, Sem. Med. (Buenos Aires), 909 (1956); CA 50, 13291 (1956). 133. C. Hanna, Publ. No. 4969, p. 54. University Microfilms, Ann. Arbor, Michigan, 1953; C A 47, 8911 (1953). 134. C. Hanna, Arch. Int. Pharmacodyn. Ther. 119, 162 (1959). 135. H. I. Russek, Postgrad. Med. 19, 562 (1956); C A 51, 6008 (1957). 136. P. I. Halonen, 0. Vartiainen, and E. V. Venho, Ann. Med. Exp. Fenn. 29, 23 (1951). 137. H. E. Essex, R. G. E. Wagner, J. F. Herrick, and F. G. Mann, Arne?. Heart J . 19, 554 (1940). 138. E. Lindner and L. N. Katz, J . Pharmacol. 72, 306 (1941); C A 35, 7028 (1941). 139. K. Hashimoto, Jap. Circ. J . 21, 290 (1957); CA 55, 23801 (1961). 140. I. E. Kisin, Byull. Exp. B i d . Med. (USSR)45, 712 (1958). 141. I. E. Kisin, Byull. Exp. R i d . Med. (USSR)53, 69 (1962). 142. V. V. Buyanov and I. E . Kisin, Vestn. Akad. Med. Nauk SSSR 18, 36 (1963). 143. 0. Heidenreich and L. Schmidt, Naunyn-Schmiedebwgs Arch. Exp. PatlwZ. Pharmakol. 227, 250 (1955). 144. K. I. Melville and F. C. Lu,J . Pharmacol. Exp. Ther. 99, 277 (1950). 145. A. Koide, Nippon Yakurigaku Zasshi 55, 725 (1959); C A 55, 1919 (1961). 146. C. Hanna and J. H. Shutt, Naunyn-SchmiedebergsArch. Exp. Pathol. Pharmakol. 220, 43 (1953). 147. W. Heimann and W. Wilbrandt, Helv. Physiol. Pharmacol. Acta 12, 230 (1954). 148. F. C. Lu, Rev. Can. B i d . 16, 390 (1957). 149. W. Persch and R. E. Nitz, Aerztl. Wochenschr. 8 , 385 (1953). Pharmacol. Znd, 1962 150. M. Fekete and J. Borsy, Hung. Conf. Ther. Res. [PTOC.], 259 (1964); CA 62, 15258 (1965). 151. I. Setnikar, Boll. Chim. Farm. 102, 308 (1963); C A 59, 14463 (1963). 152. E. D. Luebs, A. Cohen, E. J. Zaleski, and R. J . Bing, Amer. J . Cardiol. 17, 535 (1966). 153. H. Gold, J . Amer. Med. Ass. 112, 1 (1939). 154. A. I. Mironenko, B’armakol. Toksikol. (Moscow) 19, 10 (1956). 155. E. Keeser, Deut. 2. Verdau- Stoffwechselkr. 8, 44 (1944). 156. S. Osada, Fdia Endocrinol. Jap. 12, 97 (1937); C A 32, 7104 (1938). 157. Z. S. Bedzhamyan and M. S. Martikyan, Zh. Eksp. Klin. Med. 8, 35 (1968).
248
V. PREININGER
E. Nyman, Acta Med. Scandr 131, 565 (1948). W. Raab and R. J. Humphreys, J. Pharmacol. 89, 64 (1947). M. Sangiorgi, Cor Vasa 13, 244 (1971). E. P. Chetverikova, Vop. Men. Khim. 7, 372 (1961). G. A. Markova, Farmakol. Toksikol. (Moscow) 24, 292 (1961). C. G. McEachern, F. H. Smith, and G. W. Manning, Amer. Heart J . 21, 25 (1941). N. B. Vysotskaya and G. A. Markova, Farmakol. Toksikol. (Moscow)28, 309 1965). A. Leslie, M. G. Mulinos, and W. S. Scott, Jr., Proc. SOC.Exp. Biol. Med. 44, 625 (1940). 166. R. Mokotoff, L. N. Katz, G. MokotoE, and H. L. Baker, Jr., Amer. Heart J . 30, 215 (1945). 167. I. E. Kisin, Farmakol. Toksilcol. (Moscow) 27, 170 (1964). 168. A. 8. Harris, A. Estandia, A. Bisteni, and H. T. Smith, Circulation 8, 874 (1953). 169. T. H. Greiner and S. Garb, J. Phurmacol. Exp. Ther. 98, 215 (1950). 170. S. R. Elek and L. N. Katz, J. Pharmacol. 74, 335 (1942); C A 36, 3848 (1942). 171. E. Castillo and J. Esplugues, Med. Espan. 28, 91 (1952); C A 47, 10710 (1953). 172. E. Lindner and L. N. Katz, Amer. J. Physiol. 133, 155 (1941). 173. R. WBgria and N. D. Nickerson, d . Phamacol. 75, 50 (1942); CA 36, 4195 (1942). 174. D. K. Jongh and E. G. Proosdij-Harzema, Acta Physiol. Phamacol. Neer. 2, 390 (1951). 175. A. Akcasu, BUZZ. B’ac. Med., Istanbul Univ. 15, 230 (1952); C A 46, 9216 (1952). 176. J. R. Di Palma and J. E. Schults, Medicine (Baltimore)29, 123 (1950); C A 44,9629 (1950). 177. K. I. Melville,
[email protected]. Biot. 7, 236 (1948). 178. C. M. Gruber, Jr., C. M. Gruber, and K. S. Lee, Arch. Int. Pharmacodylz. Ther. 93, 248 (1953). 179. H. H. Prey and A. Donhardt, Arch. Exp. Vetel.iltaermed. 10, 384 (1956). 180. C. Hanna and J. R. Schmid, Arch. Int. Pharmacodyn. Ther. 185, 228 (1970). 181. A. Quevauviller and M. Choix, Therapie 9, 64 (1954). 182. P. Duchene-Marullaz, G. Schaff, F. Lantier, and J. Lavarenne, C . R . SOC.Bid. 161, 318 (1967). 183. T. D. Darby, J. H. Sprouse, and R. P. Walton, J. Pharmacol. Exp. Ther. 122, 386 (1958). 184. C. V. Winder, R. W. Thomas, and 0. Kamm, J. Phamacol. Exp. Ther. 100, 482 (1950). 185. C. V. Winder and M. E. Kaiser, J. Phurmacol. Exp. Ther. 93, 86 (1948). 186. H. Mercker, W. Lochner, and E. Schiirmeyer, Naunym-Schmiedeberg8 Arch. Exp. Pathol. P h a m a h l . 228, 213 (1956). 187. W. Lochner, H. Mercker, and E. Schiirmeyer, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 227, 373 (1955). 188. W. Lochner and H. Hirche, Natum’sa. 49, 259 (1962). 189. P. Heistracher, 0. Kraupp, and G. Spring, Arzneim.-Forsch. 14, 1098 (1964). 190. C. J. Cam, F. K. Bell, M. J. Rehak, and J. C. Krantz, Jr., Proc. SOC.Exp. B i d . Med. 89, 184 (1955). 191. J. Dorner and E. Paas, Naumyn-Schmiedebergs Arch. Exp. Pathol. Phurmakol. 226, 152 (1955). 192. F. A. Kyser and R. Trump, Amer. Heart J . 36, 133 (1948). 193. F. Mercier, J. Delphaut, and P. Jouttret, C.R. SOC.B i d . 135, 1661 (1941). 194. D. Littauer and I. S. Wright, Amer. Heart J. 17, 325 (1939). 195. M. Martinez, Sem. Med. (BUelz08 Aires), 1113 (1954); C A 49, 4881 (1955).
158. 159. 160. 161. 162. 163. 164. 165.
5. THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
249
196. A. I. Mironenko, Farmakol. Toksikol. (Moscow) 7, 46 (1944); 17, 33 (1954); 20, 28 (1957). 197. I. I?. Shvarev, Farmakol. Toksikol. (Moscow)23, 242 (1960). 198. M. Sakamoto, Folia Endocrinol. Jap. 11, 76 (1936); C A 32, 8007 (1938). 199. J. Vacher and P. Ducheue-Marullaz,C.R.SOC.Biol. 158, 1522 (1964). 200. M. Bergamashi and A. M. Glasser, Circ. Res. 15, 371 (1964). 201. G. Gasperoni, a. Clin. Med. (Bologna) 31, 421 (1950); C A 44, 10180 (1950). 202. A. A. Nikulin, Fiziol. Zh. SSSR im I . M . Sechenova 43, 435 (1957). 203. J. C. Stoclet and J. Y . Videau, J . Pharmacol. ( P a r k )2, 11 (1971). 204. R. C. Batterman, G. Jensen, and L. Jensen, Angiology 21, 612 (1970). 205. Z. M. Shishkina, T r . Astrakhan. Qos. Med. Inst. 11, 227 (1954); C A 50, 8897 (1956). 206. R. A. Murphy, Jr., J. N. McClure, Jr., F. W. Cooper, Jr., and L. G. Crowley, Surgery 27, 655 (1950). 207. S. Ito, Folia Endocrinol. Jap. 12, 35 (1936); C A 32, 8007 (1938). 208. Y. Sai, Igaku Kenkyu 24, 1278 (1954); C A 48, 13968 (1954). 209. S. Burgi, Helv. Physiol. Pharmacol. Acta 3, 215 (1954). 210. C. Heymans, A. L. Delaunois, and A. L. Rovati, Arch. I n t . Pharmacodyn. Ther. 109, 245 (1957). 211. L. I. Zgoda, Farmakol. Toksikol. (Moscow) 30, 691 (1967). 212. I. E. Kisin and G. G. Chichkanov, Parmakol. Toksikol. (Moscow) 33, 432 (1970). 213. A. F. Heck and I. Hawthorne, Angiology 22, 408 (1971). 214. C. Hanna and R. C. Parker, Arch. Int. Pharmacodyn. Ther. 126, 386 (1960). 215. R. Meier, H. J. Bein, F. Gross, and J . Tripod, Acta Med. Scand. 154, Suppl. 312, 165 (1956). 216. R. Meier, J. Tripod, and C. Bruni, Arch. Int. Pharmacodyn. Ther. 101, 158 (1955). 217. M. Bariety and D. Kohler, C.R.SOC.B i d . 135, 706 (1941). 218. A. Enders and L. Schmidt, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 216, 353 (1952). 219. R. Hazard, M. Beauvallet, and R. Giudicelli, Arch. Int. Pharmacodyn. Ther. 77, 504 (1948). 220. S . Landgren, E. Neil, and Y . Zotterman, Acta Physiol. Scand. 25, 24 (1952). 221. A. A. Pykhtina, T r . Vses. Obshchest. Fiziol., Biokhim. Farmakol. 2, 181 (1954); C A 49, 8491 (1955). 222. J. H. Tyrer, Quart. J. E x p . Physiol. Cog. Med. Sci. 38, 155 (1953). 223. P. G. Royo, An. I m t . Invest. Vet., Madrid 11, 11 (1961); C A 57, 9153 (1962). 224. H. Genuit and W. Kubel, Naunyn-Schnaiedebergs Arch. Exp. Pathol. Pharmakol. 202, 110 (1943); C A 38, 1561 (1944). 225. C. I. Marolda and M. Martinez, Rev. Asoc. Med. Argent. 68, 5 (1954); C A 48, 9545 (1954). 226. J. F. Schvarev, Farmakol. Toksikol. (Moscow) 21, 86 (1958). 227. F. Rothschild and C. Meili, Helv. Med. Acta 6, 255 (1939). 228. C. E. Toth and E. S. Soncin, Arch. Ital. Sci. Parmacol. 14, 89 (1964); C A 63, 4831 (1965). 229. N. Tashiro and T. Tomita, Brit. J. Pharmacol. 39, 608 (1970). 230. H. J. Kuschke and E. Paas, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 228, 215 (1956). 231. T. A. Shirkova, Vrach. Delo 71 (1964); C A 62, 8302 (1965). 232. L. Schmidt, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 241, 538 (1961). 233. V. N. Mentova, Farmakol. Toksikol. (Moscout) 17, 13 (1954). 234. W. D. Holden, Surg., Gynecol. Obstet. 88, 23 (1949).
250
V. PREWINGER
235. L. Friedberg, L. N. Katz, and F. S. Steinitz, J. Pharmacol. 77,80 (1943); C A 37, 1513 (1943). 236. H. RagkovB, K. Ragka, V. Mat6jovskB, and B. RybovB, Physiol. Bohemoslow. 3, 306 (1954). 237. F . Mercier and J. Delphaut, C.R. Soc. Biol. 128, 907 (1938). 238. A. Ohga, Nippon Yakurigaku Zasshi 53, 850 (1957); C A 52, 20635 (1958). 239. E. Koml6s and I. Foldes, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 234, 26 (1958). 240. G. Ben-Ziv and F. G. Sulman, Arch. Int. Pharmacodyn. Ther. 149, 200 (1964). 241. M. A. Alekperov, Azerb. Med. Zh. 42, 27 (1965); C A 62, 16746 (1965). 242. F. Mercier, C.R. SOC.Bid. 138, 645 (1944). 243. G. Bornmann and A. Loeser, Arch. Int. Pharmacodyn. Ther. 79, 332 (1949). 244. G. Grupp and E. Sailer, Arch. Int. Pharmacodyn. Ther. 121, 348 (1959). 245. S. Lecannelier, L. Bardisa, and I. Pfister, Bol. SOC.Bid. Concepcion 25, 3 (1950); C A 45, 9747 (1951). 246. M. Ganglio and A. Blasi, Boll. SOC.Ital. Biol. Sper. 41, 105 (1965); CA 62, 15276 (1965). 247. T. Yosida, Folia Pharmacol. Jap. 27, 133 (1939); C A 33, 8808 (1939). 248. T. Yosida, Folia Pharmacol. Jap. 27, 294 (1939); C A 34, 2068 (1940). 249. M. Sepulveda, C. Muiioz, and J. Mardones, Bol. SOC.B i d . Santiago Chile 6, 17 (1948); C A 43, 5872 (1949). 250. P. Forni, Cow. Farm. 20, 341 (1965); C A 05, 19157 (1966). 251. K. Haruta, Jap. J. Pharmacol. 11, No. 2/3 (1938); C A 34, 7425 (1940). 252. S. T. Coker and T. S. Miya, J . Amer. Pharm. Aes. 45, 626 (1956). 253. G. Segre, Boll. SOC.Ital. Biol. Sper. 29, 1269 (1953); C A 49, 8494 (1955). 254. R. Dahlbom, T. Edlung, T. Ekstrand, and A. Lohi, Acta Phrmncol. Tom‘col. 9, 168 (1953). 255. L. Ther, Naunyn-SchmiedebergsArch. Exp. Pathol. Pharmakol. 204, 98 (1947). 256. R. Meier and J. Tripod, Helw. Physiol. Pharmacol. Acta 8, 137 (1950). 257. J. Mercier, C.R. Soa. Biol. 142, 362 (1948). 258. A. K. Banerjee and J. J. Lewis, J . Pharm. Pharmacol. 16, 702 (1964). 259. N. Tashiro and T. Tomita, Brit. J. Pharmacol. 39, 608 (1970). 260. F. Carpenedo, G. C. Toson, M. Furlanut, and M. Ferrari, J. Pharm. Phamawl. 23, 502 (1971). 261. T. Tachibana, Kobe Ika Daigaku Kiyo 13, 622 (1958); CA 56, 4045 (1961). 262. C. G. Schmiterlow, Acta Physiol. S c a d . 16, 128 (1948). 263. Y. Okushima, Folia Pharmacol. Jap. 39, 244 (1943); C A 41, 5218 (1947). 264. M. Ferrari, M. Furlanut, and R. De Pirro, Agents Actions 2, 50 (1971). 265. P. Brummer and A. Bundul, Acta Med. S c a d . 130, 559 (1948). 266. M. Vodovota, Hem. Med. (Buenos Airee) 673 (1955). 267. G. Nava and C. De Bac, Arch. “E. Maragliam” Patol. Clin. 7, 691 (1952); CA 49, 13510 (1955). 268. D. Bromster, E. Lindgren, A. Rose%, and M. Theorell, Acta Radiol., Diagn. 8, 354 (1969). 269. H. Rhode, Fortschr. Ther. 19, 189 (1943); C A 39, 129 (1945). 270. Y. V. Borin and R. P. Makoss, Ter. Arkh. 33, 46 (1961); C A 62, 2163 (1965). 271. K. Fromherz, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 200, 571 (1943). 272. G. A. Petrovskij, A. G. Kravchenko, and N. G. Severin, Byull. Eksp. Biol. Med. 9, 459 (1940); CA 36, 162 (1942).
5. THE BIOLOGY OF PAPAVERACEAE ALKALOIDS
25 1
273. J. Delphant, M. Lanza, and H. Sarles, C.R. Soc. Biol. 150, 1407 (1956). 274. W. D. Erdmann and H. F. Henne, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 218, 462 (1953). 275. B. Juhksz and Z. Mester, Acta Vet. (Budapest) 7, 49 (1957);C A 51, 16893 (1957). 276. M. Eisenstein and H. Necheles, Qmtroenterology 9,576 (1947). 277. W. Neuendorf, Deut. 2. Verdau-Stoffwechselkr. 24,263 (1965);C A 63,18912 (1965). 278. F. Sandberg, A. Ingelman-Sundberg, L. Lindgren, and G. Ryden, Collect. Phamn. Suecica 16, 1000 (1962);C A 57, 10493 (1962). 279. A. I. Petchenko, Akush. Uinekol. (Moscow)No. 7-8, 8 (1940). 280. W. Lehmann, Med. Monatsschr. 6,25 (1952). 281. H. Ohara, Folia Pharmacol. Jap. 48, 273 (1952);C A 47, 6037 (1953). 282. L. PBrel, B. Chauchard, and P. Chauchard, C.R. Soc. Biol. 139, 986 (1945). 283. B. Chauchnrd, P.Chauchard, and L. PBrel, C.R.SOC.Biol. 140, 9 (1946). 284. G. Kuschinski, H. Liillmann, and K. H. Mosler, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 237, 495 (1959). 285. H.Wagner and R. Kessler, Uynaecologia 146, 459 (1958). 286. A. N. Kudrin and G. S. Koroza, Famnakol. Toksikol. (Moscow) 27, 464 (1964). 287. T. Yosida, Folia Pharmacol. J a p . 27, 221 (1939):C A 34, 819 (1940). 288. J. R. Mardones and H. 0. Torres, Bol. Sm. B i d . Santiago Chile 2, 109 (1945); C A 41, 5985 (1947). 289. M. S. Martikyan, Farmakol. Toksikol. (Moscow)33, 436 (1970). 290. R.Eliasson and A. Astrom, Acta Pharmacol. Toxicol. 11, 254 (1955). 291. R Nyberg and B Westin, Acta Physiol Scand. 39, 216 (1957). 292. H. F. Hausler and R. G. Filippi, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 225, 147 (1955). 293. M. L. McCall, T. V. Finch, end H. W. Taylor, Amer. J. Obstet. Uynecol. 61, 393 (1951). 294. T. Martius, J. R. Valle, and A. Porto, J. Urol. 44, 682 (1940). 295. T. Martius and J. R. Valle, C.R. SOC.Biol. 129, 1152 (1938). 296. S. Loewe and S. L. Puttuck, J. Phamnacol. E z p . Ther. 107, 379 (1953). 297. L. Harsing, G. Kover, M. Malynsz, G. Toth, and T. Harza, PJEuegers Arch. Gmamte Physiol. Menschen Tiere 281, 346 (1964). 298. H.Lokkegaard, Acta Med. Scand. 189, 21 (1971). 299. Z.T. Samoilova, Famakol. Toksikol. (Moscow)25, 38 (1962). 300. J. P. Gilmore, Circ. Res. 15, Suppl., 148 (1964);C A 62, 9640 (1965). 301. M. Malynsz and G. Kover, Acta Physiol. 27, 59 (1966). 302. A. A. Pykhtina, Farmakol. Toksikol. (Moscow) 19,27 (1956). 303. L.N. Sinitsin and I. E. Kisin, Farmakol. Toksikol. (Moscow)27, 138 (1964). 304. A. A. Pykhtina, Pamakol. Toksikol. (Moscow)23, 220 (1960). 305. D. E. Frank, J. Inamunol. 52, 69 (1946). 306. G. Kuschinsky, H. Lullmann, and E. Muscholl, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 223, 369 (1954). 307. W.Feldberg and W. D. M. Paton, J. Physiol. (London) 114, 490 (1951). 308. N.Brook and H. Druckrey, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 223, 314 (1954). 309. H. Druckrey, P. Danneberg, end D. Schmlil, Arzneim-Forsch. 3, 151 (1953). 310. H.Schmitz, 2;. Krebsforsch. 57, 405 (1951). 311. S. Hasegawa and N. Tanaka, Jap. J. Exp. Med. 22, 77 (1952). 312. S. Tyo, Taiwan Igakkai Z m s h i 39, 1394 (1940);C A 38, 6384 (1944). 313. P.J. Gineste, C.R.SOC.Biol. 137, 519 (1943).
252
V. PREININQER
J. Axelrod, Biochem. J . 63, 634 (1956). A. A. Pykhtina, Farmakol. Toksikol. (Moscow) 16, 12 (1953). M. Iida, Folia Pharmacol. Jap. 51, 84 (1955); C A 49, 16314 (1955). H. S. Buttar, Arch. Int. Pharmacodyn. Ther. 180, 68 (1969). V. Bauer and R. capek, & s k . Fyssiol. 18, 320 (1969). V. Bauer and R. capek, Neuropharmacology 10, 499, 507 (1971). P. Holtz, W. Langeneckert, and D. Palm, Naunyn-Schmiedebergs Arch. Pharmakol. Exp. Pathol. 259, 290 (1968). 321. I. A. Rakhimova, Mater. Simp. Vysokogore Krasnaya Krov Konf. Vysokogore Lek., 156 (1968). 322. M. T. Nanaeva and I. A. Rakhimova, Mater. Simp. Vysokogore Krasnaya Krov Konf. Vysokogore Lek., 155 (1968). 323. S. Glaubach, Proc. Soc. Exp. Biol. Med. 42, 325 (1939). 324. H. A. Oelkers and E. Wanowius, Klin. Wochenschr. 21, 752 (1942). 325. P. Durel and V . Ratner, C.R.SOC.Biol. 137, 214 (1943). 326. F. Hahn, W. Rummel, and R. Vormann, Arch. Int. Pharmacodyn. Ther. 87, 147 (1951). 327. S. Markees and V. Demole, Helv. Physiol. Pharmacol. Acta 1, 241 (1943). 328. J. Pellevat and M. Murat, C.R.SOC.Bid. 147, 704 (1953). 329. A. A. Pykhtina, Farmakol. Toksikol. (Moscow) 19, Suppl., 11 (1956). 330. F. Mercier, J. Delphaut, and P. Jouffret, C.R.SOC.Biol. 135, 1664 (1941). 331. H. Lettr.4, R. LettrB, and C. Pflanz, Hoppe-Seyler’s 2. Phyeiol. Chem. 287, 150 (1951). 332. K. Mezey, F. Monroy, and B. Uribe, An. Roc. Bid. Bogota 5 , 124 (1952); C A 48, 12295 (1954). 333. H. Freund, Ned. Tijdschr. Geneesk. 85, 955 (1941); C A 37, 6342 (1943). 334. H. A. Oelkers, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 196,493 (1940). 335. K. Fujita, Folia Pharmacol. Jap. 50, 173 (1954); C A 49, 10392 (1955). 336. H. Ekerfors, Upsala Laekarefoeren. Foerh. 46, 169 (1941); C A 37, 3825 (1943). 337. H. D. Kempe, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 223,541 (1954). 338. E. P. Pick and G. V. Richards, J. Pharnaacol. 90, 1 (1947). 339. A. L. Remezzano and B. I. Caivano, Prensa Farm. Argent. 2, 193 (1944); C A 40, 2936 (1946). 340. J. Miyazaki, Y. Totani, and S. Shinozaki, Yakuzaigaku 16, 31 (1956); C A 51, 8365 (1957). 341. H. H. Frey, G. Holtz, and K. Soehring, Arch. Pharm. (Weinheim) 289, 29 (1956). 342. T. Maeda, Folia Pharmacol. Jap. 61, 506 (1955); C A 50, 15924 (1956). 343. L. B. Cobbin and R. H. Thorp, Auat. J . Exp. Biol. Med. Sci. 35, 249 (1957). 344. A. Novelli and H. Huidobro, Ann. Pharm. Fr. 21, 821 (1963). 345. F. Mercier, J. Mercier, and M. R. Sestier, C.R. SOC.Biol. 145, 408 (1951). 346. T. Vitali and G. Azzolini, Boll. SOC.Ital. Bid. Sper. 31, 1025 (1955); C A 50, 8139 (1956). 347. A. Quevauviller, Ann. Pharm. Fr. 5 , 464 (1947). 348. F. Mercier, J. DBtrie, J. Mercier, m d M. R. Sestier, Trav. SOC.Pharm. Montpellier 9, 17 (1949); C A 48, 7184 (1954). 349. F. Mercier, J. Mercier, and M. R. Sestier, C.R.SOC.B b l . 143, 92 (1949). 350. G. David and L. Gyarmati, Hung. Conf. Ther. Pharmacol. Res. [Proc.], 2nd 1962 453 (1964); C A 62, 8280 (1965). 351. F. Leuschner, A. Leuschner, and F. Heim, Naunyn-Schmiedebergs Arch. ESP. Pathol. Pharmakol. 227, 129 (1955).
314. 315. 316. 317. 318. 319. 320.
5. THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
253
352, 2. Sheikova and M. Nikolova, Izv. I m t . Fiziol., Bulg. Akad. Nauk 6 , 253 (1963); 7, 243 (1964); C A 60, 4672 (1964); 62, 16783 (1965). 353. C . Viel, Chim. Ther. 149 (1966); C A 65, 9561 (1966). 354. T. N. Ghosh and B. K. Ghosh, J . Sci. Ind. Res., Sect. B 20, 400 (1961); C A 57, 12430 (1962). 355. E. Frommel, D. Vincent, P. Gold-Aubert,and C. Fleury, Helv. Physiol. Pharmacol. Acta 17, 288 (1959). 356. P. Niccolini, Sperimentale, Sez. Chim. Biol. 5 , 60 (1954); CA 49, 14183 (1955). 357. M. Brunaud, Praxis 42, 356 (1953); CA 49, 14199 (1955). 358. S. Biniecki and L. Rylski, Acta. Pol. Pharm. 11, 9 (1954); C A 49, 8158 (1955). 359. S. Teitel, J. O’Brien, and A. Brossi, J. Med. Chem. 15, 845 (1972). 360. M. J. Walsh, V. E. Davis, and Y. Yamanaka, J. Pharmacol. Exp. Ther. 174, 388 (1970). 361. P. Simon, M. A. Goujet, R. Chermat, and J. R. Boissier, Therapie 26, 1175 (1971). 362. N. M. Kabiv, Atti Accad. Med. Lomb. 22, 381 (1967); C A 71, 158 (1969). 363. S. E. Reed and M. L. Bynoe, J. Med. Microbiol. 3, 346 (1971). 364. C. C. Cheng, J. Pharm. Sci. 61, 645 (1972). 365. D. R. Feller, R. F. Shonk, and D. G. Miller, J. Pharm. Pharmacol. 22, 869 (1970). 366. H. Nakajima, M. Hoshiyama, and A. Kiyomoto, Nippon Yakurigaku Zaashi 6 5 , 34 (1969). 367. M. Sato, T. Nagao, S. Murata, H. Nakajima, and A. Kiyomoto, Jap. J. Pharmacol. 21, 401 (1971). 368. F. Fogelman and H. F. Grundy, Brit. J. Pharmacot. 38, 416 (1970). 369. J. Hamm and H. Kleinsorg, Arch. Int. Pharmacodyn. Ther. 103, 310 (1955). 370. Y. Ishida, T. Hiyama, and T. Tomimatsu, Tokushima Daigaku Yakugaku Kenkyu Nempo 19, 17 (1970); C A 77, 15 (1972). 371. 0. Hesse, Ber. 4, 696 (1871). 372. W. A. Lieb and H. J. Scherf, Klin. Monatsbl. Augenheilk. 128, 686 (1956). 373. N. Babel, Rev. Med. Suisse Romande 19, 657 (1900). 374. J. Mercier and E. Mercier, C.R. SOC.Biol. 149, 760 (1955). 375. 0. Hesse, J. Prakt. Chem. 65, 42 (1902). 376. J. Dose, Dissertation, Kiel (1890). 377. 8. Junusov, R. A. Konovalova, and A. P. Orechov, Zh. Obshch. Khim. 10, 641 (1940). 378. I. M. Scharapov, P’armakol. Toksikol. (Moscow) 13, 44 (1950). 379. S. M. Kupchan, B. Dasgupta, E. Fujita, and M. L. King, Tetrahedron 19,227 (1963). 380. R. A. Hahn, M. G. Kelly, M. Shamma, and J. L. Beal, Arch. Int. Pharmacodyn. Ther. 198, 392 (1972). 381. J. Slavik, Collect. Czech. Chem. Commun. 25, 1663 (1960). 382. S. F. Fakhrutdinov and I. K. Kamilov, Farmakol. Alkaloidow 1, 29 (1962); C A 60, 15017 (1964). 383. M. Kroutil, M. Grundmann, J. Marek, J. Lenfeld, V. Jezdinskh, and V. Preininger, 6mk. Fy&l. 17, 137, 488 (1968). 384. S. Pfeifer and L. Kiihn, Pharmazie 23, 267 (1968). 385. R. S. C. Gaskin and P. C. Feng, J. Pharm. Pharmacol. 19, 195 (1967). 386. S. A. Siphar, Belg. Pat. 688,814 (1966). 387. P. E. Sonnet and M. Jacobson, J. Pharm. Sci. 60, 1254 (1971). 388. V. Pavesi, Atti I m t . Bot. Univ. Pavia 9, 45 (1906); Chem. Zentralbl. I, 690 (1906). 389. S. F. Fakhrutdinov and I. K. Kamilov, Yop. Ispol’z. Miner. Raat. Syr’ya Srednei Azii 181 (1961); C A 58, 2765 (1963).
254
V. PREWINGER
390. S. F. Fakhrutdinov and I. K. Kamilov, Dokl. Akad. Nauk Uzb. S S R 19, 40, 42 (1962). 391. I. K. Kamilov and S. F. Fakhrutdinov, Farmakol. Alkaloidov 1, 5 (1962); CA 60, 16383 (1964). 392. S. F. Fakhrutdinov and I. K. Kamilov, Farmakol. Alkaloidov 1, 14, 19, 24 (1962); C A 60, 15029 (1964). 393. S. F. Fakhrutdinov and M. B. Sultanov, Farmakol. Alkaloidow fflikozidov 207 (1971). 394. J. Gadamer, Arch. Pharm. (Weinheim)249, 39 (1911). 395. B. L. Konson and P. P. Saksonov, Farmakol. Toksikol. (Moscow) 9, 14 (1946). 396. J. Lenfeld, M. Kroutil, J. Jezdinskf, and V. Preininger, Actu Univ. Olomuc., Fac. Med. 66, 169 (1973). 397. J. Go, J. Pharm. SOC.Jap. 50, 122 (1930). 398. H. Probst, Ann. 31, 241 (1839). 399. N. Donev, Farmatsiya (Sofia) 12, 17 (1962); C A 58, 4941 (1963). 400. N. Donev, Farmatsiya (SoJiu)14, 49 (1964); C A 61, 9928 (1964). 401. A. K. Reynolds and L. 0. Randall, see M. Shamma and W. A. Slusarchyk, Chem. Rev. 64, 59 (1964). 402. E. E. Aleshinskaya and V. V. Berezhinskaya, Farmakol. Tolwikol. (Moscow) 29, 611 (1966). 403. N. Donev, TT.Nauch-Issled. Khim.-Farm. In&. 5, 92 (1966); C A 67, 9286 (1967). 404. 0. Angelova and S. Zarkova, Suvrem. Med. 22, 33 (1971). 405. J. Gadamer, H. Ziegenbein, and H. Wagner, Arch. Pharm. (Weinheim) 240, 81 (1902). 406. J. Go, J. Pharm. SOC.Jap. 49, 125 (1929). 407. V. Peters, J. L. Hartwell, A. J. Dalton, and M. J. Shear, Cancer R w . 6,490 (1946). 408. K. S. Shamirzaeva and S. F. Fakhrutdinov, Farmakol. Alkaloidov Glikozidov 141 (1971). 409. J. Dobbie and H. Lauder, J. Chem. SOC.,(London) 63, 485 (1893). 410. H. Lettr6, R. Lettr6, and C. Pflanz, Hoppe-Seyler’s 2. Physiol. Chem. 287, 53 (1951). 411. S. F. Fakhrutdinov and I. K. Kamilov, Farmakol. Alkaloidov Olikozidov 149 (1967). 412. S. F. Fakhrutdinov, Farmakol. Alkaloidov Olikozidov 155 (1971). 413. M. Freund and J. Josephi, Ber. 25, 2411 (1892). 414. P. Simon, R. Chermat, C. Larousse, and J. R. Boissier, Therapie 25, 939 (1970). 415. L. F. Tseng, Dks. Abstr. Int. B 31, 6797 (1971) [available from University Microfilms, Ann. Arbor, Michigan, Order No. 71-13,3741. 416. L. F. Tseng and E. J. Walaszek, Pharmacology 7 , 255 (1972). 417. A. Loizzo, A. Scotti de Carolis, and V. G. Longo, Psychopharmacologiu 22, 234 (1971). 418. W. D. Willis, G. W. Tate, J. C. Willis, R. D. Ashworth, and G. N. Gross, Exp. Neurol. 18, 79 (1967). 419. A. Matsushita, H. Takesue, and R. Kido, Jup. J. Pharmacol. 20, 237 (1970). 420. G. Stille, Arzneim.-Forsch. 21, 528 (1971). 421. T. Fakouchi, T. D. Darby, and R. S. McCutcheon, J . Pharm. Sci. 60, 1045 (1971). 422. J. M. Maraiion, Philipp. J . Sci. 38, 259 (1929); Chem. Zentralbl. II, 759 (1929). 423. J. Go, J. Pharm. SOC.Jap. 49, 126 (1929). 424. E. Moisset de Espanes, Rev. SOC.Argent. Biol. 31, 241, 253 (1955); C.R. SOC.Biol. 149, 1789, 1791 (1955). 425. E. Moisset de Espanes, Rev. SOC.Argent. Biol. 32, 108 (1956); CA 51, 5992 (1957).
5 . THE BIOLOGY O F PAPAVERACEAE ALKALOIDS
255
426. K. S. Shakhabutdinova, S. F. Fakhrutdinov, and I. K. Kamilov, Farmakol. Alkaloidov Glikozidov 146 (1967). 427. V. V. Berezhinskaya, E. E . Aleshinskaya, and Y. A. Aleshkina, Farmakol. Toksikol. (Moscow)31, 44 (1968). 428. P. N. Patil, A. M. Burkman, D. Yamauchi, and S. Hetey, J . Pharm. Pharmacol. 25, 221 (1973). 429. K. S. Shakhabutdinova, I. K. Kamilov, and S. F. Fakhrutdinov, Farmakol. Alkaloidov Glikozidov 142 (1967). 430. B. Borkowski, A. Desperak-Naciazek, K. Obojska, and Z . Szmal, Dks. Pharm. Pharmacol. 18, 455 (1966). 431. J. A. Weisbach, C. Burns, E . Macko, and B. Douglas, J . Med. Chem. 6, 91 (1963). 432. R. J. Vavrek, J. G . Cannon, and R. V. Smith, J . Pharm. Sci. 59, 823 1970). 433. R. V. Smith and S. P. Sood, J . Pharm. Sci. 60, 1654 (1971). 434. A. M. Burkman and J. G. Cannon, J . Pharm. Sci. 61, 813 (1972). 435. W. S. Fogg, J . Pharmacol. Exp. Ther. 54, 167 (1935). 436. D. Warthen, E. L. Gooden, and M. Jacobson, J . Pharm. Sci. 5 8 , 637 1969). 437. R. W. Doskotch and F. S. El-Feraly, J . Pharm. Sci. 58, 877 (1969). 438. K. L. Stuart, Chem. Rev. 71, 47 (1971). 439. P. J. Pelletier, Ann. 16, 27 (1835). 440. G. B a h t , A. K. Szabo, and M. Nemeth, Acta. Physiol. 27, 187 (1965). 441. K. van Dongen; Acta. Brew. Neer. Physiol., Pharmacol., Microbiol. 10, 23 (1940); CA 34, 7406 (1940). 442. A. Teraoko, Nippon Yakurigaku Zasshi 61, 396 (1965); C A 65, 9580 (1966). 443. J. W. Sloan, J. W. Brooks, A. J. Eisenman, and W. R. Martin, Psychopharmacologia 3, 291 (1962). 444. K. van Dongen, Arch. Int. Pharmacodyn. Ther. 64, 494 (1940). 445. N. B. Eddy, J . Pharmacol. Exp. Ther. 66, 182 (1939); C A 33, 5914 (1939). 446. G. Malorny, Arzneim.-Porsch. 5 , 252 (1955). 447. G. Navarro and H. W. Elliott, Neurophamnacology 10, 367 (1971). 448. A. Taormina, Arch. Int. Pharmacodyn. Ther. 82, 16 (1950). 449. A. Taormina, Boll. SOC.Ital. Biol. Sper. 25, 909 (1949); C A 46, 2679 (1952). 450. A. P. Corrado and V. G. Longo, Arch. Int. Pharmacodyn. Ther. 132, 255 (1961). 451. Y. Kamimura, Nippon Yakurigaku Zasshi 53, 836 (1957); C A 52, 18870 (1958). 452. A. Cannava and A. M. Atzori, Boll. SOC.Ital. Biol. Sper. 29, 1254 (1953). 453. A. Cannava and A. M. Atzori, Med. Sper. 24, 318 (1953). 454. A. Cannava, Boll. Soc. Ital. Biol. Sper. 28, 1941 (1952). 455. A. Cannava, Arch. Ital. Sci. Parmacol. [ 3 ] 3, 137 (1953). 456. M. H. Seevers and F. E. Shideman, J . Pharmacol. Exp. Ther. 71, 373 (1941). 457. G. Carbonaro, BolI. SOC.Ital. Biol.Sper. 22, 661 (1946). 458. S. Hirano, Folia Pharmacol. Jap. 29, 7 (1940); C A 35, 1125 (1941). 459. R. Stoll, C.R. SOC.Biol. 139, 151 (1945). 460. R. E. Lister, J. Pharm. Pharmacol. 16, 364 (1964). 461. Y. S. Fang, Folia Pharmacol. Jap. 24, 168 (1937); C A 32, 1788 (1938). 462. R. B. Nelson and H. W. Elliott, J . Pharmacol. Exp. Ther. 155, 516 (1967). 463. G . Maxwell [U.S. Pat. 3,285,9141 CA 66, 11100 (1967). 464. L. Leadbeater and D. R. Davies, Biochem. Pharmawl. 17, 219 (1968). 465. K. W. Bentley [Brit. Pat. 1,173,2151 C A 72, 466 (1970). 466. J. W. Lewis, M. J. Readhead, I. A. Selby, A. C. B. Smith, and C. A. Young, J. Chem. SOC.,London 1158 (1971). 467. J. W. Lewis and M. J. Readhead, J. Chem. SOC.,London 1161 (1971).
256
V. PREININGER
I. Irnaseki, Y. Kitabatake; and H. Taguchi, J . Pharm. Soc. Jap. 81, 1281 (1961). Z. Supek, Farmakol. Toksikol. (Moscow)9, 12 (1946). T. Furuya, Bull. Osaka Med. Sch. 3, 62 (1957); CA 53, 1555 (1959). H. Fukuda and K. Watanabe, Chem. Pharm. Bull. 18, 1299 (1970). J. A. Buchner and C. A. Buchner, Ann. 24, 228 (1837). K. Daniel and D. Schmaltz, Das Schollkraut, Stuttgart (1939). S. Uchizumi, Nippon Yakurigaku, Zasshi, 53, 63 (1957); CA 52, 4016 (1958). K. Shimamoto, S. Uchizumi. and K. Inoue, Nippon Yakurigaku Zasshi 53, 75 (1957); C A 52, 7520 (1958). 476. S. K. Kulkami, P. C. Dandiya, and N. L. Varandani, Jap. J . Pharmacol. 22, 11 (1972). 477. A. D. Turova, A. I. Leskov, and V. I. Bichevina, Lek. Sredstva Rast. 303 (1969); CA 58, 2763 (1963). 478. S. M. Shanbhag, H. J. Kulkami, and B. R. Gaitonde, Jap. J. Pharmacol. 20, 482 (1970). 479. B. G. Vad, P. H. Raman, and V. K. Deshmukh, Indian J . Pharm. 33, 23 (1971). 480. C. C. Velluda, T. Goina, I. Tiesa, P. Petcu, S. Pop, and W. Csutak, Luer. Conf. Nat. Farm. 351 (1958); C A 53, 15345 (1959). 481. P. Peten and T. Goina, Planta Med. 18, 372 (1970). 482. B. A. Vartazaryan and E. E. Koltochnik, Sb. Nauch. T r . Vladivostoksk. Med. Inst. 2, 113 (1964); C A 62, 15304 (1965). 483. A. D. Turova, M. N. Konovalov, and A. I. Leskov, Med. Prom. SSSR 18, 59 (1964); CA 61, 15242 (1964). 484. Z. Samaj, A. Desperak-Naciaaek, and K. Obojska, Diss. Pharm. 17, 429 (1965). 485. M. Sabir and N. K. Bhide, Ifidian. J . Physiol. Pharmacol. 15, 111 (1971). 486. S. Suzuki, Tohoku J. Exp. Med. 36, 134 (1939); C A 33, 9452 (1939). 487. C. S. Jang, J . Pharmacol. Exp. Ther. 71, 178 (1941); C A 35, 2608 (1941). 488. T. Furuya, Nippon Yakurigaku Zasshi 55, 1152 (1959); CA 55, 791 (1961). 489. F . Honda, M. Oka, A. Akashi, and Y. Nishino, Yakugaku Kenkyu 32, 836 (1960); CA 55, 10695 (1961). 490. F. Mercier, C.R. SOC.Bid. 125, 1066 (1937). 491. G. L. Nardi and J. H. Seipe1,Sul-g.Forum Proc. 4lst Congr. 381 (1955); C A 52, 1490 (1958). 492. V. B. Schatz, B. C. O’Brien, W. M. Chadduck, A. M. Kanter, A. Burger, and W. R. Sandusky, J . Med. Pharm. Chem. 2, 425 (1960). 493. F. T. Schein and C. Hanna, Arch. I n t . Pharmacodyn. Ther. 124, 317 (1960). 494. M. B. Bhide, S. R.Chavan, and N. K. Dutta, Indian J . Med. Res. 57, 2128 (1969). 495. H. Ogakurayama, I. Aramori, T. Murata, N. Sato, and S. Shibamoto, Yakkyoku 7, 1089 (1956); CA 51, 7652 (1957). 496. K. Nakagawa and S. Sado, J . Pharm. SOC.Jap. 67, 132 (1947). 497. S. Sado, J . Pharm. SOC.Jap. 67, 166 (1947). 498. F. Honda, M. Oka, A. Akashi, and Y. Nishino, Yakugaku Kenkyu 32, 830 (1960); C A 55, 10695 (1961). 499. V. V. Berezhinskaya, E. E. Aleshinskaya, and E. A. Trutneva, FarmakoE. Toksikol. (Moscow)31, 296 (1968). 500. H. Schmitz, 2. Krebsforsch. 57, 137 (1950). 501. I. Hilwig and H. Schmitz, Naturwiss. 38, 336 (1951). 502. M. N. Meisel, T. M. Kondrateva, and N. A. Pomoschnikova, Zh. Obshech. Bid. 12, 312 (1951). 503. H. H. Hirsch, 2. Krebsforsch. 58, 504 (1952).
468. 469. 470. 471. 472. 473. 474. 475.
5. T H E BIOLOGY OF PAPAVERACEAE ALKALOIDS
257
504. Liu Keng-T’ as, Chu Ya-Chun, and Lui Hai-P’eng, Yao Hsueh Hsueh Pao 13, 356 (1966); CA 65, 17532 (1966). 505. N. Tanaka, Jap. J . Exp. Med. 22, 87 (1952). 506. J. Kudo, Folia Pharmacol. Jap. 49, 255 (1953). 507. S. Hasegawa and N. Tanaka, Jap. J . Exp. Med. 22, 77 (1952). 508. M. Sabir and N. K. Bhide, Indian J . Physiol. Pharmacol. 15, 97 (1971). 509. F. W. Morthland, P. P. M. De Bruyn, and N. H. Smith, E z p . Cell Res. 7 , 201 (1954). 510. L. A. Mitscher, W. N. Wu, R. W. Doskotch, and J . L. Beal, Deut. Apoth.-Ztg. 111, 1704 (1971). 511. L. A. Mitscher, W. N. Wu, R. W. Doskotch, and 5. L. B e d , Chem. Commun. 589 (1971). 512. A. Qayum, Pak. J . Sci. Ind. Res. 10, 34 (1967). 513. N. K. Dutta, P. H. Marker, a n d N . R. Rao, Brit. J. Pharmacol. 44, 153 (1972). 514. T. Ukita, D. Mizuno, and T. Tamura, Jap. J . Exp. Med. 20, 103 (1949). 515. J. C. Gupta and B. S. Kahali, Indian J . Med. Res. 32, 53 (1944). 516. T. M. Seery and R. N. Bieter, J . Pharmacol. 69, 64 (1940). 517. H. Bersch and W. Dopp, Arzneim.-Forsch. 5 , 77 (1955). 518. S. Lambin and J. Bernard, C . R . SOC.B i d . 147, 638 (1953). 519. H. Aoyama, Jap. J . Pharm. Chem. 23, 93 (1951). 520. L. Brzezinska-Jezova and F. Kaozmarek, Biul. Inst. Rosl. Lecz. 9, 115 (1963); C A 61, 3570 (1964). 521. N. Homma, M. Kono, H. Kadohira, S. Yoshihava, and S. Masuda, Arzneim.Forsch. 11, 450 (1961). 522. Nai Ch’u Chang, Proc. Int. Congr. Microbiol., 5th, 1950 Abstr. Pap., 47 (1950); CA 48, 1478 (1954). 523. E. C. Cushing, Mil. Med. 121, 17 (1957). 524. C. C. Johnson, G. Johnson, and C. F. Poe, Acta PharmacoZ. Toxicol. 8, 71 (1952). 525. R. A. Neal, Ann. Trop. Med. Pat-asitol. 58, 420 (1964); C A 62, 15271 (1965). 526. N. I. Geonya and M. M. Progressov, Mikrobiol. Zh. (Kiev) 23, 24 (1961). 527. G. A. Greathouse and G . M. Watkins, Amet-. J . Bot. 25, 743 (1938); C A 33, 2939 (1939). 528. S. Lambin and J. Berbard, Ann. Inst. Pasteur, Paris 85, 757 (1953). 529. P. H. H. Gray and R. A. Lachand, Plant. Soil 8, 354 (1957); C A 52, 12071 (1958). 530. S. Akiya, Jap. J . Exp. Med. 26, 91 (1956). 531. M. Makawi and M. A. Gohar, PTOC.Pharm. Soc. Egypt, Sci. Ed. 39, 77 (1957); C A 52, 20651 (1958). 532. T. V. Subbaiah and A. M. Amin, Nature (London) 215, 527 (1967). 533. A. Rossi, Pubbl. Cent. Stud. Citogenet. Veg. Cons. Naz. Ric. 178, 179 (1955); C A 51, 16732 (1957). 534. I. F. Shvarev and A. L. Tsetlin, Farmakol. Toksikol. (Moscow) 35, 73 (1972). 535. N. M. Turkevich, M. S. Olevskaya, Y. M. Pashkevich, A. I. Potopalskij, and V. M. Novitskij [Fr. Pat. 2,052,972 (1971)l C A 76 (6), 489 (1972). 536. A. Gheorghiu, E. Ionescu-Matin, G. Maltezeanu, and V. Dobre, Farmacia (Bucharest) 18, 671 (1970). 537. N. V. Luchnik, Biofizika 3, 332 (1958). 538. N. V. Luchnik, Tr. Inst. B i d , Akad. Nauk SSSR, Ural. Filial 46 (1960); C A 57, 4985 (1962). 539. J. Haginiwa and M. Harada, Yakugaku Zmshi 82, 726 (1962); C A 57, 9145 (1962). 540. Z. Supek and D. TomiCt, G j e . Vjesn. 68, 16 (1946); C A 43, 9246 (1949).
258
V. PREININGER
541. F. E. Shideman, Bull. Nat. Formulary Comm. 18, 57 (1950); C A 44, 7986 (1950). 542. Y. Kitabatake, K. Ito, and M. Tajima, Yakugaku Zasshi 84, 73 (1964); C A 61, 7575 (1964). 543. M. M. Carvalhas and A. S. Grapa, J . SOC.Cien. Med. Lisbao 132, 211 (1968). 544. Mu-Ch’un Ch’en and Chen-Yu Chi, Y a o Hsueh Hsueh Pao 12, 185 (1965); C A 63, 3492 (1965). 545. T. Savada, J. Yamahara, K. Goto, and M. Yamamura, Shoyakugaku Zasshi 25, 74 (1971). 546. H. LettrB, Naturwiss. 30, 34 (1942); 33, 75 (1946). 547. Kuo-Chang Chin, Hsin-Ying Chu, Hsi-Ts’an T’ang, and Pin Hsu, Sheng Li Hsueh Pao 25, 182 (1962); C A 59, 13249 (1963). 548. Kuo-Chang Chin, Yueh-Ngo Wang, Ting-Yueh Pao, and Pin Hsu, Sheng Li Hsueh Pao 28, 72 (1965); CA 63, 12151 (1965). 549. F. Satritdinov, Med. Zh. Uzb. 48 (1966); C A 65, 14306 (1966). 550. F. Satritdinov and M. B. Sultanov, Farmakol. Alkaloidov 2, 319 (1965); C A 66, 6996 (1967). 551. F. Satritdinov and N. Tulyaganov, Med. Zh. Uzb. 12 (1968); C A 70, 212 (1969). 552. D. G. Patel, A. Typ, P. N. Patil, A. M. Burkman, and J. L. Beal, Lloydia 33, 36 (1970). 553. Bin Hsu and K. C. Kin, Arch. I n t . Pharmacodyn. Pher. 139, 318 (1962). 554. Bin Hsu and Kwang-Lu Hsu, Sheng Li Hsueh Pao 22, 40 (1958); CA 52, 17518 (1958). 555. Kuo-Chang Chin and Pin Hsu, Sheng Li Hsueh Pao 21, 150 (1957); C A 53, 13390 (1959). 556. Pin Hsu and Kuo-Chang Chin, Farmakol. Neirotropnykh Sredstv 126 (1963); C A 60, 13741 (1964). 557. Kuo-Chang Kin, Jui-Ting Chen, Tao-Yuan Wang, and Bin Hsu, Yao Hsueh Hsueh Pao 6, 26 (1958); C A 52, 17519 (1958). 558. Kuo-Chang Chin, Kang Chou, Hsi-Ts’an Tang, Shui-Ting Chen, and Pin Hsu, Sheng Li Hsueh Pao 24, 110 (1960). 559. Hsi-Ts’an T’ang, Kuo-Chang Chin, and Pin Hsu, Sheng Li Hsueh Pao 25, 143 (1962); C A 59, 13253 (1963). 560. Kuo-Chang Chin, Chen-Te Chang, and Pin Hsu, Sheng Li Hsueh Pao 26, 347 (1963); C A 60, 12559 (1964). 561. Kuo-Chang Chin, Hsin-Feng Cheng, and Pin Hsu, Sheng Li Hsueh Pao 27, 47 (1964): C A 61, 7571 (1964). 562. Kuo-Cheng Chin, Yueh-Ngo Wang, and Pin Hsu, Y a o Hsueh Hsueh Pao 11, 754 (1964); C A 62, 7013 (1965). 563. T. Seki and S. Sato, Chiba Igakkai Zasshi 47, 331 (1971). 564. Y. Soji, T. Kadokawa, Y. Masuda, K. Kawashima, and K. Nakamura, Nippon Yakurigaku Zasshi 65, 196 (1969). 565. G. Muller and A. Poittevin [Fr. Pat. 5,644 (1968)l C A 71, 441 (1969). 566. Roussel-UCLAF Patents, C A 69, 59475m (1968); 71, 707852, 70787b, 707880, 917353. (1969); 72, 3210313 (1970); 73. 15063d (1970). 567. L. Szabo, L. Toke, and C. Szantay [Hung. Pat. 155,959 (1969)l C A 71, 329 (1969). 568. G. Muller and A. Poittevin [Fr. Pat. 7,292 (1969)l C A 76, 408 (1972). 569. N. K. Khanna, B. R. Madan, 0. P. Mahatma, and S. C. Surana, Indian J . Med. Res. 60, 472 (1972). 570. S. Sasagawa, K. Kanetani, and S. Kiyofuji, Chem. Pharm. Bull. 17, 1 (1969). 571. Zee-Cheng, Kwang Yuen, and C. C. Cheng, J . Pharm. Sci. 62, 1572 (1973).
5. T H E
BIOLOGY OF PAPAVERACEAE ALKALOIDS
259
572. J. Iwasa, S. Naruto, N. Ikeda, and Y. Sohji [Brit. Pat. 1,265,627 (1972)l C A 77, 24823m (1972). 573. G. A. Alles and C. H. Ellis, J . Pharmacol. Exp. Ther. 104, 253 (1952). 574. F. Selle, Arch. Pharm. (Weinheim) 228, 441 (1890). 575. 2. S. Akbarov, K. V. Aliev, and M. B. Sultanov, Dokl. Akad. Nauk Uzb. SSR 29, 38 (1972). 576. H. Meyer, Naunyn-Schmiedebergs Arch. E x p . Pathol. Pharmakol. 27, 419 (1890). Jap. 69, 307 (1949). 577. K. Goto and R. Ode, J . Pharm. SOC. 578. B. Y. Aizenman, M. 0. Shraiger, T. P. Mandrik, and A. M. Bredikhina, Mikrobiol. Zh. (Kiev) 25, 52 (1963); C A 60, 3383 (1964). 579. J. Smiles, Pharm. J . 8, 595 (1867). 580. J. Delphaut and P. Blache, C.R. SOC.Bid. 127, 554 (1938). 581. K. I. Tashbaev and M. B. Sultanov, Farmakol. Alkaloidov Glikozidov 165 (1967). 582. F. P. Luduefia, Rev. Soc. Argent. B i d . 14, 339 (1938); C A 33, 742 (1939). 583. F. Mercier, C.R. SOC.B i d . 127, 1018 (1938). 584. F. Mercier, J. Delphaut, and P. Blache, C.R. SOC.B i d . 127, 1022 (1938). 585. 0. Hesse, Ber. 4, 693 (1871). 586. V. B. Pandey, B. Dasgupta, S. K. Bhattacharya, R. Lal, and P. K. Das, Curr. Sci. 40, 455 (1971). 587. W. Bolm, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 195, 304 (1940). 588. K. U. Aliev and 0. B. Zakirov, Dokl. Akad. Nauk Uzb. SSR 27, 28 (1970). 589. 0. Stickel, 2. Hyg. Infektionskr. 108, 567 (1928). 590. H. Lettr6, Ergeb. Enzymforsch. 10, 269 (1949); G A 48, 13740 (1954). 591. B. Sokolov, C. C. Saelhof, Y. Takeuchi, and R. Powella, Growth 28, 225 (1964). 592. C. Derosne, Ann. Chim. Phys. [l] 45, 274 (1804). 593. P. Robiquet, Ann. Chim. Phys. [2] 5 , 275 (1817). 594. Togaku Ri, J. Med. Ass. Formosa 35, 237, 747, 1295 (1936); C A 32, 9284 (1938). 595. C. Tanaka, Nippon Yakurigaku Zasshi 57, 538 (1961); C A 57, 17333 (1962). 596. C. Tanaka, Nippon Yakurigaku Zasshi 58, 225 (1962); C A 60, 11241 (1964). 597. L. C. Weaver, W. M. Alexander, B. E. Abren, A. B. Richards, W. R. Jones, and R. W. Begley, J . Pharmacol. Exp. Ther. 123, 287 (1958). 598. J. La Barre and H. Plisnier, Arch. Int. Pharmacodyn. Ther. 119, 205 (1959). 599. J. La Barre and H. Plisnier, Bull. Narcotics 11, 7 (1959); C A 54, 10139 (1960). 600. Y. Ota, N. Endo, and M. Hirasawa, Ghem. Pharm. BUZZ. 12, 569 (1964). 601. H. T. Donev, Farmacija ( S o j a ) 14, 51 (1964). 602. H. Konzett and E. Rothlin, Experientia 10, 472 (1954). 603. H. A. Bickerman and A. L. Barach, Amer. J . Med. Sci. 228, 156 (1954). 604. J. S. Gravenstein, R. A. Devloo, and H. K. Beecher, J. Appl. Physiol. 7, 119 (1954). 605. H. Konzett, Wien. Klin. Wochenschr. 67, 306 (1955). 606. C. A. Winter and L. Flataker, J. E x p . Med. 101, 17 (1955). 607. C. Reichle and H. Friebel, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 226, 558 (1955). 608. J. S. Gravenstein and H. Beecher, Arzneim.-Forsch. 5 , 364 (1955). 609. A. F. Green and N. B. Ward, Brit. J . Pharmacol. Chemother. 10, 415 (1955). 610. Pham Hun Chanh and Pham Hun Chanh (Mrs.), Arch. Int. Phamacodyn. Ther. 181, 27 (1969). 611. H. A. Bickerman, E. German, B. M. Cohen, and S. E. Itkin, Amer. J . Med. Sci. 234, 191 (1957). 612. K. Tagaki, H. Fukuda, and K. Yano, Yakugaku Zasshi 77, 1358 (1957).
260
V. PREININGER
613. R. Engelhorn and E. Weller, Naunyn-SchmiedebergsArch. Exp. Pathol. Pharrnakol. 254, 170 (1966). 614. I. C. Albricht, Acta. Brev. Neer. Physiol., Pharmacol., Microbiol. 9, 109 (1939); C A 33, 8794 (1939). 615. J. Szegi, J. Rausch, K. Magda, and J. Nagy, Acta Physiol. 16, 325 (1959); C A 54, 15663 (1960). 616. J. C. Bloch, P. Rolland, and R. Vieillefosse, Anesth. Analg. (Paris) 3, 484 (1937). 617. J. Jeske, R. Langwinski, and E. Przegalinski, Acta. Pol. Pharm. 21, 193 (1964). 618. H. J. Kiessig, Schmerz, Narkose-Anaesth. 13, 86 (1940); C A 39, 4695 (1945). 619. H. Lettr6 and M. Albrecht, Naturwiss. 30, 184 (1942). 620. H. Lettr6, Chem.-Ztg. 67, 52 (1943). 621. H. Lettr6 and M. Albrecht, Hoppe-Seykr’s 2. Physiol. Chem. 281, 133 (1944). 622. H. Lettr6, R. Lettr6, and C. Pflanz, NatumuiSs. 37, 563 (1950). 623. B. Salzgeber, C.R. Soc. Biol. 149, 190 (1955). 624. J. L. Parrot and C. Laborde, J. Physiol. (Pa&) 51, 546 (1959). 625. 0. Rygh, 2. Vitaminforsch. 8, 166 (1938). 626. W. Neuweiter, 2. Vitaminforsch. 9, 251 (1939). 627. “The Merck Index,” 8th ed. Merck t Co., Inc., Rahway, New Jersey, 1968. 628. R. H. F. Manske, Can. J. Res. 8, 142 (1933). 629. I. Khamdamov and F. S. Sadritdinov, Dokl. Akad. Nauk Uzb. S S R 29, 58 (1972). 630. A. Nistry and G. Papeu, Brit. J. Pharmacol. 45, 173 (1972). 631. D. R. Curtis, A. W. Duggan, and D. Felix, Brain Res. 23, 117 (1970). 632. D. R. Curtis, A. W. Duggan, D. Felix, and G. A. R. Johnston, Brain Res. 32, 69 (1971). 633. D. R. Curtis, A. W. Duggan, D. Felix, and G. A. R. Johnston, Brain Res. 33, 57 (1971). 634. D. R. Curtis and D. Felix, Brain Res. 34, 301 (1971). 636. D. Felix and H. McLennan, Brain Res. 25, 661 (1971). 636. J. M. Benoist, J. M. Besson, C. Conseiller, and D. Le Bars, Brain Res. 43, 672 (1972). 637. W. C. De Groat, P. M. Lalley, and M. L. Block, Brain Rea. 26, 665 (1971). 638. W. C. De Groat, Brain Res. 38, 429 (1972). 639. W. C. De Groat, P. M. Lalley, and W. R. S a m , Brain Res. 44, 273 (1972). 640. R. D. Huffman and L. S. McFadin, Life Sci. 11, 113 (1972). 641. R. D. H u h a n and L. S. McFadin, NeurophamnawZogy 11, 789 (1972). 642. D. W. Straughan, M. J. Neal, M. A. Simmonds, G. G. S. Collins, and R. G. Hill, Nature (London) 233, 352 (1971). 643. R. G. Hill, M. A. Simmonds, and D. W. Straughan, Brit. J. Phamzacol. 42, 639 (1971). 644. R. G. Hill, M. A. Simmonds, and D. W. Straughan, Brit. J. Pharmacol. 45, 176 (1972). 646. R. A. Davidoff, Science 175, 331 (1972). 646. R. A. Niooll, Brain Res.36, 137 (1971). 647. R. A. Levy, A. H. Repkin, and E. G. Anderson, Brain. Res. 32, 261 (1971). 648. W. E. Davies and S. D. Comis, Nature (London) 281, 156 (1971). 649. R. J. Walker, A. R. Crossman, G. N. Woodruff, and G. A. Kerkut, Brain Res. 33, 75 (1971). 650. A. Takeuchi and K. Onodero, Nature (London) 236, 55 (1972). 651. J. Earl and W. A. Large, J. Physiol. (London) 224, 45 (1972). 652. N. Davidson and H. Resine, Nature (London)234, 223 (1971).
5. THE 653. 654. 655. 656. 657. 658. 659. 660. 661. 662. 663. 664. 665. 666. 667. 668. 669. 670. 671. 672. 673. 674. 676. 676. 677. 678. 679. 680. 681. 682. 683. 684. 686. 686. 687. 688. 689. 690. 691.
BIOLOGY O F PAPAVERACEAE ALKALOIDS
261
H. McLennan, Nature (London) 228, 674 (1971). A. W. Duggan and H. McLennan, Brain Res. 25, 188 (1971). N. R. Banna, A. Naccache, and S. J. Jabbur, Eur. J. Pharmacol. 17, 301 (1972). B. S. Meldrum and R. W. Horton, Brain Res. 35, 419 (1971). L. P. Felpel, Exp. Brain Res. 14, 494 (1972). A. K. Tebecis, L. Hoesli, and H. L. Haas, Experientia 27, 548 (1971). S. Bisti, G. Iosif, and P. Strala, Brain Res. 28, 591 (1971). G. A. R. Johnston and J. F. Mitchell, J. Neurochem. 18, 2441 (1971). G. A. R. Johnston, P. M. Beart, D. R. Curtis, C. J. A. Game, R. M. McCulloch, and R. M. Maclachlan, Nature (London) (Biol.) 240, 219 (1972). J. Pelletier, Ann. Chim. Phys. [2] 50, 240, 262 (1832). B. Kelentei, E. Stenszky, and F. Czollner, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 233, 550 (1958). F. Oehlkers, Sitzungsber. Heidelberg. Akad. Wiss., Math.-Naturwiss. Kl., Abh. 9, 40 (1949); CA 44, 8004 (1950). 0. Hesse, Ann. Suppl. 4, 50 (1865). L. Kiihn and S. Pfeifer, Pharmazie 18, 819 (1963). S. A. E. Hakim, J. Physiol. (London) 138, 40 (1957). W. Awe, Arch. Pharm. (Weinheim)279, 116 (1941). P. J. Hanzlik, J. Pharmawl. Exp. Ther. 7 , 99 (1915). H. Kraitmaier, Phccrmazie 5, 85 (1950). J. Lenfeld, private communication. M. L. Bentura, C. R. Murcia, and J. J. Arroyo, ffenet.Iber. 21, 177 (1969). Z . Ziolkowski, Farm. Pol. 20, 17 (1965). H. Meyer, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol. 27, 419 (1890). V. A. Chelombito and D. A. Muraveva, Aktml. Probl. Farmakol. Farm., Vses. Nauch. Konf., 183 (1971). J. Kabellk, 6-k. Oftalmol. 22, 49 (1966). S. N. Sarker, Nature (Lcndon) 162, 265 (1948). B. Kelentei, Arzneim-Forsch. 10, 135 (1960). S. A. Vichkanova, M. A. Rubinchik, V. V. Adgina, and T. S. Fedorchenko, Famnakol. Toksikol. (Moscow) 32, 326 (1969). P. Franciscis and C. Anfiero, Boll. SOC.Ital. Biol.Sper. 25, 26 (1948). T. Bodalski, H. Pelczarske, and M. Ujec, Arch. Immunol. Ter. D o m . 6, 705 (1958); CA 53, 13425 (1959). G. A. Greathouse and N. E. Riegler, Phytopatblogy 30, 475 (1940); C A 34, 6877 (1940). T. Bodalski and H. Rzadkowska, DiSs. Pharm. 9, 266 (1957). T. Bodalski, M. Kantoch, and H. Rzadkowska, DiSs. Pharm. 9, 273 (1957). J. R. Meyer, Science 108, 188 (1948). B. S . Nikolskaya, Famnakol. Tobikol. (Moscozv) 29, 76 (1966). S. A. E. Hakim, V. Mijovid, and J. Walker, Nature (London) 189, 198 (1961). S. N. Sarker, Indian Med. Qazz. 61, 62 (1926). G. C. Dobbie and M. E. Langham, Brit. J. Ophthalmol. 45, 81 (1961). M. Tin-Wa, N. R. Farmworth, H. H. S. Fong, and J. Trojhnek, Lloydia 33, 267 (1970). M. Tin-Wa, H. K. Kim, H. H. S. Fong, N. R. Farnsworth, J. Trojbnek, and D. J. Abraham, Lloydia 35, 87 (1972).
This Page Intentionally Left Blank
-CHAPTER
6-
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE R. H. I?. MANSKE University of Waterloo, Waterloo, Ontario, Canada
I. Introduction ........................................................ 11. Plants and Their Contained Alkaloids .................................. References ..........................................................
263 263 300
I. Introduction Much of the data collected in the following chapter was gleaned from Chemical Abstracts and is so indicated by listing a CA reference although such a reference is often included for the convenience of readers even where the original was available. Most of the alkaloids are of structural types not treated in recent chapters of earlier volumes. This chapter is supplementary to Volume XIV, Chapter 12, p. 507. 11. Plants and their Contained Alkaloids 1. Abuta imene Eichl, and A . rufescens Griseb. (Menispermaceae) (XIII, 397)*
Two azafluoranthine alkaloids, a new type of alkaloid structure, were isolated. Imeluteine (1) and rufescine (2) were isolated from the stems of the plant and their structures were assigned on spectra1 evidence. These structures were confirmed by syntheses. The amide 3 prepared from known compounds was reacted with phosphorus oxychloride in acetonitrile to generate a dihydroisoquinoline which on reduction, diazotization, and treatment with activated copper gave dihydroimeluteine. Dehydrogenation to the natural alkaloid was effected by
* The Roman numeral followed by a n Arabic number refers t o volume number and page where the subject of the heading has been treated in previous volumes.
264
R. H. F. MANSKE
heating in p-cymene with palladium/charcoal. Rufescine was synthesized by a parallel series of reactions from the amide 4 (I). 2. Adalia bipunctata L. (Coleoptera; Coccinelidae)
The above-named insects have a chemical defense and an extract of them has yielded the alkaloid adaline ( C,,H,,ON; amorphous; [aID - 13') ( 5 ) .It was shown to have a carbonyl and an NH group, and NMR spectroscopy indicated certain features which were confirmed by an X ray study of adaline hydrochloride crystals (mp 204-205'). Adalia quadrimaculata Scopoli and A. pantherina L. also yielded adaline (2). 3. Alchornea jloribunda Muell. Arg. (Euphorbiaceae) (VIII, 696; XI, 25)
Alchorneine (C,,H,,ON,; mp 43";[.ID - 105') was isolated from the above-named plant as well as from A . hirtella Benth. Its structure (6), largely determined by spectral methods including an X-ray examination of its methiodide, was confirmed by chemical degradation to recognizable Me0
, \ /
OMe
OMe 8 4
1 R-OMe 2 R = H
8
R=OMe R = H
1-8
6.
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
265
fragments. Isoalchorneine (C12H190N3;liquid; [a]= 5 0) (7)and alchorneinone (C12H2,0,N,; liquid) (8) were minor constituents of A . jioribunda. Their structures were also largely based on spectral studies and confirmed in whole and in part by chemical transformations ( 3 ) . 4. Ammodendron argenteum Kuntze (A. sieversii DC.) (Leguminosae)
(VII, 255) Argentine (9) and argentamine (10) are two new alkaloids whose structures were determined by spectral methods ( 4 ) . 5. Ancistrocladus heyeanus Wall. (Ancistrocladaceae; Dipterocarpaceae) ( x r v , 509)
The new alkaloid, ancistrocladisine (C26H,g0,N; mp 178-1 80'; [a]=- 16.13') was given structure 11 on the basis of a spectral study,
a Hofmann degradation, and further chemical manipulation ( 5 ) .
e2 N+
0
9
M
e
OMe e
O
Me0 0 10
Me0
'
13
11
Me M
e
266
R. H. F. MANSKE
6. Anona glabra L. (Anonaceae) (XIV, 228) The first natural occurrence of N-methylactinodaphnine is reported. Reticuline was also isolated ( 6 ) . 7. Anona squamosa L. (IV, 8 6 )
The following aporphine alkaloids were isolated : anonaine, roemerine, norcorydine, corydine, norisocorydine, isocorydine, and glaucine (7'). 8. Anopterus macleyanus F. Muell. and A . glandulosus Labill. (Escalloniaceae)
Anopterine (C,,H,,O,N; mp 222-223"; [.ID - 12") is an 0,O-ditigloyl ester with two secondary and one tertiary hydroxyls. Hydrolysis with alkali afforded tiglic acid and the pentahydroxy base, anopteryl alcohol (C,,H,,O,N; mp 258-261"; [a],,+ 4"). Acetic anhydride reaction served to generate a tetraacetyl anopteryl alcohol (C29H,gOgN;mp 156-158'; [.ID oJ,88'). X-ray examination of a derivative of the latter showed that it has structure 12 (R = CH,CO) and therefore anopteryl alcohol is 12 (R = H). Spectral evidence indicates that anopterine is 12 in which the two radicals R on the right-hand side of the given formula are tigloyl (8). 9. Argemone fruticosa Thurber and Gray and A . echinata G. B. Ownb. (Papaveraceae) (XII, 335) The main alkaloid in A. fruticosa is hunnemanine along with allocryptopine; A. echinata contains mostly cryptopine and berberine (9). 10. Argemone mzlnita Dur. and Hilg. (XII, 335; XIII, 398; XIV, 512)
2,9-Dimethoxy-3-hydroxypavinane(13) (C,,H,,O,N; mp 197-198"; - 254") was isolated from this plant. Its structure was confirmed by a total synthesis involving the penultimate 1,2-dihydroisoquinoline and its cyclization with formic and phosphoric acids (10).
[a];'
11. Argemone spp. (XIII, 397)
+
Argemone turnerae A. M. Powell yielded mostly ( )-armepavine and ( - )-tetrahydropalmatine neither of which had been reported as occurring in Argemone species. Argemone brevicornuta G. B. Ownbey gave mostly norargemonine with traces of berberine. Argemone albi$ora Hornem. gave sanguinarine, protopine, and allocryptopine along with small amounts of berberine and coptisine (11).
6.
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
267
12. Argemone subfusiformis Ownb. (XIII, 397)
Berberine, protopine, allocryptopine, chelerythrine, sanguinarine, and three unidentified bases (12). 13. Argyreia spp. (Convolvulaceae) (XIV, 512) Fourteen species of Argyreia and two plants of closely related genera were shown to contain ergoline type of alkaloids twenty-one of which were identified. Argyreia nervosa Boj. previously investigated had already yielded most of these (13). 14. Atalantia ceylonica Oliver (Rutaceae) (XII, 500; XIV, 513) Two new alkaloids, atalanine (C3,H3,0gN2; mp 216-217") (14) and ataline (C3,H,,0gN2; mp 209-210") (15)were obtained. They represent a new type of acridone base in which two acridone rings are joined by an ether bridge. Mass spectral data supplemented by other physical measurements and by analogy with other natural acridones served to provide the given structures (14). Further examination yielded alkaloid A (CI9Hl7O4N;mp 252-254O) as red needles in 0.0470 from the bark of this plant. It was shown to have structure 16 complete methylation of which gave the 0,O-dimethyl ether (mp 97-98'). Alkaloid B (C,,H,,O,N; mp 190-191"), also obtained in red needles in only 0.003% yield, was given structure 17. It reacted with diazomethane to yield the ll-O-monomethyl ether (mp 126'). All structures were dependent upon spectral studies (15). 15. Atalantia monophylla Correa (XII, 500) An earlier report disclosed the presence of atalaphylline (C23H2504N; mp 246") (18) and of its N-methyl derivative (mp 192") in this plant (16).The presence of the cyclized derivative of the latter, namely, N-methylbicycloatalaphylline (Cz4NZ,O4N;mp 185") (19) has now been reported (17). 16. Banisteriopsis inebrians Morton (Malpighiaceae) (X, 495; XI, 12) I n addition to the known harmine this plant yielded harmaline, tetrahyldroharmine, and harmol (18). 17. Bellendine (XIV, 514)
A synthesis of racemic bellendine (19a) has been announced. Tropinone was condensed with 3-methoxymethacrylyl chloride in the
268
R. H. F. MANSKE
$ p--Q -0
OMe
Me
\
\ OH
OH
0
14
OH
0
OH
0
15
17
16
OH
19
18
19a
6.
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
269
presence of sodium hydride. The product (mp 128') had UV, IR, NMR, and mass spectra identical with those of bellendine (mp 162') (18a). 18. Camptothecine (XII, 464, XIV, 515)
The potent antileukemic and antitumor activity of this alkaloid served to inspire other syntheses of it. The keto acid 20 (19) was reduced with sodium borohydride to 21 and the latter on an a-methylene lactam rearrangement in acetic anhydride generated 22 as a mixture of isomers. Oxidation of the latter with selenium dioxide in acetic acid gave 23. Hydrolysis of 23 gave 24 and this on heating with excess trimethyl orthobutyrate in the presence of a trace of propionic acid gave a mixture which was hydrolyzed to 25. Oxidation of 25 to the corresponding ketone (26) was achieved by means of dicyclohexylcarbodiimide in DMSO. The latter, when condensed with N (2-aminobenzylidine)-p-toluidineunder the Friedliinder conditions gave 27. The subsequent reactions to achieve the synthesis involved aromatization of the pyridine ring and the formation of the a-hydroxylactone. This was achieved by selenium dioxide oxidation in acetic acid, and the resulting deoxycomptothecine (28) on further oxidation (CuC1,-DMF-0,) was converted into camptothecine (29) (20). In another synthesis of this alkaloid the tricyclic lactone 30 was prepared by a series of reactions in which most of the steps gave satisfactory yields. Hydrolysis with aqueous oxalic acid and condensation with anthraniladehyde generated compound 31 which had already been converted into camptothecine (21). It should be added that the early promise of this alkaloid as a therapeutic agent in cancer therapy has not been confirmed in clinical trials (22). Still another synthesis has been announced. Compound 33 was obtained by heating 32 with diethyl acetonedicarboxylate and then converted to 34 by heating with piperidine in acetonitrile. The latter was hydrolyzed and decarboxylated by heating with concentrated hydrochloric acid a t 150" to 35 which was methylated to 36 with dimethyl sulfate and alkali, and this in turn converted to the aldehyde 37 by the Vilsmeier reaction. Reduction of 37 gave 38, formylation of which gave 39 and then 40 by another Vilsmeier reaction and the latter in turn was condensed with di-t-butyl malonate to 41, reduction of which with sodium borohydride generated 42. Lactone formation and deformylation of 42 by treatment with hydrochloric acid gave 43, and this on dehydrogenation with dicyanodichloroquinone (DDQ) afforded 44. Finally, ethylation of 44 with ethyl iodide and sodium hydride gave 28 convertible into dl-camptothecine (29) by oxidation (2323).
270
R. H. F. MANSKE
Continued interest in camptothecine stimulated yet another synthesis. This involved the synthesis of the penultimate material 45 which is readily convertible into the alkaloid. The key intermediate 46 was prepared by a series of six synthetic operations from furfuraldehyde dimethylacetal although the actual number of reactions was twice that number. While there were no entirely new reactions involved the experimental skill was evidently of a high order (24).
20 X + Y = O 21 X = H, Y = OH
25 26
23 X = H , Y = CH3.CO2, R = CH3.CO 24 X = H, Y = OH, R = H
22
28 R = H 29 R = O H
27
X = H , Y =OH X + Y = O
0
0 30
AR-
0
31
N
b R = H 33 R = -CO.CHZ.CO.CH2.CO2Et
38
34 35 36 37
R' R = -COzEt, R' = OH, R2 = H R = R2 = H, R' = OH R = R2 = H, R' = OMe R. = H, R' = OMe, R2 = -CHO
6.
271
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
R
H
/
R'
TT % 38 R =
RZ
= H, R' = OMe
/
0 44
0
OMe 45
0
,c=o
\'0
c' 46
19. Cassia carnaval Speg. (Leguminosae) (XI, 492)
Prosopinone (C,,H,,O,N) from this plant has structure 47 and alkaloid D is probably represented by 48 (25). 20. Cephalotaxine (X, 552)
The structure of cephalotaxine (49) has been determined by X-ray crystallographic studies supplemented by chemical methods (26). A synthesis of the racemic form has now been reported (27).Condensation of prolinol with 3,4-methylenedioxyphenylacetylchloride gave the alcohol 50 (R = CHOH) which upon oxidation to the aldehyde 50 (R = CHO) and condensation generated 51 (R = H; X = 0).Reduction of this with LAH gave 51 (R = H; X = H,). Condensation of the latter with 2-acetoxypropinyl chloride gave 51 (R = COCH(0AC)Me; X = H2). This on hydrolysis and oxidation gave the diketone 51 (R = CO.CO.Me; X = H,) which ultimately on condensation with magnesium methoxide gave 52. Methylation of 52 with 2,2-dimethoxypropane in the presence of p-toluenesulfonic acid gave the O-methyl ether 53 whose reduction with sodium borohydride proceeded stcreo-
rpeciiczdy to meemie eephalotuike (49).
272
R. H. F. MANSKE
(CH,),. CH(0H).(CH2)Io.CH(OH)Me
HO * CHZ H
H
48
47
(:at-$ H'
OMe 51
50
49
(o
\
-3 q
O
H'
OMe
0
0 54
5a
52
R R' RQ
MeO" 55 56
R + R' = O.CHZ.0 R = R 1= OMe
57 58 I9
R + R' = O.CHa.0 R = OMe, R' : :OH R = R ' = OMe
21. Cephalotaxusfortunei Hook. (Taxaceae) (X, 552; XIII, 400)
Cephalotaxinone (C1,H,,O,N; mp 200'; [a]g4 - 155') (53) is identical with alkaloid B previously isolated from C. hrringtonia (28).Alkaloid C (mp 141-143') from the above source proved to be acetylcephalotaxine; alkaloid D (mp 109'; [a]i5- 110') proved to be O-demethylcephalotaxine (54) obtainable by mild hydrolysis of the O-methyl base; - 150) was shown to be epicephalotaxine alkaloid E (mp 136-137'; (29). 22. Cephalotaxus harringtonia C. Koch ( C . pedunculata Sieb. & Zucc.) (X, 552; XIII, 400)
Five new homoerythrina alkaloids have been isolated from this plant in addition to others which were known. Their properties and
6.
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
273
structures are as follows: alkaloid 11, [.ID + 76" (55); 111, [.ID + 118" (56); IV, [a],,+123" (57); V, mp 150-152", [a],,+115" (58); VI, [.ID +122" (59) (30). 23. Chaenorhinum origanifolium (L.) Willk. et Lge. (Scrophulariaceae)
Thealkaloid chaenorhine (C,,H4,0,N4; mp 263-268" dec. ;[aID+ 46.7') proved to be macrocyclic containing a spermine moiety. The entire gamut of spectral studies was involved to determine its structure (60). Of special interest is the observation that the hydrogenolysis of the alkaloid with sodium in liquid ammonia occurred at the ether linkage and generated 61 with concomitant reduction of the cyclic double bond. Hydrolysis, some chemical degradation, and further spectral studies served to elucidate the entire structure (31).
81
24. Cinnamomum laubatii F. Muell. (C. tamala T. Nees & Eberm.) (Lauraceae) (X, 419; XIV, 518)
The chief alkaloid proved to be ( +)-reticdine (32). 25. Clausena heptaphylla Wt. & Am. (Rutaceae) (XIII, 467)
The alkaloid heptaphylline (CI3H,,O3N) was shown to have structure 62 by means of spectral methods and confirmation by a synthesis. Girinimbine was also present in this plant (33). 26. Coccinella septempunctata L. (XIV, 518)
The base, coccinellin (C,,H,,ON; mp 235' dec.) from this Coleoptera was shown to have structure 63 by means of an X-ray analysis. It is the N-oxide of precoccinellin. It had been shown to protect the insect from attack by predators, especially ants (34).
274
R. H.F. MANSKE
27. Cocculine and cocculidine (VI,443; XII,468)
NMR and mass spectral studies as well as a Hofmann degradation call for a revision of the assigned structures. The new structures are 64 and 65, respectively, for cocculine and cocculidine (35).
CHa*CH:CH, 62
Me 63
Me0
/ R = H 65 R = M e
64
28. Convolvulus erinacius Ledeb. & 6. subhirsutus Regel & Schmalh. (Convolvulaceae)(X,554) The roots of these plants yielded cuscohygrine and convolvine, respectively (36). 29. Coryphunthu macromeris (Engelm.) Lem. (Cactaceae) (XII, 468, 505) The following were isolated largely by chromatography and identified by spectral properties and by comparison with known bases: N formylnormacromerine, metanephrine, N-methylmetanephrine, synephrine, N-methyltyramine, N-methyl-4-methoxy-/3-phenethylamine, N-methyl-3,4-dimethoxy-/3-phenethylamine,tyramine, hordenine, macromerine, and normacromerine (37). 30. Coryphntha ramillosa Cutak
(XII,468)
The following bases were isolated as their hydrochlorides: N-methyl4-methoxy-/3-phenethylamine, hordenine, N-methyltyramine, synephrine, and O-methylsynephrine (38). 31. Crotalaaria albida Heyne (Leguminosae) (XII, 253) The alkaloid croalbine (66)(mp 208-209') was shown to be the cyclic diester of croalbinecine and trichodesmic acid (39).
6.
275
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
67
66
(F \
CH,
I
0L O
O Ro\ I
H
Me I
I
I
y
7
(N]
C H 'H I H Ph
Ph
68
Me
Me
H
69
70 R = H 71 R = P h * C O .
32. Crotalaria barbata R. Grah. (XII, 247)
The structure 67 of the new alkaloid, crobarbatine (mp 142"), is based on spectral evidence and hydrolysis to retronecine and to crobartic acid (C,H,,O,; mp 177-178") (40). 33. Crotalaria madurensis Wight (XII, 247)
Crispatine (mp 134"; [a]E3+39.5") was the major alkaloid accompanied by fulvine (mp 212-213"; [a]hg- l.6"),a diastereoisomer of the former (41). 34. Cryptoearya odorata (Panch. et Seb.) Guillaum. (Lauraceae) (XI, 453; XII, 471)
Reticuline, laurotetanine, N-methyllaurotetanine, isocorydine, and a new alkaloid, cryptodorine (C18H1504N;[a]hg + 61"; sulfate, mp 219-221") were isolated. The latter on N-methylation generated neolitsine; hence, it has structure 68 (42). 35. Cynometra ananta Hutchinson & Dalziel (Leguminosae)
Three imidazole alkaloids have been isolated from this plant. Their structures were ascertained largely by spectral methods and confirmed wholly or partly by limited chemical reactions: anantine (C,,H,,ON,; mp 204"; [.ID - 549; N-acetyl, mp 99") (69);cynometrine
276
R. H. F. MANSKE
(CI6Hl9O2N3;mp 213'; [a]= - 30") (70); and cynodine (C,,H,,O,N,; mp 155"; [aID + 15') (71) which is the benzoyl ester of cynometrine (43). 36. Cyphomandra betaceae Sendtn. (Solanaceae) (X, 1 7 ) In addition to the known solamine, tropinone, cuscohygrine, hyoscyamine, tropine, +tropine, and tigloidine there was isolated solacaproine (C,,H,,ON,; dipicrate, mp 149') whose structure proved to be [Me,N (CH2)4]2N .CO(CH,),Me. Hydrolysis generated solamine and caproic acid and recombination of these fragments gave the natural base ( 4 4 ) . 37. Cytisus hirsutus I,. and related spp. (Leguminosae) (VII, 255)
Cytisus hirsutus gave 1-sparteine, D-lupanine, 13-hydroxylupanine, and a new alkaloid, 7-hydroxysparteine. The main alkaloid from C. supinus (Auth.) was D-lupanine. Cytisus nigricans L. was almost devoid of alkaloids. Genista sessilifolia DC. gave chiefly retamine and anagyrine. Lotus aegeus Boiss. gave chiefly lupanine (45). 38. Daphniphyllidine (XII, 471)
This alkaloid (C,,H,,O,N; mp 204") is an isomer of deacetyldaphniphylline and the latter was converted to daphniphylline (72)by heating with sodium methylate in methanol (46). 0
72
OAQ
71 R = O 74 R = H, OH
6. ALKALOIDS
75
UNCLASSIFIED AND OF UNKNOWN STRUCTURE
H
277
76
39. Daphniphyllum macropodum Miq. (Euphorbiaceae) (X, 556; XII, 472)
In addition to the eight new alkaloids previously reported upon, this plant has yielded the new daphmacropodine (C,,H,,O,N; mp 214";[a],,+ 4.9").Spectral studies indicated the essential features of its structure (74).Mild alkaline hydrolysis afforded the deacetyl derivative and Jones oxidation converted it into a lactone which proved to be identical with daphmacrine (73)of known structure ( 4 7 ) . 40. Dendrobates histrionicus and D. purnilio
A general review of the toxins elaborated by the Columbian frogs of the genus Dendrobates. The structures of two of the more important toxins, pumiliotoxin (75)and histrionicotoxiii (76),are reproduced (48, 49). A later communication describes dihydrohistrioCnicotoxin which proved to be a powerful anticholinergic agent and which differs from 76 only in that the side of the piperidine ring of the latter chain is altered to -CH,. CH, .CH=C=CH,. The structure is based upon an X-ray study of the hydrochloride (50). 41. Dendrobine (X, 558; XII, 475; XIV, 525) The enol acetate 77 of 3,4-dihydro-7-methoxy-5-methyl-l-(2H)naphthalenone was converted to the acid 78 by ozonolysis and hydrolysis and this by a Wittig reaction with a-methoxyethyltriphenylphosphonium chloride gave 79.Compound 79 was converted into 80 by a series of reactions, five in number, which in turn was converted into 81 by reaction with potassium in t-butanol. The methyl ester of compound 81, one isomer of which was recognized as that having the correct stereo structure, was converted to 82 by heating with acetic anhydride and 1 O-camphorsulfonic acid. Subsequent steps involved ozonization, reaction with N,N'-carbonyldiimidazole, lactam formation, reaction with pyridinium bromide perbromide, reaction with sodium hydride, and a further series in which ( t- )-oxodendrobine (83) was ultimately obtained. Reduction of the latter to ( -I )-dendrobine
278
R. H. F. MANSKE
(84) was achieved by reacting it first with triethyloxonium fluoroborate in methylene chloride and then reducing with sodium borohydride in diglyme (52). Me
OAC 77
Me
Me
78 79
81
R = COzH R = -CH,.CO.Me
80
81 R = O 84 R = H,
82
H
Ho&
0 ".H
6.
ALKALOIDS UNCLASSIFIED
AND OF UNKNOWN STRUCTURE
279
42. Dendrobium primulinum Lindl. (Orchidaceae) (XIV, 525) Dendroprimine (oil; [a],, -38"; methiodide, mp 263") (52) (85) was converted to ( + )-4-methylnonane by a series of Hofmann degradations (53). 43. Dendrobium wardianum Wr. (XIV, 525) Spectral studies indicated that the new quaternary base dendrowardine (C,,H,,O,N.Cl; mp 168-172"; [a]g5 - 28") isolated from this plant has structure 85a. When treated with lithium hydride in DMF there was generated 85b which on hydrogenolysis (PtO,) gave dihydronobilinone (8512) (53a). 44. Desmodium tiliaefolium G . Don (Leguminosae) (XIII, 406)
Tyramine, hordenine, 3,4-dimethoxy-P-phenethylamine, N-methyl3,4-dimethoxy-P-hydroxyphenethylamine(86; amorphous; a new natural base), salsoline, salsolidine, tryptamine, abrine, and hypaphorine ( 5 4 ) .
45. Dictamnus albus L. (Rutaceae) (IX, 229)
Two new bases have been isolated from this much investigated plant: isomaculosidine (C14H,,0,N; mp 170-172") (87), identical with a known degradation product of maculosidine ; and preskimmianine (C,,H,,O,N; mp 151-152"), whose proposed structure (88) was confirmed by a synthesis (55, 56). 46. Dictamnus caucasicus (Boiss.) Fisch. (IX, 229) Dictamnine, y-fagarine, skimmianine, 6,8-dimethoxydictamnine (maculosidine), 6-methoxydictamnine, robustine, and isodictamnine. Dictamnus caucasicus appears to be a variety of D . fraxinella Pers., which in turn has been regarded as synonymous with D . albus L. (57).
280
R. H. F. MANSKE
47. Dipsacus azureus Schrenk (Dipsaceae) (VI, 133)
The alkaloid (CllH1303N;mp 130-131") from the seeds was shown to be identical with cantaleine (58). 48. Elaeagnus umbellata Thunb. (Elaeagnaceae) (XI, 10; XII, 481)
Seratonin was shown to be present in the leaves, stems, and cotyledons of this plant (59). 49. Emilia flammea Cass. (Compositae)
The alkaloid emiline (89) is given the structure shown on the evidence of spectral data. Strong hydrogen bonding of the hydroxyl to the nitrogen is indicated. The basic moiety is otonecine (60). 50. Euonymus alatus Thunb. (Celastraceae) (X, 561; XI, 489)
This plant has yielded the known evonine, evonymine, wilfordine, and a new alkaloid alatamine (C,,H,,018N; mp 185-193"; + 44"). Its structure (91)was indicated by an examination of its various spectra and a series of chemical transformations gave credence to that structure. It was finally converted into wilfordine (90) by reduction (NaBH, - DMF) and acetylation in which the C-7 epimer was also generated (61). 51. Euonymus europaeus L. (X, 561; XI, 489)
The new 4-deoxyevonine (92) was isolated from this plant. Evonine (93) and neoevonine (94) were also reported (62).In another report the isolation of evonine and isoevonine (amorphous; [aID 30.5") was described. The structure of the latter differed from the former only in the nature of the pyridine moiety. Methanolysis afforded methyl 2-(3-(methoxycarbonyI)propyl)nicotinate (63, 64).
+
52. Euonymus sieboldiana Blume (X, 561; XI, 489) Two new alkaloids, evonimine (C2,H3,012N; mp 184") (95) and evonine (96) have been isolated. Spectral studies, interconversions, and critical chemical reactions prove the given structures (65).Further extensive chemical and spectral studies confirmed these assignments (66, 67').Earlier assignments of structures gave 97 to evonine and 95 to evonoline (68). 53. Festuca arundinaceae Vill. (Gramineae) (X, 562; XII, 322) The presence of three new alkaloids from the seeds of this plant was demonstrated. A combination of adsorption and gas chromatography
6. ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
281
I
Me 89
OAc
90
x=(
91
x=o
‘H
o@
AcO Ac
---Me
0 NMe X=O,R=OH OAc 96 X = ( ,R=OH ‘H 97 X = O , R = H 96
Me 92 R = H, R1 = AC 98 R = OH, R’ = AC 94 R = O H , R ’ = H
served to identify N-formylloline, N-acetylloline, and demethy1-Nacetylloline identified by spectral methods (69). 54. Ficus septica Forst. f. ( 2) (Urticaceae)
The major alkaloid was antofine. Bases of the phenanthroindolizidine type appeared to be present but were not identified (70). 55. Gebeline (IX, 213)
The structure of gebeline which had been proposed (71, 72) was
282
R. H. F. MANSKE
revised to 98 on the basis largely of its mass spectrum. It had been isolated from Sophora pachycarpa Schrenk. (mp 231"; [.ID - 12.9")and yielded a dihydro derivative (mp 207"; picrate, mp 192') (73). 56. Genista tinctoria L. (Leguminosae) (IX, 188;XIII, 408)
On the basis of spectral studies the new alkaloid tinctorine has structure 99. Its hydrogenation product was enantiomeric with that similarly obtained from N-methylangustifoline (74). 57. Gentiana olivieri Griseb. (G. decumbens 563; XI, 487)
L.) (Gentianaceae) (X,
This plant yielded gentioflavine, gentianaine, and oliveramine whose structure, based on spectral study, was given as 100. It was not indicated whether or not these bases are artifacts generated during isolation
(75). 58. Glycozolidine (XIII, 279)
On the basis of NMR and other data this base has been reformulated as 2,6-dimethoxy-3-methylcarbazole (76). 59. Gymnema sylvestre
R.Br. (Asclepiadaceae)
Gymnamine (C,,H2,0,N2; amorphous; picrate, mp 260") has structure 101 as determined by spectral methods. Hydrolysis followed by Wolff-Kishner reduction converted it into lycodine (102) (77).
0
98
99
0
\ 100
101
102
6.
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
283
60. Gymnocalycium schickendantzii Britton & Rose and Cereus aethiops Haw. (C. caerulescens Salm-Dyck) (Cactaceae)
The former yielded hordenine and candicine while the latter yielded these as well as tyramine (78). 61. Halfordia kendack Guillaumin (Rutaceae) (XI, 498) The structure of halfordamine (C12N1304N; mp 240-244") (103) (78a)was confirmed by a synthesis (79). Another synthesis involved the condensation of malonic acid with 2,4-dimethoxyaniline followed by heating with polyphosphoric acid a t 105". The resulting quinoline (104) on treatment with diazomethane generated halfordamine (80). 62. Haplophyllum acutifolium G. Don (Ruta acutifolium DC.) (Rutaceae) (X, 565; XII, 480; XIII, 408) Acutine (C,,H,,ON; mp 122-123") from this plant was given structure 105 on the basis of spectral studies. Hydrogenation generated
0 OM0 108 R = Me 104 R = H
101
0
108
1078
108
284
R. 3.F. MANSKE
a dihydrobase which was also prepared by acid-catalyzed condensation of Me(CH,), .CO .CH,CO,Me with aniline and subsequent ring closure in boiling diphenyl ether (81, 82). 63. Haplophyllum foliosum Vved. (XIV, 534) Folimidine (C,,H,,O,N) a spectral study (83).
has been given structure 106 on the basis of
64. Haplophyllum hispanicum Spach ( 2 ) (IX, 225) Evoxin and its secondary monoacetate (mp 169") were isolated (84). 65. Huplophyllum pedicellatum Bge. (X, 565; XII, 480)
The above plant yielded haplopine and robustine; H . obtusifolium Ldb. yielded skimmianine and evoxine; and H . bucharicum Litv. yielded dictamnine, skimmianine, y-fagarine, robustine, haplopine, bucharine, benzamide, and a new alkaloid, bucharamine. Of several possible structures for the latter the more probable is 107 (85). 6 6. Helmint hosporium sativum
A base, first isolated from H . victoriae (86),and named victoxinine (oil, [a]g5 -78"; hydrochloride, mp 172"; O-acetyl, oil, [a]g5 -56") has been obtained from the above fungus. Its structure (107a) was largely deduced from spectral data and chemically confirmed by its preparation from prehelminthosporal (108) of known structure (87). 67. Hernandia ovigera L. (Hernandiaceae) (IX, 30) In addition to the known alkaloids from this plant the trunk bark yielded the new hernandonine (C,,H,O,N; mp > 280") whose structure (109) was determined largely by spectral methods and confirmed by its synthesis from N-methylhernovine by known reactions (88). 68. Hippodamia convergens (Coleoptera) (XIV, 518) The American ladybug was shown to elaborate two alkaloids: hippodamin (CI3H,,N), which gives a mass spectrum almost identical with that of precoccinellin (110) (89), and convergin (C,,H,,ON) (111 or 112), which on reduction of its carbonyl generates a base regarded as hydroxyhippodamin; it is therefore 3-methyl-13-azabicyclo[7.3.lltrideca n-&one (111) or 1l-methyl-l3-azabicyclo[7.3.1]tridican-5-one (112) (90).
6.
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
285
69. Hotarrhena febrifuga Klotzsch (Apocynaceae) (IX, 3 18)
A reexamination of this plant yielded 2.4y0alkaloids from the bark. The principal alkaloids were holafebrine and conessine (113), but the following eight were also isolated: conessimine, isoconessimine, conarrhirnine, conessidine, conkurchine, holaminol, holarrhimine, and holaphylline (91).
109
111 112
110
R = Me,R' = H R = H,R' = Me
Me
113
R
R'
R =R' = P h 115 R = CsHll-, R' = CTHT5118 R = C,H:,-; R' = -CHz.CH(OH)(CHz),-Me 117 R = Ph, R' = -CHz.CH(OH)(CH2),.Me 114
Ph 118
70. Homaliurn pvonyense Guillaum (Flacourtiaceae) (Samydaceae) (XII, 481; XIII, 409)
This plant, native to New Caledonia, has yielded four new alkaloids which show affinities with spermine and spermidine. Homaline (C,,H,,02N4; rnp 34";[a],,- 34")was given structure 114 although other possibilities were discarded only after careful study and the final decision was based on the synthesis of a derivative.
286
R. H. F. MANSKE
Hopromine (C30H5,0,N4; oil; [.ID - lo") offered similar problems concerning its structure but 115 is preferred. Hoprominol (C30K5803N4 oil; [a],,-19") and hopromalinol (C3,H5,03N4 oil; [a],,-17") are hydroxy derivatives of similar structures represented by 116 and 117, respectively (92). The structure for homaline (114) was confirmed by a synthesis of bisdihydrodioxohomaline. The diazacyclooctane (118) was reacted with succinyl chloride and the bisamide reduced with LAH. The product 114 was identical with that prepared from homaline (93). 71. Hypecoum erectum L. (Papaveraceae) (XII, 337) Hypecorine (C2,H,,0,N; mp 154-156') and hypecorinine (CZoH,,O,N; mp 197-198') from this plant were given structures 119 and 120, respectively (94). 72. Isolongistrobine (XIV, 540) Following an earlier synthesis of dehydroisolongistrobine (95) the same authors have reported a synthesis of isolongistrobine (121) and
119 X = 2H 120 x = 0
R ) T k O R 1
124a R lZ4b R 124~ R 124d R
122 R = H 128 R = -CO.CHz.CHz.CH=CHP 124 R = -CO .CH,.CHZ.CHO
121
CH2 * Ph = H,R' = -CO.Ph = H,R1 = -CO*Me = Ph.CO,-, R' = H = OH, R' = -CO*CH=CH.Ph
aw3 0
0 125
126
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
287
shown that the structure originally proposed is in error. The amino alcohol 122 on reaction with 4-pentenoyl chloride generated 123. The latter was first oxidized to the corresponding ketone with chromic oxide in pyridine and then to the aldehyde 124 with sodium periodate and osmium tetroxide. Compound 124 was identical with isolongistrobine (96). 73. Knightia dqdanchei Vieill. (Proteaceae) The four alkaloids isolated from this plant are derivatives of the structure shown. Mass spectra supplemented by other spectral studies served to determine these. Alkaloid A (Gl5H2,ON; r n p 123-1Z4"; [.ID f0'; 124a);B (C1,&30N; oil; [a]D + O ; 124b); c (C2,HZ5O3N; mp 168-170'; [.ID f O ; 142c); and D (C2*H2,03N; mp 174-175"; [.ID & 0; 124d). Some chemical reactions confirmed these structures
(96a). 74. Leontice darvasica (Auth. 2) (Berberideceae) Darvasamine (Cl6HZ40N2;mp 102'; was given structure 125 (97).
[.ID
+72"), a new alkaloid,
75. Leontice 1eonto.petalum Hook. f. et Thorns. (X, 570: XII, 486) a-Isolupine, 3-(2-piperidiny1)quinolizidine (leontiformidine), ( + )lupanine, leontiformine, palmatine, and tetrahydropalmatine (98). 76. Leontidine (XII, 486) The structure of leontidine (126),based on mass spectral evidence, was confirmed by its preparation from cytisine (99). 77. Lindera oldhami Hemsl. (Lauraceae) (XIII, 412)
D-Dicentrine, N-methylnandigerine, N-methylovigerine, and the first natural occurrence of O-methylbulbocapnine (mp 129°-1300; + 248'). Some others were not identified; dicentrinone was probably present (100). 78. Litsea glutinosa Hook. (Lauraceae) (XIII, 412) From the var, glabraria the following aporphines were isolated : norboldine, boldine, laurotetanine, N-methyllaurotetanine, actinodaphnine, and N-methylactinodaphnine (101).
288
R. H. F. MANSKE
79. Litsea leefeana Merr. and Cryptocarya foveobta White et Francis
The alkaloids of the former consisted essentially of boldine, laurolitsine, and ( + )-reticuline. The last named was the chief alkaloid in C. foveolata (102). 80. Litsea sebifera Pers., L. wightiana, Hook. f., and Actinodaphne obovata Bl. (IX, 1 7 )
The first plant yielded boldine, laurotetanine, N-methyllaurotetanine, and actinodaphnine; the second yielded boldine and norboldine ; the last yielded laurotetanine, N-methyllaurotetanine, and actinodaphnine (103). 81. Lobelia nicotianaefolia Heyne (Lobeliaceae) (XI, 462; XII, 488)
Lobeline constituted 20y0 of the total alkaloids (103a). 82. Lobelia polyphylla Hook. & Am. (VI, 126)
The main alkaloid, in amounts up to 1.4Oj,, was norlobelanidine (mp 254') (104). 83. Lophanthera lactescens Ducke (Malpighiaceae)
An amorphous base, lophanterine, of undisclosed formula ([.IF hydrochloride (mp 188-189") sparingly soluble in cold ethanol. It is intensely bitter and the plant is used as a tea by some Amazonians (105).
- 92.7") forming a
84. Lunaridine (X, 572)
An exhaustive spectral study, particularly of mass spectra, has indicated that lunaridine has structure 127. It is thus isomeric with lunarine 128 (106). 85. Mandragora autumnalis Bertol. and M . vernalis Bertol. ( M . oficinarum L.) (Solanaceae)
The same alkaloids (hyosciamine, hyoscine, cuscohygrine, apoatropine, 3a-tigloyloxytropane, and 3,6-ditigloyloxytropane) and approximately to the same extent were found in the roots of these two species. This is the first known occurrence of tiglic acid esters in the genus Mandragora (107).
6. ALKALOIDS
UNCLASSIFIED AND OF UNKNOWN STRUCTURE
289
I
NH
127 n = 4,n1 = 3 128 n = 3, n1 = 4
129
Me0
Me0
OH 130
86. Maytenus chuchuhuasha Raymond-Hamet et Calas (XIV, 541)
Maytenine (C,,H,,O,N,; mp 158") was shown by exhaustive spectral methods to be di-transcinnamoylspermidine (129) (108).It i s evidently not related to the tumor-active alkaloids which have been isolated from M . ovatus (109, 110). A synthesis of HN[(CH,),NH.CO-CH:Ph],, which was stated to be maytenine, was achieved by treating spermidine with 1-cinnamoyloxypiperidine (111). 87. Merendera raddeana Regel (Liliaceae) (XI, 412)
The new alkaloid merenderine from this plant was given structure 130 (112). 88. Mitrella kentii ( B l . ) Miq. (Anonaceae)
Liriodenine, anonaine, asimilobine, and egeline (113). 89. Monnieria trifolia L. (Rutaceae) (XIII, 414)
Arborinine (mp 176-178") (114). 90. Monodora angolensis Welw. (Anonaceae)
The main alkaloid was isoboldine (115).
290
R. H. F. MANSKE
91. Mucuna spp. (Leguminosae) (VIII, 12; XI, 12)
A procedure for the isolation of L-dopa from Mucuna seed has been reported. Of the nine species examined eight gave recovery of 3.1 to 6.1 from mature seeds (116). 92. Murrayacine (XII, 491; XIII, 282)
The synthesis of this base (131) has been achieved by a series of reactions in which the phenylhydrazone 132 was prepared by a JappKlingemann reaction of the appropriate compounds and subsequently subjected to ring closure. Though the subsequent steps present no novel features i t is evident that their execution demanded considerable manipulative skill (117). 93. Murraya koenigii Spreng. (Rutaceae) (XII, 491; XIII, 274, 414)
Murrazoline isolated from the stem bark has structure 133 as determined by spectral studies which chemical reactions confirmed (118).
OMe
Me0
Me
OH 1a4
133
Me
GQ
HO
Me
iaa
136
6.
ALKALOIDS UNCLASSITIED AND OF UNKNOWN STRUCTURE
291
94. Nandina domestica Thunb. (Berberidaceae) (IX, 13)
Isocorydine, as well as a number of bases previously reported, was isolated (119). 95. Nelumbo nucifera Gaertn. (Nymphaeaceae) (X, 410; XIV, 544)
I n addition t o a number of previously recognized alkaloids the following were isolated: dehydroroemerine, dehydronuciferine, dehydroanonaine, and N-methylisococlaurine (120). 96. Nemuaron vieillardii Baill. (Monimiaceae)
The known alkaloids laurotetanine, N-methyllaurotetanine, norisocorydine, atheroline, and O-methylflavinantine were isolated. A new - 42.7'; 0alkaloid, nemuarine (C3,H4006N2; mp 222-223"; methyl, mp 154-156'; [a]$0-43.8")) which is the major constituent of the leaves, has structure 134 (121). 97. Nitraria schoberi L. (Zygophyllaceae)
The alkaloid nitramine (CloH,,ON) was given structure 135. Dehydrogenation in the presence of Pd/C generated 8-methylquinoline (122). 98. Nuphar luteum Sibth, et Sm. (Nymphaeaceae) (IX, 441; XIV, 545)
Neothiobinupharidine (136)and the isomeric thionuphlutine A were isolated from plants grown in Poland. They were not obtained from plants of American origin. Thionuphlutine A is identical with thiolunupharidine (123). 99. Obregonia denegrii Fri6. (Cactaceae)
Small yields of tyramine, N-methyltyramine, and hordenine were isolated by thin layer chromatography; TLC (124). 100. Ocotea variabilis Mart. (Lauraceae) (IX, 6; XII, 349, 492)
Glaziovine, apoglaziovine, nantenine, and a new base variabiline (C,,H,,O,N,; mp 116'; [.ID 5 0") have been isolated from this plant. Spectral examination pointed t o structure 137 for the new alkaloid and its preparation from ( + )-glaziovine (138)by heating it with dibenzylamine and the hydrochloride for 2 hr a t 200-210" confirmed the structure (125).
292
R. H. F. MANSKE
101. Oldenlandia afinis DC. (0. dichotoma Kook. f.) (Rubiaceae)
(X, 574) Serotonin(5-hydroxytryptamine) was isolated from the dried aerial parts of this plant (126). 102. Oricia suaveolens Verdoorn (Teclea smveolens Engl.) (Rutaceae)
The new alkaloid oricine (C,,H,,O,N; mp 150-152") was given structure 139 on the basis of spectral evidence. A synthesis was reported. The method was one (127) used earlier in an analogous base. Diethyl y,y-dimethallylmalonate, when heated with aminoveratrol, gave an intermediate which on cyclodehydration and subsequent methylation generated oricine (128). 103. Orixa japonica Thunb. (Rutaceae) (IX, 227; XIV, 546)
Orixinone (Cl7Hl9O5N; mp 10ZO),a new alkaloid, was shown to have structure 140, largely by means of spectral data and confirmed by dehydration of orixine (141). The quaternary 0-methylbalfouradinium ion was also isolated as its perchlorate (129). MHe 0
O
~~p~ &
T
Me0
Ph *
CH2-T
\
Me0 0
CHa. Ph
139
OMe
OCH@Me
Q-0
\
L O 140
R
0
I
R = OH R -CHI. CO .M e E
N
142
141
143 144
N
I
Me 138
137
'
145
0
6. ALKALOIDS UNCLASSIFIED AND 104. Pedicularidine
OF UNKNOWN STRUCTURE
293
(X,575;XIII, 416;XIV, 548)
The structure of this base (142) was determined by spectral methods and the aldehyde portion was converted to carboxyl by oxidation with silver oxide (130).
L. (Zygophyllaceae) (XI, 14; XIV, 548; XII,
105. Peganum harmala 528)
Feganol (C,,H,,ON,;
mp 178-180") is a new alkaloid of structure
143 from this plant (131).Also reported was deoxypeganidine (C14H,,ON,) (144), which on permanganate oxidation generated vasicinone (145) (132).
106. Pelecyphora aselliformis Ehrenberg (Cactaceae) (IV, 8)
Hordenine, anhalidine, pellotine, 3-demethyltrichocereine, mescaline, 3,4-dimethoxyphenethylamine,and the N-methyl derivatives of the last two. Several of these had not been isolated from plants other than Lophophora species ( 133). 107. Phyllanthidine
(IX,270; XIII, 417; XIV, 481)
This alkaloid (Cl3H1,O3N; mp 189-170"; [a]=-450") was first obtained from Phyllanthus discoides Muell. Arg. (134) and presently from Securinega suffruticosa Rehd. Its structure (146) was mooted on the basis of a spectral study and confirmed when it was obtained in excellent yield by the hydrogen peroxide oxidation of allosecurinine (147) (135).
146
147
\
(o
\ O
P
-
148
2 94
R. H. F. MANSKE
108. Piper sylvaticum Roxb. (Piperaceae) (XII, 495; XIII, 417; XIV, 557)
Sylvatine (C,,H3,03N; mp 112'; [a]D k 0') isolated from this plant was shown to be an amide of piperic acid. Mass and other spectra indicated structure 148 and confirmation was achieved by reduction, hydrolysis, and/or oxidation, the product of the latter process being 5-methylhexanoic acid (136). 109. Pisum sativum L. (Leguminosae) (XIV, 551)
Cadaverine was present in concentration of 2 5 pg/g of fresh young plants grown under various conditions (137). 110. Plantago arenaria Waldst. & Kit. (Plantaginaceae) (X, 5 7 5 )
The remarkable occurrence of narcotine in this plant is recorded. A second base (C,,H,,ON,) appears to be a terpenoid (138). 11 1. Pogonopus patchouli Pellet (Labiatae) (XII, 496)
The alkaloids, guaipyridine (149) and epiguaipyridine (150), have been synthesized from guaiol (151) and from a-gurjunene (152), respectively (139). 112. Poranthera corymbosa Brogn. (Euphorbiaceae) (XIV, 5 5 7 )
+
The main alkaloid, porantherine (C,,H,,N; mp 36-40"; [a]D 29") was shown, by X-ray analysis, to have structure 153. Other spectral studies are consonant therewith (140).Two further alkaloids have been reported and their structures have also been elucidated by X-ray methods. Poranthericine (C1,H,,ON; oil; [.ID - 20°; B.HBr, mp 308") has structure 154. Its acetyl derivatives (oil) was also isolated from the plant. Porantheridine (C1,H,,ON; oil; [a]=- 26"; B.HBr, mp 165-166"; [.ID - 19') has structure 155 (140-142). 11 3. Propylea quatuordecimpunctata L. (Coleoptera; Coccinellidae)
The structure of the alkaloid propyleine (C,,H,,N; amorphous; levorotatory) (156) from this beetle was determined by spectral methods supplemented by chemical methods. It is the dehydro derivative of coccinellin (143) into which it was converted (144). 114. Prosopis alba Griseb. (Leguminosae) (XI, 12, 492)
Tyramine, 8-phenethylamine, and tryptamine were isolated (145).
6.
149 150
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
Me R = Me, R' = H R = H, R' = Me
153
152
151
154
295
155
115. Pseudoprotopine (XIII, 427)
This is the name given to an alkaloid (mp 200-201") isomeric with protopine, isolated from Zanthoxylum conspersipunctum Merr. ( l 4 6 ) , whose structure (157) has been confirmed by a synthesis. The reaction sequence, beginning with the corresponding berberine, was essentially that described in the original protopine synthesis (147). 116. Rhamnaceae from Chile (X, 407)
( - )-Friedelin was a common constituent of the following species. I n addition the named alkaloids were identified. Colletia hystrix Clos, ( - )-magnocurarine; Retanilla ephedra Brongn., coclaurine. Neither Colletia spinosa Lam., Trevoa trinervia Miers, nor Talguenea quinquinervia I. M. Johnston (Trevoa puinquinerwia Gill. & Hk.) yielded alkaloids although an earlier examination indicated the presence of D-( -)-magnocurine in C. spinosissima Gmel. ( = C . spinosa Lam.) (148).
296
R. H. F. MANSKE
117. Ruta graveolens L. (Rutaceae) (XII, 498) Some quinolinium alkaloids related to those found in Balfourodendron have been isolated (149). 118. Sarcopetalum harveyanum F. Muell. (Menispermaceae) Stepharine and coclaurine were isolated (150). 119. Sarothamnus patens (Auth 1 ) (Cytisus striatus (Hill) Rothm.; Genista straita Hill) (Leguminosae) (IX, 182; XIII, 418) In addition to sparteine three derivatives of 13-hydroxylupanine were isolated; namely, the veratric ester (cineverine), the trimethoxybenzoic ester (sarodesmine), and the isovanilic ester which is new and named isocinevanine (151, 152). 120. Sceletium namaquense (L.) Bolus (Aizoaceae) (Ix,468; XIV, 553) An alkaloid from this plant has been shown t o be identical with Sceletium A, previously reported from Channa. Its structure was shown to be 158 by an X-ray study of its crystals grown from an ethyl acetate solution (153). 121. Schefferomitra subaequalis (Scheff.) Diels (Anonaceae) (XIV, 552) Anonaine, liriodenine, asimilobine, isoboldine, and anolobine, all known alkaloids, were isolated : in addition two potoberberine bases, - 283") (159) and schefferine aequaline (C,,H,,04N; mp 232"; (C,,H,,O,N; mp 176"; [a];, -303") (160). Both on methylation with diazomethane generate ( - )-tetrahydropalmatine. A third base, alkaloid Y (C,,H,,O,N; mp 257"), was obtained in amounts insufficient for structural elucidation although it is apparently not a benzylisoquinoline, an aporphine, or a berberine type (154). OMe
158
159 160
R =H R =Me
lf3Oa
6.
ALKALOIDS UNCLASSIFIED
AND OF UNKNOWN STRUCTURE
297
122. Schelhammera undulata R.Br. (Liliaceae) (XIII,418; XIV, 271)
Alkaloids B (mp 152-153"; [elD+ 112') and E ([.ID + 125'; picrate mp 169-172") from this plant had both been isolated from S. pendunculata F. Muell. and from S. muZtijZora R.Br. (255). 123. Senecio nemorensis L. (Compositae)
The alkaloid nemorensine (C,,H,,O,N; mp 132-134"; [a]E4 - 58") was shown to have structure 160a on the basis of spectral and chemical evidence. The basic moiety resulting from the alkaline hydrolysis could not be crystallized either as such or as its picrate. The acidic fragment was named nemorensic acid (mp 174-178'; [a]g4+87'). The same alkaloid was isolated from a number of subspecies ( 2 5 5 ~ ) . 124. Senecio propinquus Schischk. (XII,251)
The main alkaloid proved to be seneciphylline (156). 125. Senecio taiwanensis Hayta & S. morrisonensis Hayata
(XII,245)
Both plants yielded rosmarinine and integerrimine (157). 126. Shihunine (XIII, 426, 421)
Appropriately labeled 4,2'-carboxyphenyl-4-oxobutanoicacid (161) was shown to be a precursor in the biosynthesis of shihunine (162) in Dendrobium pierardi Roxb . (158).
SYL
COaH
161
mNH2 OAo
OAc
165
164
127. Slaframine (X, 579; XII,501)
An earlier synthesis of this base (163) (159) has been superseded by a stereoselective one. The starting materials were glutamic acid and
298
R. H. F. MANSKE
acrylonitrile which generated an oxopyrrolidine. Dieckmann cyclization followed by hydrolysis, decarboxylation, catalytic reduction, N-alkylation with methyl bromoacetate, another Dieckmann cyclization, more hydrolysis, decarboxylation, and acetylation gave 164. The oxime of the latter on catalytic hydrogenation gave dl-slaframine (160). 128. Sophora grifithii Stocks (Keyserlingia grifithii Boiss.) (Leguminosae) (XIV, 557) Cytisine, N-methylcytisine, and matrine (161). 129. Spathelia sorbifolia (L) Fawc. & Rendle (Rutaceae) (XII, 480)
N-Methylflindersine (mp 83-85'), not previously recognized as a natural product, was isolated by a procedure involving chromatography. Spectral examination indicated its identity although no chemical transformations were reported. This plant had at one time been placed in Simarubaceae but the chemical constituents along with some taxonomic studies indicate the above relegation (162). 130. Stemona japonica Miq. (Roxburghiaceae) (IX, 545; XII, 502; XIII, 421; XIV, 5 5 8 )
Stemonamine (CI8Hz3O4N;mp 172-174'; hydrochloride (2H20), mp 148-151') and isostemonamine (mp 165-169') are two new alkaloids. The structure of the former (165) was revealed by an X-ray study of its hydrochloride. Structure 166 is suggested for isostemonamine. Both are optically inactive (163). 131. Tecoma stans Juss. (XI, 502)
A reexamination of this plant yielded the new A5-dehydroskytanthine (liquid; [ c z ] ~-~ 89'; picrate, mp 167') and S-skytanthine (liquid; + 10.0";picrate, mp 144-146') (164). 132. Trichocereus chiloensis Britten & Rose (Cereus chiloensis DC.) (Cactaceae) (XII, 506)
Candicine was identified as its iodide (165). 133. Tylophora asthmatica Wight et Am. (Asclepiadaceae)(XIII, 425; XIV, 562)
The phenolic alkaloid tylophorinidine (C,,H,,04N; mp 216-218'; +105') was subjected to a spectral reexamination and the
6 . ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
299
revised structure 167 has been suggested. Two minor alkaloids, also isolated, were shown to be d-septicine and d-isotylocrebrine (166).
0
OMe
OM.3 165
167
166
v
M e O - e C H . CHz. N H R
_ . I
OMe
168
169 170
OH R = Ph.CO. R = Ph.CH=CH.CO.
134. Urtica pilzclifera L. (Urticaceae)
Bufotenine was identified as a constituent of the leaves and stems (162’). 135. Uvariopsis guineensis Keay (Anonaceae) (XIV, 563)
Five of the eight alkaloids isolated from this plant are derivatives of aminoethylphenanthrene, “ open aprophines,” chief of which is uvariopsine (168). The others of this type represent various 0-and N-substituted bases. The remaining new alkaloids proved to be oxoaporphines in addition to which liriodenine and a methoxy and a dimethoxy derivative of it were present (168). 136.
Vandopsis gigantea Pfitz. (Orchidaceae) (XIV, 563)
Vandopsis gigantea yielded laburnine and lindelofidine as well as their acetates. Vanda hindsii Lindl. and Vanda helvola B1. gave the acetate of laburnine and the latter also gave laburnine. Vanda luzonica Loher gave the acetate of either laburnine or of its enantiomer. Vandopsis parishii Schltr. showed the presence of hygrine (169).
300
R. H.F. MANSKE
137. Verbascum songaricum Schrenk (Scrophulariaceae) (XIV, 563) Anabasine, plantagonine, an unidentified base (mp 195-196"), and acetamide were isolated (170). 138. Zanthoxylum inerme Koidz. (Fagara boninense Koidz.) (Rutaceae) (XI, 13; XII, 506;XIII, 427) The wood of this plant yielded, among other and neutral products, 4-methoxy-1-methyl-2-quinolone (mp 99-103'). The bark yielded nitidine, aricine, chelerythrine, isolated as derivatives, and oxynitidine (mp 283-285'). I n addition L-(+)-armepavine metho salt was also found (171). 139. Zanthoxylum ocumarense (Pittier) Steyerm. (Fagara ocumarensis Pittier) I n addition t o neutral compounds the bark of this plant yielded N-methyl-a-( - )-canadine, ( + )-laurifoline, chelerythrine, and two bases (C,,H,,O,N. HC1, mp 245"; and C,,Hl103N, mp 216"). A number of nonnitrogenous compounds were also isolated as well as two amides 169 (C,,H,,O,N; mp 149-151"), which proved to be tembamide (172), and 170 (Cl,H,903N; mp 175-176'), which appears to be new (173).
REFERENCES 1. M. P. Cava, K. T. Buck, and A. J. da Rocha, J . Amer. Chem. Soc. 94, 593 (1972). 2. R. B. Tursch, J. C. Braeckman, D. Daloze, C. Hootele, D. Losman, R. Karlsson, and J. M. Pasteels, Tet. Lett. 201 (1973). 3. F. Khuong-Huu, J.-P. Le Forestier, and R. Goutarel, Tetrahedron 28, 5207 (1972). 4. K. A. Aslanov, Y. K. Kushmurador, and A. S. Sadykov, C A 77, 140388~(1972). 5. T. R. Govindachari, P. C. Parthasaraty, and H. K. Desai, I n d i a n J. Chern. 10, 1117 (1972); G A 78, 121359t (1973). 6. T.-H. Yang, C.-M. Chen, and S.-S. Kuan, J . Chin. Chem. SOC.( T a i p e i ) 18, 133 (1971); C A 77, 16567r (1972). 7. D. S. Bhakuni, S. Tewari, and M. M. Dahr, Phytochernistry 11, 1819 (1972); C A 77, 16535d (1972). 8. W. A. Denne, S. R. Johns, J. A. Lamberton, A. M. Mathieson, and H. Suares, Tet. Lett. 2727 (1972). 9. F. R. Stermitz, R. J. Ito, S. M. Workman, and W. M. Klein, Phytochem.istry 12, 381 (1973); C A 78, 94792~(1973). 10. R. M. Coomes, J. R. Falck, D. K. Williams, and F. R. Stermitz, J . Org. Chem. 38, 3701 (1973); C A 79, 13733213 (1973). 11. F. R. Stermitz, D. K. Kim, and K. A. Larson, Phytochernistry 12, 1355 (1973); C A 79, 113193q (1973). 12. A. L. Bandoni, R. V. D. Rondina, and J. D. Coussio, Phytochemistry 11, 3547 (1972); C A 78, 55299v (1973).
6.
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
301
13. J.-M. Chao and A. H. DerMarderosian, Phytochemistry 12, 2435 (1973); C A 79, 144182 (1973). 14. A. W. Fraser and J. R. Lewis, J . Chem. Soc., Chem. Commun. 615 (1973). 15. A. W. Fraser and J. R. Lewis, J . Chem. SOC.,Perkin Trans. 1, 1173 (1973). 16. T. R. Govindachari, N. Viswanatha, B. R. Pai, V. N. Ramachandran, and P. S. Subramanian, Tetrahedron 26, 2905 (1970). 17. D. Basu and S. C . Basa, J. Org. Chem. 37, 3035 (1972). 18. I. Ribas, J. Sea, and L. Castedo, An. Asoc. Quim. Argent. 68, 299 (1972); C A 77, 123811n (1972). 1%. I. R. C. Bick, J. B. Bremner, and J. W. Gillard, Tet. Lett. 5099 (1973). 19. J. J. Platner, R. D. Gless, and H. Rapoport, J . Amer. Chem. Soc. 94, 8613 (1972). 20. C. Tang and J. H. Rapoport, J . Amer. Chem. Soc. 94, 8615 (1972). 21. E. Winterfeldt, T. Korth, D. Pike, and M. Bach, Angew. Chem., Int. Ed. Engl. 11, 289 (1972); Ber. 105, 2126 (1972). 22. M. Shamma, D. A. Smithers, and V. St. Georgier, Tetrahedron 29, 1949 (1973). 23. T. Sugasawa, T. Toyoda, and K. Sasakura, Tet. Lett. 5109 (1972). 24. A. S. Kende, T. J. Bentley, R. W. Draper, J. K. Jenkins, M. Joyeux, and I. Kubo, Tet. Lett. 1307 (1973). 25. D. Lythgoe, A. Busch, N. Schvarzberg, and M. J . Vernengo, A n . Asoc. Quim. Argent. 60, 317 (1972); C A 77, 164901k (1972). 26. K. L. Mikolajzak, R. G. Powell, and C. R. Smith, Jr., Tetrahedron 28, 1995 (1972), and references therein. 27. J. Auerbach and S. W. Weinreb, J . Amer. Chem. SOC.94, 7172 (1972). 28. R. G. Powell, Phytochemistry 11, 1407 (1972). 29. W. W. Paudler and J. McKay, J . Org. Chem. 38, 2110 (1973). 30. R. G. Powell, Phytochemistry 11, 1467 (1972); C A 77, 5637n (1972). 31. H. 0. Bernhard, I. KompiS, S. Johne, D. Groger, M. Hesse, and H. Schmid, Helv. Chim. Acta 56, 1266 (1973). 32. J. Ellis, E. Gellert, and R. E. Summons, A w t . J. Chem. 26, 1829 (1972); C A 77, 85606q (1972). 33. B. S. Joshi, V. N. Kamat, D. H. Gawad, and T. R. Govindachari, Phytochemistry 11, 2065 (1972); C A 77, 48671m (1972). 34. B. Tursch, D. Daloze, M. Dupont, C. Hootele, M. Kaisin, J. M. Pasteels, and D. Zimmermann, Chimia 25, 307 (1971); 26, 74 (1972); Ezperientia 27, 1380 (1971). 35. N. S. Vul'fson and V. N. Bochkarev, Izv. Akad. Naulc SSSR, Ser Khim. 500 (1972); C A 77, 621949q (1972). 36. S. F. Aripova, V. M. Malikov, and S. Y. Yunnsov, Khim. Prir. Soedin. 401 (1972); C A 77, 1 6 2 0 1 0 ~(1972). 37. W. J. Keller, J. L. McLaughlin, and L. R. Brady, J. Pharm. Sci. 62, 408 (1973); C A 78, 1 2 1 2 9 7 ~(1973). 38. P. Sato, J. M. Neal, L. R. Brady, and J. L. McLaughlin, J . Pharna. Sci. 62, 411 (1973); C A 78, 121296~(1973). 39. R. S. Sawhney and C . K. Atal, Indian J. Chem. 11,88 (1973); C A 79,8479d (1973). 40. S. C. Puri, R. S. Sawhney, and C . K. Atal, Experientia 29, 390 (1973); C A 79, 2 9 5 2 2 ~(1973). 41. A. A. M. Habib, M. R. I. Saleh, end M. A. Farag, Lloydia 34, 455 (1971); CA 76, 124179d (1972). 42. R. C. Bick, N. W. Preston, and P. Potier, Bull. SOC.Chim. Fr. 4596 (1972); C A 78, 9483221 (1973). 43. F. Khuong-Huu, X. Monseur, G. Ratle, G. Lukas, and R. Goutarel, Tet. Lett. 1757 (1973).
302
R. H. F. MANSKE
44. W. C. Evans, A. Ghani, and V. A. Wooley, J . Chem. Soc., Perkin Trans. 1, 2017 (1972). 45. N. M. Mollov, I. K. Ivanov, and P. P. Panov, Dokl. Bolg. Akad. Nauk 24, 657 (1971); C A 76, 1 3 8 2 1 4 ~(1972). 46. M. Toda, N. Haruki, and Y. Hirata, Tet. Lett. 797 (1973). 47. T. Nakano, M. Hasegawa, and Y. Saeki, J . Org. Chem. 38, 2404 (1973). 48. B. Witkop, Ezperientia 27, 1121 (1971). 49. J. W. Daly, I. L. Karle, C. W. Myers, T. Tokuyama, J. A. Waters, and B. Witkop, Proc. Nat. Acad. Sci. U.S. 68, 1870 (1971). 50. I. L. Karle, J . Amer. Chem. Soc. 95, 4036 (1973). 51. K. Yamada, M. Suzuki, Y. Hayakawa, K. Aoki, H. Nakamura, H. Nagase, and Y Hirata, J . Amer. Chem. SOC.94, 8278 (1972). 52. B. Liining and K. Leander, Acta Chem. Scand. 19, 1607 (1965). 53. L. Blomquist, K. Leander, B. Liining, and J. Rosenblom, Acta Chem. Scand. 26, 3203 (1972); C A 78, 586469 (1973). 53a. L. Blomquist, S. Brandange, L. Gawel, K. Leander, and B. Liining, Acta Chem. Scand. 27, 1439 (1973); C A 79, 79001p (1973). 54. S . Ghosal and R. S. Srivastava, Phytochemistry 12, 193 (1973); C A 78, 553473 (1973). 55. R. Storer and D. W. Young, Tet. Lett. 2199 (1972). 56. R. Storer and D. W. Young, Tetrahedron 29, 1217 (1973). 57. I. M. Kikvidze, I. A. Bessanova, K. S. Mudzhiri, and S. Y. Yunusov, Khim. Prir. Soedin. 675 (1971); CA 76, 124107d (1972). 58. T. U. Rakhmatullaev and S. Y. Yunusov, Khim. Prir.Soedin. 400 (1972); C A 77, 162011~ (1972). 59. I. Regula, Acta. Bot. Croat. 31, 105 (1972); C A 78, 19631, (1973). 60. S. Kohlmuenzer, H. Tomczyk, and A. Saint-Firmin, Diss. Pharm. Pharmacol. 23, 419 (1971); C A 76, 96972m (1972). 61. Y. Shizuri, K. Yamada, and Y. Hirata, Tet. Lett. 741 (1973). 62. H. Budzikiewioz, A. Roemer, and K. Taraz, 2. Naturforsch. B 27, 800 (1972); C A 7 7 , 123847d (1972). 63. L. Dubravkova, J. Tomko, and I;.Dolejs, Phytochemistry 12, 944 (1973); C A 79, 2759j (1973). 64. L. Dubravkova, L. Dolejs, and J. Tomko, Collect. Czech. Chem. Commun. 38, 2132 (1973); C A 79, 1 1 5 7 4 6 ~(1973). 65. K. Sugiura, K. Yamade, and Y. Hirata, Tet. Lett. 113 (1973). 66. Y.Shizuri, H. Wada, K. Sugiura, K. Yamada, and Y. Hirata, Tetrahedron 29, 1773 (1973). 67. Y. Shizuri, H. Wada, K. Yamada, and Y. Hirata, Tetrahedron 29, 1795 (1973). 68. M. Pailer, W. Streicher, and J. Leitich, Monatsh. 102, 1873 (1971); C A 76, 1134062 (1972). 69. J. D. Robbins, J. G. Sweeny, B. R. Wilkinson, and D. Burdock, J . Agr. Food Chem. 20, 1040 (1972); C A 77, 12377313 (1972). 70. R. B. Moody and C. J. Moody, Phytochemistry 11, 1184 (1972); C A 76, 1381432 (1972). 71. Y. I. Pakanaev and A. S. Sadykov, Zh. Obshch. Khim. 33, 1374 (1963); C A 56, 3522i (1962). 72. K. A. Aslanov, Y. K. Kushmuratov, U. N. Zaimutdinov, and A. S. Sadykov, Dokl. Akad. Nauk. Uzb. SSR 24 (1969); C A 72, 67161L (1970). 73. S. Iskandarov, B. Sadykov, Y. V. Rashkes, and S. Y. Yunusov, Khim. Prir. Soedin. 347 (1972); C A 77, 152423t (1972).
6. ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE
303
74. D. Knoefel, C A 77, 1403903 (1972). 75. T. U. Rakhmattullaev and S. Y. Yunusov, Khim. Prir. Soedin. 9, 64 (1973); CA 78, 159956g (1973). 76. F. Anwer, R. S. Kapil, and S. P. Popli, Indian J. Chem. 10, 959 (1972); CA 78, 84600s (1973). 77. G. S. Rao, J. E. Sinsheimer, and H. M. Mcllhenny, Chem. Ind. (London) 537 (1972); C A 77, 101973q (1972). 78. S . 0. Ruiz, G. Neme, M. Nieto, and A. T. D’Arcangelo, An. Asoc. Quim. Argent. 61,41 (1973); C A 79, 15842f (1973). 78a. W. D. Crow and J. H. Hodgkin, Aust. J . Chem. 21, 3075 (1968). 79. R. Storer and D. W. Young, Tet. Lett. 1555 (1972). 80. P. Venturella, A. Bellino, and F. Piozzi, Chem. Ind. (London)887 (1972). 81. D. M. Gulyamova, I. A. Bessonova, and S. Y. Yunusov, Khim. Prir. Soedin. 850 (1971); C A 76, 138169n (1972). 82. D. M. Razzakova, I. A. Bessonova, and S. Y. Yunusov, Khim. Prir. Soedin. 206 (1973); CA 79, 321478 (1973). 83. D. M. Razzakova, I. A. Bessonova, and S. Y. Yunusov, Khim. Prir.Soedin. 755 (1972); C A 78, 84605x (1973). 84. A. G. Gonzalez, 0. Moreno, and L. F. Rodriguez, An. Asoc. Quim. Argent. 68, 1133 (1972); C A 78, 82069b (1973). 85. K. Ubaidullaev, I. A. Bessonova, and S. Y. Yunusov, Khim. Prir. Soedin. 343 (1972); CA 78, 2010n (1973). 86. R. B. Pringle and H. C. Brown, Nature (London)181, 1205 (1958). 87. F. Dorn and D. Arigoni, Chem. Commun. 1342 (1972). 88. H. Furukawa, F. Uedo, M. Ito, K. Ito, H. Ishii, and J. Haginiwa, Yakugaku Zasshi 92, 150 (1972); CA 76, 153982r (1972). 89. R. Karlsson and D. Losman, Chem. Commun. 626 (1972). 90. B. Tursch, D. Daloze, J. M. Pasteels, A. Cravador, J. C. Braekman, C. Hootele, and D. Zimmermann, Bull. SOC.Chim. Belg. 81, 649 (1972); CA 78, 43798w (1973). 91. H. Dadoun, A. Cave, and R. Goutarel, Ann. Pharm. Fr. 31, 237 (1973); C A 79, 134330~(1973). 92. M. Pais, R. Serfati, F.-X. Jarreau, and R. Goutarel, Bull. SOC.Chim. Fr. (in press); Tetrahedron 29, 1001 (1973). 93. M. Pais, R. Sarfati, and F.-X. Jarreau, Bull. SOC.Chim. Fr. P a r t 2, 331 (1973); C A 78, 148102r (1973). 94. L. D. Yakhontova, M. N. Komarova, M. E. Perel’son, K. F. Blinova, and 0. N. Tolkachev, Khim. Prir. Soedin. 624 (1972); C A 78, 188177n (1973). 95. M. A. Wuonola and R. B. Woodward, J . Amer. Chem. SOC.95, 284 (1973). 96. M. A. Wuonola and R. B. Woodward, J . Amer. Chem. SOC.95, 5098 (1973). 96a. C. Kan-Fan and M. Lounasmaa, Acta Chem. Scand. 27, 1039 (1973); C A 79, 79003r (1973). 97. A. Zunnunzhanov, S. Iskandarov, and S. Y. Yunusov, Khim. Prir. Soedin. 851 (1971); CA 76, 12414413 (1972). 98. P. P. Panov, L. N. Panova, and N. M. Mollov, Dokl. Bolg. Akad. Nauk 25, 55 (1972); C A 77, 72554w (1972). 99. S. Iskandarov, R. A. Shaimardanov, and S.-Y. Yunusov, Khim. Prir. Soedin. 631 (1971); CA 76, 99884v (1972). 100. S.-T.Lu, S.-J. Wang, P.-H. Lai, C.-M. Lin, and L.-C. Lin, Yakugaku Zasshi 92, 910 (1972); C A 77, 101949m (1972). 101. S . Tewari, D. S. Bhakuni, and M. M. Dhar, Phytochemistry 11, 1149 (1972); CA76, 138158h (1972).
304
R. H. F. MANSKE
102. J. A. Lamberton and V. N. Vashist, Aust. J. Chem. 25, 2737 (1972). 103. H. Uprety, D. S. Bhakuni, and M. M. Dhar, Phytochemistry 11, 3059 (1972); C A 77, 19660n (1972). 1038. C. S. Shad, J. S. Qadry, and M. G. Bhatt, Phytochemistry 11, 2884 (1972); C A 77, 123837a (1972). 104. K. Weinges, W. Baehr, W. Ebert, and P. Kless, Ann. 756, 177 (1972). 105. 0. Ribeiro and A. Machado, An. Ass. Chim. BrasiZ 5 , No. 2, 39 (1942); C A 41, 3109a (1947). 106. H. Poupat, H.-P. Husson, B. C. Das, P. Bladon, and P. Potier, Tetrahedron 28, 3103 (1972). 107. B. P. Jackson and M. I. Berry, Phytochemistry 12, 1165 (1973); C A 79, 40016x (1973). 108. C. Englert, K. Klinga, R. Hamet, E. Schlittler, and W. Vetter, Helv. Chim. Acta 56, 474 (1973). 109. S. M. Kupchan, R. M. Smith, and R. F. Bryan, J. Amer. Chem. SOC.92,6667 (1970). 110. S. M. Kupchan, Y. Komoda, W. A. Court, G. J. Thomas, R. M. Smith, A. Karim, C. J. Gilmore, R. C. Haltiwanger, and R. F. Bryan, J. Amer. Chem. SOC.94, 1354 (1972). 111. H. P. Husson, C. Poupat, and P. Potier, C . R . Acad. Sci., Ser. C 276, 1039 (1973); C A 79, 548413 (1973). 112. M. K. Yusupov, A. A. Trozyan, K. A. Aslanov, and A. S. Sadykov, Khim. P&. Soedin. 777 (1972); C A 78, 94874y (1973). 113. J. Ellis, E. Gellert, and R. E. Summons, Aust. J. Chem. 25, 2735 (1972); C A 78, 40463v (1973). 114. A. Cave, J. I. Ramos de Souza, and R. R. Paris, Planta Med. Phytother. 5 , 327 (1971); C A 76, 150988m (1972). 115. M. Leboeuf, J. Parello, and A. Cave, Planta Med. Phytother. 6, 112 (1972); C A 77, 111494y (1972). 116. M. E. Daxenbichler, C. H. VanEtten, F. R. Eerle, and W. H. Talent, J. Agr. Pood Chem. 20, 1046 (1972); C A 77, 123772a (1972). 117. D. P. Chakraborty, A. Islam, and P. Bhattecharyya, J. Org. Chem. 38, 2728 (1973). 118. D. B. Chakraborty, S. N. Ganguly, P. N. Maji, A. R. Mitra, end K. C. Das, C h . Ind. (London) 322 (1973); C A 79, 18904p (1973). 119. J. Kunitomo, K. Morimoto, S. Tanaka, and S. Hagata, Yakugaku Zasshi 92, 207 (1972); CA 76, 124117g (1972). 120. J. Kunitomo, Y. Yoshikawa, S. Tanaka, Y. Imori, K. Isoi, Y. Masada, K. Hashimoto, and I. Inoue, Phytochemistry 12, 699 (1973); C A 78, 121330h (1973). 121. I. R. C. Bick, H. M. Leow, N. W. Preston, and J. J. Wright, Aust. J. Chem. 26, 455 (1973); C A 78, 846190 (1973). 122. N. V. Novgorodova, S. K. Maekh, and S. Y. Yunusov, Khim. Prir. Soedin. 196 (1973); C A 79, 32150w (1973). 123. R. T. LaLond and C. F. Wong, Phytochemistry 11, 3305 (1972); C A 77, 164921s (1972). 124. J. M. Neal, P. T. Sato, and J. L. McLaughlin, Econ. Bot. 25, 382 (1971); C A 76, 151035k (1972). 125. M. P. Cava, M. Behforouz, and M. J. Mitchell, Tet. Lett. 4647 (1972). 126. L. Gran, Lloyd& 35, 461 (1972); C A 78, 1212636 (1973). 127. F. Piozzi, P. Venturella, and A. Bellino, Gazz. Chim.Ital. 99, 711 (1969).
6.
ALKALOIDS UNCLASSIFIED AND O F UNKNOWN STRUCTURE
305
128. M. 0. Abe, Phytochemistq 10, 3328 (1971); C A 76, 9 6 9 6 7 ~(1972). 129. W. J. Donnelly and M. F. Grundon, J. Chem. SOC.,Perkin Trans. 1, 2116 (1972). 130. S. Khakimdzhanov, A. Abdusamatov, and S. Y. Yunusov, Khim. Prir. Soedin. 9, 132 (1973); C A 78, 159944t (1973). 131. M. Telezhenetskaya, K. N. Kashimov, and S. Y. Yunusov, Khim. Prir. Soedin. 7 , 849 (1971); CA 76, 110310~(1972). 132. B. K. Zharekeev, M. V. Telezhenetskaya, and S. Y. Yunusov, Khim. Prir. Soedin. 279 (1973); CA 79, 321588 (1973). 133. J. M. Neal, P. T. Sato, W. N. Howald, and J. L. McLaughlin, Science 176, 1131 (1972); CA 77, 588240 (1972). 134. J. Parello and S. Munavalli, C.R. Acad. Sci. 260, 337 (1965). 135. Z. Hori, T. Imanishi, M. Yamauchi, M. Hanaoka, J. Parello, and S. Munavalli, Te’et.Lett. 1877 (1972); CA 77, 62195r (1972). 136. A. Banerji and P. C. Ghosh, Tetrahedron 29, 977 (1973). 137. J. N. Anderson and R. 0. Martin, Phytochemistq 12, 443 (1973); C A 78, 94893d (1973). 138. J. Peyroux, M. Mehri, M. Hachem, M. Plat, P. Rossignol, and G. Valette, Ann. Pharm. Fr. 30, 51 (1972); C A 77, 16511t (1972). 139. A. Van der Gen, L. M. Van der Linde, and 5. G. Witeveen, Rec. Trav. Chim. Pays-Bas 91, 1433 (1972); CA 78, 5864313 (1973). 140. W. A. Denne, S. R. Johns, J. A. Lamberton, and A. M. Mathieson, Tet. Lett. 3107 (1971). 141. W. A. Denne, S. R. Johns, J. A. Lamberton, A. M. Mathieson, and H. Suares, Tet. Lett. 1767 (1972). 142. W. A. Denne and A. M. Mathieson, J . C9yst. Mol. Struct. 3, 139 (1973); CA 79, 1 1 5 7 5 2 ~(1973). 143. B. Tursch, D. Daloze, M. Dupont, C. Hootele, M. Kaisin, J. M. Pasteels, and D. Zimmermann, Chimia 25, 307 (1971). 144. B. Tursch, D. Daloze, and C. Hootele, Chimia 26, 74 (1972); CA 77, 19847t (1972). 145. M. N. Graziano, G. E. Ferraro, and J. D. Coussio, Lloydia 34, 453 (1971); C A 76, 1 3 8 2 1 2 ~(1972). 146. S . R. Johns, J. A. Lamberton, N. J. Tweedale, and R. I. Willing, Aust. J . Chem. 25, 385 (1972). 147. R. B. Sotelo and D. Giaoopello, A w l . J . Chem. 25, 385 (1972); C A 76, 1 2 7 2 1 2 ~ (1972). 148. E. Sanchez and R. Torres, An. Asoc. Quim. Argent. 59, 343 (1971); C A 77, 85620q (1972). 149. K. Szendrei, J. Reisch, I. Novak, L. Simon, Z. Rozsa, E. Minker, a n d M. Koltai, Herba Hung. 10, 131 (1971); C A 79, 15853k (1973). 150. B. 0. Sowemimo, J. L. Beal, R. W. Doskotch, and G. H. Svoboda, Lloydia 35, 90 (1972); CA 77, 72581c (1972). 151. G. Faugeras, R. R. Paris, and E. Valdes-Bermejo, C.R. Acad. Sci., Ser. C 273, 1372 (1971); C A 76, 110320f (1972). 152. G. Faugeras, R. R. Paris, and E. Valdes-Bermejo, Ann. Pharm. Fr. 30, 527 (1972); C A 78, 40430g (1973). 153. P. A. Luhan and A. T. McPhail, J. Chem. SOC.,Perkin Trans. 1, 2006 (1972). 154. E. Gellert and R. Rudzats, Awrt. J. Chem. 25, 2477 (1972); C A 77, 1496852 (1972). 155. A. A. Sioumis, Awrt. J. Chem. 24, 2737 (1971); C A 76, 110299f (1972). 1558. A. KAlsek, P. Sedmera, A. Boeva, and F. Bantavy’, Collect. Czech. Chem. Commun. 38, 2504 (1973); C A 79, 1266825. (1973).
306
R. H. F. MANSKE
156. D. S. Khalikov, I. A. Damirov, and M. V. Telezhenetskaya, Khim. Prir. Soedin. 656 (1972); C A 78, 109214~(1973). 157. S.-T. Lu, C.-N. Lin, T.-S. Wu, and D.-C. Shieh, J . Chin. Chem. SOC.(Taipei) 19, 127 (1972); C A 77, 161936q (1972). 158. E. Lette and G. B. Bodem, Chem. Commun. 522 (1973). 159. D. Cartwright, R. A. Gardiner, and K. L. Rinehart, Jr., J . Amer. Chem. SOC.92, 7615 (1970) 160. W. J. Gensler and M. W. Hu, J. Org. Chem. 38, 3848 (1973). 161. I. Primukhamedov, K. A. Aslanov, and A. S. Sadykov, Khim. Prir. Soedin. 398 (1972); C A 77, 162009b (1972). 162. C. D. Adams, D. R. Taylor, and J. M. Warner, Phytochemistry 12, 1359 (1983); C A 79, 50709q (1973). 163. H. Iizuka, H. Irie, N. Masaki, K. Osaki, and S. Uyeo, Chem. Commun. 125 (1973); C A 78, 1 1 1 5 6 6 ~(1973). 164. D. Gross, W. Berg, and H. R. Schuette, Phytochemistry 12, 201 (1973); CA 78, 55364n (1973). 165. M. Cortes, J. A. Garbarino, and B. K. Cassels, Phytochemistry 11, 849 (1972); C A 76, 96935b (1972). 166. T. R. Govindachari, N. Viswanathan, V. Radhakrishnan, B. R. Pai, S. Natarajan, and P. S. Subramanian, Tetrahedron 29, 891 (1973). 167. I. Regula, Acta Bot. Croat. 31, 109 (1972); C A 7 8 , 1962n (1973). 168. M. Leboeuf and A. Cave, Phytochemistry 11, 2833 (1972); C A 77, 101944f (1972). 169. S. Brandange and I. Granelli, Acta Chem. Scand. 27, 1096 (1973); C A 79, 1 2 3 6 0 9 ~ (1973). 170. R. Ziyaev, A. Abdusamatov, and S. Y. Yunusov, Khim. Prir. Soedin. 853 (1972). 171. H. Ishi, H. Ohida, and J. Haginiwa, Yakugaku Zaeshi 92, 118 (1972); CA 77, 165303. (1972). 172. S. M. Albonico, A. M. Kuck, and V. Deulofeu, J . Chem. SOC.,Londolz 1327 (1967). 173. D. Della Case de Mareano, M. Hasegawa, and A. Castaldi, Phytochemistry 11, 1531 (1972); C A 77, 31553b (1972).
SUBJECT INDEX A
Anagyrine, 276 Anantine, 275 Ancistrocladisine, 265 Ancistrocladus heyneanus, 265 Anhalidine, 293 Anhydrogalanthamine, 114 Anhydrolycorine, 99 Anolobine, 296 Anona glabra, 266 Anona sufusiformis, 266
A b u t a imene, 263 A b u t a rufescens, 263 Abrine, 279 Abyssenine-A, 176, 201. Abyssenine-B, 176, 201 Abyssenine-C, 176 Acetylcephalotazine, 272 N-Acetylloline, 281 Actinodaphne obovata, 288 Actinodaphnine, 287, 288 Acutine, 283 Adalia bipunctata, 264 Adalia quadrimaculata, 264 Adalia pantherina, 264 Adouetine-X, 170 Adouetine-Y, 172, 179 Adouetine-Z, 172, 179 Aequaline, 296 Agroclavine, 34 Albomaculatine, 105 Alchornea fioribunda, 264 Alchornea hirtella, 264 Alchorneine, 264 Alchorneinone, 265 Alkaloid A,, 43, 64 Alkaloid AI, 43, 64 Alkaloids A,B,C,D, 287 Alkaloids B,E, 297 Allium cepa, 235 Allocryptopine, 236, 237, 266 Americine, 170 Ammodendron argenteum, 265 Ammodendron siever,sii, 265 Amphibine-A, 178 Amphibine-B, 166, 173, 183, 193 Amphibine-C, 173, 194 Amphibine-D, 173, 194 Amphibine-E, 173 Amphibine-F, 173 Amphibine-G, 174 Amphibine-H, 175, 197 Anabasine, 300
Anonaine, 266, 289, 296 Anopterine, 266 A n o p t e m glandulosus, 266 A n o p t e m s macleyanus, 266 Anopteryl alcohol, 266 Antofine, 281 Apoatropine, 288 Apoglaziovine, 291 Aporheine, 226 Aralionine-A, 173, 179, 183 Aralionine-B, 172 Araliorhamnus vaginatus, 177 Arborinine, 289 Argemone albiflora, 266 Argemone brevicornuta, 266 Argemone echinata, 266 Argemone fruticosa, 266 Argemone mexicana, 242 Argemone munita, 266, 267 Argemone turnerae, 266 Argentamine, 265 Argentine, 265 Aricine, 300 Armepavine, 203, 224, 266, 300 Argyrein species, 267 Arolycoricidine, 143 Asimilobine, 289, 296 Atalanine, 267 Atalantia ceylonica, 267 Atalantia monophylla, 267 Atalaphylline, 267 Ataline, 267
307
308
SUBJECT INDEX
Atheroline, 291 Aulamine, 88
B Bacihus anthracis, 237, 242 Banisteriopsis inebrians, 267 Bellendine, 267 Benzamide, 284 Berbamine, 232 Berberine, 231, 266 Berberis vulgaris, 231 Bicuculline, 239 Bodamine, 111 Boldine, 287, 288 Bucharamine, 284 Bucharine, 284 Bufotenine, 299 Eulbocapnine, 228 C Cadaverine, 294 Camptothecine, 269 Canadine, 235 Candicine, 283, 298 Candimine, 105 Cantaleine, 280 Caranine, 83, 88, 102 Cassia carnaval, 271 Ceanothamine-A, 171 Ceanothamine-B, 170 Ceanothine-B, 170 Ceanothine-C, 170 Ceanothine-D, 171 Ceanothine-E, 172 Ceanothus americanus, 177 Ceanothus integerrimw, 177 Centium eurvoides, 177 Centhiumine, 172, 197 Cephalotaxine, 171 Cephalotaxionone, 272 Cephalotaxus harringtonia, 272 Cephalotamis fortunei, 272 Cephalotaxus peduncuhta, 272 Cereus aethiops, 283 Cereus caerulescens, 283 Chaenorhine, 273 Chaenorhinum origanifolium, 273 Chanoclavines, 1, 3, 24 Chelidonine, 241
Chelerythrine, 242, 300 Chelidonium majus, 237 Cheryline, 83, 84, 139 Chlidanthus frangrans, 85, 154 Cineverine, 296 C i n n a m o m u m laubatii, 273 Cinnamomum tamala, 273 Clausena heptaphylla, 273 Claviceps fusiformis, 5 Claviceps paspali, 2, 7, 20 Claviceps purpurea, 2, 22 Clavicipitic Acid, 1, 5 Clidanthine, 83, 111, 112 Clivia miniata, 85, 109, 149 Cliviasine, 83, 110 Clividine, 83, 107, 109 Clivonine, 83, 106 p-Codeine, 208 Coccinells s e p t e m p n c t a t a , 273 Coccinellin, 273, 294 Coccinine, 137 Cocculidine, 274 Cocculine, 274 Coclaurine, 295, 296 Codaphniphylline, 41, 43, 47 Colletia hystrix, 295 Colletia spinosa, 295 Colletia spinosiasima, 295 Colubrina texensis, 178 Columbamine, 232 Conarrhimine, 285 Conessidine, 285 Conessimine, 285 Conessine, 285 Conkurchine, 285 Convergin, 284 Convolvine, 274 Convolvulus erinacius, 274 Convolvulus hirsutus, 274 Cooperanthes, 85 Coptisine, 235, 266 Corydine, 227, 266 Coryphantha m?acromris, 274 Coryphantha ramillosa, 274 Corytuberine, 227 Cotarnine, 209 Crinine, 121 Crinum dijixum, 85 Crinum erubescens, 85 Crinum latifolium, 85 Crinum longifolium, 85
309
SUBJECT INDEX
Crinum powellii, 85 Crinum pratense, 85 Criwelline, 126 Crispatine, 275 Croalbine, 274 Croalbinecine, 274 Crobartic Acid, 275 Crobartine, 275 Crotalaria albida, 274 Crotalaria barbata, 275 Crotalaria madurensis, 275 Cryptocarya foveolata, 288 Cryptocarya odorata, 275 Cryptodorine, 275 Cryptopine, 236, 237, 266 Cularine, 230 Cuscohygrine, 274, 288 Cycloclavine, 1, 6 Cynodine, 276 Cynometra ananta, 275 Cynometrine, 275 Cyphomandra betaceae, 276 Cyrthanthus mackenii, 85 Cytisine, 287, 298 Cytisus hirsutw, 276 Cytisus nigricans, 276 Cytisus striatus, 296
D Daphmacrine, 43, 50, 277 Daphmacropodine, 43, 51, 277 Daphnijsmine, 79 Daphnimacrine, 42 Daphnimacropine, 43, 49 Daphnilactone-A, 41, 43, 55 Daphnilactone-B, 41, 43, 57 Daphniphyllamine, 43 Daphniphyllidine, 43, 48, 276 Daphniphylline, 41, 43, 44 Daphniphyltum calycium, 42 Davhnivhullum humile. 42 ~Daphniphyllum macropodum, 41, 277 Daphniphyllum teiismanni, 42 Daphniteijsmine, 78 Darvasamine, 287 Dehydroanonaine, 291 Dehydronuciferine, 291 Dehydroroemerine, 291 As-Dehydroskytanthine, 298 Delonix regia, 183
Demethyl-N-acetylloline, 281 N-Demethylgalanthamine, 111, 116 3-Demethyltrichocereine, 293 Dendrobates histrionicus, 277 Dendrobates pumilio, 277 Dendrobine, 277 Dendrobium pierardii, 297 Dendrobium primulinum, 279 Dendrobium uiardianum, 279 Dendroprimine, 279 Dendrowardine, 279 4-Deoxyevonine, 280 Deoxypeganidine, 293 Desmodium tiliaefolium, 279 Dicentrine, 287 Dictamnine, 279, 284 Dictamnus albus, 279 Dictamnus caucasicus, 279 Dictamnus fraxinella, 279 Dihydrocotarnine, 208 Dihydroergosine, 1, 9 Dihydrogalanthamine, 111 DihydrohistrioCnicotoxin, 277 Dihydrohydrastinine, 208 Dihydrolycorine, 99 Dihydronobilinone, 279 Dihydrosanguinarine, 241 Dihydrosetoclavine, 8 6&Dimethoxydictamine, 279 2,9-Dimethoxy-3-hydroxypavinane,266 3,4-Dimethoxy-,3-phenethylamine, 279, 293 4-Dimethylallytryptophan, 1, 3 Discaria longispina, 177 Discarine-A, 170 Discarine-B, 170 Dipsacus azureus, 280 3,6-Ditigloyloxytropane,288 L-Dopa, 290
E
~
Egeline, 289 Elaeagnus umbellata, 280 Elymoclavine, 24 Elymoclavine-O-,3-D-fructofuranoside, 1, 6 Emilia flammea, 280 Emiline, 280 Epicephalotaxine, 272 3-Epielwisiine, 132
310
SUBJECT INDEX
Epigalanthamine, 111 Epiguaipyridine, 294 11-Epihaemanthamine, 83, 124 Ergine, 27 Ergocristine, 14 Ergocristinine, 15 Ergokryptine, 28 P-Ergokryptine, 1, 11 Ergolenes, 20 Ergometrine, 26 Ergonine, 14 Ergoptine, 14 Ergosine, 1, 10, 14 Ergosinine, 1, 10 Ergostine, 1, 10, 14 Ergotamine, 14, 28, 31 Ergotaminine, 32 Ergotoxine, 35 Ergovaline, 14 Euonymus alatus, 280 Euonymus europaeus, 203, 280 Euonymus sieholdiana, 280 Evonimine, 280 Evonine, 280 Evonoline, 280 Evonymine, 280 Evoxin, 284
F Fagara boninense, 300 Fagara coco, 228 Fagara ocumarensis, 300 7-Fagarine, 279, 284 Falcatine, 88 Festuca arundinaceae, 280 Ficus septica, 281 Folimidine, 284 N-Formyllolire, 281 N-Formylnormacromerine, 274 Franganine, 171 Frangufoline, 171 Frangulanine, 166, 171, 179, 191 Fulvine, 275 Fumaria indica, 237
G Galanthamine, 83, 111, 114, 153 Galanthine, 89 Galanthusine, 83, 106
Galanthus caucasicus, 85, 106 Galanthus elwesii, 88 Galanthus nival8, 85, 86 Galanthus krasnovii, 85 Galanthus woronovii, 86 Gebeline, 281 Genista sessilifolia, 276 Genista tinctoria, 282 Gentiana decumbens, 282 Gentiana olivieri, 282 Gentianaine, 282 Gentioflavine, 282 Girinimbine, 273 ,Glaucine, 227, 266 Glaziovine, 225, 291 Glycozolidine, 282 Golceptine, 88 Goleptine, 88 Guaipyridine, 294 Gymnamine, 282 Gymnema sylvestTe, 282 Gymnocalycium schiekendantzii, 283
H Habranthine, 83, 111 Habranthus brychyandrus, 86 Haemanthamine, 121, 158 Haemathidine, 83, 124, 133 Haemanthus coccineus, 160 Haemanthus katherinae, 86 Haemanthus puniceus, 88 Halfordamine, 283 Haljordia kendack, 283 Haplophyllum acutifolium, 283 Haplophyllum bucharicum, 284 Haplophyllum joliosum, 284 Haplophyllum hispanicum, 284 Haplophyllum obtusijolium, 284 Haplophyllum pedicellatum, 284 Haplopine, 284 Harmaline, 267 Harmine, 267 Harmol, 267 Helminfhosporium satitwm, 284 Helminthospotium victoriae, 284 Heptaphylline, 273 Hernandia ovigera, 284 Hernandonine, 284 Hippamine, 88 Hippeastrine, 105
31 1
SUBJECT INDEX
Hippeastrum brachiandrum, 86 Hippeastrum equense, 86 Hippeastrum johnsonii, 86 Hippodamia convergens, 284 Hippodamin, 284 Histrionicotoxin, 277 Holafebrine, 285 Holaminol, 285 Holaphylline, 285 Holarrhena jebrifuga, 285 Holarrhimine, 285 Homaline, 285 Homalium pronyense, 285 Homochelidonine, 242 Homoerythrina alkaloids, 272 Homolycorine, 105 Hopromalinol, 286 Hopromine, 286 Hoprominol, 286 Hordenine, 274, 279,283,291,293 Hovenia dulcis, 178 Hovenia tomentella, 178 Hovenine-A, 178 Hunnemanine, 266 Hydrastine, 239 Hydrastinine, 209 6-Hydroxybuphanidrine, 83, 121 6-Hydroxycrinamine, 121 Hydroxyhippodamin, 284 13-Hydroxylupanine, 276 6-Hydroxypowelline, 83, 121 7-Hydroxysparteine, 276 6-Hydroxyundulatine, 123 Hygrine, 299 Hymenocallis concinna, 86 Hymenocardia acida, 177 Hymenocardine, 177, 187 ayosciamine, 288 Hyoscine, 288 Hypaphorine, 279 Hypecorine, 286 Hypecorinine, 286 Hypecoum erectum, 286
I Imeluteine, 263 Integerrimine, 297 Integerrenine, 172 Integerrine, 166, 172, 182, 191 Ipomoea argyrophylla, 10
Ipomoea hildebrandtii, 6 Ismene calathana, 86 Isoalchorneine, 265 Isoboldine, 289, 296 Isocinevanine, 296 Isoconeesimine, 285 Isocorydine, 228, 266, 275, 291 Isodaphniphylline, 46 Isodictamine, 279 Isoevonine, 280 Isolongistrobine, 286 a-Isolupine, 287 d-Isolysergic Acid, 31 Isomaculosidine, 279 Isopavine, 230 Isosetoclavine, 12 Isostemonamine, 298 Isotaeettine, 125 Isothebaine, 226 Isotylocrebine, 299
J Jatrorrhizine, 232 Jonquilline, 89
K Keyserlingia grafithii, 298 Knightia deplanchei, 287 Krigeine, 104 Krigenamine, 105 Krigmamine, 104
L Laburnine, 299 Laudanine, 223 Lasiodine-A, 177, 187 Lasiodine-B, 171, 179 Lasiodiscus marmoratus, 177 Laudanosine, 223 Laurifoline, 300 Laurolitsine, 288 Laurotetanine, 275, 287, 288, 291 Leontice darvasica, 287 Leontice leontopetalum, 287 Leontidine, 287 Leontiformidine, 287 Leontiformine, 287 Leucojum aestivum, 88, 153
312
SUBJECT INDEX
Leucojum vernum, 86 Lindelofidine, 299 Lindera oldhami, 287 Liriodenine, 288, 289, 296, 299 Litsea glutinosa, 287 Litsea leefeana, 288 Litsea sebifera, 288 Litsea wightiana, 288 Lobelia nicotianaefotia, 288 Lobelia polyphylla, 288 Lobeline, 288 Lophanthera lactescens, 288 Lophanterine, 288 Lotus aegeus, 276 Lunaridine, Lupanine, 276, 287 Lycodine, 282 Lycoramine, 83, 111, 117 Lycorenine, 104, 105 Lycoricidine, 142 Lycoricidinol, 142 Lycorine, 83, 84, 88 Lycoris radiata, 88 Lysergic Acid, 12, 20 Lysergic Acid Amide, 27
M Macleya cordata, 237 Macrodaphnidine, 43 Macrodaphnine, 43, 61 Macrodaphniphyllamine, 43, 60 Macrodaphniphyllidine, 43, 63 Macromerine, 274 Mandragora autumnalis, 288 Mandragora offieinarum, 288 Mandragora vernalis, 288 Manthidine, 137 Magnocurine, 295 Margetine, 143 Maritidine, 121, 131 Masonine, 105 Matrine, 298 Mauritine-A, 174, 183, 194 Mauritine-B, 174, 194 Muaritine-C, 174 Mauritine-D, 174 Mauritine-E, 174 Mauritine-F, Maytenin, 289 Maytenw chuchuhuasha, 289
Maytenus ovatus, 289 Mecambrine, Mecambroline, 226 Meconopsis cambrica, 226 Melochia corchorifolia, 177 Merendera raddeana, 289 Merenderine, 289 Mescaline, 293 Metanephrine, 274 6-Methoxydictamnine, 279 N-Methylactinodaphine, 266, 287 N-Methylangustifoline, 282 6-O-Methylapogalanthamine, 111 0-Methylatheroline, 229 0-Methylbulbocapnine, 287 N-Methyl-ol-canadine, 300 N-Methylcoclaurine, 203 N-Methylcytisine, 298 N-Me thyl3,4dimethoxy-p-phenethylamine 274, 279 6-Methyl~-ergolene-8-carboxylic, 1, 7 0-Methylflavinanthine, 291 N-Methylflindersine, 298 0-Methylgalanthamine, 113 N-Methylhernovine, 284 Methyl homodaphniphyllate, 43,52 Methyl homosecodaphniphyllate, 43, 53 N-Methylisococlaurine, 291 N-Methyllaurotetanine, 275, 287, 288, 291 N-Methylmetanephrine, 214 N-Methyl4methoxy-p-phenethylamine, 274
N-Methylnandigerine, 287 0-Methynorbelladine, 105 N-Methylovigerine, 287 Methylpseudolycorine, 89 8-Methylquinoline, 291 0-Methylsynephrine, 274 N-Methytyramine, 274, 291 Miniatine, 83, 110 Mitrella kentii, 289 Monnieria trifolk, 289 Montanine, 137 Monodora angulensis, 289 Morphine, 207, 229 Mucronine-A, 166, 176, 184, 200 Mucronine-B, 176, 201 Mucronine-C, 176 Mucronine-D, 175, 197 Mucronine-E, 176, 201 Mucronine-F, 176, 201
313
SUBJECT INDEX
Mucronine-G, 176, 201 Mucronine-H, 176 Myrianthine-A, 176 Mucuna Species, 290 Murrayacine, 290 Murraya koenigG, 290 Murrazoline, 290 Myrianthes arborens, 177 Myrianthine-B, 170 Myrianthin,-C, 170
N Nandina domestica, 291 Nanteine, 94 Nantenine, 291 Narceine, 239 Narciclassine, 141 Narciprimine, 141 Narcissamine, 111 Narcissidine, 83, 103 Narcissus canaliculatus, 88 Narcissus cyclaminem, 88 Narcissus folli, 86 Narcissus incomparabilis, 87 Narcissus kristalli, 86 Narcissus jonquilla, 87 Narcissus odorus, 88 Narcissus poeticus, 88 Narcissus pseudonarcissus, 86 Narcissus serotinus, 88 Narcissus tazetta, 86 Narcissus triandrus, 87 Narcotine, 238, 294 Narsiclasine, 83, 84, 154 Nartazine, 89 Narwedine, 111 Neisseria gonorrhoeae, 235 Nelumbo nucifera, 291 Nemorensine, 297 Nemuaron uieillardii, 291 Neodaphniphylline, 43 Neoevonine, 280 Neolitsine, 275 Neothiobinupharidine, 291 Neoyuzurimine, 43 Nerine bowdenii, 86, 156 Nerinine, 104 Neronine, 105 Neruscine, 105 Neopine, 208, 229
Nitidine, 300 Nitramine, 291 Nitraria schoberi, 291 Nivalidine, 111, 114 Nivaline, 105 Norargemonine, 266 Norarmepavine, 224 Norboldine, 287, 288 Norcorydine, 266 Norisocorydine, 266, 291
0 Orixinone, 292 Oxodendrobine, 277 Oxynitidine, 300 Oxocrinine, 131 13-0xoprotopine, 236 Oxysanguinarine, 241
P Paliclavine, 8 Palmatine, 233, 235, 287 Pancracine, 137 Pancratium miritimum, 86, 156 Pandamine, 177, 186 Pandaminine, 177, 186 Panda oleosa, 167,177, 186 Papaver armeniacum, 224 Papaver dubium, 226 Papaver orientale, 226 Papaver rhoeas, 240 Papaver somnijerum, 207 Phymatotrichum omniuorum, 235 Papaverine, 209 Parkacine, 103 Paspaclavine, 8 Paspalicin, 13 Paspalin, 1, 2 Paspalum dilatatum, 7 Pavine, 230 Pedicularidine, 293 Peganol, 293 Peganum harmala, 293 Pelecyphora aselliformis, 293 Pellotine, 293 Penicillium concauo-regulosum, 4 Penniclavine, 8 Pennisetum typhoideum, 20 8-Phenethylamine, 294
314
SUBJECT INDEX
Phyllanthidine, 293 Phyllunthus discoides, 293 Piper sylvaticum, 294 Pisum sativum, 294 Plantago arenaria, 294 Plantagonine, 300 Pluviine, 89 Poetaminine, 88 Pogonopus patchouli, 294 Poinciana regia, 183 Poranthera corymbosa, 294 Poranthericine, 294 Porantheridine, 294 Porantherine, 294 Precoccinellin, 273, 284 Precriwelline, 126 Pronuciferine, 225 Propylea quatuordecimpunctata, 294 Propyleine, 294 Preskimmianine, 279 Pretazettine, 83, 124 Prosopinone, 271 Prosopis alba, 294 Protopine, 236, 237, 266 Pseudoprotopine, 295 Pumiliotoxin, 277
R Retamine, 276 Retanilla ephedra, 295 Reticuline, 266, 273, 275, 208 Retronecine, 275 R hamnus frangula, 177 Rhodophiala bifida, 87 Rhoeadine, 240 Roemerine, 266 Robustine, 279, 284 Rosmarinine, 297 Rufescine, 263 Rugulovasines, 1, 4 R u t a acutifolium, 283 R u t a graveolens, 296
Sarodesmine, 296 Sceletium A,, 296 Sceletium namaquense, 296 Schefferine, 296 Schefferomitra subaequalis, 296 Schelhammera multiflora, 297 Schelhammera undulata, 297 Schelhammera pedunculata, 297 Scutianine-A, 171, 179 Scutianine-B, 171 Scutianine-C, 171 Scutianine-D, 171 Scutianine-E, 171 Scutia buxifolia, 177 Secodaphniphylline, 43, 53 Securinega suffruticosa, 293 Seneciphylline, 297 Senecio morrisonensis, 297 Senecio nemorensis, 297 Senecio propinquus, 297 Senecio taiwanensis, 297 Septicine, 299 Seratonin, 280, 292 Shigella dysenterieae, 235 Shihunine, 297 Skimmianine, 284 6-Skytanthine, 298 Slaframine, 297 Sophora grifithii, 298 Sophora papchycarpa, 282 Sorghum vulgare, 9 Sparteine, 276, 296 Spathelia sorbifolia, 298 Spermidine, 285, 289 Spermine, 285 Sphacelia sorghi, 9 Sprekelia formosissima, 87, 158 Stemona japonica, 298 Stemonamine, 298 Stepharine, 296 Sternbergia lutea, 87 Sternbergia sicula, 87 Sylvatine, 294 Synephrine, 274
S
T Saccharomyees carlsbergensis, 235 Salsolidine, 279 Sanguilutine, 241 Sanguinarine, 241, 242, 266 Sarcopetalum harveyanum, 296
Tulguenea quinquinervia, 295 Takatonine, 223 Tazettine, 83, 121, 124 Teclea suaveolens, 292
315
SUBJECT INDEX
Tecoma stans, 298 Tembamide, 300 Tetrahydroharmine, 267 Tetrahydroberberine, 234, 235 Tetrahydropalmatine, 234, 236, 266, 287 Texensine, 178 Thebaine, 208, 229 Thiolunupharidine, 291 Thionuphlutine A, 291 3a-Tiglogloxytropane, 288 Tinctorine, 282 Trevoa quinquinervia, 295 Trevoa trinerva, 295 Trichocereus chiloensis, 298 Trichodesmic Acid, 274 Trichomonas vaginal&, 242 Tryplamine, 279, 294 Tylophora asthmatica, 298 Tylophorinidine, 298 Tyramine, 274, 279, 283,291, 294
U Ungernia minor, 87 Ungernia severtzollrii, 87 Ungernia spiralis, 87 Ungernia trisphaera, 87 Ungiminorine, 103 Ungminoridine, 83 Unsevine, 104 Urtica pilulifera, 299 Uvariopsine, 299 Uvariopsis quineensis, 299
v Vallota speciosa, 87 Vanda helvola, 299 Vanda hindsii, 299 Vanda luzonica, 299 Vandopsis gigantea, 299 Vandopsis parishii, 299 Variabiline, 291 Vasicinone, 293 A 5 8 6
c 0 E F G H 1 J
7 0 9 O 1 2 3 4
Verbascum songaricum, 300 Veronamine, 224 Victoxinine, 284 Vittatine. 121
W Waltherica americana, 177 Wilfordine, 280
x Xylopinine, 236
Y Yuzurimine, 43, 58 Yuzurimine-A, 43, 59 Yuzurimine-B, 43, 61 Yuzurimine-C, 43, 63 Yuzurimine-D, 43, 64 Yuzurine, 80
z Zizyphus abyssinica, 168, 177 Zizyphus amphibia, 177, 178 Zizyphus mauritinna, 177 Zizyphus mucroizata, 168, 177 Zizyphus nummularia, 178 Zizyphus oenoplia, 177, 178 Zizyphus spina christi, 177 Zizyphine-A, 166, 175,183,197 Zizyphine-€3, 175, 184 Zizyphine-C, 175, 197 Zizyphine-D, 178 Zizyphine-E, 178 Zanthoxylum conspersipunctum, 295 Zanthoxylum inerme, 300 Zanthoxylum ocumarense, 300 Zephranthes candida, 148 Zephyranthes sulfurea, 87 Zephyranthine, 89
This Page Intentionally Left Blank
