THE ALKALOIDS Chemistry and Physiology
VOLUME XIV
This Page Intentionally Left Blank
THE ALKALOIDS Chemistry and P...
45 downloads
1342 Views
23MB Size
Report
This content was uploaded by our users and we assume good faith they have the permission to share this book. If you own the copyright to this book and it is wrongfully on our website, we offer a simple DMCA procedure to remove your content from our site. Start by pressing the button below!
Report copyright / DMCA form
THE ALKALOIDS Chemistry and Physiology
VOLUME XIV
This Page Intentionally Left Blank
THE ALKALOIDS Chemistry and Physiology Edited by
R. H. F. MANSKE Department of Chemistry, University of Waterloo Waterloo, Ontario, Canada
VOLUME XIV
1973 ACADEMIC PRESS * NEW YORK LONDON A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT 0 1973, 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 b y ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London N W l
LIBRARY OF CONGRESS CATALOG CARDNUMBER:50-5522
PRINTED IN THE UNITED STATES OF AMERICA
CONTENTS LIST OF CONTRIBUTORS .................................................. PREFACE .............................................................. CONTENTSOF PREVIOUS VOLUMES.........................................
ix xi xiii
Chapter 1. Steroid Alkaloids: The Veratrurn and Buxw Groups J . TOMEOand Z . VOTICEP
I . Introduction ................................................... I1. Structures and Chemical and Physicochemical Properties of Veratrurn Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. Structures and Chemical and Physicochemical Properties of Buxus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Biosynthetic Notes .............................................. References ..................................................... Chapter 2
1 5 32 78 79
.
Oxindole Alkaloids JASJIT S . BINDRA
I . Introduction ................................................... I1. Oxindoles of Gelsemiurn Species ................................... I11. Oxindoles of Secoyohimbane and Heteroyohimbane Type ............ IV . Secoyohimbane-Type Oxindoles ................................... V . Heteroyohimbane-Type Oxindoles ................................. References .....................................................
84 84 92 94 108 119
Chapter 3 . Alkaloids of Mitragyna and Related Genera J . E SAXTON
.
I. Introduction ................................................... I1. Stereochemistry of the Ring E seco Oxindole Alkaloids ............... I11. Stereochemistry of the Ring E seco Indole Alkaloids . . . . . . . . . . . . . . . . . I V. The Oxindole Analogs of the Heteroyohimbine Alkaloids . . . . . . . . . . . . . V . Mitrajavine and Isomitrajavine ................................... VI . Ourouparine. Gambirtannine. and Related Alkaloids . . . . . . . . . . . . . . . . . VII . Roxburghines .................................................. V I I I. Addendum ..................................................... References ..................................................... Chapter 4
.
123 127 134 135 145 146 148 154 154
Alkaloids of Picralirna and Alstonia Species
. .
J E SAXTON
.
I The Picralima Alkaloids ......................................... I1. The Alstonia Alkaloids .......................................... I11. Addendum ..................................................... References ..................................................... V
157 168 177 178
CONTENTS Chapter 5 . The Cinchona Alkaloids and G GRETHE M . R . USEOKOVIC
.
I . Introduction ............................... I1. Isolation ....................................................... I11. Syntheses .......................................
IV . V. VI . VII .
Biosynthesis . . . . . . . . . . . . . . . . . . ......... .......... Configuration of Cinchonamine a t C-3 ............................. Miscellaneous . . . . . ........................................... Pharmacology of Cinchona Alkaloids .............................. References .....................................................
181 181 182 209 217 219 220 222
Chapter 6 . The Oxoaporphine Alkaloids
.
MAURICESRAMMA and R . L CASTENSON I . Introduction ................................................... 226 I1. Oxoaporphines Isolated from Natural Sources ...................... 226 I11. Some Oxoaporphines not Isolated from Natural Sources . . . . . . . . . . . . . 250 IV . The Oxidation of Aporphines to Dehydroaporphines and Oxoaporphines 253 V . Biogenesis ..................................................... 254 VI . Pharmacology .................................................. 254 VII . Ultraviolet Spectroscopy ......................................... 254 254 VIII . Nuclear Magnetic Resonance Spectroscopy ......................... I X . Mass Spectroscopy .............................................. 257 X . Addendum ..................................................... 262 References ..................................................... 262 Chapter 7 . Phenethylisoquinoline Alkaloids TETSIJJIKAMETANI and MASUOKOIZUMI
. Introduction ................................................... Structural Elucidation. Chemical Reaction. and Stereochemistry . . . . . . . Biosynthesis ...................................................
I I1. I11 IV . V. VI . VII .
Synthesis ...................................................... The Hypothetical Alkaloids (New Phenethylisoquinoline Skeletons) . . . Spectroscopy ................................................... Addendum ..................................................... References .....................................................
265 277 286 290 310 314 319 320
Chapter 8 . Elaeocarpus Alkaloids S. R JOHNS and J . A LAMBERTON
.
.
I . Occurrence ..................................................... I1. The C16 Aromatic Alkaloids ...................................... I11. The Ct6 Dienone Alkaloids ....................................... IV . Ct2 Alkaloiils of Elaecarpus kaniensis .............................. V Elaeocarpidine ................................................. VI . Biosynthesis ................................................... References .....................................................
.
326 327 331 338 343 346 346
CONTENTS Chapter 9
.
vii
The Lycopodium Alkaloids
. .
D B MACLEAN
.
I Introduction ................................................... I1. The Alkaloids and Their Occurrence I11. Annotinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV . Lycopodine and Related Alkaloids V Alopecurine and Related Alkaloids ................................ VI Annopodine ................................... VII . Serratinine and Related Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V I I I . Luciduline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I X . Cernuine and Related Alka X . Selagine ....................................................... XI . Synthesis of the Alkaloids XI1. Biogenesis and Biosynthesis of the Alkaloids ....................... References ....................................................
. .
348 348 353 354 360 364 366 370 372 380 380 394 403
Chapter 10. The Cancentrine Alkaloids RUSSELLRODRIGO
I . Introduction and Occurrence ..................................... I1. The Structure ofcancentrine ..................................... I11. Dehydroeancentrine-B ...........................................
IV . Dehydrocancentrine-A ........................................... V . Stereochemistry ................................................ V I . Biogenesis ..................................................... VII . Physical Properties .............................................. References .....................................................
407 408 418 419 419 420 421 423
Chapter 11. The Securinega Alkaloids
.
V SNIECKUS
I . Introduction and Occurrence ..................................... I1. Securinine-TypeAlkaloids ....................................... I11. Norsecurinine-Type Alkaloids .................................... IV . Synthesis ...................................................... V Biological Activity .............................................. VI . Analytical Methods ............................................. VII Biosynthesis ................................................... References .....................................................
. .
.
Chapter 12
425 427 489 495 499 500 500 502
Alkaloids Unclassified and of Unknown Structure
. .
R . H F MANSKE
. .
I Introduction ................................................... I1 Plants and Their Contained Alkaloids .............................
..................................................... AUTHORINDEX........................................................ References
SUBJECTINDEX ........................................................
508 508 564 575 598
This Page Intentionally Left Blank
LIST OF CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors’ contributions begin.
JASJIT S. BINDRA,Medical Research Laboratories, Pfizer, Inc., Groton, Connecticut (84) R. L. CASTENSON,Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania (226) G. GRETHE,Chemical Research Department, Hoffmann-La Roche, Inc., Nutley, New Jersey (181) S. R. JOHNS, Division of Applied Chemistry, C.S.I.R.O., Melbourne, Australia (325) Pharmaceutical Institute, Tohoku University, TETSUJI KAMETANI, Aobajama, Sendai, Japan (265) MASUO KOIZUMI, Pharmaceutical Institute, Tohoku University, Aobajama, Sendai, Japan (265) J. A. LAMBERTON, Division of Applied Chemistry, C.S.I.R.O., Melbourne, Australia (325) D. B. MACLEAN, McMaster University, Hamilton, Ontario, Canada (348) R. H. F. MANSKE,Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada (508) RUSSELL RODRIGO, Waterloo Lutheran University, Waterloo, Ontario, Canada (407) J. E. SAXTON, The University, Leeds, England (123) MAURICESHAMMA, Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania (226) V. SNIECKUS, University of Waterloo, Waterloo, Ontario, Canada (325) J. TOMKO, Department of Pharmacognosy, Pharmaceutical Faculty, Comenius University, Bratislava, Czechoslovakia (1) M. R. USKOKOVIC, Chemical Research Department, Hoffmann-La Roche, Inc., Nutley, New Jersey (181) Z. VOTICKP,Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Czechoslovakia (1)
ix
This Page Intentionally Left Blank
PREFACE
The editor, the publishers, and particularly the authors of previous volumes in this treatise are pleased with the reception accorded their efforts. Since there has been no abatement in the flood of publications dealing with alkaloids we have the temerity to add another review. There are times when we would welcome more information than is accessible to us, so this is another invitation to authors to supply us with reprints.
R. H. F. MANSKE
xi
This Page Intentionally Left Blank
CONTENTS OF PREVIOUS VOLUMES
Contents of Volume 1 CHAPTER 1 Sources of Alkaloids and Their Isolation BY R . H . F. MANSKE . 2. Alkaloids in the Plant B Y W . 0 . JAMES. . . . . . . 3 . The Pyrrolidine Alkaloids BY LEO MARION . . . . . . 4 . Senecio Alkaloids BY NELSONJ . LEONARD . . . . . . . 5. The Pyridine Alkaloids BY LEOMARION . . . . . . . . . 6 The Chemistry of the Tropane Alkaloids BY H . L . HOLMES 7 . The Strychnos Alkaloids BY H . L . HOLMES . . . . . . .
.
. . . . . .
. . . .
.
. . . .
1
15 91 107 165
271 375
Contents of Volume II
.
1 8.1 The Morphine Alkaloids I BY H . L . HOLMES. . . . . . . . 8.11 . The Morphine Alkaloids BY H . L . HOLMES AND (IN PART) GILBERTSTORK 161 9 . Sinomenine BY H . L . HOLMES . . . . . . . . . . . . 219 . . . . . . . . 261 10. Colchicine BY J . W . COOKAND J . D . LOUDON 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 III
.
16 . The Chemistry of the Cinchona Alkaloids BY RICHARD B TURNER AND R . B . WOODWARD. . . . . . . . . . . . . . . 17 Quinoline Alkaloids. Other than Those of Cinchona BY H . T . OPENSHAW 18 The Quinazoline Alkaloids BY H . T . OPENSHAW . . . . . . . 19. Lupine Alkaloids BY NELSONJ . LEONARD. . . . . . . . . AND H . T . OPENSHAW . 20 . The Imidazole Alkaloids BY A . R . BATTERSBY AND 21 The Chemistry of Solanum and Veratrum Alkaloids BY V . PRELOG 0. JEGER . . . . . . . . . . . . . . . . . 22 8-Phenethylamines BY L RETI . . . . . . . . . . . . 2 3 Ephreda Bases BY L . RETI . . . . . . . . . . . . . . . . . . . . 24. The Ipecac Alkaloids BY MAURICE-MARIE JANOT
. .
. . .
.
1 65 101 119 201 247 313 339 363
Contents of Volume I V 25 . 26 . 27 28. 29
. . 30 .
The Biosynthesis of Isoquinolines BY R . H . F. MANSKE . . . . . Simple Isoquinoline Alkaloids BY L . RETI . . . . . . . . . Cactus Alkaloids BY L . RETI . . . . . . . . . . . . . The Benzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . The Protoberberine Alkaloids BY R . H . F . MANSKE AND WALTER R ASH-
.
FORD
. . . . . . . . . . . . . . . . . . .
The Aporphine Alkaloids
BY
R . H . F. MANSKE xiii
. . . . . . .
1 7 23 29 77 119
xiv
CONTENTS O F PREVIOUS VOLUMES
CHAPTER 31 The Protopine Alkaloids BY R . H F. MANSKE . . . . . . . 32 Phthalideisoquinoline Alkaloids BY JAROSLAV S T A N ~ AND K R H. F. MANSEE . . . . . . . . . . . . . . . . . . 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 AlkaIoids BY E . S. STERN . . . .
. .
.
.
.
.
Contents of Volume 38 . 39 . 40 . 41 . 42 43. 44 45 . 46 . 47 . 48.
. .
.
. . . .
. . . . . . . . . . .
1 79 109 141 163 211 229 243 265 295 301
. . . . . . . .
1 31 35 123 145 179 219 247 289
.
.
167 199 249 253 265 275
V
Narcotics and Analgesics BY HUGO KRUEQER . . . . . Cardioactive Alkaloids BY E . L MCCAWLEY . . . . . Respiratory Stimulants BY MICHAEL J DALLEMAGNE . . Antimalarials BY L H . SCHMIDT . . . . . . . . Uterine Stimulants BY A K REYNOLDS. . . . . . Alkaloids as Local Anesthetics BY THOMAS P. CARNEY . . Pressor Alkaloids BY K . K CHEN . . . . . . . . Mydriatic Alkaloids BY H . R . ING . . . . . . . . Curare-like Effects BY L E . CRAIG . . . . . . . . The Lycopodium Alkaloids BY R H . F . MANSICE. . . . Minor Alkaloids of Unknown Structure BY R . H F MANSKE
.
147
. .
. . . . . . . . . . .
. . . . . . . . . . .
Contents of Volume V I
. . . .
1 2 3. 4 5. 6 7. 8. 9
.
.
Alkaloids in the Plant BY K MOTHES . . . . . . The Pyrrolidine Alkaloids BY LEOMARION . . . . Senecio Alkaloids BY NELSONJ . LEONARD. . . . . The Pyridine Alkaloids BY LEO MARION . . . . . The Tropane Alkaloids BY G. FODOR. . . . . . The Strychnos Alkaloids BY J B . HENDRICKSON . . . The Morphine Alkaloids BY GILBERTSTORK . . . . Colchicine and Related Compounds BY W . C . WILDMAN. Alkaloids of the Amaryllidaceae BY W . C WILDMAN. .
.
.
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
Contents of Volume V I I
.
10 11 . 12. 13. 14 15. 16. 17. 18. 19. 20 . 21
.
.
. .
The Indole Alkaloids BY J E SAXTON. . . . . . . . . . 1 The Erythriruc Alkaloids BY V . BOEKELHEIDE. . . . . . . . 201 Quinoline Alkaloids Other Than Those of Cinchona BY H . T . OPENSHAW 229 The Quinazoline Alkaloids BY H . T OPENSHAW . . . . . . . 247 Lupine Alkaloids BY NELSONJ . LEONARD. . . . . . . . . 253 AND V . PRELOG319 Steroid Alkaloids: The Holarrhena Group BY 0 . JEGER Steroid Alkaloids: The Solanurn Group BY v . PRELOG AND 0 JEGER . 343 Steroid Alkaloids: V e r a t r m Group BY 0 JEGER AND V PRELOG . 363 The Ipecac Alkaloids BY R . H . F. MANSKE . . . . . . . . 419 Isoquinoline Alkaloids BY R . H F MANSKE . . . . . . . . 423 STANHK . . . . . 433 Phthalideisoquinoline Alkaloids BY JAROSLAV KULKA . . . . . 439 Bisbenzylisoquinoline Alkaloids BY MARSHALL
.
.
. .
.
.
.
xv
CONTENTS OF PREVIOUS VOLUMES
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. . . . . . . . . . . 27 Alkaloids of the Calabar Bean BY E COXWORTH . . . . . . . The Carboline Alkaloids BY R . H F MANSKE. . . . . . . . 47 55 The QuinazolinocarbolinesBY R H F MANSEE . . . . . . . Alkaloids of Mitragyna and Ouroupariu Species BY J E . SAXTON . 59 93 Alkaloids of Gelsemium 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 Voacanga Alkaloids BY W . I. TAYLOR . . . . . . 203 The Chemistry of the 2.2'.Indolylquinuclidine Alkaloids BY W I TAYLOR238 The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids BY W I TAYLOR . . . . . . . . . . . . . . . 250 The Vinca Alkaloids BY W I TAYLOR. . . . . . . . . . 272 Rauwolfia Alkaloidswith Special Reference t o 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 Strychws Species BY A R BATTERSBY AND H F. HODSON . . . . . . . . . . . . . . . 515 The Alkaloids of Calycanthaceae BY R H F MANSKE . . . . . 581 Strychws Alkaloids BY G F SMITH. . . . . . . . . . . 592 Alkaloids of Haplophyton cimicidum BY J E SAXTON . . . . . 673 The Alkaloids of Geissospermum Species BY R H . F MANSEE AND W ASHLEYHARRISON. . . . . . . . . . . . . . . 679 Alkaloids of Pseudocinchona and Yohimbe BY R H F MANSKE . . 694 . . . . . . 726 The Ergot Alkaloids BY A STOLL AND A HOFMANN 789 The Ajmaline-Sarpagine Alkaloids BY W I TAYLOR
. . . . . .
.
.
. .
..
..
..
.
.
. .
. .
. . . . .
.
. ..
.
. . . .
.
. . . . . .
Contents of Volume I X
. . . . 5. 6. 7.
1 2 3 4
8.
. .
9 10
. . . . . . .
1 The Aporphine Alkaloids BY MAURICESHAMMA The Protoberberine Alkaloids BY P W JEFFS . . . . . . . . 41 Phthalideisoquinoline Alkaloids BY JAROSLAV S T A N ~ K. . . . . 117 Bisbenzylisoquinoline and Related Alkaloids BY M CURCUMELLIRODOSTAMO AND MARSHALL KULKA. . . . . . . . . . 133 Lupine Alkaloids BY FERDINAND BOHLMA"AND DIETERSCHUMANN . 175 Quinoline Alkaloids Other Than Those of Cinchona BY H T OPENSEAW223 The Tropane Alkaloids BY G FODOR. . . . . . . . . . 269 Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae BY V . ~ E R N P and F SORM . . . . . . . . . . . . . . . . . 305 The Steroid Alkaloids: The Salamandra Group BY GERHARD HABERMEHL427 441 N u p h r Alkaloids BY J T WROBEL
. .
.
.
. .
.
..
. . . . . . . . . . .
wi
CONTENTS OF PREVIOUS VOLUMES
CHAPTER 11. The Mesembrine Alkaloids BY A. POPELAK AND G. L E T T E N B A ~ R 12. The Erythrina Alkaloids BY RICHARD K. HILL . . . . . . 13. Tylophora Alkaloids BY T. R. GOVINDACHARI . . . . . . 14. The Galbulimima Alkaloids BY E. RITCHIEAND W. C. TAYLOR. 15. The S t e m n a Alkaloids BY 0. E. EDWARDS . . . .
. . . . . . . . . .
.
467 483 517 529 545
Contents of Volume X
. . . . . . .
1. Steroid Alkaloids: The Solanun Group BY KLAUSSCHRIEBER . . 1 2. The Steroid Alkaloids: The Veratrum Group BY S . MORRISKUPCHAN AND ARNOLD W. BY . . . . . . . . . . . . . . . 193 287 3. Erythrophleum Alkaloids BY ROBERT B. MORIN . . . . . 4. The Lycopodium Alkaloids BY D. B. MACLEAN . . . . . 306 5. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . , 383 6. The Benzylisoquinoline Alkaloids BY VENANCIO DEULOFEU,JORGE 402 COMIN,AND MARCELOJ. VERNENGO . . . . . . . . , 7. The Cularine Alkaloids BY R. H. F. MANSKE. . . . . . . . 463 8. Papaveraceae Alkaloids BY R. H. F. MANSKE . . . . . . . . 467 485 9. a-Naphthaphenanthridine Alkaloids BY R. H. F. MANSKE . . . . . . . . . . . 491 10. The Simple Indole Bases BY J. E. SAXTON . . 501 11. Alkaloids of Picralima nitida BY J. E. SAXTON . . 12. Alkaloids of Mitragyna and Ourouparia Species BY J. E. SAXTON . . 521 13. Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE 545 597 14. The T a m s Alkaloids BY B. LYTHGOE . . . . . . . . .
.
. .
. . .
.
Contents of Volume X 1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12.
I
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 99 The Vinca Alkaloids BY W. I. TAYLOR. . . . . . . . . . The Eburnamine-Vincamine Alkaloids BY W. I. TAYLOR . . 125 145 Yohimbine and Related Alkaloids BY H. J. MONTEIRO . . . . Alkaloids of Calabash Curare and Strychnos Species BY A. R. BATTERSBY AND H. F. HODSON . . . . . . . . . . . . 189 The Alkaloids of Aspidosperma, Ochrosia, Pleiomrpa, Melodinus, and Related Genera BY B. GILBERT . . . . . . . . . . . 205 The Amaryllidaceae Alkaloids BY W. C. WILDMAN . . . . . 307 Colchicine and Related CompoundsBY W. C. WILDMAN AND B. A. PTJRSEY407 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 Garrya Species: 2 The CIS-DiterpeneAlkaloids BY S. W. PELLETIER AND L. H. KEITE . 2. Diterpene Alkaloids from Aconiturn, Delphinium, and Garrya Species: The C2,-Diterpene Alkaloids BY S. W. PELLETIER AND L. H. KEITH . . 136
.
xvii
CONTENTS OF PREVIOUS VOLUMES
CHAPTER 3. 4. 5. 6. 7.
.
Alkaloids of Alstonia Species BY J. E. SAXTON . . . . . . FRANK L. WARREN . . . . . . . . . Papaveraceae Alkaloids BY F. SANTAVY . . . . . . . . . Alkaloids Unclassified and of Unknown Structure BY R. H. F. MANSKE The Forensic Chemistry of Alkaloids BY E. G. C. CLARKE . . .
Senecio Alkaloids BY
.
207 246 333 455 514
Contents of Volume X I I I 1 1. The Morphine Alkaloids BY K. W. BENTLEY . . . . . . . . 2. The SpirobenzylisoquinolineAlkaloids BY MAURICESRAMMA . . . 165 3. The Ipecac Alkaloids BY A. BROSSI,S. TEITEL,AND G. V. PARRY. . 189 4. Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . 213 5. The Balbulimirna Alkaloids BY E. RITCHIEAND w. C. TAYLOR. . . 227 6. The Carbazole Alkaloids BY R. S. KAPIL . . . . . . . . . 273 7. 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
This Page Intentionally Left Blank
-CHAPTER
1-
STEROID ALKALOIDS: THE VERATRUM AND BUXUS GROUPS J. TOMKO* AND Z. VOTICK% Institute of Chemistry Slovak Academy of Sciences, Bratislava, Czechoslovakia
I. Introduction..
1
Alkaloids ........................................................... A. The Jervanine and Veratranine Subgroup .......... .. B. The Cevanine Subgroup .......................................... C. The Solanidanine Subgroup. ....................... ............ D. The 22,26-Epiminocholestane Subgroup . . . . . . . . . . . . ............ E. Other Alkaloids .................................................. 111. Structures and Chemical and Physicochemical Properties of Buxus Alkaloids A. Dibasic Buxus Alkaloids .......................... B . Monohasic Buxus Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Alkaloids of Unknown Structure ................................... D. Syntheses in the Buxus Alkaloids . . . . . . . . . . . . . . . IV. Biosynthetic Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References ....... ..... ...........
5 5 17 19
20 24 32 32 58 67 68
78 79
I. Introduction Reviews of the chemistry of Veratrum alkaloids have been written by Kupchan and By (1)and of Buxus alkaloids by Cernf and Sorm ( 2 ) . I n addition to the recently published results in the chemistry of plant steroids ( 3 ) , steroidal and abnormal steroidal alkaloids have been reviewed by Sat0 and Brown ( 4 ) .Goutarel(5)has summarized the latest advances among Buxus alkaloids. Some physicochemical and other data of Veratrum and Buxus alkaloids are given in the monograph by Raffauf ( 6 ) . The progress in the Veratrum and Buxus alkaloids since the appearance of Volumes I X and X of this series is summarized in this chapter. *and Department of Pharmacognosy, Pharmaceutical Faculty, Comenius University, Bratislava.
2
J. TOMKO AND
z. VOTICKP
I n agreement with the IUPAC Corrected Tentative Rules (7) for Steroid Nomenclature the Veratrum alkaloids are classified in the jervanine (l),veratranine (2), cevanine (3),and solanidanine (4) groups. 21
18
>H
H CH3H
H3C 2 s
5 4
14
lOh8 7 , 6
'
H
15
16
0
H CH3H FH3
PH3
23
24
CH3
H
27
H 1
HH
H3C
25
H
H
H (22S,23R,25S)-5a-Jervanine
2
(22R,25S)-5a-Veratranine 27
H 3
(22S,25S)-5a-Cevanine
Veralkamine and veralinine are regarded as derivatives of the rearranged steroid hydrocarbon cholestane (5). However, there are also alkaloids possessing a normal cholestane skeleton (the 22,26-epiminocholestanes; cf. Vol. X, p. 60). The alkaloid veramine could be considered a derivative of rearranged tomatanine (6) (Z).*
* Semisystematic names proposed by the IUPAC Committee for nomenclature could well be applied to Veratrum alkaloids with the exception of veramine. The (3-16 hydrogen in veramine is 8-oriented,whereas the side chaia at C-17 is a-oriented; hence tomatanine, which has a C-16 a-and a C-17 a-hydrogen, could not be taken for the fundamental skeleton. Some other Veratrum alkaloids (e.g., veralkamine, veralinine) having the C-17 side chain a-oriented are entered among the (2-17 8-methyl-18-nor-epiminocholestanes. To demonstrate the stereochemistry in the side chain we have applied the common graphic signs accepted in organic chemistry.
1.
3
STEROID ALKALOIDS
Attempts have been made to classify Buxus alkaloids according to various features. Thus cycloartenol (7)and cycloeucalenol (8) were proposed to be the fundamental skeletons characterizing two groups of Buxus alkaloids (7a).Another proposal was to divide Buxus alkaloids into cyclo-9/?,19- (9) and 9(10 +- 19)deo-pregnane (10) groups (8), or to classify them according to various substitution patterns (9-11). It seems, however, reasonable to distinguish Buxus alkaloids according to the number of nitrogen atoms incorporated. The letter suffixes A
H 4
(22S,25S)-5&01anidanine
5
5a-Cholestane
H 6
(22S,25S)-5a-Tomatanine
to P (Table I), indicating the number of methyl groups attached to nitrogen atom or atoms (12), offer a further subdivision of Buxus alkaloids. This classification has been used throughout this chapter. The designation of Buxus alkaloids shown in Table I is, however, not based on general principles of organic chemical nomenclature; it is somewhat inconvenient to memorize; and it refers only to the methyl substitution on nitrogen. Nonetheless, the creation of new semisystematic names for all possible Buxus alkaloids would complicate still more the nomenclature hitherto used. Since Buxus alkaloids have the
4
J. TOMKO AND
z.
VOTICK~
fundamental pregnane skeleton, it seems reasonable to designate them as derivatives thereof, applying the recommended IUPAC rules ( 7 ): for example, buxamine-A (139) = 3P,20a-bis(dimethylamino)-4,4,14atrimethyl-9( 10-+ 19)-abeo-5a-pregna-9(1l),lO-diene; buxarine-F (209) = 16a-hydroxy-3P-benzamido-20a- dimethylamino - 4,4,14a- trimethyl-9P,
7 Cycloartenol
8 Cycloeucalenol
H 9
9~,19-Cyclo-5a-pregnane
H 10
g(10 --f 19)-abeo-5a-Pregnane
19-cyclo-5a-pregnan-l l-one; trans-cyclosuffrobuxinine-M (262) = trans3~-methylamino-4-methylene-l4a-methyl-9~, 19-cyclo-5a-pregn - 17-en 16-one; etc.
1.
5
STEROID ALKALOIDS
TABLE I EXTENDED NOMENCLATURE OF Buxus ALKALOIDS R3
R1
C-3 N
suffix
R1
/
R2
(3-20 N
R3
/
R4
Dibasic alkaloids
A B C D E F G H I
CH3 CH3 H H CH3 H CH3 H H
Monobasic alkaloids
K L M N 0 P
CH3 -
CH3 H -
11. Structures and Chemical and Physicochemical Properties of Veratrum Alkaloids A. THEJERVANINE AND VERATRANINE SUBGROUP I n accordance with the nomenclature in this chapter the alkaloids veratrobasine, jervine, 1l-deoxojervine (identical with cyclopamine), veratramine, verarine and the glycoalkaloids veratrosine, pseudojervine, and cycloposine belong t o the bases of jervanine and veratranine type. 1. Veratrobasine
The empirical formula of veratrobasine (11) isolated from Veratrum album L. ( 1 3 , 1 4 ) was revised and the structure, including the stereochemistry, determined by means of X-ray diffraction analysis (15).
6
J. TOMKO AND
z. VOTICKP
On the basis of this result the alkaloid is identical with ll-hydroxyjervine [(22S,23R,25S)-jerva-5,12-dienine-3P7 1Ip-diol] (11). The determination of the structure of veratrobasine definitely settled the discrepancies in the structure of the related bases, the jervanine and veratranine subgroup and particularly of jervine.
H H
11
12 13 16 17
H
RO
R R' H H CH,CO NO CH,CO H CpH5CO NO C E H ~ C OH
The photolysis of 11-nitrite esters of veratrobasine was studied by Suginome et al. (16). Thus, with nitrosyl chloride in pyridine, 3 - 0 , N diacetylveratrobasine (13) afforded the corresponding stable nitrite 12, which was photolyzed. The starting material 12, the 19-oximino derivative 14, and the substance of assignable structure 15 were isolated from this reaction. The photolysis of 3-0,N-dibenzoylveratrobasine-11-nitrite (16) led to 3-0,N-dibenzoylveratrobasine (17) and the compound formulated as 19-nitro-N,O-dibenzoylveratrobasine (18).
H
RO 14 18
R
R1
R2
H CEHSCO
CH,CO CEHSCO
CH=NOH CHZNOZ ,,HH TOCH,
H
;
\H
H
HO 15
1 . STEROID ALKALOIDS
7
Suginome and associates (17) have also photolyzed, under the conditions of the Barton reaction, the nitrite of (22S,25S)-N-acetyl-11hydroxy-veratra-4,13( 17)-dienine-3,23-dione(19)prepared from jervine.
20
The structure 20 (a-hydroxycyclic nitrone) was assigned to the resulting rearranged product of this reaction on the basis of the mass, IR,UV, and PMR spectroscopy, chemical evidence, and in consideration of the mode of its formation. 2. Jervine
The structure elucidation and stereochemistry of jervine uncorrectly represented by formula 21 was reviewed by Kupchan (cf, Volume X, p. 201). The C-17 a-oxide and C-20 a-methyl configurations were originally suggested solely on the basis of biogenetic analogy with normal steroids (1 8,19).A chemical argument has been advanced by Masamune et al. who reported the total synthesis of jervine (20). An X-ray diffraction study of veratrobasine (11) and its identity with jervin-11/3-01 (21)prepared by reduction of jervine (22) evidenced the /3-orientation of the C-17 oxide and the a-orientation of the C-20 methyl group in jervine and related alkaloids. The revised assignment of the C-22 P-H and (2-23 a-H configuration of 22 was unequivocally confirmed by the correlation of veratrobasine with jervine (23).
8
J. TOMKO AND
z.
VOTICK~
Veratramine, verarine, and 1l-deoxojervine were interrelated with jervine (24-26) and therefore these alkaloids have the same stereochemical arrangement of substituents a t the respective positions. 1l-one] is corJervine [ (22S,23R,25S)-3P-hydroxyjerva-5,12-dieninrectly represented by formula 22 and 1l-deoxojervine [ (22S,ZSR,25X)jerva-5,12-dienin-3P-o1] by 23.
H
22
23 78
R
R1
0 H, H,
H H D - G ~
21
I n 1969 Masamune et al. (2'7)showed that the p configurational assignment t o the hydrogen a t (2-12 is preferred for the dihydro- (24)and tetrahydrojervine (25).Furthermore, the configuration a t (2-12 was revised in an acetolysis product (27)of 3-0,N-diacetyltetrahydrojervine (26)(28). The assignment of C/D trans annelation to 24,25,and 26 was supported by the ORD studies of 11-oxoetiojervanes (29). The Il-ketones showed ORD curves with negative Cotton effects. The amplitudes for C/D trans-fused compounds fall within the limits of 150-190", and those for the cis-fused, 70-100". Compound 27 revealed a negative Cotton effect with an amplitude of 172". It follows that 27 is correctly represented by a formula with C/D trans (12P-H) rather than C/D cis (12a-H)fusion. Reexamination of the structure of the Birch reduction products of jervine-lip-ol (11)and 11-deoxojervine (23),as well as the correlation of jervine (22)and ll-deoxyjervine (23)with veratramine (33)through
1.
9
STEROID ALKALOIDS
a series of reactions involving no epimerization at C-9, has been performed (30).The latter studies confirmed the a-configuration of the C-9 hydrogen in jervine and related alkaloids (cf. Volume X, p. 206).
R 24 25 26
A6
5a-H 5a-H
H H
COCH,
0
II
CHXO 27
Jervine, one of the most readily available Veratrum alkaloids, was the starting material for the synthesis of C-nor-D-homo steroid hormone analogs. Kupchan and Abu El-Haj (31) degraded jervine to the 3pl,l7-dione (28) and prehydroxy-14( 13 + 12P-H)-abeo-androst-5-ene-l (29) pared 17a-hydroxy-14(13 --f 12PH)-abeo-pregn-4-ene-3,11,20-trione and its 1713-isomer (30).
29 28
30
R = a-OH R = ,3-OH
10
J. TOMKO AND z. V O T I C K ~
Continued interest in the synthesis of modified steroids to obtain analogs with more specific pharmacological properties resulted in the preparation of the 3-hydroxy-14(13 + 12PH)-abeo-estra-l,3,5(10)-trien17-one (31) (32, 33). Also C-12-uH and C-12-PH isomers of 17a-hydroxy21-acetoxy-14(13 + 12,$H)-abeo-pregn-4-ene-3,11,20-trione(32) were synthesized from the 3/3-hydroxy-14(13 + 12PH)-abeo-androst-5-ene11,17-dione (28) (34).
32
31
3. Cyclopamine
The alkaloid cyclopamine (35)) previously designated alkaloid V, has been isolated (36) from Veratrum californicum Durand in addition to veratramine, jervine, pseudojervine, veratrosine, and alkaloid X (cycloposine) ( 3 7 ) . Cyclopamine has been found by chemical and physicochemical investigation to be identical with 1l-deoxojervine (23) (38). 4. Verarine The structure and stereochemistry of verarine (39) was confirmed both by the correlation with veratramine ( 2 5 , 4 0 )and by total synthesis (41, 42). Veratramine (33) treated with acetic anhydride in pyridine afforded 3-0,N-diacetylveratramine (34). On oxidation, 34 was converted into 23-dehydro-3-0,N-diacetylveratramine(35). Compound
11
1. STEROID ALKALOIDS
35 was transformed into the 23-deoxoderivative 37 via the 23-ethylene thioketal derivative (36) which was desulfurated with Raney nickel in refluxing ethanol. The hydrolysis of 37 with a base in diethylene glycol afforded the N-deacetyl derivative (58). This and substance 37 have been found to be identical with verarine, [(22R,25S)-veratra-5,12,14,16tetraenin-3P-ol)l and N-acetylverarine, respectively.
33 34 35 36 37
R
R'
R=
H CH,CO CH,CO CH,CO H
H CH,CO CH,CO CH,CO CH,CO
OH, aH OH,aH 0
SC,H,S H,
The total synthesis of verarine was reported by Kutney et al. (41, 42). The diol aldehyde 38 prepared via a multistep sequence starting from P-naphthol (43) was acetylated to the diacetate 39. Compound 39 was converted into the olefin 40. Hydroboration of the C-9-C-11 olefinic linkage led to 41, which was further transformed into the intermediate 42. This was dehydrated to the dienone 43 and hydrogenated
fl CHO
RO H 38 39
H
R = H R = CH,CO
40
41
12
J. TOMKO AND
z.
VOTICKY
to give a mixture of saturated (44) and unsaturated (45) ketones. Introduction of a methyl group a t C-13 in compound 44 led to 46 which after acetylation was shown to be identical with 3/3-acetoxy-14(13 ---f 12aH)-abeo-androstan-17-one(47) obtained earlier from hecogenine (74) (43, 44). Reintroduction of the C-12-C-13 olefinic linkage yielded the reaction product 48. This, when coupled with 2-ethyl-5-
fl f l o H
H
HO HO
H H
43 42
@ H
O& H
H
H
RO
HO
H
H 44 45
46 47 48
126-H 412"3,
R = H R = CH,CO R = CH3C0, 4'2"3'
methylpyridine (49) and acetylated, afforded a mixture of epimers from which the desired isomer 50 was isolated. Aromatization of ring D of compound 50 yielded 51. The selective hydrogenation of the pyridine
H
49
0
50
1.
13
STEROID ALKALOIDS
ring in 51 furnished a mixture of isomers from which 3-0-acetyl-5~,6dihydroverarine (52) was separated. N-Acetylation of 52 led to 53. Selective hydrolysis of the 3-O-acetate function of 53 afforded N-acetyl5a,6-dihydroverarine (54). Oxidation of 54 yielded the C-3 ketone (55) which was converted (45) into the a,P-unsaturated compound 56 and further (46) into the &y-unsaturated alcohol 57. Removal of the N-acetyl group yielded the product 58 which is identical with authentic verarine isolated from Verutrum album subsp. lobeliunum. R
\ R'
H
~
H
52 53 54 55 56 57 58
R
R'
H CH&O CH3C0 CH3C0 CH3C0 CH&O H
CH,CO, a-H CH,CO, a-H OH,a-H 0 0, A 4 OH, a-H, A 5 OH, a-H, A s
5 . Veratramine
A formal total synthesis of veratramine from 3P-hydroxy-l4( 13 + 12)-abeo-5a-pregna-l2,13( 17),15-trien-ZO-one (59) was reported by Johnson et al. (47). The starting compound (59) has been obtained by degradation of hecogenine (74) or synthetically (43, 48). The ketone 59 was converted into the aldehyde 60 which was submitted to a Strecker reaction with 1-t-butyl 3-methyl-4-aminobutyrate and potassium cyanide to give, after benzoylation, the cyano ester 61 as a mixture of stereoisomers. This mixture was cyclized and saponified to afford the enamino ester 62 which was transformed into the ketone 63. The noncrystalline fraction of the ketone 63 was hydrolyzed and oxidized. The main constituents of this reaction were the diketone 64 and its C-22 epimer. Both isomers were identified by comparison with authentic specimens prepared from 5a,6-dihydroveratramine (73).
14
&
J. TOMKO AND
HO
z. VOTICKP
H O&CHO
H
H 59
60
0 I1
&V&
CBH5CO
H
COC,H5
CO2tBu
ir. 61
COC,H5
HO 62
H
0 H 63 70
R R' C6H5C0 CH, CH&O H
7 COC,H,
0 H 64
R2 H
CH,, 22a-H
1.
15
STEROID ALKALOIDS
Reduction of the dione 64 with sodium borohydride gave two compounds; one of them was identified as N-benzoyl-5a,6-dihydroveratramine (65). Compound 65 was further converted into the dibenzoyl derivative 66 which on oxidation afforded the 3-0x0 compound 67. The product 67 was transformed by a known reaction sequence into (33). veratramine [ (22S,25S)-veratra-5,12,14,16-tetraenine-3/3,23/3-diol] Masamune and associates ( 4 9 ) converted the ketone 59 into the two epimeric C-20 bromides 68. Treatment of 68 with pyrrolidine enamine (69) produced 3-0,N-diacetyl-23-dehydro-22-epiveratramine (70); this
H 65 66 67
0 II CH,CO
R R' OH, a-H H OH, a-H CeHSCO 0 C6H5C0
#
COCH,
xi
H 68
69
H 71 72
73
R
R'
R2
CH,CO H H
CH,CO CH,CO H
0 O H , a-H OH, a-H
16
J. TOMKO AND
z.
VOTICKY
was isomerized into its 22-epimer (71) which possesses the natural veratramine configuration. Reduction of 71 followed by hydrolysis afforded N-acetyl-&, 6-dihydroveratramine (72).Removal of the N-acetyl group from 72 led to 73, this being converted into veratramine. Kutney and co-workers started the total synthesis of veratramine, jervine, and veratrobasine from 3P-acetyl-l4(13 + l2aH)-abeo-androstan-17-one (47) which is available either by total synthesis (41) or by degradation of hecogenine (74) (50). A synthetic approach to the alkaloids of C - ~ O Y -homo -D steroidal skeleton (veratramine, jervanine, and cevanine type) has been examined by Huffman and associates (51). They attempted to prepare compounds 75 and 76 from the exocyclic olefin 77. The conversion of 77 into a compound bearing a nitrogen atom a t C-18 (75) proceeded in small yield and this approach to the cevine alkaloids was therefore abandoned. The use of compound 76 as a starting material for the synthesis of veratramine was also abandoned.
H 74
R = CH,NH,, H 77 R = CHa 75
H 76
1.
STEROID ALKALOIDS
17
Recently (2-13 magnetic resonance (CMR) spectrometry has been applied to the structural elucidation of jervine and veratramine ( 5 2 ) . 6. Cycloposine
Cycloposine (78)(see Section 11, A, 2 ) was isolated from Veratrum californicum ( 3 7 ) .Its structure was elucidated as follows. The I R , PMR, and mass spectra of 78 showed many similarities to those of cyclopamine (23).The I R spectrum exhibited an intensive absorption due to the hydroxyl groups of the glucosyl moiety of the molecule. The acid hydrolysis of cycloposine produced D-glucose and veratramine (33),the latter being identified by TLC and by I R spectroscopy. The expected cyclopamine was not obtained since it readily aromatized in ring D in acid conditions t o veratramine. Veratramine could not be the original aglycone of cycloposiiie by reason of the molecular weight, lack of aromatic character, the presence of an ether bridge, and mass spectrometric fragmentation. These results were interpreted as proving the structure of cycloposine t o be 3/3-D-glucosyl-11-deoxojervine (3/3-D-glucosylcyclopamine).
B. THE CEVANINESUBGROUP Esters derived from the alkamines protoverine, germine, zygadenine, zygadenilic acid S-lactone, sabine, and veracevine (cf. Volume X, p. 217) isolated from Veratrum plants are the representatives of the cevanine subgroup. Pritillaria alkaloids ( 1 ) and veramarine isolated from V . album subsp. lobelianum (53, 5 4 ) also have the cevanine skeleton. The latter differs from the former in having a lower oxygen content. 1. Veramarine
The elucidation of the stereochemistry of veramarine [ (22S,25S)cev-5-enine-3/3,16a,20/3-triol)](79) was based primarily on interpretation of physicochemical measurements (IR and PMR spectroscopy) (55). The comparison of spectral data as well as the similarity in basicity of veramarine, verticine, and cevine suggested that the E and F rings in veramarine are in the chair forms and that the tertiary hydroxy group a t C-20 has an axial configuration ( S O ) . The evidence for the 16a (equatorial) orientation of the hydroxy group was supported by the rate of the methanolysis of the 16-acetoxy group in 81.
18
J. TOMKO AND
z. VOTICKP
The configuration Sp-, 9a-,12a-, 14a-hydrogen in veramarine was inferred from the analogy with the other alkaloids of the cevanine group and from the consideration of biogenesis of the C-nor-D-homo steroidal skeleton (56).
79 R = H 81 R = CH,CO
H
OH
H
H 80
2. Esters of Germine
The structure of two novel esters of germine containing an aromatic acid was elucidated as follows ( 5 7 ) . Both alkaloids isolated from Veratrum album subsp. lobelianum were cleaved by alkaline hydrolysis to germine (82) and isogermine (83), respectively. One mole equivalent of veratric acid was isolated from the acidic portion after saponification of 84. I n addition, compound 85 afforded one mole of acetic acid (53). As acetylveratroylgermine (85) did not undergo oxidation with periodic acid no a-diol grouping should be present. On the basis of this argument the one hydroxyl of germine is acylated at C-15; the other a t C-3 or C-4. The consumption of periodic acid for oxidizing veratroylgermine (84) was found t o be one mole equivalent, indicating one a-diol grouping. The 3P-position of the acetyl group of acetylveratroylgermine was deduced from the difference in molecular optical rotation between acetylveratroyl- and veratroylgermine.
1. STEROID
19
ALKALOIDS
The isolation of protoveratrine A and germidine from V . lobeli(58, 59). Bondarenko further investigated the UV spectra of some ester alkaloids in concentrated sulfuric acid ( 6 0 ) . The relationship between the melting point and the position of an acyl group on the cevanine skeleton was studied ( 6 1 ) . anum Bernh. was reported by Shinkarenko and Bondarenko
H
OH
."OH OR' OH
82
R H
R1
OCH,
H
I
0 83
C. THESOLANIDANINE SUBGROUP Isorubijervine, rubijervine, veralobine, and isorubijervosine are the Veratrum bases of the solanidanine subgroup. The presence of solanidine in Veratrum has also been reported (53, 62, 63). No new Veratrum alkaloids of the solanidanine subgroup appear to
20
J. TOMKO AND 2. VOTICKY
have been isolated since the review in Volume X. However, the isolation of isorubijervine from V . californiczcm has been described (36).
D. THE22,26-~PIMINOCHOLESTANESUBGROUP Verazine (verasine), baikeine, veralozine, veralozinine, veralozidine, and etioline represent the Veratrum alkaloids with the 22,26-epiminocholestane skeleton. 1. Verazine
The synthesis of verazine [ (25S)-22,26-epiminocholesta-5,22(N)-dien3/3-01)] (95) from tomatid-5-en-3/3-01 was described (64-66). Reduction of 86 with sodium borohydride in methanol afforded diol 87 which, when acetylated, furnished the N,O,O-tri-acetate (88). Alkaline hydrolysis of 88 yielded the diol89. Through partial oxidation with one equivalent of chromium trioxide, the N-acetyldiol (89)gave the ketone 90. Treatment of this ketone with ethanedithiol-hydrochloric acid, followed by desulfurization of the resulting thioketal 91 with Raney nickel, yielded 92.
CH3C0
I)
"
RO 88 89 90 91 92
R CH&O H H H H
R1
CH,CO, a-H OH, a-H 0 SC,H,S H,
H
86
21
1. STEROID ALKALOIDS
Saponification of the amide 92 furnished the amine 93 which was chlorinated to 94 with N-chlorosuccinimide. Treatment of the N-chloro derivative 94 with sodium methoxide in methanol led to verazine (95). Since the starting compound is already synthetically obtainable (6'7) the conversion of 86 into 95 represents the formal total synthesis of verazine.
R' H
HO R OH H H
87
93 94
95
R1 H H C1
R = H
102 R = OH
2; Veralozine
Veralozine (96) (C,,H,,NO,; mp 213-215'; [a]:0 - 147.7' in methanol) has been found in Veratrum lobelianum. The IR spectrum of this alkaloid showed the absorption characteristic of an ester and a C-N group (68). Acid hydrolysis of 96 yielded veralozidine (97) and compound A (98). D-Glucose has been identified chromatographically in the neutral portion of the hydrolysis product. The saponification of veralozine gave compound A and acetic acid. Since veralozine did not give a
J. TOMKO AND z. VOTICKY
22
precipitate with digitonin, it was considered that the glucose is bound in the C-3 position. Because of the presence of veralozidine in the hydrolysis product of 96 it was concluded that the second hydroxy group in veralozine is located in the C-16 position. Compound A, after acetylation with acetic anhydride a t room temperature, was identical with veralozine. On the basis of the foregoing findings compound A was presumed to be 16-deacetylveralozine (98). Structure 96 (3P-D-glucopyranosyl-16-acetylveralozidine) has been proposed for veralozine. H
RO
R 96 97 98
R1
D - G ~ u CH,CO H H D-Glu H
RO 99 100
R = CH,CO, A6*aa(a3) R =H
HO 101
1.
23
STEROID ALKALOIDS
3. Veralozidine Veralozidine (97) (C27H43N02;mp 153-155"; [a];6 - 92.2" in ethanol) was isolated from the green part of Veratrum Zobelianum (69). The mass spectrum of veralozidine exhibited a fragmentation pattern indicative of a 22,26-epiminocholestane skeleton. The UV spectrum of this alkaloid showed a maximum attributable to the C-N double bond. Veralozidine displayed I R absorption due to a hydroxy, a 3phydroxy-5-ene, and a C-N group. The PMR spectrum of veralozidine showed protons associated with the C-18, C-19, C-21, and C-27 methyl groups and a C-6 vinyl proton. On acetylation with acetic anhydride a t room temperature veralozidine afforded N,O,O-triacetylveralozidine (99) whose I R spectrum revealed the maxima of an ester and an amido group. Catalytic hydrogenation of 97 with platinum catalyst in acetic acid produced a mixture of stereoisomers, one of them (100) being identical with a tetrahydro compound prepared from solasodine (101). On the basis of the above-mentioned results the structure of veralozidine should 16p-diol (97). be (25R)-22,26-epiminocholesta-5,22(N)-diene-3P,
4. Etioline Etioline (C,,H,,NO,) was isolated from the dried leaves of budding Veratrum grandiJorum Loesen. fil. (63). Its empirical formula pointed to a steroidal alkaloid (102). The presence of a C-5 double bond, seen in the PMR spectrum, was confirmed by oxidation of 102 into an a$-unsaturated ketone. The I R and UV spectra showed the presence of a C=N grouping; it was confirmed by mass spectral fragmentation. Two oxygen functions in 102 were found to be alcoholic since etioline formed N,O,O-triacetate (103)) displaying an enamine acetate functionality in the PMR and UV spectra. 0
II
C-CHS
103
24
J. TOMKO AND
z.
VOTICK$
As a result of the chromic acid oxidation the location of the second hydroxyl function in etioline appeared to be at C-16. The 0x0 product of 102 showed the absorption of a five- and a six-membered ring ketone in its I R spectrum. Compound 102 failed to cyclize to the spirosolane and therefore the a-orientation was assigned to the hydroxyl function at C- 16. Biogenetic consideration indicated the 25s configuration for ieneetioline. The structure 102,(25S)-22,26-epiminocholesta-5,22(N)-d' 3/3,16a-diol, was proposed for the alkaloid.
E. OTHER ALKALOIDS 1. Veralkamine
Veralkamine (104) is the first member of a steroidal alkaloid type skeleton. Its comwith an 18-nor-l7/3-methyl-22,26-epiminocholestane plete structure and stereochemistry have been established by recent chemical and physicochemical reinvestigation (70, 7 l ) ,including X-ray structural analysis (72).Its steroidal nature was demonstrated by selenium dehydrogenation. The base 104 was further characterized by
105 106
R = CH,CO R =H
1.
STEROID ALKALOIDS
25
conversion into the N,O,O-triacetate 105 and the N-monoacetate 106 obtained by alkaline partial hydrolysis of 105. The formation of the unsaturated ketone 107 by Oppenauer oxidation of 104 confirmed that one hydroxyl in veralkamine is located at C-3 and the double bond is in the C-5 position. Partial hydrogenation of 104 with Adams catalyst in ethanol gave dihydroveralkamine (108) characterized further by its N,O,O-triacetate (109) and N-monoacetate (110). Complete hydrogenation of 104 or 108 in glacial acetic acid afforded tetrahydroveralkamine (111). Acetylation and subsequent partial hydrolysis of 111 yielded the tetrahydro-N-monoacetate 112. Oxidation of 110 with chromium
H
108
H 109 110
R = CH,CO R =H
H 111 116 121
R H
R' OH C1 O H H H
26
J. TOMKO AND z.
VOTICKP
trioxide led to the unconjugated diketone 113. The I R spectrum showed a six- and a five-membered ring ketone, confirming that the second hydroxy group of veralkamine has to be located in ring D and the second double bond in ring C. Veralkamine (104) as well as its hydrogenated derivatives (108,112) possessed a strong hydrogen bond (seen in the I R spectrum) which excluded the C-15 position. for the second hydroxy group. Chromic acid oxidation of 112 afforded the saturated 3,16-diketone
H 112
H 113
H 114 111 119
R 0 OH, a - H OH, a-H
R' 0 0 SC,H,S
1.
STEROID ALKALOIDS
27
114 which, by partial catalytic hydrogenation, gave the 16-monoketone 115. The positive Cotton effect of the carbonyl group in 115 verified
the cis fusion of rings C and D and consequently the a-position of the hydrogen at C-13. This is in accord with the more favored a-hydrogenation of the C-12 double bond from the less hindered rear side of 104. N-Chlorination of 111 with N-chlorosuccinimide led to the N-chloro derivative (116). The negative molecular rotation difference between 116 and 111 established the 22S-configuration. Alkaline-catalyzed elimination of hydrogen chloride in 116 afforded the cyclic azomethine 117. The latter compound did not cyclize to the corresponding spiroaminoketal, thus demonstrating the trans orientation of the C-16 hydroxy group to the heterocyclic side-chain moiety at C-17. The weak negative Cotton effect of the azomethine 117 proved the 25s-configuration (73) of veralkamine and its derivatives.
H
117
The unusual 17~-methyl-18-nor-cholestane carbon skeleton of veralkamine has been determined by X-ray analysis of veralkamine hydroiodide (72), confirming the chemical and spectroscopic evidence of its structure. 2. Veralinine Veralinine, a minor alkaloid from Veratrum album subsp. lobelianum, also has the rearranged 22,26-epiminocholestane skeleton ( 7 4 ) . From chemical and spectroscopic evidence this Veratrum base is regarded as (22S,25S)-22,26-epimino-17p-methyl-18-nor-cholesta-5,12-dien-3/3-01 (118). This structure was confirmed by correlation with veralkamine. The ketone 115 prepared from veralkamine was treated with ethaaedithiol. Desulfurization of the resultant thioketal 119 with Raney nickel yielded the (2-16 deoxo compound 120, which is identical with (22S,25S)-22,26-acetyl-epimino17P-methyl-18-nor-5a,13a-cholestan-3P01, also prepared from veralinine (118) via catalytic hydrogenation
28
J. TOMKO AND
z.
VOTICKY
(121),acetylation (122),and partial saponification. The positions of the double bonds in veralinine were derived from the molecular rotation difference between 118 and 121.
H
HO 118
120 122
R
=H R = CH,CO
3. Veramine
Veramine (124)is the first known member of a steroidal alkaloid type with the rearranged tomatanine skeleton (75, 7 6 ) . Selenium dehydrogenation of 124 afforded, in addition to 2-ethyl-5-methylpyridine (49),Diels’ hydrocarbon 123, indicating the steroidal nature of the alkaloid. Acetylation of veramine (124) yielded N-acetylveramine (125), N,O-diacetylveramine (126),and a C-20,C-22 unsaturated N,O-diacetylpseudoveramine (127).Veramine underwent fission of ring E during lithium aluminum hydride reduction, affording the 178methyl- 18-nor-22,26-epiminocholestanediol(128) which can be recyclized to veramine by reaction with N-chlorosuccinimide and subsequent ; reduction alkaline treatment of the resultant N-chloro derivative (129) of the C-5 double bond in 128 over platinum oxide in ethanol gave the C-12 ene 130. The difference in molecular rotation between 128 and
1.
29
STEROID ALKALOIDS
130 is in good agreement with the reported increment for a C-5 double bond. Acetylation of 130 afforded the amorphous triacetyl derivative 131 which, after alkaline saponification, gave the N-monoacetate 132. H
RO 123
124 125 126 133
R H H
R' H
CH&O
CH&O CH&O
H
NO
0
II
CH,CO 127
Oxidation of the latter compound with chromium trioxide led to the N-acetyl-lZ-ene-3,16-dione(113), which is identical with (223,255)22,26-acetylepimino-17p-methyl-18-nor- 5a-cholest -12-ene- 3,16-dione prepared from veralkamine. carbon skeleton, the C-12 The unusual 17~-methyl-l8-nor-cholestane position of the second double bond, and the stereochemistry of veramine at C-25 were established from this correlation. As there is no identity between veralkamine (104), (which possesses a 16p-hydroxy group) and the diol (128), the only structural difference was in the configuration at C-16. The N-chloro derivative (129) of 128 recyclizes in contrast to the N-chloro derivative of veralkamine (116); therefore veramine has a 16a,17a structure of the spiroaminoketal side chain. The negative Cotton effect of N-nitrosoveramine (133) corresponding to the ORD
30
J . TOMKO AND Z . VOTICKY
curve of N-nitrosotomatidine indicated the 2 2 s configuration (22,$N) of veramine (124).
128 R = H, A s 129 R = C1, d 6 130 R = H. 5a-H
H RO 131 132
R = CH,CO R =H
4. Veracintine
Veracintine (134)was isolated from the part of Veratrum subsp. lobelianum (77) which is above the ground. By catalytic hydrogenation the alkaloid afforded, in ethanol, a dihydro derivative (135);in acetic acid, tetrahydroveracintine (136). The amorphous N,O-diacetyl derivative (137)was isolated in the reaction of veracintine with acetic anhydride in pyridine. The bands in the IR spectrum of 137 showed the amido group and the presence of a double bond. The absorption in the UV
I
l
l
spectrum also confirmed the CH3CON-C=Cgrouping in the structure of 137. Saponification of 137 with methanolic potassium hydroxide furnished N-acetylveracintine (138).Biogenetic considerations led to the proposed attachment of the pyrroline ring to C-17. The PMR spectrum of veracintine showed two singlets, indicating
1.
STEROID ALKALOIDS
31
C-18 and C-19 angular methyl groups of a normal steroid ring system with a C-5 double bond, one doublet corresponding to a secondary methyl group a t C-20, signals of a C-6 vinyl, and a C-22 proton. The
HO 135 A 5 136 5a-H
134
137 R = CH&O 138 R = H
singlet at 6 2.1 ppm suggested a C-26 methyl group in the neighborhood of the double bond. The base peak in the mass spectrum a t m/e 82 was advanced for a pyrroline ring resulting from the C-20 and C-22 bond fission. The IR spectrum indicated the presence of a hydroxy group and an azomethine double bond. Therefore veracintine was assigned the constitution 20-(2methyl- l-pyrrolin-5-yl)pregn-5-en-3/3-01 (134). 5 . Alkaloid Q
Alkaloid Q (C,,H,,NO,; mp 209-210"; -95" in chloroform) has been isolated by Keeler from Veratrum californicum (35). 6. Alkamine X
Alkamine X (mp 215-217") was found in Veratrum lobelianum; its IR spectrum exhibited absorption due to a double bond and a hydroxy and an amino group (58).
32
J. TOMKO AND
z.
VOTICK+
7. Alkaloid Y
Alkaloid Y (C,,H,,NO,,; mp 181-183"; [a],,+ 7.6" in chloroform) isolated from Veratrum lobelianum, was proposed to be an ester of protoverine (60). 8. Tienmulilmine
On the basis of their I R spectra, tienmulilmine (C,,H4,NO; mp 172-174"; [a]:: - 99.3" in methanol) and verazine (C,,H4,NO; mp 176-178"; - 91.7" in chloroform) were shown not to be identical (78) (cf. Volume X, pp. 198, 217). 9. Veralozinine I n its IR spectrum, veralozinine (mp 161-163"; [a];' -186.2" in chloroform) revealed absorption of a hydroxyl, a n ester group, and a double bond (69). 111. Structures and Chemical and Physicochemical Properties of Buxus alkaloids
A. DIBASICBuxus ALKALOIDS 1. Subgroup A
a. Buxamine-A. Buxamine-A (139) isolated from Buxus madagascarica subsp. xerophilla, forma salicicola showed in its UV spectrum bands indicative of a conjugated trans diene (79). (For a list of Buxus alkaloids with formulas and properties see Table 11.)I n its PMR specTABLE I1
Buxus ALKALOIDS Compound
Molecular formula
Alkaloid-E Buxaltine-H Buxamine-A Buxamine-E Buxaminol-E Buxandonine-L Buxandrine-F Buxanine-M Buxarine-E' Buxazidine-B Buxazine Hnxene-0 Buxeridine-C Buxidienine-B Buxidine-B ~~~~~~~~~
~
Buxiramine-D Buxitrienine-C Bnxocyclamine-A Buxpiine-K ( = cyclomicrobnxine)
C32H43N02 C33H48N203 Cz7H4eNaOa
CzsH4eNzoz
Compound
No.
M.w.
M.p('C)
[aID
231 139 140 307 256 208
450 544 412 384 400 357 564
287-289 188-191 134
+12 +40
157-159 289-290
+ 24 -
259 209 144 -
473 520 430 444
-38 +98 -31 +93
265 161 215
427 502 416
19kyi?9 210-212 234-236 235:239 (aec) 202-204 208-211 237 254 154-157 213-215 192 187-188 173 173
f
210 178 162 141 243
-
520 428 412 400 385
-
(aPC\
Source= Refs 99 90 79 86a 86a 91
-
+14 +S
76.5 67.5
++ 57
+ 87 + 159
92
a a
96
a
101
a a
102
a
-
94
85
85
97
-
9fi " "
a a a
95 92 90
79 80 103 86a
1.
33
STEROID ALKALOIDS TABLE 11-continued
Compound Bnxpsiine-K ( = buxamideine-K, alkaloid C) Buxtauine-M ( = cyclomicrobuxinine)
Molecular formula
Compound
No.
M.w.
Alp ("C)
[aID
308 309
381 371
180-183 170 178 207-212 221-224 188-189 230-233 235-237 245-247 195-197 194-196 181-182 174 201-204 182-183 234-236
+118 +153
-
-
145 146
387 400 386
Cyclobuxoniicreine-K Cyclobuxophylline-K Cyclobuxophyllinine-M ( = buxenone-M) Cyclobuxosriffrine-K Cyclobuxoviridine-L Cyclobuxoxazine-C
240 245 257
369 383 369
235 252 310
369 383 430
Cyclokoreanine-B
148
414
251 311
367 430
163 255 142
534 401 414
Cycloprotobnxine-C
143
400
Cpcloprotobuxiiie-F Cvcliisuffrohiisine-K ('s,.loauffrol)uxiiiiiie-~I trans-Cyclosuffrobuxinine-M Cyclovirobuxeine-C Cyclovirobuxine-D
218 312 260 262 166 181
386 367 353 353 414 402
205-210
Cyclovirobuxine-C Cycloxobuxidine-F ( = buxidine-F)
165
416
221 201
196
432
227-230
168 171 173 227
444 414 428 520
292 200-201 221-224 286-288 (dec) 291 252-255 235-238 (dec) 274-276 (dec) 277 214-216 (dec) 214-217 255-256 (dec) 292-294 278-279
Cyclomicrosine-C Cyclomicuranine-L C ycloprotobuxine-A
Cvcloxobuxoxazine-C ( = haleabuxo'sazine-C) 16-lleoxvbuxidienine-C
N-3-Benzoylcyclosobuxine-F
-
-
180 179
520 506
195
536
197
504
N-3-Benzoylcycloxobuxoline-F
200
520
N-3-Benzoyldihydrocyclomicrophylline-F ( = buxepidine)
193
522
201 156 230 226
562 442 504 486
( = buxatine)
N-3-Benzoyl-0-acetylcycloxobuxoline-P
N-3-Isohutyrylcycloxobuxidine-F ( = N-isobutyrylbaleabuxidine-F) N-3-Isobutyrylcycloxobuxidine-H N-3-Mcthylbuxene-M 0-Tigloylcyclovirobnxeine-B 0-Vanilloylcyclovirobuxine-D Pseudobaleabuxine-F
170
502
232 264 158 191
488 441 496 552 470
-
235-236 235 141-142 228-230 282-284 209-211 206-207 205 195 163 167-172 181-182
-
-
216-218 290 275 253 260-262 257 236-238 285 180-182 178-183 210 236-240
Sourcea Refs.
-
f6.7 +ll9 +96.1 +lo3 +37 -72 - 51
-48 -62 +16 +48 (EtOH) +lo9
-
f h i
a
i
a a h b b h a
b b h
d
i04 103 86a 90 90 86a
86 105 103 81 81
81 94 81 81 103 Ya
+I26 -90
b f
86a 81 104
-33 -3 +76 +75 +40 (EtOH) +42
b b b c h
81 81 81 8 103
g b b a
79 81 81 106 87 103
-92 -51 -47
-
I
C
+25 h (EtOH) i e + 65 f f 114
+ + 116 + 55 + 53
C
6 5
- 36
a
- 29
C
+ 43
+ 42
+ 56 + 52 + 90 + 112 + 76 + 19 - 20
+ 114
- 157 - 32 - 67 - 60
+ 71
+ 76 + 75
- 104 - 150
f 2 120.7
+
86a
87 99 98
10 79
88a 88a
a a
10 88a 88a
a
88a
C
10 880
a a
z
93 88a
a a
8Xa
a e
88a 87
C C
10 10 99 10 98,99 11 102 8Xa 87 98,99, 104
f C
f C
a
a e f
91
a Key to letters: a. B u m s semBervirens L.; b. B. microph2/lla Sieb. et Zucc. var. suffruticosa Makino; c. B . balearica Willd.; d. B. koreana Nakai; e. B . malayana Ridl.; f. B. balearica Lam.; g . B. madagascarica Baillon. h. B. wallichiana Baillon; i. B. microphylla Sieb. et Zucc. var. sinica. Rehd. et Wils. Optical rotations were measured in chloroform unless stated otherwise.
34
J. TOMKO AND z. V O T I C K ~
trum, signals attributable to four tertiary methyls, one secondary methyl, two dimethylamino groupings, and two olefinic protons were apparent. The mass spectrum of 139 was characteristic of both dimethylamino groupings a t C-3 and C-20. Although buxamine-E (140) has already been described (c.. Vol. I X , p. 405) no correlation between the two alkaloids has been made in order to confirm the structure of 139.
139 140
R
= CH, R =H
b. Buxocyclamine-A. This alkaloid was found to be a component of Buxus sempervirens and was obtained from the residues of the alkaloid mixture by repeated chromatographic purification (80). I t s I R spectrum was characteristic of a cyclopropyl methylene grouping and the mass spectrum showed, besides the molecular ion peak, fragments indicative of C-3 and C-20 dimethylamino groups. On the basis of these results structural formula 141 was ascribed to it. Buxocyclamine-A is a Buxus alkaloid with the C-4 monomethyl substitution pattern. The 8-assignment of this group might be erroneous, as was shown with cyclobuxosuffrine-K (235) (Section 111, B, 1, a ) (81, 82).
141
c. Cycloprotobuxine-A. Cycloprotobuxine-A (142) is a minor alkaloid from the leaves of Buxus balearica. (8) and B. microphylla. var. suflruticosa (81). According to its PMR spectrum 142 contained a
1.
STEROID ALKALOIDS
35
cyclopropyl methylene grouping, four tertiary methyls, and two dimethylamino groups. The proposed structure was confirmed by comparison with the methylation product obtained from cycloprotobuxine-C (143) [Schlittler’s alkaloid L. (83, 84)].
142 143
R = CH, R =H
2. Subgroup B
a. Buxaxidine-B. According to its IR spectrum buxazidine-B, occurring in Buxus sempervirens (85))was shown to possess a primary hydroxyl and a carbonyl group; species in the mass spectrum were indicative of a methylamino group a t C-20 and a dimethylamino group at C-3. Consequently, the structural formula 144 has been ascribed to this alkaloid.
144
b. Cyclobuxine-B. Cyclobuxine-B (145)was isolated from the acetone-insoluble portion of the strong-base fraction of Buxus sempervirens by chromatography on alumina (86). Its IR spectrum indicated the presence of a terminal methylene, a cyclopropane ring, a secondary
J. TOMKO AND z. VOTICK+
36
hydroxyl, and mono- and dimethylamino groups; it was similar to that of cyclobuxine-D (146). Signals due to two tertiary C-methyl groups and one secondary C-methyl group were seen in the PMR spectrum. The proper assignment of the methyl- and dimethylamino groups to the steroidal skeleton was based on the mass spectral fragmentation. To confirm the assumed structure 145 cyclobuxine-B was methylated and compared with cyclobuxine-A (147). The spectra of both preparations were found to be superimposable, thus proving the postulated structural formula and stereochemistry of this base.
R 145 146 147
CH, H CH,
R’ H H CH,
c. Cyclokoreanine-B. As is apparent from the name, cyclokoreanine-B (148) was isolated from Buxus koreana (7a). Moreover, it has been
identified also in B. microphylla var. sinica (86a). From its mass spectrum it was evident that the dimethylamino group is attached to C-3, whereas the methylamino group is a t C-20. This alkaloid showed I R absorption bands indicative of a hydroxyl, a secondary amine, a cyclopropyl methylene, and a cis-disubsituted double bond. According to the UV spectrum this double bond should be conjugated with the cyclopropane ring. I n the PMR spectrum of 148 one of the two cyclopropyl methylene protons was found downfield. The signal due to the other proton, which ought to be observed as another distinct doublet, shifted still farther downfield and lay in the bounds of the C-methyl envelope so that it could not be located. Two olefinic protons were observed to display a typical coupling pattern indicating that both the neighboring carbon atoms are quaternary. Signals due to four tertiary C-methyls, one secondary methyl, one N-dimethyl, and one N-methyl group were identified. The methine proton of the )CHOH grouping appearing as a septet showed the same splitting pattern as
1.
STEROID ALKALOIDS
37
C- 1 6 /3-protons of other Buxus alkaloids. Attempted N-methylation of 148 to 150 according to the Eschweiler-Clarke method resulted in the cleavage of the cyclopropane ring and in production of an amorphous mixture; therefore the N-methylation had to be carried out with methyl iodide. On the other hand, the dihydroderivative (149) can be readily methylated by the Eschweiler-Clarke method. Oxidation of cyclokoreanine-B with chromium trioxide led to the proper ketone which, in turn, was deaminated to give the cisoid a7/3-unsaturated cyclopentenone 151 as the sole product. On catalytic
CH3,
N
CH,’
148 150 153
R H CH3 CH,CO
R’ H H CH,CO
hydrogenation cyclokoreanine-B and its N-methyl derivative afforded the respective dihydro derivatives 149 and 152. I n the PMR spectra of the above-mentioned dihydro derivatives the signals of the C - 2 1 methyl and the cyclopropyl methylene protons appear a t the normal positions. Therefore the downfield shifts of these proton resonance signals were attributed to the paramagnetic effect from the double bond between C-11 and C-12. Acetylation of 148 and its N-methyldihydro derivative 152 yielded the N ’,O-diacetate 153 and the O-acetate 154, respectively. The negative molecular rotation increment of compound 152 after acetylation confirmed the a-orientation of the C-16 hydroxy group. Dihydrocyclokoreanine-A (152) and cyclovirobuxine-A (155) have different melting points although their PMR and I R spectra differ in minor points only. Therefore it was assumed that the difference between them was due to the opposite orientation of the C-3 dimethylamino group. As the orientation of the dimethylamino group at C-3 in cyclovirobuxine-A (155) has been proved to be @equatorial, that of
38
J. TOMKO AND z.
VOTICKP
&
dihydrocyclokoreanine-A (152)should be axial by analogy with some other steroids. An attempt to synthesize the latter failed.
Z H ,
CH,,”.. CH3 ,N,.
.
CH,’
O& /
,
149
CH,’
152 154
151
’
3
R H H CH,CO
R’ H CH3 CH,
CH,, N
CH,’ 155
d . N - Formylcyclovirobuxeine- B. N-Formylcyclovirobuxeine-B (156) was reported to be the component of the weak base fraction of Buxus malayana (87). I n its PMR spectrum the signal characteristic of a
156 157
R
= CHO R =H
1.
STEROID ALKALOIDS
39
cyclopropyl methylene was shifted to the negative region on the ppm scale as observed in other cyclovirobuxeines possessing the C-6=C-7 double bond. Other signals iii the PMR spectrum were interpreted as being attributable to four tertiary methyls, one secondary methyl, one dimethylamino group, an N(CH,)(CO)R grouping, one proton adjacent to a secondary alcohol, two olefinic hydrogens, and finally one N-methylformamide grouping. These data, together with those obtained by the mass spectrometry, indicated the structural formula 156 for N-formylcyclovirobuxeine-B. A proof for this assignment was provided by the alkaline hydrolysis of 156 to furnish cyclovirobuxeine-B (157))the constitution of which was already established
(88). e. Tigloylcyclovirobuxeine-B. Tigloylcyclovirobuxeine-B (158) was isolated from the “additional weak bases fraction obtained from Buxus sempervirens (88a). Elucidation of its structure was based on spectroscopic evidence. The PMR spectrum of 158 indicated the presence of two vinyl protons and a cyclopropyl methylene. The high upfield shift of the half of the cyclopropyl methylene AB quartet suggested a C-6=C-7 double bond. Further signals are characteristic of a ))
>C=&CH,) grouping. This and the I R spectrum suggested that compound 158 might be an 0-acyl derivative of cyclovirobuxeine-B (159) (cf. Vol. I X , p. 391). Saponification of 158 with methanolic potassium hydroxide yielded 159 and tiglic acid, in support of assignment of the C- 16 tigloylcyclovirobuxeine-B structure for this alkaloid. The C-16 angelate ester structure 160 also could not be precluded since under the same reaction conditions some other naturally occurring steroidal angelate ester alkaloids yielded tiglic acid. Nonetheless, the tiglate configuration for the ester a t C-16 was considered to be more favorable on the basis of the PMR spectral evidence.
40
J . TOMKO AND
z.
VOTICKY
3. Subgroup C
a. Buxeridine-C. Buxeridine-C (85) was separated from the residue of the extract from leaves of Buxus sempervirens. Its mass spectrum indicated a benzamide a t C-3 and a dimethylamino grouping a t C-20. This and the IR spectrum of the alkaloid under study indicated the structural formula 161 for buxeridine-C. Nevertheless, further support for this assignment is needed.
0 161
b. Buxitrienine-C. Buxitrienine-C (162) was found in Buxus madagascarica subsp. xerophila, forma salicicola (79). It is the first representative of Buxus alkaloids possessing a conjugated triene in positions C- 1-C-2, C-1O-C- 19, and C-9-C- 11. The structural formula of buxitrienine-C was inferred on the basis of its UV, IR, PMR, and mass spectral data; starting from cycloxobuxidine-F (79), the partial synthesis was intended to confirm this assumption.
162
c. Cyclomicrosine-C. Cyclomicrosine-C (163) was found in Buxus microphylla var. suffruticosa (81) and its structure was deduced as
1. STEROID
41
ALKALOIDS
follows. The IR spectrum of this substance showed the presence of an N-benzamide grouping and, on hydrolysis with methanolic potassium carbonate, it afforded cyclomicrophylline-C (164) (cf. Vol. IX, p. 396).
R\
N
CH,/
CH20H 163 164
R = COC,H, R =H
d . Cyclovirobuxine-C and Cyclovirobuxeine-C. Cyclovirobuxine-C (165) and cyclovirobuxeine-C (166) were obtained by a countercurrent distribution of the alkaloid mixture prepared by extracting the leaves of Buxus malayana (87). Cyclovirobuxine-C was not obtajn\:d pure because it crystallized with cyclovirobuxeine-C as shown in its PMR spectrum. To get a single product the mixture of 165 and 166 was hydrogenated over platinum catalyst and identified by spectral methods. The proposed structural formula of N-acetylated cyclovirobuxineC (167) was verified by comparison with the synthetically prepared product.
H\
R 165 167 250
H COCH, CH,
R' CH3 CH3 CH3
R2 H H H
N
CH/ 166
e. Cycloxobuxoxazine-C ( Baleabuxoxazine-C). Cycloxobuxoxazine-C (baleabuxoxazine-C) (168) was isolated from Buxus balearica (10, 89)
42
J. TOMKO AND z. VOTICK+
from the weaker bases by countercurrent distribution. The UV spectrum and circular dichroism curve resembled those of N-S-isobutyryl-
168
cycloxobuxine-F (169) (baleabuxine; cf. Vol. IX, p. 402) and N-3-iso(10). butyrylcycloxobuxidine-F (170) (N-3-isobutyrylbaleabuxidine-F) The PMR spectrum of cycloxobuxoxazine-C revealed singlets characteristic of three tertiary methyls, one doublet due to a secondary methyl, a singlet indicative of a dimethylamino group, and finally signals characteristic of an R-CH2-Oand >N-CH2-Ogrouping. The mass spectrum of 168 located the dimethylamino group a t c-20. Evidence for the structure assignment 168 was confirmed by partial synthesis when N-3-isobutyrylcycloxobuxidine-F (11) (see Section 111, A, 5 , k) was transformed into cycloxobuxoxazine-C.
0
0 169
170
f. 16-Deoxybuxidienine-C. 16-Deoxybuxidienine-C (171) obtained from Buxus madagascarica subsp. xerophila, forma salicicola (79)) showed in its UV spectrum a trans conjugated diene. The PMR spectrum of 171 revealed signals of three tertiary and one secondary methyl
1.
43
STEROID ALKALOIDS
groups, one dimethylamino and one methylamino grouping, as well as two protons of a methylene adjacent to primary hydroxy group and two olefinic protons. The mass spectrum confirmed the dimethylamino substitution a t C-20 and methylamino substitution a t C-3. When reacting with formaldehyde 16-deoxybuxidienine-C furnished tetrahydrooxazine (172) which was characterized by spectral methods.
171
172
4. Subgroup D
a. N-Acetylcycloprotobuxine-D. N-Acetylcycloprotobuxine-D (173) was obtained from Buxus sempervirens (88a). Elucidation of its structure was based upon spectral and analytical data which showed the close relation of this alkaloid to cycloprotobuxine-D (174).The naturally occurring base 173, being an amide, was presumed to possess structure 173 or 175. N-Methylation of 173 gave N-methyl-N-acetylprotobuxineD (176) isomeric with the known N-acetylcycloprotobuxine-C (177). The nonidentity of 176 with 177 indicated that the acetyl group in N-acetylcycloprotobuxine-D is located in the C-20 nitrogen position.
R 173 174 175 176 177
R1
COCH, H H H H COCH, COCH3 CH, CH3 COCH3
44
J. TOMKO AND z. V O T I C K ~
6. Buxirumine-D. Buxiramine-D (178) was reported (90) to accompany buxaltine-H (see Section 111, A, 6, a). The structural formula of buxiramine-D was deduced from its spectral data: the PMR spectrum displayed a doublet corresponding to the C-21 methyl group, a multiplet indicative of a hydroxy group attached to ring C, and N-methyl and N-acetyl group, as well as a cyclopropyl methylene. The I R spectrum showed the presence of an amide and a band characteristic of the C-6=C-7 double bond. On the basis of these data and those obtained from the mass spectrum the structural formula of buxiramine-D is probably 178. A proof of this assignment is desirable.
178
c. N- Benxoylcycloprotobuxoline-D and N-benxoylcycloprotobuxoline-C. N-Benzoylcycloprotobuxoline-D (179) and N-benzoylcyclosempervirens ( 8 t h ) . protobuxoline-C (180) were obtained from BUXUS The PMR spectrum of 179 indicated an N-methyl group with restricted internal rotation, one N-methyl group, one proton adjacent to a hydroxyl, five aromatic protons, and a cyclopropyl methylene; a n amide was inferred from the I R spectrum. The assumption that 179 might be a benzamide of cyclovirobuxine-D (181) proved to be erroneous since benzoylation of 179 furnished a dibenzamide (182) isomeric to, but not identical with, N,N’-dibenzoylcyclovirobuxine-D(183). N-Benzo ylcycloprotobuxoline-C ( 180) displayed spectral properties which closely resembled those of the N-benzoylcycloprotobuxoline-D with the exception that the PMR spectrum of the former showed the presence of an N-dimethylamino group. Acetylation of N-benzoylcycloprotobuxoline-C led to an O-acetate (188). Hydrolysis of 179 led to the debenzoylated compound 184 and benzoic acid. Similarly, hydrolysis of 180 furnished cycloprotobuxoline-C (185). It was postulated that the ease of hydrolysis of N-benzoylcycloprotobuxolines might be attributable to the effect of a neighboring hydroxy group. To verify this assumption 185 was treated with phosgene, whereupon the oxazolidone
45
1. STEROID ALKALOIDS
&2i3
R2R1O.. &c:H3
N '
"
CH,' 179 180 182 184 185 188
CH,/
R
R'
R2
H CH, C,H5C0 H CH, CH,
H
C6H5C0 C6H5C0 C6H5C0 H H C,H,CO
H H H H COCH,
,' 181 183
R R
=H = C6H5C0
186 was formed. The -CH(OH)-CH(NHCH3)grouping in cycloprotobuxoline-D (184) was also indicated by its periodic acid consumption. Oxidation of N-benzoylcycloprotobuxoline-D with chromic acid furnished 187 in the I R spectrum of which there appeared a band indicative of a six-membered ring ketone. Consequently, the hydroxy group was assigned to C-2. I n order to determine the configuration of the C-2 hydroxy group 179 was reduced with LiAlH,, was N methylated, and then acetylated. Compound 179 was compared with the isomers of known configuration, 189 and 190, prepared synthetically. Since 189 was identical with that prepared from 179 the a-orientation of the C-2 hydroxy group was ascribed to the naturally occurring bases.
186
187 189
R1
R 0
C~HBCO H
>
CpH,CH2
CH,COO" 190
CH3c00\ H
CBH5CH2
46
J. TOMKO AND
z.
VOTICK$
d. 0-Vanilloycyclovirobuxine-D. 0-Vanilloycyclovirobuxine-D (191) (misnamed 0-vanillyluyclovirobuxeine) was isolated from the strongbase fraction of Buxus malayana (87). Its I R spectrum indicated the presence of an aromatic ester whereas the PMR spectrum showed signals due to a cyclopropyl methylene, four tertiary methyls, one secondary methyl, two methylamino groups, one hydrogen in the a-position to the ester group, one methoxyl, and one aromatic trisubstituted system. The mass spectrum provided further evidence of the presence of both methylamino groups and vanillic acid. On saponification 191 afforded cyclovirobuxine-D (192) and m-hydroxy-pmethoxybenzoic (vanillic) acid.
191 R = CO
OH 192
R =H
5. Subgroup F
a. N-Benzoyldihydrocyclomicrophylline-F. N-Benzoyldihydrocyclomicrophylline-F (Ma)and buxepidine (91, 92), two names given to the same base isolated from Buxus sempervirens by substantially different procedures, are represented by structural formula 193. It is worth noting that the optical rotation of N-benzoyldihydrocyclomicrophylline, [a]g8 19" (CHCl,), differs notably from that of buxepidine, [a]:4 -20" (CHCl,), although there can be no doubt that both substances are identical. According to its I R spectrum 193 is a secondary benzamide with at least one hydroxyl but no keto group. The PMR spectrum displayed the presence of five aromatic protons, one amido proton with hindered rotation about the C-N bond, one proton adjacent to a secondary hydroxyl, two hydroxymethyl protons, two N-methyls, three tertiary C-methyls, one secondary C-methyl, and a cyclopropyl methylene.
+
1. STEROID
ALKALOIDS
47
The position of the C-4 hydroxymethyl signals indicated the proximity of the protons to the rtmide carbonyl, thus supporting the evidence for the location of the benzamide a t C-3. Hydrolysis of this alkaloid furnished dihydrocyclornicrophylline-F(194) (88a),the structure elucidation of which was reported earlier (cf. Vol. IX, p. 397). On the basis of these data structure 193 was assigned to N-benzoyldihydrocyclomicrophylline-F. The correctness of the proposed structural formula (193) was proved by correlation with buxidine-F (see Section 111, A, 5, g) ( 9 4 .
193 194
R = CeH,CO R =H
b. N-Benxoylcycloxobuxidine-F (N-Benzoylbdeabuxidine-F). NBenzoylcycloxobuxidine-F (N-benzoylbaleabuxidine-F) (195) (see p. 54) was found in Buxus sempervirens (88a)and B . balearica (10)and its structure was elucidated independently by two research groups. Goutarel and co-workers based their investigation on the product of hydrolysis as the result of which 195 yielded cycloxobuxidine-F. (baleabuxidine-F, 196) (see Section 111, A, 5, k), a product identical with that obtained from N-isobutyrylcycloxobuxidine-F (170) by saponification. Kupchan et al. (88a) derived the structure of N-benzoylcycloxobuxidine-F from the following observations. The UV spectrum showed that 195 is a secondary benzamide having the carbonyl group conjugated with the cyclopropane ring. The IR spectrum revealed its close relationship to N-benzoylcycloxobuxine-F (197) (see p. 50). The PMR spectrum showed the presence of aromatic protons, one amido proton, and other substitution pattern practically identical with that mentioned above ( 8 8 ~ ) . The presence of two hydroxyl groups in this alkaloid was evidenced
48
J. TOMKO AND z. VOTICKY
by acetylation. The diacetate thus formed (198) was characterized by its IR spectrum. Cycloxobuxidine-F (196) was reduced with lithium aluminum hydride t o yield dihydrocycloniicrophylline-F (199) (cf. Vol. IX, p. 397). This interrelation with the already known alkaloid constituted a basis for assignment of structure 195 to N-benzoylcycloxobuxidine-F.
'\c/
:?A
I1
0
0 198
199
c. N-Benzoylcycloxobuxoline-F and N-Benzoyl-O-acetybcycloxobuxoline-F . N-Benzoylcycloxobuxoline-F and N-benzoyl-0-acetylcycloxobuxoline-F were isolated from Buxus sempervirens by a procedure described for 0-tigloylcyclovirobuxeine-B(88a) (see Section 111, A, 2, e). Structures for both alkaloids were based upon the following findings. The IR spectrum of N-benzoylcycloxobuxoline-F (ZOO) revealed that this alkaloid possesses a secondary amido group, a S~,lS-cyclopropane ring, and a C-11 carbonyl, and its spectrum differs from that of N-benzoylcycloxobuxidine-F (195) in the hydroxyl and fingerprint regions only. The results of microanalysis indicated the presence of three oxygens in the molecule. The UV spectrum showed a maximum
1.
STEROID ALKALOIDS
49
indicating the C-3 secondary benzamide and a carbonyl in conjugation with the cyclopropane ring. Five aromatic protons, one amido proton, two hydroxymethyl protons, an a-carbonyl methylene, two N-methyls, three tertiary and one secondary C-methyl could be seen in the PMR spectrum. These data suggest structural formula 200 for this alkaloid.
200 201
R =H R = COCH:,
The UV, I R , and PMR spectra of the naturally occurring O-acetate of N-benzoylcycloxobuxoline-F (201) resemble those of the parent alkaloid 200. Moreover, signals due to an a-carbonylmethyl (ClT,COO) and an acetoxymethyl (CH,COO-CH,) grouping seen in the PMR spectrum of 201 suggested that this base is an O-acetate. Support for the structure assignment was achieved by acetylation of 200 to 201. d . N- Benxoylcycboxobuxine-F. N-Benzoylcycloxobuxine-F (197) (buxatine) was found in the extract of leaves from Buxus sempervirens ( M a , 93). It possessed ( M a ) ,according to its I R spectrum, an amido, a cyclopropyl methylene, a carbonyl conjugated with the cyclopropyl methylene, a sec-amide, and an a-carbonyl methylene group, the last being characteristic of only those compounds which have a conjugated carbonyl group and possibly indicative of a C-11 ketone in this series of alkaloids. The UV spectrum showed a maximum attributable to the additive absorption of the two isolated chromophores-a sec-benzamide and a cyclopropylcarbonyl. The PMR spectrum of 197 revealed the presence of five aromatic protons, two N-methyls, and four tertiary and one secondary C-methyl. Signals due to the cyclopropyl methylene were missing. The above-mentioned physical data corresponded closely with those reported for N-isobutyrylcycloxobuxine-F (baleabuxine; cf. Vol. IX, p. 402) and (89), except for the presence of the isobutyramide group.
50
J. TOMKO AND z. V O T I C K ~
Convincing support for structure 197, assigned to N-benzoylcycloxobuxine-F, was deduced from its relation with cycloprotobuxine-C (204). Treatment of 202, prepared from 197 by reduction with LiAlH, in dioxane, with formic acid-formaldehyde, gave N-benzylcycloprotobuxine-C (205), which was characterized by physical means. The same product (205) was obtained when cycloprotobuxine-C (204) was benzoylated to give N-benzoylcycloprotobuxine-C (206) and then reduced.
/I R =O R = H. OH
197 207
202 203 205
204 206
R R' H H OH H H CH,
R =H R = CBH,CO
1.
STEROID ALKALOIDS
51
The LiAIH, reduction of 197 in ether for 3 hr led to a C-11 alcohol (207) having the benzamide substitution a t C-3 retained; 14 hr reduction time afforded 203, whereas in dioxane under reflux 202 was obtained. The hydrogenolysis reaction has been applied to synthesize 9p,l 9-cyclosteroid analogs of Buxus alkaloids from the proper C-11 ketones.
e. Buxandrine-F. Buxandrine-F (208) was found in Buxus sempervirens and its structure was determined on the basis of I R and mass spectra as well as the correlation with buxidine-F (210) (92).
0
208
f. Buxarine- F . Buxarine-F was isolated from Buxus sempervirens (94) and its structure elucidated as 209 by means of its PMR and I R spectra. Although the assumed structure is plausible, further evidence for it is desirable.
I1
0
209
g. Buxidine-F. Buxidine-F [misprinted as buxizine (95)] (N-3benzoylcyclomicrophylline-F) (210) occurs in Buxus sempervirens (92, 95, 96). Its molecular formula was revised twice (see Table 11) and only by mass spectrometry confirmed to be C,,H,,N,O,. The search for the structural formula was based upon the I R and mass
J. TOMKO AND z. VOTICKY
52
spectrometric data and examination of its derivatives. Thus, under consumption of one molecule of hydrogen, catalytic hydrogenation of buxidine-F led to N-benzoyldihydrocyclomicrophylline-F [buxepidine (193)l.The position of the double bond in buxidine-F was determined from the difference in the molecular optical rotation. Methylation of buxidine-F by the Eschweiler-Clarke method gave cyclomicrosine-C (163)the structural formula of which was established after debenzoythereby confirming not only lation to yield cyclomicrophylline-C (164), the structure but also the stereochemistry. To avoid possible misunderstanding with another Buxus alkaloid (cf. cycloxobuxidine-F), 210 should be renamed N-3-benzoylcyclomicrophylline-F.
H>N 'C
/I
0
210
h. Buxidienine-F. The physicochemical properties of this base were reported in connection with the synthetic approach from the 9/3,19-cyclo-ll-ketocyclo-buxines and -buxidines to 9( 10 + 19)-abeolo(19),9(11) conjugated dienes. Although not yet found in nature, buxidienine-F has been synthesized from N-3-isobutyryl- (211)or
H R'
"
CH,OH
R 211 212 213 214
R'
(CH3)ZCHCO 0 C6H5C0 0
H
0
H
H
215 216 217
R =H R = (CH3),CHC0 R = C6H5C0
1.
STEROID ALKALOIDS
53
N-3-benzoylcyclobuxidine-F(212) via acidic hydrolysis to furnish cycloxobuxidine-F (213)(97). The latter compound upon LiAlH, reduction in dioxane gave an alcohol (214)which, after treatment with dilute sulfuric acid in dioxane, afforded a mixture containing buxidienine-F (215).Its structural formula was confirmed both by spectral methods (UV, IR, and PMR spectrometry) and, after N-acylation (with isobutyryl chloride or benzoyl chloride), by direct comparison with authentic samples of the respective N-isobutyryl- (216)and N-benzoylbuxidienine-F (217). i. Cycloprotobuxine-F. Cycloprotobuxine-F (218)was isolated from the bark of twigs and roots of Buxus madagascarica subsp. xerophila, forma salicicola and its structure was elucidated by chemical and physicochemical means (79). The base revealed PMR signals due to four tertiary and one secondary methyl, a cyclopropyl methylene, and a dimethylamino group. I n acetone 218 gave the N-3-isopropylidene derivative (219). Cycloprotobuxine-F, when treated with formic acid, furnished the N-3-formyl compound (220)which, upon LiAlH, reduction, yielded cycloprotobuxine-C (cf. Vol. IX, p. 388).
218
R H
219 220
H
R' H
(CH&C CHO
j. Cycloxobuxidine-F. Cycloxobuxidine-F (196) (11) should be the name of the alkaloid isolated from Buxus balearica, originally named buxidine-F (98). The name buxidine-F (210)had already been given t o another alkaloid (95,96). As shown in its spectra, cycloxobuxidine-F has a dimethylamins grouping a t C-20, a hydroxyl, a carbonyl group which is in conjugation with the cyclopropane ring, a primary amine, three tertiary and on2 secondary C-methyl, and a primary hydroxy group. When methylated
54
J. TOMKO AND
z.
VOTICK~
with methyl iodide 196 afforded a methiodide of cycloxobuxidine-A (221),thereby proving the deduced structure.
@
-.N°CH3 'CH, ,-OH
R'\
N
R' CHzOH 170 195 196 221
R (CH,),CHCO CaH5C0 H CH3
R1
H H H CH3
'CH3
CHzOH 0 223
k . N-3-Isobutyrylcycloxobuxidine-F (N-Isobutyrylbaleabuxidine-F). N-3-Isobutyrylcycloxobuxidine-F (N-isobutyrylbaleabuxidine-F) (170) (see Section 111, A, 3,e) was extracted from the leaves of Buxus balearica Willd. (10) and B. balearica Lam. (98, 99). The elucidation of the structure of this alkaloid was based upon the spectral measurements and correlation with cyclobuxazine-A (225).Thus, according to its I R absorption and PMR signals, 170 revealed the presence of three tertiary and one secondary C-methyl group, two methyls of the isobutyramide side chain, one dimethylamino group, one primary alcohol, one proton in the a-position to a secondary alcohol, and one proton adjacent t o the amido group. Moreover, the UV spectrum located the ketone in the neighborhood of the cyclopropyl methylene; this was confirmed also
1. S T E R O I D ALKALOIDS
55
by the positive CD curve. Mass spectrometry assigned the C-20 position to the dimethylamino group. On acetylation 170 afforded the 0,O'diacetyl derivative. (222)N-3-isobutyrylIn analogy with N-3-isobutyrylcycloxobuxine-F cycloxobuxidine-F (170) undergoes isomerization with boron trifluoride in benzene to yield iso-N-3-isobutyrylcycloxobuxidine-F(223). The amide 170 can be hydrolyzed in acidic medium to afford 196; this hydrolysis is promoted by the presence of the primary alcoholic function at C-4. Cycloxobuxidine-F (196) was reduced and hydrogenolyzed, without the cyclopropane ring being opened, with LiAlH, to furnish dihydrocyclomicrophylline-F (224) which, when N-methylated with formic acid-formaldehyde, gave cyclobuxoxazine-A (cf. Vol. IX, p. 399) (225) identical with that isolated from B. rolfei Vidal.
0
H, N H'
222
EH,OH 224
56
J . TOMKO AND Z . l70TICK$
1. N-3-Isobutyrylbuxidienine-F and N-Benzoylbuxidienine-F. N-3Isobutyrylbuxidienine-F (226) and N-benzoylbuxidienine-F (227) were isolated from Buxus balearica Willd. ( l o ) , the former also from B. balearica Lam. (99) and the latter from B. sempervirens (88a). Their structures were elucidated independently by two research groups; both results were based on physical data. From the UV spectrum it became apparent that a conjugated heteroannular diene comparable with that of buxamine-E and buxaminol-E (cf. Vol. IX, p. 405) is involved. The I R spectra showed the amide bands and the PMR spectra revealed the presence of three tertiary and one secondary C-methyl, one dimethylamino group, one primary alcohol, a proton adjacent to the secondary alcohol, and one amidic and two methylene protons. Moreover, 226 displayed signals of two methyls of the isobutyramide side chain whereas 227 showed benzamide substitution. The measured values are in accordance with the massspectrometric fragmentation pattern. N-Benzoylbuxidienine-F (227), when oxidized with chromium trioxide, gave a seemingly homogeneous oily product (88a).It was shown to be a mixture of the conjugated cis (228) and trans (229) enones. The formation of 228 and 229 indicated that oxidation with a subsequent deamination took place and provided evidence that the secondary hydroxyl in the parent alkaloid is at C-16. R-R’
226
227
R = (CH3)2CHC0 R = CeH5C0
228 229
R CH, H
R’ H CH,
m. N-Isobutyrylbaleabuxaline-F. N-Isobutyrylbaleabuxaline-F (230) was isolated from Buxus balearica (10).Its structure was deduced from spectral data. Thus the amide grouping was recognized in the I R spectrum; three tertiary and one secondary C-methyl, two methyls in the isobutyramide side chain, one dimethylamino group, the methylene of a primary alcohol, one proton adjacent to a secondary alcohol,
1.
STEROID ALKALOIDS
57
a proton in an amide grouping, and a single ethylenic proton were discerned in the PMR spectrum. On acetylation 230 gave an 0,O‘diacetyl derivative which was characterized by physical methods. The fourth oxygen seemed to constitute a tertiary alcohol in a position homoallylic to the double bond which, when removed by dehydration, led to a diene characteristic of buxamines (100). With these facts in mind it is reasonable to write the structural formula of N-isobutyrylbaleabuxaline-F as 230.
230
6 . Subgroup H
a. Buxaltine-H. Buxaltine-H (231) was obtained from Buxus sempervirens (90) by repeated chromatographic purification on alumina. Its spectral data revealed the presence of an ester group, a cyclopropyl methylene, and a benzamide grouping. The positive hydroxamic acid test, as well as the difference in molecular rotation between the base and its dihydro derivative, led to the assignment of structure 231. Further evidence of the structure is desirable.
)c=o,CH, CH=C ‘CH, 231
J. TOMKO AND z. VOTICKY
58
b. N-3-Isobutyrylcycloxobuxidine-H. N-3-Isobutyrylcycloxobuxidine -H (232)was found in Buxus balearica ( 1 1 ) . The first approach t o the structure determination used mass spectrometry which indicated the presence of a methylamino group a t C-20. The conjugated system formed by a carbonyl group in the neighborhood of a cyclopropyl methylene grouping was seen in the UV spectrum. I n the I R spectrum a secondary amide, a hydroxy, and a secondary amino group were observed. The positive CD curve was superimposable on that of N-3isohutyrylcycloxobuxidine-F(170). Signals in the PMR spectrum were interpreted as belonging to three tertiary and one secondary C-methyl, two side-chain methyls, one N-methyl, one primary and one secondary hydroxyl, and an amido proton. The degradation according to Rushig gave, after acidic hydrolysis, the conjugated ketone 233.Upon methylation of 232 with formaldehyde and formic acid a permethylated product (234)was obtained. The amino group a t C-20 in 232 was methylated by catalytic reduction in the presence of formaldehyde to yield N-3-isobutyrylcycloxobuxidine-F(170).
@::i3
,,-OH
'ZRR \ N
RCH,OH R'
RZ
H
(CH,),CHCO H (CH,),CHCO CH,
170 196
H
232 234
H CH,
CH, CH, H CH,
H" H'
@ O I'
CH,OH 233
B. MONOBASICB u x u s ALKALOIDS 1. Subgroup K
a. Cyclobuxosuflrine-K. Cyclobuxosuffrine-K (235)was isolated from the weak-base fraction of Buxus microphylla var. suflruticosa, forma major (81).This alkaloid displayed in its mass spectrum peaks indicative of 3P-dimethylamino substitution. Its I R and UV spectra showed the
1.
59
STEROID ALKALOIDS
presence of an a,P-unsaturated ketone, and the PMR spectrum revealed signals due to the cyclopropyl methylene and a C-4 methyl group in the a-configuration as in cyclobuxomicreine-K (240)(81).To confirm the assumed structural formula (235)the opposite C-4 /3-methyl stereoisomer of dihydrocyclobuxosuffrine-K (237) was synthesized by methylation of dihydrocyclobuxine-D (238)followed by oxidation and deamination. The cis and trans isomers 236 were hydrogenated to give 237. Cyclobuxosuffrine-K catalytically hydrogenated afforded 239 which was not identical with 237.
235
236
Cis
trans
239
R
R1
CH3 H
H CH,
238
60
J. TOMKO AND
z.
VOTICK~
b. Cyclobuxomicreine-K. Cyclobuxomicreine-K (240) occurs in the weakly basic fraction of the alkaloids obtained from B u x u s microphyllu var. suffruticosu (81). The UV and I R spectra indicated the presence of an a,P-unsaturated ketone system. The mass spectrum showed peaks characteristic of CH,-C=O+ ions and a fragmentaion pattern of a C-3 P-dimethylamino substitution. The signals in the PMR spectrum suggested the presence of a C-4 secondary methyl group and a cyclopropyl methylene. The configuration of the C-4 methyl group in 240
240
was inferred as follows. The positions of the cyclopropyl methylene protons in all synthetically prepared C-4 p-methyl derivatives were shifted approximately 0.20 and 0.29 ppm downfield when compared with those of 240. Alkaloids bearing a 4,4-dimethyl group exhibited the resonance of cyclopropyl protons at. nearly the same scale position as did the synthetic C-4 P-methyl derivatives. This observa,tion led to the conclusion that the fL(axia1) methyl group a t C-4 should be responsible for the large doN-nfield shift of the cyclopropyl methylene proton signals unless it was caused by the neighboring C-3 amino group. Therefore 3a- and 3p-aminated derivatives of cycloeucalenol (8) were subjected to PMR study. No appreciable differences in the positions of the cyclopropyl methylene proton signals in both series have been found. These signal positions were consistent with those observed in the naturally occurring C-4 methyl derivatives and, as the substituents at C-3 did not markedly affect the position of the cyclopropyl methylene proton resonance signals, there can be no doubt that the equatorial (a)orientation of the C-4 methyl group in 240 is correct. On catalytic hydrogenation over platinum oxide cyclobuxomicreineK (240) yielded the dihydroderivative 241. The 4P-methyl isomer (242) of cyclobuxomicreine-K was prepared by catalytic hydrogenation of buxpiine [cyclomicrobuxine-K (243)] and subsequent dehydration of the resulting dihydro derivative 244.
1.
STEROID ALKALOIDS
CH3\ NO&
CH3’
*‘
H 241
242
243
-*H .OH
CH3\ CH,’ N
;:)“:1“* H
244
61
62
J. TOMKO AND
z. VOTICKP
c. Cyclobuxophylline-K. Cyclobuxophylline-K (245) was isolated from the weakly basic fraction of Buxus microphylla var. suffruticosa, forma major (81).Structural formula 245, based on spectroscopic data, was confirmed by a partial synthesis starting from cyclomicrophylline-A (246) which was converted into the mono-p-toluenesulfonate (247).The latter was treated with mercaptomethylbenzene and sodium in dimethylformamide and the resulting monobenzylthio compound (248) was desulfurized to the 4,4-dimethyl derivative 249. Hydrogenation of 249 over platinum catalyst gave the dihydro derivative 250 (see Section 111,A, 3, d). Chromic acid oxidation of 250 and subsequent deamination of the resulting aminoketone afforded the cyclobuxophylline-K identical with that occurring in nature.
246 247 248 249
R R R R
= OH
245 257 258 259
= OSOZCpH4-CH3
= SCH1;CeHE =H
R R R R
= CH, =H
= CH3C0 = CaH,CO
d . Cyclomicrobuxeine-K. Cyclomicrobuxeine-K was obtained from Buxus microphylla var. suffruticosa (81).I n its spectra this alkaloid exhibited bands associated with a terminal methylene and a cisoid a,/?unsaturated ketone. Spectroscopic data indicate structure 251 for this
251
1.
63
S T E R O I D ALKALOIDS
base. The correctness of this presumption was established by direct comparison with the synthetically prepared substance obtained by dehydration of buxpiine-K[cyclomicrobuxine (243)l. 2. Subgroup L
a. Cyclobuxoviridine-L. Cyclobuxoviridine-L (252) present in Buxus microphylla var. suflruticosa, forma major (81) exhibited in its I R spectrum a characteristic absorption ascribable to a conjugated six-membered ketone moiety. The UV spectrum showed a maximum suggesting the presence of an a$-unsaturated six-membered ketone in conjugation with the cyclopropyl methylene group. Additional evidence for this grouping was provided by the PMR spectroscopy. Catalytic hydrogenation of cyclobuxoviridine-L afforded a saturated ketone (253) and an alcohol (254).The former, 253, was shown to be identical with the compound obtained by Rushig degradation of cycloprotobuxine-C (143); the latter was formulated on the basis of its I R and PMR spectra where
&
H
0
253
254
the 3a-proton appeared as a broad multiplet suggesting the 3P-hydroxyl orientation. These findings indicate structural formula 252 for cyclobuxoviridine-L.
64
J. TOMKO AND z. VOTICKY
b. Cyclomicuranine-L. Cyclomicuranine-L (255) was isolated from Buxus microphylla var. suflruticosa, forma major (81).The I R spectrum showed vibrations of a hydroxyl and a six-membered ring ketone. The PMR spectrum of 255 resembled that of cyclobuxoviridine (252). I n addition, the former displayed a signal of the C-16 P-proton split as a septet, thereby revealing the C-16 a-orientation of the hydroxy group. The presence of the C-20 a-dimethylamino group was clearly proved by the m/e 72 species in the mass spectrum. Cyclomicuranine-L revealed a negative Cotton effect curve typical of 4,4-dimethyl3-keto-5a-H-steroids. The structural formula satisfying all the data must therefore be 255.
255
c. Buxandonine-L. The structure assignment of buxandonine-L (256) occurring in Buxus sempervirens was deduced from the IR, UV, and mass spectroscopic data. Evidence for this assignment is to be published later (91).
H 256
3. Subgroup M
a. Buxanine-M. Buxanine-M (259) (see Section 111, B, 1, c) was reported to be (96) one of the alkaloids obtained from B. sempervirens.
1.
65
STEROID ALKALOIDS
Its I R spectrum was closely related to that of the cyclobuxophylline-K (245).N-Benzoylation of 257 afforded buxanine-M, thereby confirming its structure.
6. Cyclobuxophyllinine-M ( Buxenone-M). Cyclobuxophyllinine-M (257) (Section 111, B, 1 , c) was found in Buxus microphylla var. suffruticosa, forma major (81)and in B. sempervirens (94).Its characteristic spectral data showed a close similarity with those of cyclobuxophylline-K (245). When acetylated cyclobuxophyllinine-M (257) afforded the N-acetyl derivative 258. Upon N-methylation with methyl iodide 257 yielded 245, thus proving the proposed structural formula of cyclobuxophyllinine-M.
c. Cyclosuffrobuxinine-M and Cyclosuffrobuxine-K. These alkaloids were isolated from Buxus microphylla var. suffruticosa, forma major (81). Structures 312 and 260 were deduced from the spectral data. In the I R spectra there are bands apparently attributable to a conjugated double bond, a ketone, and an exomethylene group; in the UV spectra, to a conjugated ketone; in the PMR spectra, to a vinyl proton coupled with vinyl methyl and vice versa. To verify the presumed structures both alkaloids were prepared; the starting material was cyclobuxine-D (146) which was oxidized to give the proper amino ketone 261. The latter was deaminated and the resulting cis-+unsaturated cyclopentenone 260 was proved to be identical with cyclosuffrobuxinine-M and the N-methyl derivative thereof with cyclosuffrobuxine-K (312).
812 260
R = CH3 R =H
261
d . trans-Cyclosuffrobuxinine-M. trans-Cyclosuffrobuxinine-M (262) was found in the alkaloid mixture extracted from Buxus sempervirens (106) together with cis-cyclosuffrobuxinine-M (260). The isomers were separated by partition chromatography. Their mass spectra were superimposable and their IR spectra were virtually identical. Significant
66
J. TOMKO AND
z.
VOTICKY
differences between them were found in their PMR spectra which showed both substances to be geometrical isomers. The recorded chemical shifts of 262 were found to be in accordance with those reported for a structurally closely related and synthetically prepared trans-des-N’16-dehydrodihydrocyclobuxine(263) ( 1 0 6 ~ ) .
262
263
Compound 262 appeared to be the first alkaloid possessing a transoid C-2 1 methyl group in the a$-unsaturated pentacyclic ketone isolated up to now from Buxus plants. It has been shown that alkaloids with this structural feature resulted from the dibasic ones by deamination at C-20 during the isolation process (106).
e. N-methylbuxene-M. N-Methylbuxene-M (264) was reported to be the minor alkaloid accompanying buxene-0 (265) (103) in Bums sempervirens. As its name indicates 264 is the N-methyl derivative of buxene-0 as proved by methylation. 4. Subgroup 0
a. Buxene-0. Buxene-0 (265) was found in the alkaloid mixture obtained from Buxus sempervirens (102).The absorption maximum of 265
1.
67
STEROID ALKALOIDS
in the UV region was clearly associated with a conjugated enone chromophore, whereas the characteristic band in the IR spectrum displayed another carbonyl group. The high-resolution mass spectrum showed the molecular ion a t m/e 427, the base peak at m/e 128 (266), revealing the amido grouping at C-3 in 265 and the second most abundant peak a t m/e 338 (267)-the last originated from the McLafferty rearrangement and elimination of ethyl carbamate from 265. The proposed structural formula for buxene-0 was confirmed by correlation with cyclobuxophyllinine-M (257) (Section 111, B, 3, b).
0
0 264 365
R = CHB R =H
266
(+I*
267
C. ALKALOIDS OF UNKNOWN STRUCTURE 1. Alkaloid E
Alkaloid E (C,,H,,N,O,; from Buxus balearica (99).
mp 287-289"; [a],, +12O) was obtained
2. Buxazine
Buxazine (C,,H,,N,O,;
mp 238-239"; [aID
+ 93") was isolated from
Buxus sempervirens (101). Characteristic bands in the IR spectrum
J. TOMKO AND z. VOTICKY
68
suggested the presence of a hydroxyl and a secondary amide in the molecule. 3. BX-6 BX-6 (mp 207-212') was isolated from Buxus sempervirens (90). 4. BX-10 BX-10, found in Buxus sempervirens, was characterized only by its mp (221-224') (90). 5. Pseudobaleabuxine-F
Pseudobaleabuxine-F (C,,H,,N,O,; mp 236-240'; [.ID + 120.7")was isolated from the leaves of Buxus balearica (98, 99, 104). According to the spectroscopic data this seemed to be N-3-isobutyrylcycloxobuxine-F (baleabuxine-F) (222).Direct comparison of pseudobaleabuxine-F with an authentic sample of 222 showed a depression in the mixed melting point, and therefore it was concluded that the alkaloid under study is an epimer of 222. The structural difference, however, has not been ascertained. 6. B-387
This base of molecular formula C,,H,,NO,
(mp 188-189";
+ 6.7") was isolated from Buxus microphylla var. sinica (86a). D. SYNTHESES IN
THE
[.ID
Buxus ALKALOIDS
An approach to the total syntheses of cycloxobuxines (baleabuxines) (268), cycloprotobuxines (269) ( 9 ) , and also those Buxus alkaloids having a 9(10 + lg)-abeo-pregnane system as in buxenine (270) (107, 108), or buxidienines (271), and cycloxobuxidines (272) (97) has been (273) reported. 3~-Acetoxy-4,4,14a-trimethyl-5a-pregnane-ll,20-dione as a possible starting material for the synthesis of Buxus alkaloids has been synthesized from lanosterol (109).Also, the degradation of cycloartenol (7) to 3P-hydroxy-4,4,14a-trimethyl-9P719-cyclo-5a-pregnane11)20-one (274) (110)and to 3P-hydroxy-4,4,14a-trimethyl-5a-pregn-9( en-20-one (275) has been described (111). Since lanosterol (112) and cycloartenol (113) have been prepared synthetically, the named reactions are looked upon as formal total syntheses of Buxus alkaloids.
1 . STEROID ALKALOIDS
R1 R2
R 268 269 272
69
R
H H H H OH OH
0
H, 0
H OH
270 271
R' H OH
&&
Ho
,,
HO
275
;
274
Cycloartenol (7) can be transformed into cycloeucalenol (8) (114))or vice versa (115))and the removal of one or both C-4 methyl groups from 8 has been reported (116). I n order to construct the cyclopropane ring, 3P-acetoxy-4,4,14a-trimethyl-5a-pregnane-l1,20-dione (273)was reduced t o yield a mixture of 3/3,llp,20a- and 3P,llp,20P-triols (276).This mixture was acetylated and the resulting acetates were separated into C-20 enantiomers (277,
V
273
276
70
J. TOMKO AND
z.
VOTICKY
278). When in reaction with nitrosyl chloride, the BOP-isomer 278 furnished the corresponding 11p-nitrite 279 which, upon irradiation in iodine containing benzene, yielded the 19-iodo compound 280.
'CH,
0
0 277 278
R
R1
H COCHS
COCH, H
R R1 279 280
H
I
NO H
The latter was oxidized to the 11-0x0 derivative 281, cyclized to the proper cyclopropyl compound 282, and reduced to afford the diol283. The final ketone (284) obtained by oxidation of 283 was found to be identical with the authentic specimen (9).
&
HO
,,'
'
283
284
1.
STEROID ALKALOIDS
71
A synthetic approach to derivatives of the 9(10 +- 19)-ccbeo-5cl-pregnane system (10) was found during a study of the reduction of the C-11 carbonyl in 9p, 19-cyclosteroid analogs of Buxus alkaloids (107, 108). Kupchan and co-workers obtained two crystalline products upon Wolff-Kizhner reduction of 9p, 19-cyclo-5a-pregnane-3,11,20-trione-3,20-diethylene ketal (285). Structures 286 and 287 were assigned to these substances in which ring B enlargement had taken place during the reduction.
285
Detailed investigation of the Wolff-Kizhner reduction showed that the cyclopropane ring cleavage is of thermal origin (117). N-3-Isobutyrylcycloxobuxine-F (288) and N-3-isobutyrylcycloxobuxidine-P (170) possess a conjugated cyclopropane-ketone system the carbonyl function of which is particularly hindered; it does not react with borohydrides, and it forms neither oximes nor hydrazones at normal reaction conditions. When, however, N-3-isobutyrylcycloxobuxine-F (288) was heated with hydrazine hydrate in glycol, the hydrazone (290) could be isolated. When heated with sodium glycolate in glycol, this hydrazone, resulting from the thermolytic cleavage afforded 291. The latter was identical with that obtained from N-3-isobutyrylcycloxobuxine-F and hydrazine hydrate in sodium glycolate containing glycol. The rupture of the cyclopropane ring makes the keto function at C-11 more readily accessible so that it can react normally. (288) was heated under the When N-3-isobutyrylcycloxobuxine-~ same reaction conditions ( L e . , either in glycol or in sodium glycolate containing glycol), a y , &unsaturated ketone (289) was isolated. The stereochemistry of N-3-isobutyrylcycloxobuxine-F favored such a rupture and the product of thermolysis was identical with that obtained previously by attempted Hofmann degradation of 288. The same reaction course as for 288 is encountered when heating N-S-isobutyrylcycloxobuxidine-F (170) with sodium glycolate in glycol, excepting that
72
J. TOMKO AND z. VOTICK$
286 287
IOa-H
lo,$-H
ti
0
291
73
1. STEROID ALKALOIDS
the isobutyryl group undergoes hydrolysis. This saponification is promoted by the neighboring primary alcoholic function. On the other hand, when N-3-isobutyrylcycloxobuxidine-Fwas subjected to the Wolff-Kizhner procedure a cyclization product was isolated to which structure 292 was assigned and for which a mechanism (170) was proposed. Additional support for this assumption has been given by the WolffKizhner reduction of cyclolaudane- 1,3-dione (293) (118). To prepare the latter cyclolaudan-3-one (294) was brominated to the Za-bromo derivative, dehydrobrominated, epoxidated, and reduced. The diol (295) thus obtained was oxidized and the required product reduced according to the Wolff-Kizhner procedure to furnish cyclolaudane (296). Hence it follows that the cleavage of the cyclopropane ring in the 1 1-keto system is thermolytic and probably the steric arrangement of the carbonyl in question is involved.
B 170
CH,OH 292
293 294 295 296
R
R'
0
0
Hz
0
H / H,
Ho\ H . Hz
J. TOMKO AND z.
74
VOTICKP
Further approach to buxidienines (271) starting from Buxus alkaloids having a SP,lS-cyclopropane ring and a carbonyl function at C-11 lay in the LiAlH, reduction to yield the corresponding 11P-alcohol (97). After standing in dilute sulfuric acid this alcohol furnished a mixture containing buxidienine. The elimination of nitrogen at C-3 and/or C-20 was investigated in Buxus alkaloids having a cyclopropane ring and a carbonyl or hydroxy function in the C-11 position (119).It has been shown (11)that cycloxobuxidine-F (196 p. 54) furnished, in a Rushig reaction, two products, 297 and 298. On the other hand, under the same reaction conditions, cycloxobuxazine-C (168) yielded a C-3 ketone (299)with the 4-primary alcoholic function retained. Alkaline treatment of the latter afforded the retroaldolization product 297 which was identical with that obtained from cycloxobuxidine-F (196). Since the tertiary amine at C-20 in N-3-isobutyrylcycloxobuxidine-F(170) resisted degradation attempts
297
298
299
by the Hofmann method other possibilities of removal were studied (119). Thus thermolysis of N-3-isobutyrylcycloxobuxidine-Fat about 200°C led to the cleavage of the bond between C-9 and C-10 and formation of a C-1=C-10 double bond, whereas heating at 90°C under diminished pressure afforded a cisoid unsaturated ketone (300). On oxidation
75
1 . STEROID ALKALOIDS
this substance furnished in the D ring a conjugated enone (301). It has been pointed out (81)that some of the Buxus alkaloids of this type may be artifacts produced from the corresponding precursors of general formula 302 during the isolation process. To verify this hypothesis the extract of Buxus alkaloids in dilute acetic acid solution was made alkaline with sodium hydroxide in an airtight apparatus a t room temperature and, while passing pure nitrogen through the mixture, alkaline reacting gases were trapped in dilute hydrochloric acid (106).Hydrochlorides of volatile bases thus obtained were identified by means of mass spectrometry and paper chromatography. Methylamine and ammonia were shown to be the bases which were liberated from the mixture of alkaloids. This and the occurrence of both cis and trans isomers of cyclosuffrobuxinine-M (260 and 262) were arguments supporting the view that all Buxus alkaloids characterized by a n a$unsaturated cyclopentenone might be decomposition products.
300
301
302
An attempt to methylate cycloxobuxidine-F (196)or cycloxobuxidine-
H by formaldehyde and formic acid to obtain cycloxobuxidine-A resulted in failure; instead cycloxobuxoxazine-A (303) was obtained. However, when methylated in a n acidic medium, cycloxobuxidines possessing an amido function a t C-3 undergo a migration of the acyl
76
J. TOMKO AND z. VOTICK$
group from the amino to the adjacent primary alcohol so that no cyclization can occur as it does with cycloxobuxidines-3’ and -H (11).
303
Recently a revision of the assignment of the C-4 methyl group in cyclobuxamine-H (304) and the conversion of cyclobuxine-D (146) into cyclobuxosuffrine-K (235) has been described (82). Brown and Kupchan (120)inferred that the configuration of the C-4 methyl group in cyclobuxamine-H is /3 (axial) whereas that of its C-4 epimer, dihydrocyclobuxine-H, is a (equatorial).
304
Nakano and Votick9 (82,121)provided evidence that the hydrogenation of cyclobuxine-D afforded dihydrocyclobuxine-D (305) with the C-4 methyl group ,&oriented. During Rushig degradation the C-4 methyl group was epimerized to the more stable a (equatorial) configuration. It follows that cyclobuxamine-H, whose configuration is the opposite of that with the methyl group a t C-4, is the a-epimer as shown in 304. To confirm the supposed C-4 a-orientation of the methyl group also in cyclobuxosuffrine-K (235)) cyclobuxine-D (146) was converted into dihydrocyclobuxosuffrine-K (306) as illustrated in Scheme 1. The identity of both products proved the a-orientation of the C-4 methyl group in 235.
77
1. STEROID ALKALOIDS
-
1 . CIO3 2. KOH
146
eH@ 0 1 . Ha/Pt
2 . LiAIH4
3. Rushig
1. HzNOH 2. LiAlHI 3. N-Methyl 4. Oxidat.
0
CH3,
N
’’
CH3/
H
@(p
H 306
SCHEME 1
@ O
CH,\
CH3\
N CH3’
1
i 140
307
N
:
H
CH,/
,’
k
R
=H R = OH
30 8
H \ N &O--OH
CH,’
309
78
J. TOMKO AND
z.
VOTICKY
810
811
IV. Biosynthetic Notes Mothes and Schiitte have summarized the work on the biosynthesis of steroidal alkaloids (122). Schreiber suggested possible biogenetic relationships for fruitful experimentation in the living plant system (123,124).Khuong-Huu (125)assumed that the reactive 1l-keto-9P,19cyclo system encountered in some Buxus alkaloids might be the biogenetic precursor of bases characterized by the conjugated transoid diene arrangement as, for example, in buxenines (270). Although much work has been done on the biosynthesis of steroids and steroid alkaloids, only a few papers dealing with the biosynthesis in Veratrum plants have been published (63, 126, 127). Experiments on the biosynthesis of Buxus alkaloids still await publication. Kaneko et al. proposed that cholesterol is an important precursor in the biosynthesis of Veratrum alkaloids (126). Cholesterol [4-14C]-3phosphate and cholesterol L26-14C] were used as precursors in Veratrum grandi&wum Loesen. fil. to establish them as biological precursors of Veratrum alkaloids. Cholesterol was incorporated in very small quantities (0.0107,)only in jervine and veratramine. Cholesterol [4-14C] fed to V . album subsp. lobelianum by the cotton wick method was found not to be incorporated into jervine and veratroylzygadenine (128). Acetate [ 1-14C]wa5 incorporated into alkaloids of the solanidanine, jervanine, veratranine, and cevanine groups. Nonradioactive 1 l-deoxojervine inhibited the incorporation of acetate [ 1-14C]into jervine. The biosynthetic activity of veratramine was affected by the concentration of jervine in the plant organ which synthesized the steroidal alkaloids. 1l-Deo~ojervine-~~C was converted into jervine but not into veratramine in the growing Veratrum plants (127).Ethioline has been found t o be an important precursor in solanidine biosynthesis in V . grandi$orum (63).
1. STEROID ALKALOIDS
79
REFERENCES 1 . S. M. Kupchan and A. W. By, i n “The Alkaloids” (R. H . F. Manske, ed.), Vol. X, pp. 193-285. Academic Press, New York, 1967. 2. V. Cern9 and F. sorm, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. I X , pp. 305-426. Academic Press, New York, 1967. 3. K. Schreiber, Pure A p p l . Chem. 21, 131 (1970). 4. Y. Sat0 and K. S. Brown, Jr., in “Chemistry of the Alkaloids” (S. W. Pelletier, ed.), pp. 591-667. Van Nostrand-Reinhold, Princeton, New Jersey, 1970. 5. R. Goutarel, “The Alkaloids,” (J.E. Saxton, senior reporter) Vol. I, p. 407. Chemical Society, London, 1971. 6. R. F. Raffauf, “A Handbook of Alkaloids and Alkaloid Containing Plants.” Wiley (Interscience), New York, 1970. 7. I.U.P.A.C. Inform. Bull. No. 33, 454 (1968). 7a. T. Nakano, S. Terao, Y. Saeki, and K. D. Jin, J . Chem. SOC.C 1805 (1966). 8. D. Herlem-Gaulier, F. Khuong-Huu-Lain&,E. Stanislas, and R. Goutarel, Bull. SOC.Chim. Fr. [5] 657 (1965). 9. T. Nakano, M. Alonso, and A. Martin, Tet. Lett. 4929 (1970). 10. F. Khuong-Huu, D. Herlem-Gaulier, Q. Khuong-Huu, E. Stanislas, and R. Goutarel, Tetrahedron 22, 3321 (1966). 11. D. Herlem-Gaulier, F. Khuong-Huu-Lain&,and R. Goutarel, Bull. SOC.Chim. Fr. [5] 763 (1968). 12. J. P. Calame, Ph.D. Thesis, Eidg. Techn. Hochschule Zurich (1965). 13. A. Stoll and E. Seebeck, J . Amer. Chem. SOC.74, 4728 (1952). 14. A Stoll, D. Stauffacher, and E. Seebeck, Helw. Chim. Actu 38, 1964 (1955). 15. G. N. Reeke, J r . , R. L. Vincent, and W. N. Lipscomb, J . Amer. Chem. SOC. 90, 1663 (1968). 16. H. Suginome, I. Yamazaki, H. Ono, and T. Masamune, Tet. Lett. 5259 (1968). 17. H. Suginome, N. Sato, and T. Masamune, Tetrahedron 27, 4863 (1971). 18. 0.Wintersteiner, M. Moore, and B. M. Iselin, J . Amer. Chem. SOC.76, 5609 (1954). 19. 0. Wintersteiner and M. Moore, J . Amer. Chem. Soe. 78, 6193 (1956). 20. T. Masamune, M. Takasugi, A. Murai, and K. Kobayashi, J . Amer. Chem. SOC.89, 4521 (1967). 21. S. M. Kupchan and M. I. Suffness, J . Amer. Chem. SOC.90, 2730 (1968). 22. B. M. Iselin, M. Moore, and 0. Wintersteiner, J . Amer. Chem. SOC.78, 403 (1956). 23. J. W. Scott, L. J. Durham, H. A. P. de Jongh, U. Burckhardt, and W. S. Johnson, Tet. Lett. 2381 (1967). 24. T. Masamune, Y. Mori, M. Takasugi, and A. Murai, Tet. Lett. 913 (1964). 25. T. Masamune, I. Yamazaki, and M. Takasugi, Bull. Chem. SOC. Jap. 39, 1090 (1966). 26. 0. Wintersteiner and M. Moore, J . Amer. Chem. SOC.75, 4938 (1953). 27. T. Masaniune, A. Murai, H. Ono, K. Orito, and H. Suginome, Tet. Lett. 255 (1969). 28. T. Masamune, K. Orito, and A. Murai, Tet. Lett. 251 (1969). 29. T. Masamune, A. Murai, K. Orito, H. Ono, S. Numata, and H . Suginome, Tetrahedron 25, 4853 (1969). 30. T. Masamune, K. Kobayashi, M. Takasugi, Y. Mori, and A. Murai, Tetrahedron 24, 3461 (1968). 31. S. M. Kupchan and M. J. Abu El-Haj, J. Org. Chem. 33, 647 (1968). 32. T. Masamune and K. Orito, Tetrahedron 25, 4551 (1969). 33. S. M. Kupchan, A. W. By, and M. S. Flom, J . Org. Chem. 33, 911 (1968). 34. T. Masamune, A. Mnrai, and S. Numata, Tetrahedron 25, 3145 (1969). 35. R. F. Keeler, Phytochemistry 7, 303 (1968).
J. TOMKO AND z. VOTICKY
80 36. 37. 38. 39. 40. 41. 42.
43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69.
R. F. Keeler and W. Binns, Can. J . Biochem. 44, 819 (1966). R. F. Keeler, Steroids 13, 579 (1969). R . F. Keeler, Phytochemistry 8, 223 (1969). J. Tomko and Bauer, Collect. Czech. Chem. Commun. 29, 2570 (1964). T. Masamune, I. Yamazaki, K. Orito, and M. Takasugi, Tetrahedron 27, 3387 (1971). J. P. Kutney, J. Cable, W. A. F. Gladstone, H. W. Hanssen, E. J. Torupka, and W. D. C. Warnock, J . A m e r . Chem. SOC. 90, 5332 (1968). J. P. Kutney, A. W. By, J. Cable, W. A. F. Gladstone, T. Inaba, E. J. Torupka, and W. D. C. Warnock, Communication on the I n t . S y m p . Chem. Natur. Prod. 5th, 1968. H. Mitsuhashi and K. Shibata, Tet. Lett. 2281 (1964). W. F. Johns and I . Laos, J . Org. Chem. 30, 4220 (1965). R. M. Evans, J. C. Hamlet, J. S. Hunt, P. G. Jones, A. G. Long, J. F. Oughton, L. Stephenson, T. Walker, and B. M. Wilson, J . Chem. SOC.,4356 (1956). W. G. Dauben and J. F. Eastham, J . Amer. Chem. SOC. 73, 4463 (1951). W. S. Johnson, H. A. P. de Jongh, C. E. Coverdale, J. W. Scott, and U. Burckhardt, J . Amer. Chem. SOC.89, 4523 (1967). W. S. Johnson, J. M. Cox, D. W. Graham, and H. W. Whitlock, Jr., J . Amer. Chem. SOC.89, 4524 (1967). T. Masamune, M. Takasugi, and A. Murai, Tetrahedron 27, 3369 (1971). J. P. Kutney, J. Cable, G. Vijayr Nair, and W. D. C. Warnock, Private Communication J . W. Huffman, D. M. Alabran, and A. C. Ruggles, J . Org. Chem. 33, 1060 (1968). P. W. Sprague, D. Doddrell, and J. D. Roberts, Tetrahedron 27, 4857 (1971). J. Tomko and A. VassovB, Pharmazie 20, 385 (1965). J. Tomko, Z. Votick?, H. Budzikiewicz, and L. J. Durham, Collect. Czech. Chem. Commun. 30, 3320 (1965). S. ItB, T. Ogino, and J. Tomko, Collect. Czech. Chem. Commun. 33, 4429 (1968). R. Hirschmann, C. S. Snoddy, Jr., C. F. Hiskey, and N. L. Wendler, J . Amer. Chem. Soc. 76, 4013 (1954). J. Tomko and A. VassovB, Chem. Zvesti 25, 69 (1971). A. L. Shinkarenko and N. V. Bondarenko, K h i m . Prir. Soedin. 293 (1966); C A 65, 20509 (1966). A. L. Shinkarenko and N. V. Bondarenko, Rast. Resur. 2, 45 (1966). N. V. Bondarenko, Zh. Obshch. Khim. 37, 332 (1967). N. V. Bondarenko, A. L. Shinkarenko, and G. J. Gerashczenko, K h i m . Prir. Soedin. 440 (1970). T. Masamune, Y . Mori, M. Takasugi, A. Murai, S. Ohuchi, N. Sato, and N. Katsui, Bull. Chem. SOC. J a p . 38, 1374 (1965). K. Kaneko, M. Watanabe, Y. Kawakoshi, and H. Mitsuhashi, Tet. Lett. 4251 (1971). J. Tomko and A. VassovB, Chem. Zvesti 18, 266 (1964). G. Adam, K. Schreiber, and J. Tomko, Ann. 707, 203 (1967). J. Tomko, G. Adam, and K. Schreiber, J . Pharm. Sci. 56, 1039 (1967). K. Schreiber and G. Adam, Ann. 666, 155 (1963). A. M. Khasimoff, R. Shakiroff, and S. Yu. Yunusoff, Khim. Prir. Soedin. 343 (1970). A. M. Khasimoff, R. Shakiroff, and S. Yu. Yunusoff, Khim. Prir. Soedin.339 (1970).
s.
1.
STEROID ALKALOIDS
81
70. J. Tomko, A. VassovP, G. Adam, K. Schreiber, and E. Hohne, Tet. Lett. 3907 (1967). 71. J. Tomko, A. VassovB, G. Adam, and K . Schreiber, Tetrahedron 24, 4865 (1968). 72. E. Hohne, G. Adam, K . Schreiber, and J. Tomko, Tetrahedron 24, 4875 (1968). 73. H. Ripperger, K. Schreiber, and G. Snatzke, Tetrahedron 21, 1027 (1965). 74. J. Tomko, A. VassovB, G. Adam, and K. Schreiber, Tetrahedron 24 6839 (1968). 75. G. Adam, K . Schreiber, J. Tomko, Z. Votickj., and A. Vassovs, Tet. Lett. 2815 ( 1968). 76. J . Tomko, A. VassovB, Z . Votickj., G. Adam, and K. Schreiber, Collect. Czech. Chem. Commun. 33, 4054 (1968). 77. J . Tomko, V. BrBzdovB, and Z . Votickj., Tet. Lett. 3041 (1971). 78. J. H. Chu, Acad. Sci. Sinica, Shanghai (personal communication, 1964). 79. F. Khuong-Huu, R. Paris, R. Razafindrambao, A. Cav6, and R. Gontarel, C . R. Acad. Sci., Ser. C 558 (1971). 80. W. Dopke, B. Muller, and P. W. Jeffs, Pharmazie 23, 37 (1968). 81. T. Nakano, S. Terao, and Y. Saeki, J . Chem. SOC.C 1412 (1966). 82. T. Nakano and Z. Votickj., J . Chem. SOC.C 590 (1970). 83. E. Schlittler, K. Heusler, and W. Friedrich, Helv. Chim. Acta 32, 2209 (1949). 84. E. Schlittler and W. Friedrich, Helv. Chim. Acta 33, 878 (1950). 85. W. Dopke and B. Muller, Naturwiss. 54, 200 (1967). 86. Z. Votickj., V. Paulik, and B. Sedlsk, Chem. Zvesti 23, 702 (1969). 86a. 0. BauerovB and Z. Votickj., Pharmazie (1972) (in press). 87. F. Khuong-Huu and M. J. Magdeleine, Ann. Pharm. Fr. 28, 211 (1970). 88. F. Khuong-Huu-Lain6, M. J . Magdeleine, N. G. Bisset, and R. Goutarel, Bull. SOC.Chim. Fr. [5] 758 (1966). 88a. S. M. Kupchan, R. M. Kennedy, W. R. Schleigh, and G. Ohta, Tetrahedron 23, 4563 (1967). 89. D. Herlem-Gaulier, F. Khoung-Huu-Lain& and R . Goutarel, Bull. SOC.Chim. Fr. [5] 3478 (1966). 90. W. Dopke and B. Muller, Pharmazie 24, 649 (1969). 91. W. Dopke and B. Muller, Pharmazie 22, 666 (1967). 92. W. Dopke, B. Muller, G. Spiteller, and M. Spiteller-Friedmann, Tet. Lett. 4247 (1967). 93. W. Dopke, B. Muller, and P. W. Jeffs, Naturwiss. 54, 249 (1967). 94. W. Dopke, B. Muller, and P . W. Jeffs, Pharmazie 21, 643 (1966). 95. W. Dopke and B. Muller, Naturwiss. 52, 61 (1965). 96. W. Dopke and B. Muller, Pharmazie 21, 769 (1966). 97. D. Herlem, F. Khuong-Huu and R. Goutarel, C. R. Acad. Sci., Ser. C 798 (1967). 98. I. 0. Kurakina, N. F. Proskurnina, A. U. Stepanyants, and D. M. Mondeshka, Khim. Prir. Soedin., 231 (1970). 99. I. 0. Kurakina, N. F. Proskurnina, and P. N. Kibaltchich, Khim. Prir. Soedin., 26 (1969). 100. D. Stauffacher, Helv. Chim. Acta 47, 968 (1964). 101. W. Dopke and B. Muller, Naturwiss. 52, 61 (1965). 102. W. Dopke, R. Hartel, and H. W. Fehlhaber, Tet. Lett. 4423 (1969). 103. A. VassovB, J. Tomko, Z. Votickj., and J. L. Beal, Pharmazie 25, 363 (1970). 104. I. 0. Kurakina, N. F. Proskurnina, and A. U. Stepanyants, Khim. Prir. Soedin. 406 (1969). 105. B. U. Khodzhayeff, R. Shakiroff, and S. Yu. Yunusoff, Khim. Prir. Soedin. 542 (1971).
82
J. TOMKO AND
z.
VOTICK+
106. Z. Votickj. and V. Paulik, Chem. Zvesti 26, 376 (1972). 106a. K. S. Brown, Jr. and S. M. Kupchan, J . Amer. Chem. SOC.86, 4414 (1964). 107. S. M. Kupchan and E. Abushanab, Yet. Lett. 3075 (1965). 108. S. M. Kupchan, E. Abushanab, K. T. Shamasundar, and A. W. By, J . Amer. Chem. SOC.89, 6327 (1967). 109. W. Voser, 0. Jeger, and L. Ruzicka, Helv. Chim. Actu 35, 503 (1952). 110. G. Adam, B. Voigt, and K. Schreiber, J . Prakt. Chem. [4] 312, 1027 (1970). 111. G. Adam, B. Voigt, and K. Schreiber, J . Prakt. Ghem. [4] 312, 1063 (1970). 112. R. B. Woodward, A. A. Patchett, D. H. R. Barton, D. A. J. Ives, and R. B. Kelly, J . Chem. Soc., 1131 (1957). 113. D. H. R . Barton, D. Kumari, P. Welzel, L. J. Danks, and J. F. McGhie, J . Chem. SOC., C 332 (1969). 114. F. F. Knapp and H. J. Nicholas, J . Chem. SOC.D 399 (1970). 115. J. S. G. Cox, F. E. King, and T. J. King, J . Chem. SOC., 514 (1959). 116. R. Kazlauskas, J. T. Pinhey, J. J. H. Simes, and T. G. Watson, J . Chem. SOC.D 945 (1969). 117. F. Khuong-Huu, D. Herlem, and J. J. H. Simes, BulLSoc. Chim. [5] Fr. 258 (1969). 118. F. Khuong-Huu, D. Herlem, and M. BBnBchie, Bull. SOC.Chim. Fr. [5] 2702 (1970). Chim. [5] Fr. 256 (1969). 119. F. Khuong-Huu, D. Herlem, and A. Milliet, Bull. SOC. 120. K. S. Brown, Jr. and S. M. Kupchan, J . Amer. Chem. SOC.86, 4430 (1964). 121. Z. Votickj., “Epimerizations of some Buzus alkaloids,” Communication on the Conference of Czechoslovakian Chemists, High Tetras, 197 1. 122. K. Mothes and H. R. Schutte, “Biosynthese der Alkaloide,” VEB Deut. Verlag Wiss., Berlin, 1969. 123. K. Schreiber, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. X, p. 115. Academic Press, New York, 1967. 124. K. Schreiber, Abh. Deuts. Akad. Wiss. Berlin p. 69 (1969). 125. F. Khuong-Huu, D. Herlem, and M. BBnBchie, Bull. SOC.Chim. Fr. [5] 1092 (1972). 126. K . Kaneko, H. Mitsuhashi, K. Hirayama, and S. Ohmori, Phytochemistry 9, 2501 (1970). . , 127. K. Kaneko, H. Mitsuhashi, K. Hirayama, and N. Yoshida, Phytochemistry 9, 2490 (1970). 128. E. Grossman, V. BrBzdovB, M. ZemBnek, and J. Tomko, unpublished data (1970/ 1971).
Note added in Proof. The stereochemistry of zygadenine, germine, protoverine, and related Veratrum alkaloids (R. F. Bryan, R. J. Restivo, and S. M. Kupchan, J. Chem. SOC. Perkin 11, in press), as well as of tetrahydroveralkamine derivatives [E. Hohne, I. Seidel, G . Adam, K. Schreiber, and J. Tomko, Tetrahedron 28, 4019 (1972)l was established by X-ray analysis.
-CHAPTER
2-
OXINDOLE ALKALOIDS JASJITS. BINDRA Medical Research Laboratories, Pfizer Inc. Croton, Connecticut
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............ 11. Oxindoles of Celsemium Species ................................ A. Gelsemine.. . . . . . . . . . . . . . . ................................ B. Gelsemicine and Gelsedine ........................... C. Gelsevirine ................................. 111. Oxindoles of Secoyohimbane and Heteroyohimbane Type . . . . . . . . . . . . . . . . A. Introduction . . . . . . . . B. Occurrence ..................................................... IV. Secoyohimbane-Type Oxindoles . . . ...... B. Conformational Analysis . . . . C. Rhynchophylline and Isorhync ........................... D. Rotundifoline and Isorotundifoline ................................ E. Rhynchociline and Ciliaphylline ...................... F. Specionoxeine and Isospecionoxeine ................................ G. Corynoxeine ................................. H. Corynoxine and Isocorynoxine .......................... I . Mytragynine Oxindoles A and .......................... J. Speciofoline ..................... .......................... V. Heteroyohimbane-Type Oxindoles .......................... A. Structure ....................................................... B. Conformational Analysis ......................................... C. Mitraphylline and Isomitraphylline . . . . . . . . . D. Formosanine and Isoformosanine ..... .......................... E. Rauvanine Oxindoles A and B . . ............................. F. Pteropodine, Isopteropodine, Speciophylline, and Uncarine-F ... G. Carapanaubine, Isocarapanaubine, Rauvoxinine, and Rauvoxine H. Rauniticine Oxindoles ............................................ I. Majdine and Isomajdine .......... J. Miscellaneous . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References .........................................................
84 84 84 90 92 92 94
103 104 105 106 107 107 108 108 108 108 111 113 113 113
116 117 118 119
84
J A S J I T S. BINDRA
f. Introduction The growing family of oxindole alkaloids represented 5-6y0 of the known naturally occurring indole alkaloids in 1967 (1).Although no new members have been added to the original four oxindoles isolated from the roots of Gelsemiurn sempervirens Ait., additions continue to be made to the list of oxindoles isolated from Aspidosperma, Mitragyna, Ourouparia, RauwolJia, and Vinca. The recent application of modern techniques of structural analysis, notably proton magnetic resonance (PMR), I3C magnetic resonance (CMR), mass spectrum, and circular dichroism (CD), has had considerable impact upon elucidation of the structure of oxindole alkaloids and has assisted greatly in laying bare the finer details of their stereochemistry and conformation. Previous reviews (2-7) make it unnecessary t o reexamine earlier aspects of the chemistry of oxindole alkaloids and, even though this chapter may be regarded as a supplement to the material which has already appeared in these volumes (2-6), important physical properties of most of the known oxindole alkaloids have been included in tabular form for purpose of comparison and t o provide a comprehensive overview of the members of this group.
11. Oxindoles of Gelsemiurn Species
A. GELSEMINE After extensive degradative studies the structure of gelsemine was eventually breached in 1959 by X-ray crystallographic studies of Love11 and co-workers (8) and independently in the same year by Conroy and Chakarbarti (9) on the basis of PMR and biogenetic considerations ( 3 , 7 ) . Since that time, however, although additional degradative work has been scarce, various sophisticated physical tools continue to be matched against the complex hexacyclic structure of gelsemine (1). Recently the mass spectrum of gelsemine has been investigated and the molecule found to undergo fragmentation by two principle pathways upon electron impact (10).The most intense ion in the gelsemine spectrum occurring a t m/e 108 (M-214) is characteristic of the fragmentation pathway (a), while a second mode of fragmentation (b) results in the ion a t m/e 279, probably by extrusion of N , as CH,=N-CH,. A further loss of elements of ethylene emanating from the m/e 279 peak gives rise to the ion a t m/e 251 and is confirmed by a metastable at m/e 225.8. A peak a t m/e 120 is attributed t o the formation of l-methyl3-vinylpyridinium ion.
2.
85
OXINDOLE ALKALOIDS
N-
1
(?i3 pCH +
HN
0'
m/e 108
m/e 279
86
JASJIT S. BINDRA
The 220 MHz PMR spectrum of gelsemine has been recorded (10) and reveals a wealth of detail not previously evident in the 60 M H z spectrum. Each proton of the aromatic region is clearly visible along with the three symmetrically split quartets for the vinyl group as noted earlier (9). The C-17 methylene protons appear as a pair of geminally coupled double doublets a t 4.10 and 3.91 6 (J = 11.0 and 2.0 cps) in which the smaller coupling is indicative of a vicinal C-16 proton in the system /
-0-CH,-CH/
\
. The N,-methylene (C-21) protons must be adjacent
to a tertiary carbon, since they appear as a pair of doublets a t 2.32 and 2.786 and exhibit no additional coupling. The magnitude of the observed spin-spin coupling constant (J = 10 cps) is in accord with an isolated pair of geminally coupled protons a t C-21. The coupling constant between C-5 and C-6 protons is negligible; therefore both methines TABLE I I3C NMR CHEMICAL SHIFTSOF Gelsemium ALKALOIDS (10, 13)
c-2 c-3 c-5 C-6 c-7 c-8 c-9 c-10
c-11 c-12 (3-13 (2-14 (2-15 C-16 (2-17 (3-18 (2-19 (2-20 (2-21 NMe N,Me OMe a
13.1b 122.9 120.4 151.9 138.4 60.3 64.4" 70.7 64. la 83.4 51.8 169.5 154.3 156.5 131.0 80.2 53.6 138.4 126.2 141.7
123.2 121.5 153.9 138.0 -
169.Sa 155.3 156.6 131.0 183.0 171.0" 140.3 129.1 142.9
136.2 121.7 121.7 152.8 140.1 74.5 64.9 83.5 64.9 93.8 42.0 169.1Q 155.9 156.2 130.9 182.6 170.3" 140.1 129.5 139.0
These values may be interchanged. Chemical shift values in ppm upfield from CS,.
17.7 117.8 126.Sa 158.4 139.4 60.4 66.9 68.7 64.3 85.2 54.1 170.9 157.6a 150.4" 128.5 180.4 170.9 132.7"
129.0
19.3 122.9 120.0 151.8 140.0 64.2 64.2 69.7 64.2 85.1 52.7 169.2 154.3 156.2 130.9 79.3 54.0 138.2 126.1 141.2 __ 129.3
2 . OXINDOLE ALKALOIDS
87
appear as singlets at 3.47 and 1.97 6, respectively. The signal for the 0-methine proton (C-3), however, is comprised of a doublet at 3.79 S ( J = 2.8), presumably as a result of coupling with only one of the C-14 methylene protons. The latter appear as multiplets a t ca. 2.0 and 2.37 S. Recent advances in the area of I3C natural abundance magnetic resonance spectroscopy (11)and accumulation of a reservoir of chemical shift data have made possible the application of this powerful new analytical method in the field of natural nitrogenous substances (12). The signals for all twenty carbons in CMR of gelsemine have been assigned (Table 1) and this constitutes the first CMR analysis of an alkaloid (13).The chemical shifts of carbonyl carbon (C-2), the tertiary carbons (C-7, 8 , 13, and 20), the terminal vinyl (C-lS), the saturated methylene group at C-14, and the N-methyl group are directly assigned by application of chemical shift theory and single-frequency decoupling. The remaining chemical shifts of gelsemine are deduced by comparison with simple models and, where ambiguities remain, by comparison with the CMR spectra of a dihydro and tetrahydro derivative taking advantage of the environmental dissimilarity of some of their carbon centers. Thus saturation of the vinyl group would be expected to affect
t
2
x=o
3
X=Hz
the neighboring C-21, C-6, and C-15 more strongly than C-17 and C-16 which are located much farther away. The CMR of 18,19-dihydrogelsemine ( 2 ) shows that of the two methylene protons at 126.5 and 131.0 ppm in the spectrum of gelsemine only the lower-field signal is affected during the transformation 1 -+ 2. Consequently, this signal must be assigned to C-21, and the signal a t 131.0 ppm must belong to C-17. Similarly, the c-16 methine signal at 156.6 ppm is distinguished from the C-6 and C-15 methines, both of which suffer upfield shifts of 1-2 pprn in the spectrum of the dihydro derivative. The latter two methines are readily distinguished from each other by a comparison of the CMR of
88
JASJIT S. BINDRA
dihydrogelsemine with 2-deoxo-2,2,18,19-tetrahydrogelsemine(3).Reduction of the oxindole carbonyl group reveals the vicinal C-3 and C-6 which are affected to a much greater extent than C-5 and C-15. The C-6 methine shows a downfield shift, while C-15 is virtually unaffected. The remaining two saturated methines, namely C-3 and C-5, are attached to heteroatoms and consequently appear downfield with respect to the other methines. Of these, only the signal at 123.2 ppm is affected upon removal of the oxindole carbonyl and must therefore represent C-3. It follows that the remaining sign&! at 121.5 belongs to C-5. Assignment of the chemical shift values to the methines in gelsemine is subsequently accomplished by a simple comparison of the CMR spectra of the alkaloid and its dihydro derivative 2 (Table I). Since the signal at 53.9 ppm in the CMR of gelsemine is absent in the spectrum of oxindole (4) it is assigned to C-19 in the alkaloid. The remaining four aromatic signals are readily assigned by a comparison with the spectra of oxindole and aniline derivatives.
49.k
4
B. GELSEMICINE AND GELSEDINE Gelsemicine and gelsedine are secondary bases isolated from the residual alkaloids of Gebemium sempervirens (14). The structure of gelsemicine ( 5 ) was revealed by the X-ray crystallographic studies of Przybylska in 1961 (15),and gelsedine (6) was shown to be ll-demethoxygelsemicine by Wenkert and his group a year later (16). The mass spectrum of gelsedine has been examined recently (10).It exhibits a molecular ion peak at m/e 238 and a peak at m/e 209 corresponding to the loss of an ethyl group. The base peak occurs at m/e 152 (M-176) and may be ascribed to an ion (7)arising as a consequence of the cleavage of ring C. The presence of an N,-methoxy unit in gelsedine is supported by at least three distinct methoxyl extrusions displayed by the alkaloid upon electron impact. A loss of 31 mass units from the parent ion, confirmed by a metastable peak at m/e 272.6, gives rise to the peak at m/e 297 and represents one methoxyl extrusion. The
2.
89
OXINDOLE ALKALOIDS 17
HN
II
19 18
OCH, 6 R = H 6 R = OCH,
+.
0
1
OCH, 7
m/e 152
ion a t m/e 268 emanating from the peak a t m/e 209 represents a second loss of 31 mass units while a third methoxyl loss is apparent in the formation of an ion a t m/e 215 from the peak a t m/e 246. Both losses are confirmed by metastable peaks a t m/e 240.2 and 187.9, respectively. Unfortunately the 220 MHz PMR spectrum of gelsedine proved nearly as ambiguous as the 60 MHz spectrum reported earlier (1 6 ).The only additional information that can be gleaned from it is the position of the oxymethylene (C-17) signal and the splitting of the aromatic signals. The latter show the usual ortho coupling (H-9, 7.35 6, doublet, J = 7 .5 cps; H-10, 7.06 6, triplet, J = 7.5 cps; H-11, 7.24 6, triplet, J = 7.5; and H-12, 6.90 6, doublet, J = 7.5 cps). The two (2-17 methylene protons are geminally coupled (4.19 6, doublet, J = 11.0 cps, and 4.27 6, double doublet, J = 11.0 and 4.0 cps) but only one undergoes further splitting by the neighboring C- 16 methine.
90
J A S J I T S. BINDRA
The CMR chemical shift assignments of carbons in the oxindole nucleus of gelsedine follow by a direct comparison with the spectrum of gelsemine (Table I).The signal a t 180.4 ppm, being the most upfield, is readily assigned to the C-18 methyl group. Similarly, the saturated methylene carbons C-6, C-14, and C-19 are readily distinguished from the O-methylene ((3-17) on the basis of gross dissimilarity of chemical shift values. Assignment of chemical shifts to methine carbons remains ambiguous, however, largely owing to a lack of models for the strained pyrrolidine unit in gelsedine ( 1 0 ) . C. GELSEVIRINE Gelsevirine is a tertiary base left after recovery of secondary bases from residual alkaloids of the roots of yellow jasmine (Gelsemium sempervirens) ( 1 4 ) .It has not yet been obtained in crystalline form, but it can be characterized as its perchlorate (mp 250-252") which analyzes for C,,H,,O,N,, containing two methoxyls, one methylamino, but no C-methyl group. However, the analytical figures obtained from the free base [bp 130-150" mm)] and the crystalline methiodide (mp 259-261") do not agree as well. The oily base analyzes for C21H26O,N,, while analyses of the methiodide yield erratic results, the methoxyl values in particular being low (14). The correctness of the formula C,,H,,O,N, for gelsevirine has been demonstrated by a molecular ion peak a t m/e 352 in the high-resolution mass spectrum of the base (10).However, the presence of two methoxyl groups in the alkaloid as reported earlier (14) must be regarded as erroneous. Gelsevirine contains only one -OCH, group as revealed by a 3.91 ppm three-proton singlet in the PMR spectrum. The only other three-proton singlet in the spectrum occurs a t 2.23 ppm and must be assigned to the N-CH, group, thus excluding the possibility of a second methoxyl. Gelsevirine has been formulated as a 1,3,3-trisubstituted oxindole on 255 mp and Amin 231 mp), which is the basis of its UV spectrum (A,, very similar to gelsedine, and on the appearance of a carbonyl band a t 1715 cm-l in its I R spectrum which is consistent with an oxindole structure. Noting the general similarity of all its spectra with those of gelsemine, Wenkert suggested that gelsevirine might be methoxygelsemine (10). Under electron impact, gelsevirine shows the characteristic fragmentation pattern of gelsemine along with additional methoxy extrusions reminiscent of the behavior of an N,-methoxy unit of gelsedine.
2.
OXINDOLE ALKALOIDS
91
Thus gelsevirine suffers a loss of N , as CH,=N-CH, in analogy with the fragmentation exhibited by gelsemine. This loss of 43 mass units resulting in the ion peak a t m/e 309 is confirmed by a metastable peak at m/e 271.3 and is followed by loss of a methoxyl group giving rise to the ion at m/e 278. A second and somewhat more diagnostic methoxyl extrusion occurs during formation of the m/e 321 peak emanating from the molecular ion and is followed by a peak at m/e 291 probably representing a loss of nitric oxide from the M-31 peak (both extrusions are confirmed by metastable peaks). All these data are taken into account to formulate gelsevirine as N,-methoxygelsemine (8).
8
The 220 MHz PMR spectrum of gelsevirine is in complete accord with the proposed structure. It is virtually identical with the gelsemine spectrum except for the position of the C-12 proton which appears somewhat upfield at 6.93 ppm. Such an upward shift is the expected consequence of N,-methoxyl substitution of the oxindole nucleus as indicated by the position of H-12 (6.90 ppm) in gelsedine. Similarly, the virtual identity of the positions of the methoxyl signals in the spectra of gelsedine (3.96 ppm) and gelsevirine (3.91 ppm) further supports structure 8 for the alkaloid. The 13C NMR spectrum of gelsevirine (Table I) is similar to the gelsemine spectrum with important differences attributed to the extra methoxyl group with affects mainly chemical shifts of carbons of the oxindole and vinyl group. It is noteworthy that the chemical shift of the gelsevirine N,-methoxyl is nearly identical with the shift of the gelsedine methoxyl function. I n analogy with the facile chemical demethoxylation of gelsedine to demethoxygelsedine, Wenkert and his group have shown that gelsevirine readily affords gelsemine upon treament with lithium in liquid ammonia and methanol, thereby conclusively establishing the structure of gelsevirine as N,-methoxygelsemine (8) (10).
92
JASJIT S. BINDRA
111. Oxindoles of Secoyohimbane and Heteroyohimbane Type
A. INTRODUCTION The oxindole alkaloids that have been isolated thus far from Aspidosperma, Mitragyna, Ourouparia, RauwolJia, and Vinca all bear a close structural resemblance to each other. They possess the same basic framework and may be regarded as derived from tryptophan via its decarboxylation product tryptamine and secologanin (9), a C-10 unit of terpenoid origin ( l 7 , 1 8 ) .For the purpose of discussion these oxindole alkaloids are conveniently classified into two structural classes: (a)
11
10
tetracyclic structures of the 17,18-secoyohimbane or corynantheidine type (10) and (b) pentacyclic structures of the heteroyohimbane or ajmalicine type (11).
B. OCCURRENCE Continuing their investigations of the alkaloids of Mitragyna species, the Chelsea group have examined the leaves of M . javanica (Koord.) Korth. var. microphylla and isolated the new oxindole alkaloid javaphylline, C,,H,,N,O,, along with the known alkaloids mitraphylline and isomitraphylline (19).The latter two alkaloids along with rhynchophylline and isorhynchophylline have been isolated from the leaves of M . hirusta Havil. (20).Shellard and his associates have examined the alkaloidal content of the leaves and bark of M . parvifolia Korth.
2 . OXINDOLE
ALKALOIDS
93
growing in Burma, Cambodia, Ceylon, and India. Mitraphylline, isomitraphylline, pteropodine, isopteropodine, speciophylline, and uncarin-F have been detected, although distinct regional and geographical variations of the alkaloidal content in the plant have been noted (21-24). A reexamination of the leaves of M . inermis (Willd.) 0. Kuntze revealed the presence of ciliaphylline, rhynchociline, speciophylline, and a small amount of uncarin-F in addition to the rhynchophylline, isorhynchophylline, rotundifoline, and isorotundifoline previously reported (25).Mitragyna speciosa Korth., which has previously afforded mitraphylline, isomitraphylline, rhynchophylline, speciophylline, and rotundifoline, contains speciofoline (26) and an isomeric pair of oxin(27). doles named specionoxeine and isospecionoxeine (C,,H,,N,O,) Methods for the quantitative determination of oxindole alkaloids by means of UV spectrophotometry, colorimetry, and densitometry after separation by TLC have been developed by Shellard and Alam (28) and applied to quantitative determination of oxindole alkaloids occurring in different species of Mitragyna (29). Recently two new oxindole alkaloids designated gambirdine and isogambirdine (C,,H,,N,O,), probably stereoisomeric with mitraphylline, have been isolated from the stem of Uncaria gambir (Hunt) Roxb. (30). Investigating alkaloids of the Aspidosperma species, Arndt has identified carapanaubine in the bark of A . rigidum Rusby (31).Carapanaubine and isocarapanaubine have been found to accompany rauvoxine and rauvoxinine (C23H,8N206),an isomeric pair of oxindole alkaloids first isolated from the leaves of RauwolJa vomitoria Afz. (32, 33). A number of oxindole alkaloids have been isolated from Vinca species. Vinine, an alkaloid isolated from V . pubescens Urv. a long time ago ( 3 4 ) )has subsequently been shown to be identical with carapanaubine (35).Mitraphylline has been found in V . rosea (L.) Reichb. ( 3 6 ) . Herbaline (C,,H,,N,O,) is a dihydro pentacyclic oxindole alkaloid present in V . herbacea Waldst. et Kit. (37, 38). From the middle polar fraction of the total alkaloidal extract of this plant two isomeric bases, A-4 and A-5, were isolated ( 3 8 , 3 9 )and subsequently proved to be identical with majdine and isomajdine (C,,H,,N,O,) (38, 40), a pair of oxindole alkaloids isolated by Russian workers from V . major L. (35).The presence of majdine in V . major has also been confirmed by Kaul and isolated from V . major is Trojhnek (41). Alkaloid V (C,,H,,N,O,) probably related to majdine (42). Elegantine, an oxindole alkaloid recently isolated from V . elegantissima Hort. (43),and herbavine, isolated from the perwinkle V . herbacea (44),have the same C,,H,,N,O,
94
JASJIT S. BINDRA
constitution. Vinerine, vineridine (45, 46), and erycinine ( 4 7 ) are three isomeric oxindole alkaloids of C22H2sH20, constitution isolated from V . erecta Regl. et Schmalh.
IV. Secoyohimbane-Type Oxindoles A. STRUCTURE The skeletal structure of oxindoles of the secoyc imbane type, typified by rhynchophylline and isorhynchophylline, rests on a mass of chemical and physical evidence which has been discussed in earlier volumes. Some physical properties of members of this group are presented in Table 11. The UV spectra of all the oxindole alkaloids are closely related (Table 111) and are satisfactorily explained on the basis of contributions of an oxindole and a /3-methoxy acrylic ester
I
(H,CO,C-C=CHOCH,) chromophore. I R and PMR spectral properties of the tetracyclic oxindole alkaloids are collected in Tables IV and V. TABLE I1 SECOYOHIMBANE-TYPE OXINDOLES
Alkaloid (synonyms) Rhynchophylline (mitrinermin) Isorhynchophylline Rotundifoline (stipulatin) Isorotundifoline (Mitragynol) Ciliaphylline Rhynchociline Specionoxeine Isospecionoxeine Corynoxeine Corynoxine Isocorynoxine Speciofoline Mitragynine oxindole A Mitragynine oxindole B a
Py = pyridine.
Formula
Melting [alD point ("C) (chloroform)
CzzHz,NzO, 212-214
CzzHZ8N205 130-132
pK,
Ref.
6.8
52
6.25 5.3
52
-8
7.4
52
- 90
7.5 8.3
52 52 27 27 5, 48 5, 49 49 26 49 49
- 14.5
+6 -
-
-
-
+ 2 3 (PY)" - 14 (Py)"
-
- 103
6.46 7.51 6.3
-
-
-
-
52
2.
95
OXINDOLE ALKALOIDS
TABLE I11
ULTRAVIOLET SPECTRA OF SOMEOXINDOLEALKALOIDS
Rhynchophylline Isorhynchophylline Rotundifoline Isorotundifoline Rhynchociline Ciliaphylline Specionoxeine Isospecionoxeine Corynoxeine Corynoxine Speciofoline Mitraphylline Isomitraphylline Formosanine Isoformosanine Rauvanine oxindole A Rauvanine oxindole B Isopteropodine Pteropodine Isocarapanaubine Carapanaubine
-
Majdine Isomajdine Speciophylline Uncarine-F Rauvoxinine Rauvonine Gambirdine Isogambirdine Vineridine
-
223 222 225 222 223 223
4.36 4.43 4.41 4.44 4.49 4.46
-
-
223 223 223 225 225 217 217 225 225 218 215
4.47 4.02 4.02 4.03 4.06 4.35 4.35 4.00 3.93 4.41 4.57
225 225 224 223 218 218
4.57 4.53 4.14 4.44 4.44
-
-
220
Elegantine Javaphylline Herbaline
-
-
245 245 243 242 242 244 245 244 245 245 242 242 242 244 245
246 246
-
4.24 4.24 4.15 4.23 4.24 4.24 4.18 4.26 4.28 4.28 4.27 4.22 4.20 4.24 4.24 -
4.22 4.20 -
244
4.23
248 248 242 242
4.23 4.16
-
-
-
-
-
280 280 292 290 286 287 288 288
3.15 3.15 3.42 3.49 3.48 3.46 3.29 3.52
-
-
290 280
3.49 3.18
-
-
278 278 280 280 280 280 280 278 300 285 285 283
3.09 3.09 3.64 3.75 3.27 3.25 3.71 3.80 3.66 3.16 3.04 3.34
280 280 280 280 282 291 288 282 291 305
3.70 3.70 3.13 3.18 4.15 4.11 3.42 4.15 4.11 3.99
-
4.97
244 244 240
4.19 4.24 4.76
228 220
4.57 4.97
278 240
3.75 4.76
215
4.56
273
4.05
The tetracyclic oxindole alkaloids possess four asymmetric centers (C-3, C-7, C-15, and C-20) and therefore can exist as sixteen possible
diastereoisomers. However, since all naturally occurring indole alkaloids of the corynane type possess a C-15ahydrogen ( l 7 ) ,the total number of isomers is restricted to eight. Taking into consideration the asymmetric
96
JASJIT S. BINDRA
TABLE IV
INFRARED SPECTRAL DATAOF SOMEOXINDOLEALKALOIDS
Alkaloid
Solventa -NH-
Ester and oxindole Double carbonyl bond
Rhynchophylline
A
3415b
1732, 1708
Isorhynchophylline
A
3420
1730, 1705
Rotundifoline Isorotundifoline Rhynchociline
B B -
1710 1695 1708, 1685
Ciliaphylline
A
Specionoxeine
A
3260 3300 3400 3280 3400 3270 3280
Isospecionoxeine
-
3260
1705
Corynoxeine
-
-
1724, 1695
Corynoxine Speciofoline Mitraphylline Formosanine Isoformosanine Rauvanine oxindole A Rauvanine oxindole B Isopteropodine Pteropodine Isocarapanaubine Carapanaubine Majdine Isomajdine Uncarine-F Rauvoxinine Rauvoxine Gambirdine Isogambirdine Javaphylline Vineridine Vinerine Elegantine Herbaline
-
-
B B
3280 3260 3200 3340
1695 1705 1725, 1704 1730, 1693 1715,1693 1712 1712 1719, 1688 1719,1688 1728 1710 1725,1705 1725,1680 1705 1712 1714 1722,1694 1722, 1702 1705, 1700 1710, 1690 1740, 1680 1716, 1670 1740, 1720
a
B B C C B B C C C C C
-
3446 3436
-
3440 3440
-
-
-
-
-
B
-
B B
-
-
B C
3500 3500 3295 3200 3444
A = KBr; B = Nujol; C = chloroform. All values in em-l.
1728, 1725 1730, 1713
Others
1646 1623 1645 1625 1630 1630 1605
-
1640 1620 1640 1619 1634 1619 1639 1613 1610 1625 1626 1626 1626 1635 1630 1627 1627 1645
995 918
-
-
-
980 912 909 -
1105 1107 1107 -
1081 1077 -
-
-
1625 1630 1627
1098 1090 -
-
-
-
-
1617 1623 1620 1620
1100
-
-
1614
-
-
-
2.
97
OXINDOLE ALKALOIDS
TABLE V
P M R SPECTRAL DATAOF SOMEOXINDOLE ALKALOIDS A . Secoyohimbane-Type Oxindoles Alkaloid Rhynchophylline Isorhynchophylline Rotundifoline Isorotundifoline Rhynchociline Ciliaphylline Specionoxeine Isospecionoxeine Speciofoline Mitragynine oxindole B
CH3 (18)
C0,CH3
0.77 0.79 0.88 0.87 0.80 0.78
3.58 3.55 3.70 3.80 3.58 3.67 3.58 3.57 3.78 3.79
-
0.93 0.86
-OC€13 3.67 3.65 3.60 3.70 3.68 3.59 3.67 3.68 3.66 3.56
Olefinic (17)
7.21 7.14 7.28 7.28 7.17 7.23 7.18 7.13 7.40 7.22
B. Heteroyohimbane-Type Oxindoles
Mitraphylline Isomitraphylline Formosanine Isoformosanine Rauvanine oxindole A Rauvanine oxindole B Isopteropodine Pteropodine Rauniticine oxindole A Reuniticine oxindole B Isocarapanaubine Carapanaubine Majdine Isomajdine Speciophylline TJncarine-F Rauniticine epi-oxindole A Reuniticine epi-oxindole B Reuvoxinine Rauvoxine Gambirdine Isogambirdine Javaphylline Elegantine Herbaline
1.11 1.13 1.29 1.30 1.30 1.29 1.38 1.38 1.44
3.57 3.54 3.52 3.51 3.55 3.57 3.56 3.55 3.57 -
-
1.40 1.40 1.38 1.37 1.22 1.21 1.29 1.29 1.26 1.23 1.32 1.31 1.12 1.40 1.15
3.61 3.61 3.58 3.58 3.32 3.60 3.32 3.53 3.43 3.58 3.56 3.58 3.59 3.63 3.50
4.36 (10) 4.46 (10) 4.30 (9) 4.30 4.15 (1.5) 4.19 (1.5) 4.13 4.02 (1) 4.19 (1.5) 4.19 (1.5) 3.78 3.82 4.40 4.35
4.34 4.39 3.73 3.75 3.80 3.80 4.31 4.49 4.34
(2.5) (2.5) (9.0) (9.0)
-
6.92 6.75 (10) (10) (5)
-
6.90 6.76 6.84 6.74
-
__ 6.71 7.02
-
6.93 6.97
98
JASJIT S. BINDRA
centers on ring D only the tetracyclic oxindole alkaloids have been classified (27) as normal, pseudo, allo, and epiallo-there being two possible orientations for the oxindole group at C-7 for each configuration (Table VI). These are classified as A or B depending on the position of the lactam carbonyl with respect t o the plane of the C/D ring system.
0
13
I n the A series the lactam carbonyl is situated below the plane of the C/D ring (13),while the B series have the lactam carbonyl oriented above the C/D ring (14). TABLE VI CONFIGURATION
Configuration Normal Pseudo Allo Epiallo a
TERMINOLOGY FOR OXINDOLE ALKALOIDS (27) C-3-H
C-15-H
a
a
B a
a a
B
a
C-%-OH
B B a
a
c-7' A or A or A or A or
B B B B
A = oxindole carbonyl below the C / D plane; B, above the C / D plane.
Typically, the alkaloids of this group are obtained as pairs of interconvertible A and B isomers, e.g., rhynchophylline and isorhynchophylline, rotundifoline and isorotundifoline, and any one stereoisomer gives a mixture of stereoisomers upon equilibration by heating in pyridine or acetic acid. Equilibration occurs at the p-aminolactam group by cleavage and reformation of the C-3, C-7 bond; consequently the stereoisomers produced by equilibration differ in configuration a t C-3 and/or a t C-7. The structures and configuration of some secoyohimbane oxindole alkaloids are given in Table VII.
2.
99
OXINDOLE ALKALOIDS
TABLE VII STRUCTURE AND CONFIGURATION OF SECOYORIMBANE OXINDOLE ALKALOIDS
12
Alkaloid
Substitution on ring A (R’)
R
Configuration
Series
Rhynchophylline (33) Isorhynchophylline (34) Rotundifoline (38) Isorotundifoline (39) Rhynchociline (40) Ciliaphylline (41) Specionoxeine (42) Isospecionoxeine (43) Corynoxeine (44) Corynoxine (45) Isocorynoxine (46) Speciofoline (49) Mitragynine oxindole A (47) Mitragynine oxindole B (48)
H H 9-OH 9-OH 9-OMe 9-OMe 9-OMe 9-OMe H H H 9-OH 9-OMe 9-OMe
ethyl ethyl ethyl ethyl ethyl ethyl vinyl vinyl vinyl ethyl ethyl ethyl ethyl ethyl
normal normal normal normal normal normal normal normal normal
B
allo allo -
allo allo
A A B A B B A A A B
A B
B. CONFORMATIONAL ANALYSIS Allocation of configuration to oxindole alkaloids in some cases is firmly based on chemical grounds. Thus rhynchophylline and corynoxeine are known to have the normal A configuration on the basis of their partial synthesis from dihydrocorynantheine and corynantheine, both indole alkaloids of known normal A configuration (48). I n other cases, however, assignment of configuration to oxindole alkaloids of unknown stereochemistry is based upon physical and spectral data. Since spectral parameters are conformation-dependent, knowledge of preferred conformation of each configuration is essential before meaningful allocation of configuration can be made on the basis of spectral data.
100
JASJIT S. BINDRA
Theoretically, each configuration can exist in four different ring D chair conformations: (i) by inversion a t the basic nitrogen N , and (ii) by chair-chair interconversion of ring D. All possible conformations of a 3a-and 3/3-H indolizidine nucleus, corresponding to C and D rings of the oxindole alkaloids and bearing a 15/3-substituent, are portrayed by the expressions 15-22. Of these, the conformations involving a
15
16
I
I
17
18
IS
20
I
I
H
H 21
22
2.
101
OXINDOLE ALKALOIDS
trans diaxial C/D ring junction (17and 20) are not possible and are therefore eliminated. The conformations involving an axially oriented Nb-CB bond (16and 21)are not favored because they involve an additional destabilization of about 1.5 kcal/mole without relieving any of the nonbonded interactions present in the corresponding conformations that have this bond equatorially situated. Hence only two ring D conformations need be seriously considered for each configuration. The preferred conformations of A and B spiro configurations in the normal and a110 series are given by structures 23-26. No significant contribution can be expected from the alternative ring D chair conformation formed by inversion of N , and concomitant flipping of ring D because of 173-diaxialinteraction between the C-3, C-7 bond and the C-15 substituent (cf. 23).
om
WCZH COaR
HN
HN
/
0 A
0
\
\
\
B normal configuration
23
24
Rz l HN !@ o
~~~~z~ HN
0
/
/
\
A
0 B
\
allo configuration 25
26
The pseudo B and epiallo B configurations should exist predominantly in conformations 27 and 28, since alternative expressions of the type 15 in which the oxindole moiety is forced under the plane of ring D, giving rise to serious nonbonded interaction between the oxindole unit and underbelly of ring D, are unfavorable.
102
J A S J I T S. BINDRA
27
pseudo B
28
epiallo B
Conformational preference of the pseudo A and epiullo A configuration is less clear-cut. Since nonbonded interactions due to the two diaxial C-20 and C-15 substituents in 29 probably outweigh the consequences of steric interference between the lactam carbonyl and the axial (2-15 and C-21 hydrogens in 30, the latter probably represents the preferred conformation of the pseudo A oxindole. I n case of the epiallo A oxindole, however, the destabilization energy associated with an axial (3-15 substituent is probably outweighed by the combined nonbonded interactions in 31 arising from an axial C-20 ethyl group and a lactam carbonyl forced under the plane of ring D. Consequently the preferred conformation of epiullo A oxindole is given by 32.
pseudo A
29
32
2.
103
OXINDOLE ALKALOIDS
Clearly, the two pseudo configurations are too unstable to exist. Consequently equilibration of any of the four isomers of the normall pseudo set in pyridine or acetic acid should result in a mixture consisting only of the two normal A and B configurations. Similarly, in the alloepiallo set, isomeriza.tion of any of the four isomers should result in a mixture in which the two allo configurations predominate almost to the exclusion of the epiallo A and B configurations. AND ISORHYNCHOPHYLLINE C. RHYNCHOPHYLLINE
Rhynchophylline (33) and isorhynchophylline (34) possess the normal B and A configuration, respectively. Assignment of stereochemistry at C-7 in the two isomers is based on pK,, isomerization, and CD data and is supported by TLC evidence (2). Rhynchophylline, the stronger of the two bases, has its lactam carbonyl situated above the plane of the C/D ring such that its conjugate acid can be stabilized by hydrogen bonding (35); whereas isorhynchophylline, which belongs to the A series, must have its aromatic ring positioned over the plane of the
35
C/D ring, causing the C-9 proton to be deshielded by the lone pair of electrons on N , . Consequently it is reasonable to expect the C-9 proton in the PMR spectrum of a normal A oxindole to resonate a t a lower field than that of a normal B oxindole. Such a downfield shift for the C-9 proton in the A series is actually observed in the 100 MHz spectrum of isorhynchophylline, which exhibits a one-proton doublet a t 7.40 6, whereas the lowest field aromatic signal in rhynchophylline occurs a t 7.20 6 (27).
36
oxindole A
37
oxindole B
104
J A S J I T S. BINDRA
A recent 13C NMR analysis of the stereoisomeric oxindole alkaloid models 36 and 37 as well as indolizidine reveals that chemical shifts of the piperidine portion of these bases are interpretable only in terms of a trans configuration of the indolizidine ring system and that the chemical shift values of C-3 and C-9 are strong diagnostic indicators of the configuration a t C-7. This is borne out by assignment of 6 values of rhynchophylline and isorhynchophylline (Table V I I I ) (12). TABLE V I I I
13C NMR CHEMICAL SHIFTP
Structure 36 37 Rhynchophylline (33) Isorhynchophylline (34) Rhynchophyllal a
c-3 120.3 117.0 117.1 120.2 117.9
c-9 67.3 69.5 69.6 67.2 69.4
Configuration at c - 7
A B B A B
Chemical shift values in ppm upfield from CSz.
Beckett et al. (49) found no significant relationship between mass spectral fragmentation and stereochemistry in a number of tetracyclic oxindole alkaloids. The relative abundance of the main mass spectral fragments in the spectra of rhynchophylline and isorhynchophylline seem to be independent of the stereochemistry a t C-7. Full details of the synthesis of rhynchophyllal, reported earlier, have now appeared (50).
D. ROTUNDIFOLINE AND ISOROTUNDIFOLINE The 9-hydroxy bases, rotundifoline (38) and isorotundifoline (39), share the same configuration a t C-15 and C-20 centers but are isomeric about C-3 and/or C-7 (2). The nonphenolic behavior of rotundifoline in contrast with that of isorotundifoline, which is typically phenolic in its reactions, is ascribed t o the formation of a strong intramolecular hydrogen bond between the phenolic hydroxyl group and N , in 38. Consequently, in pyridine solution, equilibrium favors rotundifoline whereas, in acid solution, presumably owing to N , protonation, the hydrogen bond t o the phenolic hydroxyl is weakened and up to 4001,
2.
OXINDOLE ALKALOIDS
105
isorotundifoline is formed in the equilibrium mixture. Since no isomers other than 38 and 39 are formed during equilibration, they must possess a normal or a110 configuration. It is possible to differentiate between the two configurations on the basis that the C-18 methyl triplet signal in the PMR spectrum of allo configuration is more symmetrical than in the corresponding normal configuration because of closer proximity of the C-19 methylene protons to the lone pair of N, in the a110 configuration. In 100 MHz PMR spectra of both 38 and 39 the C-18 methyl triplet signal has a nonsymmetrical appearance, very similar to that of rhynchophylline, suggesting that both alkaloids have a normal configuration. Consequently, rotundifoline must have the normal A configuration and the normal B configuration has been assigned to isorotundifoline (27).This assignment is further supported by the TLC studies of Phillipson and Shellard (51).
E. RHYNCHOCILINE AND CILIAPHYLLINE Rhynchociline (mp 178-180') and ciliaphylline (mp 222-223") are an interconvertible pair of isomeric oxindole alkaloids of C,,H,,N,O, constitution isolated from Mitragyna ciZiata Aubrev et Pellegr. (52). Physicochemical data indicate that both isomers are oxindoles of the rhynchophylline type bearing an extra methoxyl group in the aromatic ring. The position of aromatic substitution is deduced from PMR spectral data (27).Both alkaloids exhibit a pattern of two doublets and one triplet for the aromatic protons consistent with a three-spin system of three adjacent protons, suggesting that substitution is in either the 9 or the 12 position. Thus rhynchociline exhibits a one-proton triplet at 7.11 6 (J = 7.5 cps) and two overlapping doublets a t 6.56 and 6.47 6 (J = 7.5 cps) for the remaining two protons, while ciliaphylline exhibits a one-proton triplet a t 7.10 6 and two one-proton doublets of slightly differing J values coincident a t about 6.52 6. Furthermore, the PMR spectrum of N-acetyl ciliaphylline shows a marked downfield shift of one of the doublets in the 6.5 6 region. Since such a shift can arise from the deshielding effect of the N-acetyl group only upon the neighboring C-12 aromatic proton, ciliaphylline must be substituted in the 9-position. Pyridine isomerization of either ciliaphylline or rhynchociline results in a mixture at equilibrium in which only ciliaphylline (6507,)and rhynchociline ( 3570) can be detected. Hence stability arguments exclude pseudo and epiallo configurations for the two alkaloids which must have either the normal or a110 configuration as a consequence. Since treatment of either ciliaphylline or rhynchophylline with
106
JASJIT S. BINDRA
acetic acid yields a 1:1 mixture of the two alkaloids and since stabilization can occur in both A and B configurations owing to association of the N , cation with either 9-OMe or the lactam carbonyl, it is not possible to differentiate between A and B configurations in 9-methoxy oxindole alkaloids solely on basis of pK, and equilibration data. Fortunately, the A and B configurations can be readily differentiated by noting the relatively stronger long-range deshielding effect of a protonated N , on the proximate 9-OMe group in a n A configuration relative to the B configuration. Thus the chemical shift of the aromatic methoxyl group of ciliaphylline is essentially unchanged (3.83 -+ 3.91 6) when its PMR spectrum is observed in acetic acid instead of deuterochloroform, while a comparatively larger downfield shift (3.86 --f 4.06 6) is observed in the spectrum of rhynchociline. The preceding evidence, along with the unsymmetrical nature of the C-18 methyl triplet signal in the 100 MHz PMR spectrum, establishes rhynchociline (40) as a n o r m a l A and ciliaphylline (41) as a n o r m a l B 9-methoxy oxindole. AND F . SPECIONOXEINE
ISOSPECIONOXEINE
Specionoxeine (mp 225") and isospecionoxeine (mp 179") are two isomeric oxindole alkaloids of C23H2,N20, constitution isolated from M i t r a g y n a speciosa (27). The similarity of their spectral data and those of other oxindoles indicates that the two alkaloids possess a rhynchophylline-type structure and carry an extra methoxyl group on the aromatic ring. The presence of vinyl bands a t 918 and 995 cm-l in the I R spectra of specionoxeine and isospecionoxeine suggests that they possess a C-20 vinyl instead of the usual ethyl group. This is substantiated by the PMR spectra of both isomers which exhibit signals in the olefinic region integrating for three protons instead of a three-proton triplet a t ca. 0.8 6 for methyl protons of the C-20 ethyl group. The splitting pattern of the olefinic protons is typical for a vinyl group and also appears in indole alkaloids such as corynantheine and payantheine known to contain a C-20 vinyl group. Further examination of the splitting pattern of protons in the aromatic region of specionoxeine and isospecionoxeine reveals an AA'B system, representing three adjacent protons on the aromatic ring, consistent only with a methoxyl substitution a t either C-9 or C-12. Hydrogenation of specionoxeine yields 41, whereas hydrogenation of isospecionoxeine affords 40, suggesting that the two alkaloids are vinyl analogs of the corresponding ethyl-containing alkaloids ciliaphylline
2. OXINDOLE ALKALOIDS
107
and rhynchociline. Consequently specionoxeine (42) and isospecionoxeine (43) have been formulated as 9-methoxy normal B and A oxindoles, respectively. This assignment is in agreement with the fact that treatment of either alkaloid with pyridine gave a mixture of 65% 42 and 35y0 43 a t equilibrium, while treatment with acetic acid gave a 1:1 mixture of only the two bases (27).
G. CORYNOXEINE Corynoxeine (C2,H,,N20,; mp 212-214') isolated from Pseudocinchona africana A. Chev. has been shown to be the vinyl analog of rhynchophylline ( 5 ) . Since dihydrocorynoxeine is identical with rhynchophylline, corynoxeine 44 may be formulated as an oxindole of normal A configuration.
H. CORYNOXINE AND ISOCORYNOXINE Corynoxine (C,,H,,N,O, ; mp 166-16So) isolated from Pseudocinchona africana has been formulated as an isomer of rhynchophylline and isorhynchophylline on the basis of spectral data and degradative studies (53).A pseudo configuration for corynoxine may be ruled out on the basis of stability arguments. Moreover, if corynoxine possesses a pseudo configuration, isomerization should result in a mixture in which the two normal configurations, rhynchophylline and isorhynchophylline, predominate. However, equilibration of the base in acetic acid results in the formation of a mixture containing SOYo corynoxine and 2007, of another oxindole now named isocorynoxine (mp 171-172"), while none of the normal A and B oxindoles are obtained (49).Equilibration in pyridine furnishes corynoxine almost exclusively. ConsequentIy, corynoxine (45) must have either the allo or epiallo configuration. This is supported by the symmetrical appearance of the C-18 methyl triplet in the 100 MHz PMR spectrum of corynoxine which indicates an axial (C-20) ethyl group (27).Conclusive evidence that corynoxine possesses an allo configuration is forthcoming from its partial synthesis from corynantheidine, an indole alkaloid of known allo configuration (49, 53). The assignment of configuration at C-7 for corynoxine is based on CD data (53)and the fact that the signal for the C-9 aromatic proton in its PMR spectrum is shifted significantly downfield in contrast to isocorynoxine (46), suggesting that 45 is an allo A oxindole (27).
108
J A S J I T S. BINDRA
I. MITRAGYNINEOXINDOLES A
AND
B
Mitragynine oxindole B (48) (mp 239”) is a 9-methoxy oxindole of the allo series obtained by synthesis from the known aklo indole alkaloid mitragynine (49).Examination of the 100 MHz PMR spectrum of the oxindole reveals a “symmetrical” C-18 methyl triplet at 0.86 6 consistent with an axial ethyl group. Isomerization of mitragynine oxindole B in pyridine gives a t equilibrium a 7 : 3 mixture of the B oxindole and a second oxindole designated as mitragynine oxindole A (47). The A and B oxindoles are readily distinguished by observing the deshielding effect of a protonated N , on the chemical shift of the 9-methoxyl group in the B isomer upon running the PMR spectrum of the two oxindoles in glacial acetic acid (49).
J. SPECIOFOLINE Speciofoline (C22H28N20,;mp 202-204”) is a phenolic oxindole isolated from the leaves of Mitragyna speciosa ( 2 6 ) .On the basis of its IR, UV, and PMR spectra speciofoline (49) has been formulated as a stereoisomer of rotundifoline. The aromatic ring in 49 is substituted in the 9-position as indicated by the splitting pattern of aromatic protons in the PMR spectrum. A one-proton triplet a t 7.08 6 and two overlapping doublets at ca. 6.45 6 integrating for two protons are consistent with a C-9 or C-12 substituent and are similar to those of rotundifoline. The phenolic hydroxyl in speciofoline is bound to the lone pair on N , by a strong intramolecular hydrogen bond as indicated by a broad peak centered around 2500 cm-l in the I R spectrum. Consequently the hydroxyl group must be at the C-9 position since this is the only position which permits an intramolecular bond with N , (26).Although it is likely that rotundifoline and speciofoline differ in stereochemistry at C-20, in the absence of isomerization data no definite assignment of configuration is possible at this stage.
V. Heteroyohimbane-Type Oxindoles A. STRUCTURE The pentacyclic oxindoles are true oxindole analogs of the heteroyohimbane alkaloids. Their st,ructure is based on chemical and physical data supported, in many instances, by their synthesis from the corresponding indole alkaloids. Some physical properties of members of this
2.
109
OXINDOLE ALKALOIDS
group are collected in Table IX. The UV spectra of pentacyclic oxindoles are collected in Table 111, and like their tetracyclic counterparts these spectra are a composite of an oxindole and an unsaturated enolTheir IR spectra contain ester chromophore (CH,O,C-C=CHOR). TABLE I X HETEROYOHIMBANE-TYPE OXINDOLES ~
~~~
~
Melting point Alkaloid (synonyms)
Formula
("C)
Mitraphylline Isomitraphylline
For mosanine (uncarine-B) Isoformosanine (uncarine-A) Rauvanine oxindole A Rauvanine oxindole B Pteropodine (uncarine-C) Isopteropodine (uncarine-E) Rauniticine oxindole A. Rauniticine oxindole B Carapanaubine (vinine) Isocarapanaubine Majdine (majorexin) Isomajdine Speciophylline (uncarine-D) Uncarine -F Rauniticine epiallooxindole A Rauniticine epiallooxindole B Rauvoxine Rauvoxinine Gambirdine Isogambirdine
~
[.ID
(chloroform) pK, -8
+ 18 + 91 + 106 C23H28NzOs 234-236 (perchlorate) CZ3Hz8N2O6167 and 210-212 C21H24N204 217-219 C21H24N204 209-211 C21H24N204 199-202 C21H24N204 C23H28N206 221-223 C23H28Nz06 amorph. C23H28N206 192-194 C23H28N206 208-210 C21H24N204 183-184 CZ1Hz4N2O4amorph. C21H24N204 227-229 CZ1HZ4N2O4 amorph.
Javaphylline Vinerine Vineridine Ecryninine
210-211 202 199-201 179-181 (hydrochloride) CzzH26Nz05 180 CzzHzsN205 202-203 C22H26N205179-180 CzzH26N205 206-207
Herbaline
C23H30N206 276-278
Elegantine
~
C23H28N206 C23H28N206 CZiH24N204 C21H24N204
+ 77 + 58
- 103 - 111 +4
-
- 120 - 68 - 141 - 90
+ 73 + 85
+ 143 + 164
+ 97 + 68 + 85
Refs.
48 I , 48
2 2 57 57 7 7 57 57 57 57 41 40 56
56 57
57
+ll6
57 57 30 30
+ 77 + 20 + 23 +44
19 46 46 47
(Me2CO) - 147 (pyridine)
37
110
JASJIT S . BINDRA
two bands in the carbonyl region consistent with the presence of an oxindole and carbomethoxy group (Table IV) along with absorptions in the 1100 cm-l region for the cyclic ether. The PMR spectral data are collected in Table V. The mass spectral fragmentation patterns of the pentacyclic oxindole alkaloids have been discussed by Gilbert (a), and the relationship between stereochemistry and intensity of fragment ions has been studied by Shamma and Foley (54). All naturally occurring pentacyclic oxindoles either are stereoisomers of the general formula 50 or differ from each other by the pattern of substituents on the aromatic ring. I n all there are five asymmetric centers (C-3, C-7, C-15, C-19, and C-20) so that 32 diastereoisomers of TABLE X STRUCTURE AND CONFIGURATION OF HETEROYOHIMBANE OXINDOLE ALKALOIDS
R
-C&Trn ‘ “0 H
Alkaloid Mitraphylline (60) Isomitraphylline (61) Formosanine (62) Isoformosanine (63) Rauvanine oxindole A (64) Rauvanine oxindole B (65) Isopteropodine (66) Pteropodine (67) Rauniticine oxindole A (68) Rauniticine oxindole B (69) Isocarapanaubine (70) Carapanaubine (71) Majdine (72) Isomajdine (73) Speciophylline (74) Uncarine-F (75) Rauniticine epi-oxindole A (76) Rauniticine epi-oxindole B (77) Rauvoxinine (78) Rauvoxine (79)
\
COzCH,
Substitution on ring A (R’)
H H H H 10,l l-(OMe)2 10,11-(OMe)2 H H H H 10,ll-(OMe), 10,11-(Ome), 11,12-(OMe)2 11,12-(OMe)2 H H H H 1 0 , l l-(OMe), 10,11-(OMe)2
(2-19 methyl
Configuration
Series
normal normal normal normal normal normal allo allo allo allo allo allo allo all0 epiallo epiallo epiallo epiallo epiallo epiallo
B A B A A B
B B B B
A
a
B A B A B B A A B A B A B
a a
a
B B a a
a a a a
B B a
a
2.
111
OXINDOLE ALKALOIDS
this general formula (R = H) are possible. Since the naturally occurring indole alkaloids of corynane type possess a C-15a hydrogen the total number of possible isomers can be restricted to 16 ( 2 7 ) . Taking into account only the asymmetric centers on ring D the pentacyclic oxindole alkaloids have been classified as normal, pseudo, allo, and epiallo, there being two possible orientations for the oxindole moiety about the C-7 spiro carbon corresponding to the A and B forms as defined for the tetracyclic oxindoles (Table VI). I n addition the 19-methyl group can be oriented up or down ( a or p) in each case. The structures and configuration of heteroyohimbane oxindole alkaloids are given in Table X.
B. CONFORMATIONAL ANALYSIS
51
52
normal A
normal B
/OI
. I )
C0,CH3
58
allo A
54
allo B
Neglecting the stereochemistry a t C-19, the A and B spiro configurations in the normal and a110 series are given by 51-54 (55).Alternative conformations, formed by inversion a t N , , involve an axially oriented
H 55
112
JASJIT S. BINDRA
N,-C, bond and consequently are not favored. The allo conformation 55 formed by inversion at N , and concomittant flipping of ring D is destabilized by severe 1,3-diaxial interaction between the C-3, C-7 and (2-15, C-16 bonds. Trans diequatorial fusion of ring D/E in the normal series does not permit flipping of ring D into an alternative chair conformation. The pseudo A and B configurations, locked into the arrangement 56, are beset by serious steric interaction between the oxindole unit and the underside of ring D and consequently are expected to be too unstable to exist (55).
56
pseudo
The epiallo A and B configurations are portrayed by structures 57 and 58. The alternative epiallo conformation 59 formed by inversion at N , and chair-chair interconversion is destabilized by steric interaction between the oxindole moiety and ring D.
0?Yc02cH 0 57
epiallo A
58 epiallo B
fO\
I
59
2.
113
OXINDOLE ALKALOIDS
C. MITRAPHYLLINEAND ISOMITRAPHYLLINE Mitraphylline (60) and isomitraphylline (61) are oxindoles of the normal B and A series, respectively (2). The 15aH, 2OPH, 19PH configuration of the two isomers is confirmed by their partial synthesis from ajmalicine (48).
D. FORMOSANINE AND ISOFORMOSANINE Formosanine (uncarine-B) (62) and isoformosanine (uncarine-A) (63) are oxindoles of the normal series ( 2 , 6 ) . CD spectra curves of formosanine and mitraphylline are almost superimposable (56)) suggesting that formosanine has a D/E trans ring junction similar to mitraphylline in contrast to the D/E cis junction previously assigned to it. Consequently formosanine and mitraphylline must differ in their stereochemistry a t C-19. The C-19 proton in the 100 MHz PMR spectrum of mitraphylline appears a t 4.34 6 and the H-19, H-20 coupling constant is small ( J = 2.5 cps). However, the C-19 proton of formosanine appears somewhat upfield a t 3.73 6 and exhibits a coupling constant of 9 cps, which is in accord with a trans pseudo diaxial arrangement of the C-19 and C-20 protons (57). The upfield shift of the C-19 signal is satisfactorily explained by the proximity of the C-19 proton to the C-16, C-17 double bond. Thus formosanine is the C-19 epimer of mitraphylline. On the basis of equilibration studies, pK, values and the sign of the 290 mp band in CD, formosanine (positive 290 mp CD band) and isoformosanine (negative 290mp CD band) have been assigned the 19P-methyl normal B and 19P-methy normal A configurations, respectively (56, 57'). These structures have been confirmed by total synthesis of the two alkaloids (57a).
OXINDOLES A E. RAUVANINE
AND
B
Oxidation of rauvanine, a 9-methoxy indole alkaloid of known 19P-methyl normal configuration, with t-butyl hypochlorite gives rise to two oxindoles designated as rauvanine oxindole A (64; mp 234-236") and B (65; mp 210-212") which must belong to the normal series (57). The relatively shielded position of the C-19 proton of both oxindoles, when compared with the mitraphyllines, is in agreement with their formulation as 19P-methyl normal oxindoles.
114
.JASJIT S. BINDRA
F. PTEROPODINE, ISOPTEROPODINE, SPECIOPHYLLINE, AND UNCARINEF The chemical structure of the four isomeric alkaloids, pteropodine (uncarine-C) (67), isopteropodine (uncarine-E) (66), speciophylline (uncarine-D) (74), and uncarine-F (75) is well established ( 6 , 58). Equilibration of any single isomer in refluxing aqueous acetic acid furnishes a mixture containing all four isomers. I n refluxing pyridine the resulting mixture contains pteropodine and isopteropodine with traces of speciophylline and uncarine-F. The formation of a mixture of four stereoisomers from any one of the isomers during equilibration suggests that epimerization occurs a t both C-3 and C-7 and therefore the four alkaloids must belong to an a l l ~ e p i a l l osystem possessing a D/E cis ring junction (56, 57). An examination of PMR spectra of the four isomers reveals striking differences in the splitting of the C-19H multiplet in a110 and epiallo configurations. The large coupling constant ( J = 10 cps) for C-19-C-20 protons, deduced from the C-19 hydrogen multiplets a t 4.53 and 4.38 6 in the spectra of pteropodine and isopteropodine, can be accommodated for a trans pseudo diaxial arrangement of the two protons in an a110 configuration. Speciophylline and uncarine F, on the other hand, must have an epiallo configuration since the coupling constant for the C-19C-20 protons is small ( J = 15 cps). The magnitude of the coupling constant is indicative of a trans diequatorial arrangement of the C-19 and C-SO hydrogen atoms in 74 and 75. Confirming evidence that all four bases have a C-19a methyl is provided by the partial synthesis of all four isomers from tetrahydroalstonine, an indole alkaloid of known C-15a hydrogen, C-2Oa hydrogen, C-19a methyl stereochemistry. The specific assignment of configuration a t C-7 in speciophylline and uncarine-F is based on the relative position of the signal for their ester methyl groups in the PMR spectrum (56). The signal appears relatively upfield a t 3.32 S in the spectrum of speciophylline but is located between 3.55 and 3.60 6 in the spectra of the other three isomers. Such an upfield displacement of the methyl ester signal is attributed to shielding by an appropriately oriented aromatic ring. Consequently, speciophylline is assigned the C- 19a methyl epiallo A configuration in which the aromatic ring is oriented above the plane of the C/D ring. It follows, therefore, that uncarine-F must have the epiallo B configuration. Unequivocal assignment of the configuration a t C-7 in all four isomers is the result of a study of circular dichroism (56, 5 7 ) . The CD curves of the four bases display bands a t 252 mp and 290 mp. For speciophylline
2.
OXINDOLE ALKALOIDS
115
and uncarine-F, which possess a C-3p hydrogen, the bands at 252 mp are positive, and for pteropodine and isopteropodine, which possess an a-hydrogen at C-3, the bands are negative. Obviously the sign of the band at 252 mp reflects the stereochemistry at C-3. On the other hand, the sign of the 290 m p band has been shown to be related to the stereochemistry a t C-7 (53).A positive sign for the band at 290 mp indicates an orientation of the oxindole carbonyl above the plane of ring D (B series), whereas a negative sign indicates an oxindole carbonyl below the plane of ring D (A series). Accordingly, the band for speciophylline is negative (A series) and that for uncarine-F is positive (B series). Since pteropodine displays a positive band at 290 mp it must be assigned the C- 19a methyl allo B configuration. Likewise, isopteropodine, which exhibits a negative band at 290 mp, must possess the C-19cr. methyl allo A configuration. The relative basic strengths of pteropodine (pK, 4.8) and isopteropodine (pK, 4.05) are in agreement with the assigned configurations since pteropodine, with its lactam carbonyl oriented toward N , , is actually the stronger base.
G. CARAPANAUBINE, ISOCARAPANAUBINE, RAUVOXININE, AND RAUVOXINE Rauvoxine (mp 210") and rauvoxinine (mp 203") are an interconvertible pair of C2,H2,N,06 oxindoles isomeric with carapanaubine (59). On the basis of its PMR spectrum, carapanaubine has been shown to possess a C-19a methyl cis DIE stereochemistry further confirmed by its partial synthesis from reserpiline ( 4 ) .The oxidation of reserpiline to oxindoles using t-butyl hypochlorite is not successful but is accomplished by using lead tetraacetate, a method applicable for the oxidation of indolic alkaloids possessing a cis DIE ring function. The acetoxy reserpiline indolenine obtained in this manner gives a mixture of carapanaubine, isocarapanaubine, and rauvoxine after refluxing with aqueous methanolic acetic acid briefly. Prolonged reflux affords a mixture of carapanaubine, rauvoxine, and rauvoxinine. In glacial acetic acid either rauvoxine or rauvoxinine gives a mixture containing 80% carapanaubine a t equilibrium, while in refluxing pyridine there is obtained a mixture containing 33y0 rauvoxinine and 66% rauvoxine with only traces of carapanaubine. The four alkaloids thus belong to the allo/epiallo series (57). A comparison of chemical shifts of the C-19 methyl groups and the
116
J A S J I T S. BINDRA
C-19-C-20 proton coupling constant with the corresponding shifts observed for carapanaubine and isocarapanaubine confirms that rauvoxine and rauvoxinine possess the epiallo configuration. The shielded position (3.43 6) for the methyl ester singlet of rauvoxinine relative to the other isomers can be explained on the basis of a shielding effect on the methyl group of the oxindole aromatic ring oriented above the plane of the C/D ring. Thus rauvoxinine is an epiallo A oxindole and consequently rauvoxine must belong t o the corresponding B series. These assignments are further substantiated by the comparative rates of quaternization at N , and the fact that rauvoxinine is more stable in acid solution than is rauvoxine (57, 59). The configurations a t C-7 in the allo series are readily assigned on the basis of expected relative stability of the allo B configuration in acid solution. These assignments are borne out by the use of circular dichroism. Carapanaubine (71) has a negative 252 mp band in agreement with an a-hydrogen a t C-3 (allo configuration), whereas the band a t 300 mp, related to the stereochemistry a t C-7, is positive, indicating that it belongs to the B series. I n the CD spectrum of isocarapanaubine (70) the bands a t 252 mp and 300 mp are both negative, in agreement with the a110 A configuration assigned to it. In the case of rauvoxine and rauvoxinine, both of which belong to the epiallo series (3P-hydrogen), the CD band a t 252 mp is positive. The negative 305 mp band displayed by rauvoxinine (78) is in accord with its formulation as an epiallo A oxindole. Likewise, the positive band a t 305 mp displayed by rauvoxine (79) is in accord with its formulation as an epiallo B oxindole ( 5 7 ) .The absolute configuration of 78 has been confirmed by X-ray crystallography (60).
H. RAUNITICINE OXINDOLES The four 19P-methyl heteroyohimbine oxindoles of the allolepiallo configuration do not occur naturally but have been obtained by synthesis from rauniticine, an indole alkaloid of known 19P-methyl allo stereochemistry (57).Oxidation of rauniticine with lead tetracetate followed by treatment of the resulting acetoxy indolenine with aqueous methanolic acetic acid afforded two major and two minor components. On the basis of physical and spectral data the major components have been named rauniticine epiallo-oxindoles A (76) and B (77). Since an axial methyl group in the 19P-methyl allo configuration would render the configuration thermodynamically less stable than the corresponding epiallo arrangement, the two minor components have been designated
2.
OXINDOLE ALKALOIDS
117
rauniticine allo-oxindoles A (68) and B (69). The deshielded position of the signal for the 19-methyl group in the PMR spectrum of the allo oxindoles reflects its close proximity to the ATblone pair in this configuration. The stereochemistry a t C-7 has been assigned on the basis of the relative stability of the allo-A isomer in refluxing pyridine over its companion oxindole. Similarly, in the epiallo series the relative stability of the A oxindole over its B counterpart in acid solution is in accord with the assigned structures (55, 57).
I. MAJDINE
AND
ISOMAJDINE
Majdine (72;mp 192-194') and isomajdine (73; mp 204-206') are an interconvertible pair of C,,H,,N,06 oxindole alkaloids closely related to carapanaubine ( 4 0 ) .The molecular ion peak a t m/e 428 and the base peak at m/e 223 resulting from cleavage of ring C in the mass spectra of majdine and isomajdine are analogous to those for carapanaubine. The I R spectra of majdine, isomajdine, and carapanaubine (Table IV) are also very similar but there are some differences in the region 750-800 cm (out-of-plane aromatic C-H vibrations) suggesting that 72 and 73 differ from carapanaubine in the substitution pattern of the aromatic ring. This is further supported by PMR spectra in which the two aromatic protons in both compounds each appear as a pair of doublets ( J = 8 cps) indicating that the two protons have an ortho relationship (40, 61).Thus the two aromatic methoxyls in majdine and isomajdine must be either a t the 9,10 or the 11,12 positions; a 9,12 substitution is considered improbable because such an occurrence is unprecedented in the natural indole alkaloids. Since neither majdine nor isomajdine reacts with acetic anhydride the effect of an N , acyl group,
H3C0 CHOzH
H3C0 80
which would be expected to deshield strongly a C-12 proton in the PMR spectrum, could not be examined. Consequently majdine was reduced with LAH in dioxane to 2-deoxy-2-dihydromajdinol (80) which exhibited the C-9 and C-10 protons a t 6.79 6 and 6.38 6. Acetylation of 80
118
JASJIT S. RINDRA
now proceeds smoothly to give a diacetyl derivative in which the two aromatic signals are shifted to 7.12 6 and 6.95 6, respectively. The relatively small downfield shift of the aromatic protons which occurs as a consequence of the N,-acetylation is in good agreement with the corresponding shift of appropriate signals in N-acetyl-6,7-dimethoxyindoline (81). Consequently, majdine must be substituted a t the 11,12 position (40). Independently, Shellard and co-workers arrived a t the same conclusion on the basis of TLC (62). 7.096
H&O
COCH,
81
A comparison of the PMR chemical shifts of majdine with pteropodine and carapanaubine suggests that all three bases have the same allo stereochemistry. This is further substantiated by the spin constant (J19-20 = 10 cps) for the C-19 methine indicative of a trans pseudo diaxial arrangement of the C- 19-C-20 protons in a n allo configuration. Together with the relative basic strength of the two alkaloids and equilibration studies, which show that majdine is unchanged in refluxing aqueous acetic acid but is converted into isomajdine in refluxing pyridine, the two alkaloids have been assigned the 1%-methyl allo B and A configurations, respectively (40).
J . MISCELLANEOW s Gambirdine (mp 199-120') and isogambirdine, the latter isolated as its hydrochloride (mp 179-181"), are a pair of interconvertible oxindoles of C21H,4N204 constitution (30). IR, UV, PMR, and mass spectral data suggest that both are alkaloids of the mitraphylloid type. Since the normal, d o , and epiallo stereoisoniers of mitraphylline in both the 19a- and 19P-methyl series are known, and pseudo configurations are expected to be too unstable to exist, the stereochemical details of gambirdine and isogambirdine remain puzzling. Elegantine (C23H28N206; mp 202-204") is an 11,12-dimethoxy pentacyclic oxindole recently assigned the same structure as majdine (43). I n the absence of equilibration data and direct comparison of the two alkaloids it is not known whether they are identical or differ in configuration a t C-3, C-7, and/or C-19.
2.
119
OXINDOLE ALKALOIDS
Herbaline (C,,H,,O,N,; mp 276-278") is the first dihydropentacyclic oxindole alkaloid to be characterized (37). Trans fusion of rings D and E and a-orientation of the 19-methyl group have been deduced from \ H,CO \
I
I
I
I
PMR spectral data. Furthermore, the proximity of the C-9 aromatic hydrogen to N , is suggested by its downfield position a t 6.97 6 leading to structure 82 for herbaline. Interestingly, 82 isomerizes t o only a small extent in refluxing acetic acid, probably owing to interaction of the protonated N , with the ester carbonyl in acid solution (63). Vinerine (mp 202-203"), vineridine (mp 179-1 SO"), and erycinine constitution (mp 206-207') are three isomeric oxindoles of C,,H,,N,O, isolated from Vinca erecta (46, 47). Their structure has been formulated as 83 on the basis of spectral and chemical data ( 4 7 , 64). Another 11methoxyoxindole (Pa 7 ; mp 179-1 SO"), isolated from Mitragynajavanica could be identical with vineridine (65). Javaphylline (C,zH,6N,0,; mp lSO"), isolated from the same plant, is a 9-methoxymitraphylline type of alkaloid of the A series (19).
83
ACKNOWLEDGMENT The author wishes to acknowledge his deep debt to Professor Ernest Wenkert for an unforgettable introduction t o the world of alkaloids. REFERENCES 1. M. Hesse, "Indolalkaloide," p. 7. Springer-Verlag, Berlin and Ncw York, 1968. 2 . J. E. Saxton, in "The Alkaloids" (R. H. F. Rlenske, ed.), Vol. 8, p. 59. Academic Press, New York, 1965.
120
JASJIT S. BINDRA
3. J. E. Saxton, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 8, p. 93. Academic Press, New York, 1965. 4. B. Gilbert, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 8, p. 335. Academic Press, New York, 1965. 5. R. H. F. Manske, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 8, p. 693. Academic Press, New York, 1965. 6. J. E. Saxton, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 10, p. 521. Academic Press, New York, 1967. 7. G. B. Yeoh, K. C. Chan, and F. Morsingh, Rev. Pure Appl. Chem. 17, 49 (1967). 8. E. M. Lovell, R. Pepinsky, and A. J. C. Wilson, Tet. Lett. 1 (1959). 9. H. Conroy and J. K. Chakrabarti, Tet. Lett. 6 (1959). 10. E. Wenkert, C.-J. Chang, D. W. Cochran, and R. Pellicciari, Ezperientia 28, 377 (1972) 11. J. B. Strothers, “Carbon-13 NMR Spectroscopy.” Academic Press, New York, 1972. 12. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochran, and F. M. Schell, to be published. 13. E. Wenkert, C.-J. Chang, A. 0. Clouse, and D. W. Cochran, Chem. Commun. 961 (1970). 14. H. Schwartz and L. Marion, Can. J . Chem. 31, 958 (1953). 15. M. Przybylska and L. Marion, Can. J . Chem. 39, 2124 (1961); M. Przybylska, Acta Crystallogr. 15, 301 (1962). 16. E. Wenkert,,J. C. Orr, S. Garratt, J. H. Hansen, B. Wickberg, and C. L. Leicht, J. Org. Chem. 27, 4123 (1963). 17. E. Wenkert and N. V. Biringi, J . Amer. Chem. SOC.81, 1474 (1959); E. Wenkert, ibid. 84, 98 (1962). 18. R. Thomas, Tet. Lett. 544 (1961). 19. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, Planta Med. 15, 245 (1967). 20. E. J. Shellard, P. Tantivatana, arid A. H. Beckott, Planta Med. 15, 366 (1967). 21. E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Illed. 16, 20 (1968). 22. E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 16, 436 (1968). 23. E. J. Shellard, J. D. Phillipson, and D. Gupta, PZanta Med. 17, 51 (1969). 24. E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 17, 146 (1969). 25. E. J. Shellard and K. Sarpong, J . Pharm. Phaarmacol. 21, Suppl., 113 (1969). 26. A. H. Beckett, C. M. Lee, E. J. Shellard, and A. N. Tackie, Tet. Lett. 1709 (1963); Planta Med. 13, 241 (1965). 27. W. F. Trager, C. M. Lee, J. D. Phillipson, R. E. Haddock, D. Dwuma-Badu, and A. H. Beckett, Tetrahedron 24, 523 (1968). 28. E. J. Shellard and M. Z. Alam, J . Chromatop. 32, 472, 489 (1968); 33, 347 (1968). 29. E. J. Shellard and M. Z. Alam, J . Chromatog. 35, 72 (1968). 30. K. C. Chan, Tet. Lett. 3403 (1968). 31. R. R. Arndt, Phytochemistry 6, 1653 (1967). 32. M. B. Patel, J. Poisson, J. L. Pousset, and J. M. Rowson, J . Pharm. Pharmacol. 16, Suppl., 163 (1964). 33. J. L. Pousset and J. Poisson, Ann. PI~arm.Fr. 23, 733 (1966);see, also, J. L. Pousset, C A 70, 88034t (1969). 34. A. P. Orekhoff, H. Gurevich, S. S. Norkina, and N. Prein, Arch. Pharm. (Weinheim) 272, 70 (1934); A. P. Orekhov, S. S. Norkina, and E. L. Gurevich, Khim. Farm. Prom. 4, 9 (1934). 36. N. Abdurakhimova, P. Kh. Yuldashev, and S. Yu. Yunusov, C . R. Acad. S c i . U S S R 33 (1964); Khim. Prir. Soedin. 1, 224 (1965); G A 63, 16396 (1965).
2.
O X I N D O L E ALKALOIDS
121
36. G. H. Svoboda, A. T. Oliver, and D. R. Bedwell, Lloydia 26, 141 (1963). 37. I. Ognyanov, Ber. 99, 2052 (1966). 38. I. Ognyanov and B. Pyuskyulev, Izw. Otd. Khim. N a u k i , Bulg. Akad. Nauk 1, 5 (1968). 39. I. Ognyanov, P. Dalev, H. Dutschevska, and N. Mollov, C. R. Acad. Bulg. Sci. 17, 153 (1964). 40. I. Ognyanov, B. Pyuskyulev, I. Kompis, T. Sticzay, G . Spiteller, M. Shamma, and R. J. Shine, Tetrahedron 24, 4641 (1968); 2. Naturforsch. B 23, 282 (1968). 41. J. L. Kaul and J. T r o j h e k , Lloydia 29, 25 (1966). 42. M. Plat, R. Lemay, J. LeMen, M.-M. Janot, C. Djerassi, and H. Budzikiewicz, Bull. Soc. Chim. Fr. [5] 2497 (1965). 43. J. Bhattacharyya and S. C. Pakrashi, Tet. Lett. 159 (1972). 44. E. Z. Dzhakeli and K. S. Mudzhiri, Shoobsch. Akad. N a u k Gruz. SSR 57, 353 (1970); CA 73, 25723h (1970). 45. S. Z. Kasymov, P. K. Yuldashev, and S. Y. Yunusov, Khim. Prir. Soedin. 2, 260 (1966); C A 66, 2673 (1967). 46. S. Z. Kasymov, P. K. Yuldashev, and S. Y . Yunusov, Dokl. Akad. N a u k S S S R 162, 102 (1965); C A 63, 5703 (1965). 47. N. Abdurakhimova, Sh. Z. Kasymov, and S. Yu. Yunusov, Khim. Prir. Soedin. 4, 135 (1968); C A 69, 675879, (1968). 48. N. Finch and W. I. Taylor, J . Amer. Chem, Soc. 84, 3871 (1962). 49. A. H. Beckett, D. Dwuma-Badu, and R. E. Haddock, Tetrahedron 25, 5961 (1969). 50. E. E. van Tamelen, J. P. Yardley, 112. Miyano, and W. B. Hinshaw, J . Amer. Chem. Soc. 26, 7333 (1969). 51. J. D. Phillipson and E. J. Shellard, J . Chromatog. 32, 692 (1968). 52. A. H. Beckett and A. N. Tackie, J . Pharm. Pharmacol. 15, Suppl. 267 (1963); A. H. Beckett, E. J. Shellard, and A. N. Tackie, ibid. p. 166. 53. J. L. Pousset, J. Poisson, and M. Legrand, Tet. Lett. 6283 (1966). 54. M. Shamma and K. F. Foley, J . Org. Chem. 32, 4141 (1967). 55. M. Shamma, R. J. Shine, I. Kompis, T. Sticzay, F. Morsingh, J. Poisson, and J.-L. Pousset, J . Amer. Chem. SOC.89, 1739 (1967). 56. A. F. Beecham, N. K. Hart, S. R. Johns, and J. A. Lamberton, Aust. J . Chem. 21, 491 (1968). 57. J.-L. Pousset, J. Poisson, R. H. Shine, and M. Shamma, Bull. 80c. Chim. Fr. [5] 2766 (1967). 57a. E. Wintcrfeldt, A. J. Gaskell, T. Korth, H. Randunz, and M. Walkowiak, Ber. 102, 3558 (1969). 58. K. C. Chan, Phytochemistry 8, 219 (1969). 59. J.-L. Pousset and J. Poisson, C. R. Acad. Sci. 259, 597 (1964). 60. C. Pascard-Billy, Acta Crystallogr., Sect. B 25, 166 (1969). 61. M. R. Yagudaev, N. Abdurakhimova, and S. Y. Yunusov, K h i m . Prir.Soedin. 4, 197 (1968); C A 69, 1069292 (1968). 62. E. J. Shellard, J. D. Phillipson, and D. Gupta, J . Chromatogr. 32, 704 (1968). 63. I. Ognyanov, B. Pyuskyulev, M. Shamma, J. A. Weiss, and R. J. Shine, Chem. Commun. 579 (1967). 64. S. Z. Kasymov, P. K. Yuldashev, and S. Y. Yunusov, Dokl. Akad. N a u k S S S R 163, 1400 (1965); CA 63, 16398 (1965). 65. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, J . Pharm. Pharmacol. 18, 553 (1966).
This Page Intentionally Left Blank
-CHAPTER
3-
ALKALOIDS OF MITRAGYNA AND RELATED GENERA
J. E. SAXTON Department of Organic Chentistry T h e University Leeds, England
I. Introduction.. .................................................... 11. Stereochemistry of the Ring E 8eco Oxindole Alkaloids ................. 111. Stereochemistry of the Ring E 8eco Indole Alkaloids . . . . . . . . . . . . . . . . . . . IV. The Oxindole Analogs of the Heteroyohimbine Alkaloids ............... A. The normal Seriea .............................................. B. The allo-epiallo Series . . . . . V. Mitrajavine and Isomitrajavine. ................................. VI. Ourouparine, Gambirtannine, and Related Alkaloids . . . . . . . . ...... VII. Roxburghines .................................................... VIII. Addendum ................................ .......... References ...............................................
123 127 134 135 136 145 146 148 154
I. Introduction During the period under review several species of the Mitragyna genus have been closely reexamined, but no new alkaloids have been isolated with the possible exception of 3-isoajmalicine ( 1 )and uncarineF ( Z ) , two bases known previously from in vitro experiments but recently isolated from plant material, apparently for the first time. The results of all these extractions have recently been summarized (3). Mitragyna parvifolia has been particularly carefully studied ( 1 , 2, 6 6 ) and the variations in alkaloid content in plants from eight different geographical sources in India and southeast Asia have been noted ( 3 , 4 ) ;the seasonal variations in alkaloid content in plants grown in Poona and Ceylon have also been studied ( 6 ) . A similar study of the alkaloid content of M . stipulosa forms the subject of another communication ( 7 ) . The results of the recent extractions of Mitragyna and related genera are given in Tables I-IV ( 1 , 4 , 5 , 7-22). One result of interest is the identification (12) of the “base line ” alkaloid, previously isolated from M . rotundifolia (23) and M . inermis (8, 9), as isorhynchophylline N-oxide; rhynchophylline N-oxide has also been isolated from M .
124
J. E. SAXTON TABLE I RINQE seco OXINDOLEALKALOIDS Alkaloid
Rhynchophylline (1)
Source"
Refs.
a
7-9 7 7 10 4, 5 , l l 7-9 7 7 10 4,5,11 12 12 7-9 7 7 7-9 7 7 7-9 7
b C
d e
Isorhynchophylline (2)
a b C
d e
Rhynchophylline Nb-oxide Isorhynchophylline Nb-oxide Rotundifoline (3)
a
a, f a
b C
Isorotundifoline (16)
a b C
Rhynchociline (12)
a
b Ciliaphylline (14)
0
4
a b
7, 9 7 4 13 13 13a
0
Specionoxeine (15) Isospecionoxeine (13) Corynoxine (4) Corynoxeine (19)
l-
a
g
g Pseudocinchona africana A. Chev.
The key to the sources of the alkaloids listed in Tables I-IV follows Table IV.
inermis ( 1 2 ) . Since the parent tertiary bases remain unaffected by the isolation procedure it is argued that the N-oxides are natural constituents of the plant and not artifacts. Tetrahydroalstonine is the major alkaloid of an unidentified Uncaria species (22); at present this species is denoted simply by its herbarium number but may prove to be a hitherto undescribed Uncaria species. Gambirdine and isogambirdine are two interconvertible stereoisomers of mitraphylline which have been isolated from stems of U . gambir, but so far there is no definitive information concerning their stereochemistry (see, however, Section IV, B). Aside from these alkaloids the only new ones reported during the last four years are the roxburghines-A-E, also obtained from leaves and stems of U . gambir originating in Singapore (14).Different batches of plant material were shown t o contain different
3.
ALKALOIDS OF M I T R A G Y N A AND RELATED GENERA
TABLE I1
RINGE 8eco INDOLE ALKALOIDS Alkaloid
Source4
Dihydrocorynantheine
Refs. 495 14 15 7, 16 17,18 17,18 10 5 799 7 17,18 17,18 17,18
Gambirine (27) Speciogynine (23) Paynantheine (28) Hirsutine (26) Mitraciliatine (24) Corynantheidine (1la) Mitragynine (21) Speciociliatine (22)
TABLE I11
OXINDOLEALKALOIDS PENTACYCLIC Alkaloid
Sourcea
Mitraphylline (29)
Isomitraphylline (30)
Uncarine-A (isoformosanine) (32) Uncarine-B (formosanine, 31) Javaphylline (Pa 7) (42) Pteropodine (uncarine-C, 45) Isopteropodine (uncmine-E,46) Speciophylline (uncmine-D,47) g
Uncarine-F (48) Gambirdine Isogembirdine
1 e m m
Refs. 10 1 17 19 20 10 1 17,18 19 21 21 19 1 21 1 21 1 17,18 21 1 20 20
125
126
J. E. SAXTON
TABLE I V HETEROYOHIMBINE ALKALOIDS Alkaloid
Source”
11 17,18 19 1 19 11 14 22 1
Ajmalicine
Isoajmalicine Mitrajavine (41) Tetrahydroalstonine (49)
Akuammigine
Roxburghine-A Roxburghine-B R0xburghine-C Roxburghine-D (80) Roxburghine-E
I
Refs.
“Sesquimric ” Alkaloids
m
14
Key to Tables I-IV. a, Mitragyna inermk (Willd.) 0 . Kuntze [M. africana (Willd.) 0 . Kuntze]. b, M. cildata Aubrev. et Pellegr. (M. macrophylla Hiern.). c, M . stipulosa (C.D.) 0 . Kuntze ( M . macrophylla Hiern.). d, M . hirsuta Havil. e, M. parvzfolia (Roxb.) Korth. f, M . rotundijolia (Roxb.) 0. Kuntze [ M . diversifolia (Hook. f.) H a d . ] . g, M . speciosa Korth. h, Nwnauclea schlechterei (Val.) Merr. et Perry. j, M . jawanica Koord et Valeton. k, Uncaria kawakamii Hayata. 1, U.florida Vidal. m. U . gambir (Hunt)Roxb. n, Uncaria species (Herbarium No. P.C.S.M. 2475).
alkaloids, but it was not possible to determine whether the leaves extracted belonged to a variety of U . gambir or whether season and locality in which the plants were grown account for the differences observed. As the difficulty of identifying the infrequently flowering Uncaria species has been mentioned elsewhere (22) it is just possible that the plant material containing the roxburghines is a variety of U . gambir; certainly no alkaloids resembling the “sesquimeric ” roxburghines have been encountered in any of the previous studies on U.gambir. In an extensive programme in which 226 Malayan plants were screened for alkaloid content it was observed that U . cirdata (Lour.) Merr., U . ovalifolia Roxb., .and U . sclerophylla Roxb. gave positive tests for alkaloids (24); however, no further studies on these species have yet been reported. In their further studies on the Mitragyna alkaloids Shellard and his
3.
ALKALOIDS O F M I T R A B Y N A AND RELATED GENERA
127
collaborators have made several contributions to the analytical chemistry of this group. These include the quantitative determination of the Mitragyna bases by UV spectrophotometry (25, 26), colorimetry using the Vitali-Morin reaction (27, 28), and densitometry (29);the reliability of the three methods has also been discussed (30).Other contributions have been concerned with the correlation between the stereochemistry of these bases and their TLC behavior (31) and with the effect of methoxy substitution and configuration on TLC (32)and GLC behavior (33). The influence of the stereochemistry on the mass spectra of the corynantheidine group and the related oxindole group of alkaloids has also been discussed (34);this study includes the first report of the preparation of 3-isocorynantheidine, 3-isopaynantheine, and two oxindoles derived from mitragynine. The dissociation constants and the rate of quaternization of the dihydrocorynantheine-corynantheidine group (35) have been shown to be in accord with the conformations deduced earlier (36).
II. Stereochemistry of the Ring E seco Oxindole Alkaloids By 1967 the stereochemistry of rhynchophylline (1)and isorhynchophylline ( 2 ) had been elucidated, and tentative proposals had been made for rotundifoline ( 3 )and isorotundifoline (37).More recently this whole group of alkaloids has been subjected to a thorough conformational analysis (13),and the stereochemistry of the newer alkaloids ciliaphylline, rhynchociline, specionoxeine, and isospecionoxeine has been clarified. The ring E seco alkaloids may be classified, following the convention adopted originally in the yohimbine series, as normal, pseudo, allo, and epiallo, according to the relative configurations a t C-3, C-15, and C-20. If stereochemical constancy a t (2-15 is assumed, and if conformations destabilized by serious nonbonded interactions are ignored, the preferred conformations for the normal series are given by 1 and 2 and the preferred conformations of the a110 series by 4 and 5, the two isomers within each series differing in the configuration at C-7. Those isomers in which the oxindole carbonyl group is below the plane of rings C and D are designated isomers A, and those in which it is above this plane are designated isomers B. (This convention coincides with that originally proposed, i.e., that the stronger base in each pair should be designated isomer B only in the normal and all0 series). Alternatively, the configuration a t the spiro carbon atom (C-7) may be designated according to the Cahn-Ingold-Prelog convention; in the A series C-7 has the S configuration and in the B series the R configuration (38).
128
J. E. SAXTON
I n the pseudo series a n entirely different situation obtains; in both the A series (6) and the B series (8) the nonbonded interactions would normal B (C-7R) Series
normal A ((2-7s) Series 11 1
H
0 Me0
Isorhynchophylline; R = H R = OH 12 Rhynchociline; R = OMe 2
a Rotundifoline;
H
11
Me0 R 1 Rhynchophylline; R = H 16 Isorotundifoline; R = OH 14 Ciliaphylline; R = OMe
10
allo B Series
allo A Series
C0,Me
0
Me0 4
Corynoxine
" /
5 17
H
H Me0
H
R Corynoxine B; R = H Mitragynine oxindole B; R = OMe
be expected to destabilize these conformations to such an extent that they are almost certainly incapable of existence. Although difficult to assess quantitatively, the steric interactions in the alternative conformations (7 and 9)) in which both the (2-15 and C-20 substituents are axially oriented, are probably hardly less serious. The obvious conclusion is that pseudo conformations are too unstable to exist, and this is borne out to some extent by the observation that where pseudo indole alkaloids occur in a plant in association with oxindole alkaloids the latter are usually normal bases. I n contrast ullo and epiullo bases often occur alongside their oxindole analogs (3, 4, 6 ) . I n the epiallo series the preferred conformations are very probably given by 10 (A isomer) and 11 (B isomer). Several well-established experimental criteria may be used to elucidate the conformations of this group of alkaloids. For example, isomerization a t C-3 and/or C-7 occurs when the alkaloids are heated in acetic acid or in pyridine. I n the normal series, isomerization a t C-7
3.
129
ALKALOIDS O F M I T I i A G Y N A AND RELATED GENERA
allows the normal A and B isomers to be equilibrated; isomerization at C-3 does not occur since this would give the impossibly highly strained pseudo A Series H
H
Et 6
7 pseudo B Series
H
0
8
9
Et
pseudo series. This statement is in accord with the experimental observation that equilibration of the normal bases rhynchophylline (1) and isorhynchophylline ( 2 ) in pyridine or in acetic acid gives a mixture in which only these two isomers are detectable. I n acetic acid rhynchophylline predominates, owing to stabilization of the protonated form by \+
hydrogen bonding between -NH
/
and the lactam carbonyl group; in
pyridine, isorhynchophylline is favored, presumably as a result of the destabilization of rhynchophylline by the electrostatic repulsion between the oxindole carbonyl group and the lone electrons on N , in the free base. I n the allo-epiallo series it should in principle be possible to equilibrate all four A and B compounds by isomerization a t C-3 and C-7. I n certain cases this has been observed, e.g., in the closed ring E oxindole alkaloids uncarines-C, -D, -E, and -F (q.v.).
130
J. E. SAXTON
The situation in the all0 series of ring E seco alkaloids is exemplified by corynoxine and corynoxine B. Corynoxine, a constituent of Pseudocinchona africa,na A. Chev. (13a), belongs t o the a110 or epiallo series since it can also be prepared from corynantheidine ( l l a ) . The configuraepiallo B Series
epiallo A Series
0
H
I
H 11
10
M e O I C y M e
H 11 a
Corynantheidine
tion a t C-3 and C-7 may be deduced from a comparison of the CD spectra of corynoxine and related oxindole alkaloids of known stereochemistry. The spectra exhibit four bands in the region 200-310 nm; of these, the sign of the band a t 255-265 nm depends on the stereochemistry a t C-3 while the signs of the bands a t 210-220 nm and 285290 nm depend on the stereochemistry a t C-7, i.e., whether the alkaloid belongs to series A or series B. Corynoxine (4) exhibits a CD spectrum closely similar to that exhibited by isomitraphylline (30) and thus belongs to the ablo A series (39). I n acetic acid, corynoxine can be equilibrated to give a mixture containing only corynoxine (2001,)and one isomer, corynoxine B (80%). Since corynoxine has the a110 A configuration the new isomer, which predominates in the acid equilibration, must be the a110 B isomer or the epiallo A isomer. I n pyridine, corynoxine gives a n equilibrium mixture of the same two isomers in which corynoxine now predominates ( 1 3 ) . [Note that other workers (39) state that corynoxine is unaffected by pyridine.] Under these conditions the epiallo B isomer would be expected
3.
ALKALOIDS O F M I T R A Q Y N A AND RELATED GENERA
131
to be stabilized at the expense of the allo B and particularly epiallo A; hence it seems likely that the new isomer, which is produced in either acidic or basic equilibrating conditions, is the allo B isomer ( 5 ) (13). Differentiation between the normal and allo series is possible from an examination of the NMR triplet owing to the C-18 methyl group. Those isomers which possess an axial ethyl group at C-20 (the all0 series) will exhibit a more symmetrical triplet than the C-20 equatorial isomers owing to the deshielding of the C-19 methylene protons by the lone electrons on N , ; in the allo series therefore there will be a larger difference in chemical shift between the C-19 methylene signal and the C-18 methyl signal than in the normal series with a consequent improvement in the resolution of the C-18 methyl triplet. This criterion has been successfully applied in the corynantheidine-mitragynine series (36, 40) and should therefore be applicable in the corresponding oxindole series, as in fact is demonstrated by a comparison of the NMR spectra of rhynchophylline and isorhynchophylline (normal series) and Corynoxine and corynoxine B (ullo series) (13). Differentiation between the A and B isomers in the spirocyclic oxindole series has often been made on the basis of pK, and isomerization data; thus the stronger bases would clearly be expected to be those isomers in which the lactam carbonyl group is in close proximity to the lone electrons on N , with the consequent stabilization of the conjugate acid by hydrogen bonding. However, an independent criterion would clearly be of value, and this is provided by the signals due to the aromatic protons in the NMR spectra of those compounds in which C-9 carries a hydrogen atom. For example, the lowest field aromatic proton in the spectrum of isorhynchophylline (2) is a doublet a t 7.40 6 which must be due to the C-9 or C-12 proton, whereas the lowest field aromatic signal in the spectrum of rhynchophylline (1) is at 7.20 6. Since the environment of C-12 is hardly affected by a change from A to B configuration, this lowest field signal must be due to the C-9 proton. I n the A isomer (isorhynchophylline) this proton is situated over ring C and in close proximity to the deshielding electrons on N , . The validity of these experimental criteria having been established, it is now possible to discuss the constitution and stereochemistry of the newer alkaloids of this group. The spectrographic data concerning ciliaphylline, rhynchociline, specionoxeine, and isospecionoxeine leave no doubt that the first two alkaloids are methoxyl derivatives belonging structurally to the rhynchophylline group while the last two are C-20 vinyl analogs (13). The relationship between these alkaloids is readily established by hydrogenation of the vinyl group; specionoxeine yields ciliaphylline, and isospecionoxeine yields rhynchociline. Moreover,
132
J. E. SAXTON
specionoxeine may be equilibrated with isospecionoxeine in pyridine or acetic acid, and rhynchociline may similarly be equilibrated with ciliaphylline. The position of the aromatic methoxyl group in these alkaloids was deduced from their NMR spectra. Both isospecionoxeine and rhynchociline exhibit a pattern of signals (two overlapping doublets and a triplet, 1H each) consistent with the presence of three adjacent aromatic protons giving rise to an ABX system. The spectra of specionoxeine and ciliaphylline exhibit two one-proton doublets and a triplet (1H each) also consistent with the presence of three adjacent aromatic protons in an A,X system. Hence all four alkaloids carry a substituent, L e . , the methoxyl group, at position 9 or 12, and the hydrogenationequilibration data indicate that it is in the same position in all four alkaloids. That it is in position 9 is proved by the NMR spectrum of N acetylciliaphylline which exhibits an ortho-coupled doublet shifted downfield by more than 1 ppm compared with the position of the analogous signal in the NMR spectrum of ciliaphylline. This signal is clearly due to a proton on C-12 and therefore the methoxyl group must be attached to C-9. These four alkaloids are thus, in a structural sense, g-methoxyrhynchophyllines or the C-20 vinyl analogs. The NMR data show that the geometry about the 16,17 double bond is the same in all these alkaloids as it is in rhynchophylline for which it has previously been established. Conformational arguments show that the preferred conformations for each isomer in the normal, (p$eudo),allo, and epiallo series are the same in the 9-methoxylated series as they are in the rhynchophylline group. Consequently, the isomerization data mentioned above indicate that all four alkaloids very probably belong to the normal series, since two, and only two, isomers can be detected a t equilibrium. The lack of resolution of the C-18 methyl triplet in the NMR spectra of rhynchociline and ciliaphylliiie also indicates that these alkaloids, and therefore specionoxeine and isospecionoxeine, belong to the normal series (13). These four alkaloids are therefore related both structurally and stereochemically to 9-methoxyrhynchophylline. I n this 9-methoxyl series the criteria used to distinguish between the A and B series in the rhynchophylline isomers are not valid; thus either the 9-methoxyl group or the lactam carbonyl group may stabilize the conjugate acid when appropriately placed so that arguments based on pK, values are inapplicable. The absence of hydrogen at C-9 removes a second criterion from the discussion. Hence a new criterion is required. This was found in the chemical shift of the aromatic methoxyl signal, which suffers a significant downfield shift ( 0.20 ppm) in changing from deuteroN
3.
133
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
chloroform to acetic acid solvent in those isomers (A isomers) in which the methoxyl group is close to N , , and therefore in acid comes under the deshielding influence of the protonated amino group. On the basis of this criterion, rhynchociline (12) belongs to the normal A series and therefore so does isospecionoxeine (13); ciliaphylline (14)and specionoxeine (15) consequently belong to the normal B series (13). Rotundifoline had earlier (41)been assigned the structure 3 although wit,hout firm evidence for the stereochemistry a t C-15 and C-20. Rotundifoline and isorotundifoline can be equilibrated in pyridine or in acetic acid solution and no other isomer is formed. These observations, together with the low basicity and noiiphenolic behavior of rotundifoline, are consistent only with a normal A (3) or (less probably) allo A (16) configuration for rotundifoline. Isorotundifoline must then have the normal B (9-OH derivative of 4) or the allo B (%OHderivative of 5 ) configuration (the phenolic properties of isorotundifoline additionally eliminate the epiallo B configuration 11). The lack of resolution of the C-18 methyl triplet in the NMR spectra of these bases indicates that they both belong to the normal series; rotundifoline is thus 3 and isorotundifoline is 16 (13). To complete this group of twelve alkaloids mention may be made of mitragynine oxindole B and corynoxeine. The former must belong to the allo or epiullo series since mitragynine has the allo configuration a t C-3, 15, and 20. Since it exhibits a symmetrical (2-18 methyl triplet in its NMR spectrum it must have an axial C-20 ethyl group, and since its 9-methoxyl group signal is hardly affected by change of solvent the methoxyl group cannot be in close proximity to the lone electrons on N , ; both these facts indicate an allo B configuration, and mitragynine oxindole B must be represented by 17 (34). Corynoxeine (23a) is the oxindole analog of corynantheine (18), from which it can be partially synthesized (42). Corynoxeine thus has the same configuration a t C-15 and C-20 as corynantheine, and since it gives rhynchophylline (1) on hydrogenation it must have the complete stereochemistry given in 19 (42).
-CH=CH2
n
n
H
H
/
Me0
13 Isospecionoxeine
15 19
Specionoxeine; P. = OMe Corynoxeine; R = H
134
J. E. SAXTON
Finally, full details of the synthesis (43) of rhynchophyllol (20) and isorhynchophyllol have now been published ( 4 4 ) .
111. Stereochemistry of the Ring E seco Indole Alkaloids Chemical evidence has recently been reported ( 4 5 ) which supports the conformations deduced earlier (36)for speciogynine, speciociliatine, mitraciliatine, and hirsutine from spectroscopic evidence. The reaction with mercuric acetate of alkaloids belonging to the corynantheine, yohimbine, or heteroyohimbine series results in formation of the corresponding 3-dehydro salts which on reduction afford mixtures of the initial alkaloids together with their C-3 epimers. Those alkaloids which contain a trans diaxial arrangement of C-3 hydrogen and lone electrons on N , react faster than their isomers in which either of these groups is equatorially disposed. I n fact, under identical conditions, mitragynine reacted more readily than speciociliatine to give a dehydro salt which was reduced by zinc and acetic acid to a mixture of mitragynine and speciociliatine. Since the complete stereochemistry of mitragynine (21) is known, the epiallo conformation (22) for speciociliatine is confirmed. Similarly, oxidation of speciogynine with mercuric acetate proceeded faster than oxidation of mitraciliatine and reduction of the 3-dehydro salt afforded a mixture of t,hese two alkaloids in which speciogynine predominated. Since these alkaloids must necessarily belong to the normal-pseudo series the experimental facts can only be reconciled with the normal conformation (23)for speciogynine and the pseudo conformation (24) for mitraciliatine. I n the parent series in which C-9 carries a hydrogen atom, dihydrocorynantheine (25) and corynantheidine ( l l a )belong to the normal and allo series, respectively. The stereoisomer hirsutine must therefore R
H 18 28
Corynentheine; R = H Paynantheine; R = OMe
20
Rhynchophyllol
3. ?Me
?Me
H
21 22
135
ALKALOIDS O F MIl'lZAGYIVA AND RELATED GENERA
H
Mitregynine; a-H at C-3 Speciociliatine;8-H at C-3
23 24
Speciogynine; a-H at C-3 Mitraciliatine; 8-H at C-3
R
H 25 26 27
Dihydrocorynantheine; R = H, a-H at C-3 Hirsutine; R = H, p-H at C-3 Gambirine; R = OH, a-H at C-3
belong to the pseudo or epiallo series. Since hirsutine can be correlated with dihydrocorynantheine, but not with corynantheidine, by mercuric acetate oxidation followed by reduction, it must have the pseudo stereochemistry expressed in 26 ( 4 5 ) .
IV. The Oxindole Analogs of the Heteroyohimbine Alkaloids The heteroyohimbine alkaloids and their oxindole counterparts form a large group of compounds that provide an ideal exercise in conformational analysis; the oxindole bases, which contain in C-7 an additional asymmetric center, have been particularly thoroughly studied. The oxindole alkaloids that occur in Mitragyna and related genera have previously been discussed in Volumes VIII and X of this series and by 1967 the complete conformations of most of these alkaloids had been elucidated. The known facts concerning the stereochemistry of these alkaloids a t that time have been summarized by Shamma et ul. (46, 4 7 ) , and the stereochemistry of the uncarines-A-F has also been
136
J. E . SAXTON
comprehensively discussed by an Australian group (48). Some new facts are added here and the opportunity is taken to review briefly the whole of this important group, which now comprises some 32 bases",? of which the complete stereochemistry of 25 is known.
A. THE Normal SERIES The first alkaloids of this group to be fully elucidated were mitraphylline (29) and isomitraphylline (30) (see Volume VIII, pp. 64-70), the stereochemistry a t carbon atoms 15, 19, and 20 being firmly established by the partial synthesis from ajmalicine. The stereochemistry of uncarine-A (isoformosanine) and uncarine-B (formosanine) was less readily established and in the initial proposal a cis fusion of rings D and E was assumed. However, the CD spectrum of formosanine is virtually superposable on that of mitraphylline (29),as is the spectrum of uncarine A on that of isomitraphylline (30);this clearly indicates a trans fusion of rings D and E in these isomers (47-49). Hence formosanine must belong to the pseudo series or be epimeric with the mitraphylline pair a t C-19. The comments made above concerning pseudo conformations apply a fortiori to the closed ring E series, since only conformations analogous to 6 and 8 are theoretically possible, and these are clearly subject to nonbonded interactions of such magnitude that they need not be seriously considered. Formosanine and uncarine-A thus probably belong to the normal series; this is supported by the fact that on equilibration formosanine gives a mixture containing only itself and uncarineA. Formosanine must then be the C-19 epimer of mitraphylline or isomitraphylline. Such a constitution requires a trans-diaxial arrangement of hydrogen atoms a t C-19 and C-20, in opposition to the axial-equatoria1 arrangement previously postulated on the basis of the 60 Me NMR spectrum from which J,,,,, was deduced to be 2.9 Hz. However, the methoxycarbonyl methyl signal obscures the C-19 multiplet in this spectrum and renders determinat,ion of JI9,,, very difficult. I n the
* This figure includes several bases only obtained, so far, in the laboratory in isomerization and rearrangement studies together with two bases which are very probably impure specimens of known alkaloids (vide infra). t Since the above account was written, one new alkaloid has been added to this group; this is 10,1l-dimethoxyisomitraphylline(l0,ll-diimethoxy derivative of 30), which has been isolated from the aerial parts of Cabucala marlagascariensis (A.DC) Pichon (48a). Elegantine, a constituent of Vinca major L., var. elegantissima Hort. (48b),appears from the published physical and spectroscopic data, and from the structnre postulated, to be identical with isomajdine (62) (q.v.).
3.
ALKALOIDS O F M I T E A G Y N A AND RELATED GENERA
137
100 Mc spectrum, however, the multiplet is completely resolved and J,,,,, is shown to be 9 Hz in consonance with a diaxial arrangement of these hydrogen atoms. Since formosanine is the stronger base it belongs to the normal B series and is formulated as 31; uncarine-A is then 32 (48,49).Independent confirmation of t,his conclusion is provided by rauvanine oxindoles A and B (33 and 34, respectively), prepared from rauvanine (35), whose stereochemistry has previously been unequivocally established. I n the NMR spectra of the rauvanine oxindoles the signals due to the ring E substituents are almost identical in chemical shift and coupling constant with those of formosanine and uncarine A and show differences when compared with the corresponding signals
0
R 29 43
30 42
Mitraphylline; R = H Isojavaphylline; R = OMe
R
H
COzMe
C0,Me Isomitraphylline; R = H Jmaphylline; R = OMe
R
H
C0,Me
R 31 34
Formosenine=uncarine-B; R = H Rauvanine oxindole B; R = OMe
35
Rauvanine
32 33
Isoformosanineancarine-A; R = H Rauvanine oxindole A; R = OMe
138
J. E. SAXTON
exhibited by mitraphylline and isomitraphylline. I n particular the (3-19 a: position is highly shielded, probably by the ring E double bond; consequently in the mitraphylline-isomitraphylline pair the methyl group attached to C-19 resonates at higher field than the corresponding group in the rauvanine oxindoles, formosanine, and uncarine-A. Conversely, in the last four alkaloids the C-19 proton resonates at higher field than the C-19 proton in mitraphylline and isomitraphylline (47-49). Final confirmation of these structures for formosanine and uncarineA is afforded by their total synthesis (50). The keto ester 36, prepared earlier together with its C-20 epimer in connection with the synthesis of aknammigine and tetrahydroalstonine (q.v.), was reduced catalytically to the lactone ester 37 which was further reduced (NaBH,) to the lactol ester 38. Polyphosphoric acid converted 38 into 3-iso-19-epiajmalicine (39)which reacted with t-butyl hypochlorite to give the chloroindolenine 40. Treatment of 40 with aqueous methanolic acid then gave a mixture of formosanine (31) and uncarine-A (32)(50). The remaining alkaloid in this group is javaphylline (Pa7) which occurs in Mitragyna javanica (51).I t s spectrographic properties indicate that it is an ar-methoxyoxindole alkaloid containing a closed ring E, and it was initially suspected of having a methoxyl group at C-11 and possibly being identical with vineridine, an alkaloid of Vinca erecta. However, the behavior of javaphylline on isomerization is different from that of vineridine, and the 100 Me NMR spectrum indicates that the methoxyl group is situated at C-9 in common with all the other methoxyl- or hydroxyl-containing Mitragyna bases. Isomerization of javaphylline in acetic acid or pyridine produces a mixture of javaphylline and isojavaphylline; apparently no other isomers are produced. The methyl group, according to the NMR spectrum, is in a shielded axial position and accordingly the C-19 hydrogen resonates at comparatively low field. All these data are consistent with the formulation of javaphylline as 9-methoxymitraphylline or its C-7 epimer (19). This is consistent with the preparation of javaphylline and isojavaphylline (52) by oxidative rearrangement of mitrajavine, for which the pseudo stereochemistry 41 has been established (53).Although no details are available it is stated (19) that javaphylline, according to its cliromatographic behavior, belongs to the A series; it must therefore have the constitution 42 and isojavaphylline is 43. Herbaline is a closely related alkaloid, which occurs in V . herbacea W.K. (54), but so far has not been encountered in Mitragyna species; nevertheless it is convenient to include it here. This alkaloid differs from the other heteroyohimbine bases in having no double bond in ring E.
3.
ALKALOIDS O F M I T R A B Y N A AND RELATED GENERA
139
This complicates the stereochemical problem since the ring E double bond in the heteroyohimbine series proper cannot be selectively hydrogenated, and therefore correlation studies by this means are rendered impossible. As in mitraphylline and isomitraphylline the methyl group attached to C-19 resonates at high field; this is characteristie of normal bases carrying an axial methyl group. The C-9 proton resonates at comparatively low field owing to deshielding by the lone electrons on N , ; herbaline would thus appear to belong to the A series. The remaining
Pt
(H '
MeOzC/
COMe CH \CO,Me
0 37
36
I
NaBH,
PPA
t-
Me "H
OH 38
formosanine (31) H + /HzO ___f
MeOH
+
isoformosanine (32)
140
J. E. SAXTON
stereochemical feature, i.e., the configuration of the methoxycarbonyl group, may be deduced from equilibration studies; herbaline is unaffected by pyridine as expected from a base of series A, but it isomerizes to only a small extent in acetic acid, presumably because the protonated N , is capable of being hydrogen-bonded to an axially disposed ester group at C-16. The complete stereochemistry of herbaline is thus given in 44. B. THE ablo-epiallo SERIES By 1967 the stereochemistry of the four allo-epiallo isomers uncarineC (pteropodine, 45), uncarine-E (isopteropodine, 46),uncarine-D (speciophylline, 47), and uncarine-F (48) had been elucidated, although there were still some inconsistencies in the literature concerning these bases and there was still some doubt concerning the stereochemistry of the C/D ring junction in uncarines-D and -F. These four stereoisomers can be equilibrated in acetic acid solution and any one isomer rapidly gives a mixture of all four isomers. I n pyridine solution the equilibrium is slowly attained and only traces of uncarines-D and -F, for example, are produced from either uncarine-C or uncarine-E. The partial synthesis of all four isomers (4548) from tetrahydroalstonine (49) renders secure the postulated stereochemistry at positions 15, 19, and 20 (48). Since in uncarine-C (45) and uncarine-E (46) Jig,,, = 11 Hz, the hydrogen atoms at positions 19 and 20 must be trans diaxially oriented ; similarly the magnitude of the corresponding coupling constant in the spectra of uncarines-D (47) and -F (48) ( J 1 9 , 2 0 = 1.5 Hz) indicates that these hydrogen atoms are trans diequatorially oriented. This obviously indicates a conformational inversion in the isomerization of the C and E isomers to uncarines-D and -F and is only consistent with a cis DIE ring junction. Conformations 45 and 46, containing the allo stereochemistry, are consistent with all the evidence for uncarines-C and -E. Inversion of configuration at C-3 would give an epiallo isomer (50) of low stability which can attain a more stable conformation by a chair-to-chair inversion of ring D. The two conformations produced, 47 and 48, represent uncarines-D and -F, respectively. A trans fusion of rings C and D is now preferred in contrast to the cis fusion originally postulated, since other studies indicate that in indolizidine derivatives the trans conformations are thermodynamically more stable than the cis (48). The choice between structures 47 and 48 for uncarine-D was made on the basis of the comparatively low chemical shift of the ester methoxyl group in
3.
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
141
OMe
H
0 Mitrajavine; 8-H at C-3 66 Isomitrajavine; a-H at C-3
41
H
46
p
44
o
Herbaline
,
Uncarine-E (isopteropodine);R1 = Ra = R3 = H
Isocarapmaubine; R' = Ra = OMe, R3 = H 62 Isomajdine; R1 = H, Ra = R3 = OMe
52
H P O ,
Uncarine-C (pteropodine); R' = Ra = R3 = H 53 Carapanaubine; R' = Ra = OMe, R3 = H 6 1 Majdine; R' = H, Ra = R3 = OMe
45
0 HN
48
55
Speciophylline=uncarine-D ; R1 = R2 = R3 = H Rauvoxinine; R1 = Ra = OMe, R3 = H
64
Majdine 4; R' = H, Ra = R3 = OMe
63
47
54
R' Uncarine-F; R' = Ra = R3 = H Rauvoxine; R1 = Ra = OMe; R3 -- H Majdine 3; R' = H, Ra = R3 = OMe
142
J. E. SAXTON
the NMR spectrum; only in conformation 47 is the methoxyl group sufficiently close to the aromatic ring to account for shielding of the observed magnitude (48).
@
COaMe
MeOaC&O 49 56
Tetrahydroalstonine;8-H at (3-19 Rauniticine; a-H at (2-19
51
50
Reserpiline
Carapanaubine, isocarapanaubine, rauvoxine, and rauvoxinine are four alkaloids closely related to uncarines-C-F. The formation of all four alkaloids by oxidative rearrangement of reserpiline (51) establishes the cis DIE ring junction and the configuration of the methyl group at C-19. The magnitude of the coupling constant between the protons = at positions 19 and 20 in carapanaubine and isocarapanaubine ( J19,20 10 Hz) compared with the much smaller coupling constant (1.5 Hz) for the analogous protons in rauvoxine and rauvoxinine suggests that the first two alkaloids are based on the allo conformations 45 and 46 (not necessarily respectively) while the last two alkaloids have the epiallo stereochemistry of 47 and 48. Several criteria were employed in order to assign the configuration a t C-7 in these four bases; these criteria included the chemical shift of the C-9 proton, the chemical shift of the N-methyl group in the quaternary metho-salts, and the rate of quaternization with methyl iodide. For example, the chemical shifts of the signals due to the C-9 proton in the NMR spectra of isocarapanaubine and rauvoxine were significantly greater than the corresponding signals in the spectra of carapanaubine
3.
ALKALOIDS O F M I T R A G Y N A A N D RELATED GENERA
143
and rauvoxinine. Consequently, isocarapanaubine must be 52 and carapanaubine must be 53; similarly rauvoxine and rauvoxinine must be 54 and 55, respectively ( 4 7 ) .The other lines of evidence, where they could be applied with confidence, pointed to the same conclusions. Rauniticine (56), the C-19 epimer of tetrahydroalstonine, gives a similar series of four oxindole bases on oxidative rearrangement ( 4 7 ) . By application of the physical and chemical methods enumerated above the four products were assigned to their conformational series. It is of interest to note that in this group rauniticine epiallo oxindoles A (57) and B (58) are the major products in the preparation from rauniticine; the epiallo A isomer (57) is also the preferred product at equilibrium in acid solution while the epiallo B isomer (58) predominates after equilibration in pyridine. This preference for the epiallo series is presumably the result of destabilization of rauniticine allo oxindoles A (59) and B (60) as a consequence of the axially oriented methyl group a t C-19 (46, 47).
R
H
H
57
Rauniticine epiallo oxindole A
58
Rauniticine epiallo oxindole B Me.jF-7
59
Rauniticine a110 oxindole A
60
Rauniticine allo oxindole B
One further interconvertible pair of isomers may be included here. These are majdine and isomajdine, two of the minor constituents of Vinca major ( 5 5 ) .The IR and NMR spectra of these isomers resemble those of a third isomer, carapanaubine, but it is clear from the NMR spectrum that majdine and isomajdine differ from carapanaubine in
144
J. E. SAXTON
the position of the aromatic methoxyl groups. Both majdine and isomajdine exhibit an ortho-coupled AB quartet indicating that the two methoxyl groups must be situated at positions 9 and 10, or 11 and 12, or (much less likely) 10 and 11. Reduction of majdine with lithium aluminum hydride, followed by acetylation, gave N,,O-diacetyl-Zdeoxy-2-dihydromajdinol. This exhibited aromatic signals at 6 7.12 and 6.95 ( J = 9 Hz) in its NMR spectrum compared with 6 6.79 and 6.38 for the parent secondary base. This small downfield shift in the acetyl derivative compares closely with that observed in compounds related to aspidospermine and is not considered sufficiently large to indicate the presence of hydrogen at C-12. Majdine and isomajdine are therefore regarded as 11,12-dimethoxyl isomers of carapanaubine. The a110 stereochemistry of majdine and isomajdine, and the configuration of the methyl group at C-19, follow from the close similarity of the IR and NMR spectra (if allowance is made for the aromatic substitution pattern) of these isomers, carapanaubine (53), uncarine-C (45)) and uncarine-E (46). Since majdine is hardly affected by acetic acid and is the stronger base, whereas isomajdine is the principal product following equilibration in pyridine, majdine (61) must belong to the B series and isomajdine is then the a110 A isomer (62). This is confirmed by the downfield position of the C-9 proton signal in the NMR spectrum of isomajdine (6 6.84, compared with 6 6.72 for majdine) which indicates deshielding of this proton by the lone electrons on N,, appropriate to a compound of the B series (55). I n consonance with the formulation of majdine and isomajdine as a110 isomers Shellard et al. (32) report that equilibration of majdine in pyridine or acetic acid yields a mixture of four stereoisomers. The two new isomers are named majdine 3 (epiablo B, 63) and majdine 4 (epiallo A, 64). The mass spectra of twelve representative oxindole alkaloids from all three known stereochemical groups have been discussed in relation to their stereochemistry (56). The results show that only the ion at m/e 180, attributed t o the fragment 65, has any value in making stereochemical assignments since this ion is intense only in the spectra of allo and epiallo alkaloids which also contain a-methyl groups at C-19 (e.g., carapanaubine, pteropodine, rauvoxine). This completes the 25 oxindole alkaloids whose stereochemistry has been completely elucidated. The alkaloids which remain to be investigated are Alkaloid V from V . major (an isomer of carapanaubine) (57), vinerine, vineridine (58), and erycinine (59) from V . erecta, herbavine from V . herbacea (669, and gambirdine and isogambirdine from U . gambir (20).The last two substances pose a problem, if they are
3.
145
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
accepted as bonafide new alkaloids, and if it is also accepted that the pseudo oxindole bases are incapable of existence, since all twelve possible isomers in the mitraphylline-uncarine-rauniticine oxindole series are
II
65
I
m/e 180
already known (see discussion above). However, inspection of the reported data for gambirdine and isogambirdine (ZO), and in particular the optical rotation and N M R data, indicates that these alkaloids are probably impure uncarine-B (formosanine) and uncarine-A, respectively.
V. Mitrajavine and Isomitrajavine Mitrajavine [C,,H,,N,O,; mp 117'; [a]i3 -37.6' (CHCl,)] is a heteroyohimbine alkaloid (IR and N M R spectra) which contains one aromatic methoxyl group, presumably at C-9, since the chemical shift and the splitting pattern of the three aromatic protons closely resemble those exhibited by mitragynine (19, 51-53). The upfield position (0.9 ppm) of the C-19 methyl signal indicates that it is shielded to a significant extent, probably by the aromatic ring, since this is a greater shielding than that experienced by an axial methyl group shielded only by the 16,17 double bond. This can be explained only by postulating that mitrajavine belongs to the pseudo series, a conclusion that is supported by the absence of Bohlmann bands in the IR spectrum and the chemical shift of the C-3 proton which indicate the presence of a cis-quinolizidine system. The stereochemistry of mitrajavine (41) is thus defined and it should be possible by lead tetraacetate dehydrogenation followed by zinc-acid reduction to convert it into its more stable C-3 epimer, isomitrajavine (66). This has been achieved (53) and it is
146
J. E. SAXTON
of interest to note that the axial methyl group a t C-19 resonates at 6 1.16, almost identical in position with the corresponding signals exhibited by mitraphylline (29)and ajmalicine. Isomitrajavine (66) is therefore 9-methoxyajmalicine.
VI. Ourouparine, Gambirtannine, and Related Alkaloids The structures assigned to ourouparine and the other alkaloids of this group have been confirmed by transformations within the series and by total synthesis. Reaction of dihydrogambirtannine (67)with iodine and sodium acetate results in dehydrogenation and formation of ourouparine iodide (68) which with alkali is readily transformed into a mixture of gambirtannine (69), oxogambirtannine (70),and neooxygambirtannine (71)(61). Oxogambirtannine (70)has also been synthesized by Bischler-Napieralski cyclization of the amide 72,itself prepared from tryptamine and 2,6-dicarboxyphenylaceticacid, followed by esterification (61). ( f.)-Dihydrogambirtannine (67)has been synthesized by two routes (62, 63). The first one is an extension of the route to indole alkaloids which involves the reductive cyclization of l-alkyl-3-acylpyridinium
41
Mitrajavine
~~~~Q~~ H He-
I2
/
/ Me02C 67
\
Dihydrogambirtannine
Me02C 68
\
Ourouparine iodide
3.
69
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
Gambirtannine
07%
147
71 Neo-oxygambirtannine
a
H
/ MeO& 70
\
Oxogambirtannine
72
salts ; for the synthesis of dihydrogambirtannine the reductive cyclization of an acylisoquinolinium salt was required. Condensation of 5,6,7,8-tetrahydroisoquinoline-4-carboxylic ester with oxalic ester gave the lactone ester 73 which was oxidized (H,O,/OH) and esterified to the diester 74. Dehydrogenation to the corresponding isoquinoline ester 75 was achieved by two consecutive treatments with N-bromosuccinimide and with collidine. Alkylation of 75 with tryptophol bromide then gave the isoquinolinium salt 76 which on palladiumcatalyzed hydrogenation gave the required dihydroisoquinoline (77). When 77 was heated with aqueous alkali hydrolysis, decarboxylation and cyclization occurred with formation of ( f )-dihydrogambirtannine (67) (62). A shorter and neater synthesis of ( )-dihydrogambirtannine involved the multiple-phase reduction of the isoquinolinium salt 78 with sodium borohydride in a methanol-ether-water system in the presence of a high concentration of cyanide ion. The intermediat,e, presumably the cyanide (79) formed by trapping of the initially generated dihydroisoquinoline derivative by nucleophilic cyanide ion, was not isolated but was converted directly into ( i )-dihydrogambirtannine (67) by heating in dilute hydrochloric acid. Dehydrogenation of the stable hydrochloride of 67 by means of iodine and sodium acetate afforded a n improved route
148
J. E. SAXTON
to ourouparine (68) while the oxidation of 68 with hydrogen peroxide in dioxane provided a n independent synthesis of oxogambirtannine (70) (63)-
77
76
7s
79
VII. Roxburghines Roxburghines-A-E are five diastereomeric alkaloids of molecular which have recently been isolated from the leaves formula C,,H,,N,O, and stems of Uncaria gambir (14).These alkaloids belong to a new structural type and their isolation is of some interest, having regard to the fact that these bases have not been encountered in any of the previous extractions of this species. The diastereomeric character of the five roxburghines is shown by the near identity of their UV spectra and by the similarity of their I R , NMR, and mass spectra. Owing to lack of material, most of the investigations were carried out on roxburghine-D for which the structure 80 was deduced although the alternative 81 cannot a t present be confidently rejected.
3.
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
149
The IR spectrum of roxburghine-D discloses the presence of two imino groups (also evident from the NMR spectrum which indicates that they are contained in indole nuclei) and an +unsaturated carbonyl group. The NMR spectrum also indicates the presence of one vinylic proton at low field, additionally deshielded by proximity to nitrogen or oxygen (i.e., \C=CHN-
/
l
or \C=CH-O-),
a methoxyl group,
/
a tertiary methyl group attached to saturated carbon, and a -CH2-
I
C~I-N/
\
proton.
The UV spectrum of roxburghine-D is not the simple summation of two independent indole chromophores since it exhibits additional absorption at 290 nm. Because an unsaturated carbonyl group is known to be present an attempt was made to hydrogenate the double bond or to reduce it by means of zinc and acetic acid but only very low yields of a reduction product could be obtained. The product, however, exhibited a typical indole spectrum and subtraction of the spectrum of this product from that of roxburghine-D gave a chromophore having A, 290 nm ( e 25,500) which could be explained only by the presence of
I
similar to that
an enamino ester chromophore, \N-CH=C-CO,Me,
/
contained in vallesiachotamine (82). The presence of this chromophore explains the difficulty encountered in attempts to reduce the double bond with zinc in acid or by catalytic methods; as predicted, however, it was readily and quantitatively reduced by means of sodium borohydride in acetic acid and, while the ester function was resistant to alkali, hydrolysis with dilute acid was accompanied by decarboxylation with formation of an unstable decarbomethoxy compound, C,,H,,N,, containing a cis-disubstituted enamine double bond: \N-CH=CH--R.
/
Since acetylation attempts failed and only two indolic NH protons were exchanged with D,O the third and fourth nitrogen atoms in roxburghine D must be tertiary. Conventional dehydrogenation experiments, designed to yield information concerning the skeleton of roxburghine-D, gave very little useful information as did attempts at Hofmann, von Braun, and other degradative methods. Reaction with iodine and sodium acetate yielded a yellow optically active compound which gave, in the mass spectrum, prominent peaks at m/e 486,471,428, and 413 which may be interpreted as arising by a thermal Hofmann reaction with elimination of HI, followed by loss of 6H3, -CO06H2, and 6H, + COOCH,. from a
150
J. E. SAXTON
hexadehydro derivative of roxburghine-D. The absence of fragments of lower mass indicates the presence of a stable polycyclic aromatic ion. From this information, together with a careful study of the NMR spectrum, the iodine-sodium acetate product was formulated as 83 or 84. The NMR spectrum indicated the presence of two indole N H
I
Hz 80
Roxburghine-D
81
"$CHO Bile
82
Vallesiachotamine
83
84
protons, three highly deshielded protons (H a t C-14, -17, and -21), eight aromatic protons, a tertiary methyl group, and an ester methoxyl group. The remaining eight protons were shown by double resonance experiments to be present in two ABXY systems which could reasonably
3.
ALKALOIDS OF M I T R A G Y N A AND RELATED GENERA
be attributed only to the two Ar-CH,CH,-N
151
300 nm) of the aromatic monoN-oxides 183 of the dihydro derivatives of quinine, quinidine, uinchonidine, and cinchonine in alcoholic solvents gave the expected carbostyrils 186 in yields of 70-8570. The same results were obtained with the corresponding N,N-dioxides 184. An interesting rearrangemen6 was observed in the case of the N,N-dioxides of dihydrocinchonine end dihydrocinchonidine. Photolysis in benzene solution afforded, in addition to the carbostyrils, the N'-formylindole methanols 188 in 307, yield. The hydrolysis-sensitive benz[d]-1,3-0xazepines 185 were proposed as the probable intermediates.
220
M. R. U S K O K O V I ~AND G . GRETHE
180
181
R
H
I
H 182
VII. Pharmacology of Cinchona Alkaloids Cinchona alkaloids have been used since the sixteenth century to treat malaria. It is well established that quinine, quinidine, cinchonidine, cinchonine, and their dihydro derivatives exhibit similar antimalarial activity (50,51). Quinine owes its favored position in malaria therapy to its earlier isolation. Its use is becoming increasingly important in treating infections caused by strains of Plasmodium falciparum which are resistant to all other antimalarial drugs (52).However, some of the
8 T
5 . THE C I N C H O N A ALKALOIDS
22 1
222
M. R. USKOKOVI~ AND G . GRETHE
P . falciparum strains are reported also to be resistant to quinine (53). It is noteworthy that quinine can now be made by total synthesis and that analogs of quinine with improved activity or fewer side effects also can be made available (52). I n this connection it is important to know that the antimalarial activity of Cinchona alkaloids is not dependent on their absolute configuration; the racemates and the unnatural enantiomers were shown to be as active as the natural alkaloids (51).An excellent summary by R. M. Pinder of the mode of action of quinine as an antimalarial drug appeared recently in Progress in Medicinal Chemistry where pertinent details can be found (52). Quinidine is used mainly in the therapy of atrial fibrillation and certain other cardiac arrhythmias. Its pharmacological actions, especially cardiac activities, as well as its toxic reactions and therapeutic uses, are adequately illustrated in a recent edition of “The Pharmacological Basis of Therapeutics” by Goodman and Gilman (54). It can be hoped that the results achieved recently in the synthesis of Cinchona alkaloids will lead to improved modifications of quinine and quinidine. REFERENOES 1. 2. 3. 4. 5.
N. L. Dutta and C. Quassim, Indian J . Chem. 6, 566 (1968). A. Buzas, M. Osowiecki, and G. Rbgnier, C. R. Acad. Sci. 248, 2791 (1959). A. Bums and C. Egnell, Ann. Pharm. Fr.23, 351 (1965). G. Schneider and W. Kleinert, Natumuiss. 58, 524 (1971). H. Bohrmann, C. Lau-Cam, J. Tashiro, and H. W. Youngken, Jr., Phytochemistq/ 8,
645 (1969). 6. N. Neuss, ed., “Physical Data of Indole and Dihydroindole Alkaloids,” Vol. 1. Eli Lilly, Indianapolis, Indiana, 1964. 7. R. Goutarel, M. M. Janot, V. Prelog, and W. I. Taylor, Helv. Chim. Acta 53, 160 (1950). 8. B. Witkop, J . Amer. Chem. SOC.72, 2311 (1950). 9. R. B. Turner and R. B. Woodward, in “The.Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.), Vol. 3, Chapter 16, p. 1. Academic Press, New York, 1953. 10. G. Grethe, J. Gutzwiller, H. L. Lee, and M. R. UskokoviO, Helv. Chim. Ackz 55, 1044 (1972). 11. J . Gutzwiller and M. R. Uskokovi6, unpublished results (1967). 12. M. UskokoviO, C. Reese, H. L. Lee, G. Grethe, and J. Gutzwiller, J . Amer. Chem. SOC.93, 5902 (1971). 13. M. Uskokovi6, J. Gutzwiller, and T. Henderson, J. Amer. Chem. SOC.92, 203 (1970). 14. M. UskokoviO, D. L. Preuss, S. J. Shiuey, C. W. Despreaux, and J. Gutzwiller, J . unpublished results (1970) 15. W. E. Doering and J. D. Chanley, J . Amer. Chem. SOC.68, 586 (1946). 16. G. Grethe, H. L. Lee, T. Mitt, and M. R. Uskokovi6, J. Amer. Chem. SOC.93, 5904 (1971). 17. E. Taylor and S. Martin, J . Amer. Chem. SOC.94, 6218 (1972).
5.
THE C H I N C H O N A ALKALOIDS
223
R. L. Augustine and S. F. Wanat, Synth. Comm. 1, 241 (1971). J. Gutzwiller and M. Uskokovib, unpublished results (1968). J. Gutzwiller and M. Uskokovi6, J . Amer. Chem. SOC.92, 204 (1970). M. Gates, B. Sugavanam, and W. L. Schreiber, J . Amer. Chem. SOC.92, 205 (1970). J. Gutzwiller, C. Reese, and M. Uskokovib, unpublished results (1971). D. L. Coffen and T. E. McEntee, Chem. Commun. 539 (1971). Ch’en Ch’an-pai, R. P. Evstigneeva, and N. A. Preobrazhenskii, Dokl. Akad. Nauk SSSR 123, 707 (1958). 25. R. P. Evstigneeva, Ch’en Ch’an-pai, and N. A. Preobrazhenskii, J . Gem. Chem. USSR 30, 495 (1960). 26. G. Grethe, H. L. Lee, and M. R. UskokoviO, Synth. Comm. 2, 55 (1972). 27. Y. K. Sawa and H. Matsumura, Tetrahedron 26, 2923 (1970). 28. N. Kowanko and E. Leete, J. Amer. Chem. SOC.84, 4919 (1962). 29. P. de Moerloose and R. Ruyssen, J . Pharm. Belg. 8, 156 (1953); P. de Moerloose, Pharm. Weekbl. 89, 541 (1954). 30. E. Leete and J. N. Wemple, J . Amer. Chem. SOC.91, 2698 (1969). 31. E. Leete, Accounts Chem. Res. 2, 59 (1969). 32. M. Bobbitt and K.-P. Segebarth, in “Cyclopentanoid Terpene Derivatives” (W. I. Taylor and A. R. Battersby, eds.), p. 17. Dekker, New York, 1969. 33. E. Leete and J. N. Wemple, J. Amer. Chem. SOC.88, 4743 (1966). 34. A. R. Battersby, R. T. Brown, R. S. Kapil, J. A. Knight, J. A. Martin, and A. 0. Plunkett, Chem. Commun. 810 (1966). 35. A. R. Battersby, E. S. Hall, and R. Southgate, J. Chem. SOC.,C 721 (1969). 36. A. R. Battersby and E. S. Hall, Chem. Commun. 194 (1970). 37. H. Inouye, S. Ueda, and Y. Takeda, Tet. Lett. 407 (1969). 38. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. Commun. 1280 (1968); J . Chem. SOC.,C 1187 (1969). 39. A. R. Battersby, A. R. Burnett, and P. G. Parsons, Chem. C o m u n . 1282 (1968); J . Chem. SOC.,C 1193 (1969). 40. A. R. Battersby and R. J. Parry, Chem. Commun. 30 (1971). 41. E. Leete, unpublished observations (1969). 42. A. R. Battersby and R. J. Parry, Chem. Commun. 31 (1971). 43. E. Leete, unpublished results (1969). 44. E. Wenkert and N. V. Bringi, J . Amer. Chem. SOC.80, 3484 (1958). 45. R. L. Augustine, Chem. Ind. (London) 1071 (1959). 46. V. I. Stenberg, E. F. Travecedo, and W. E. Musa, Tet. Lett. 2031 (1969). 47. V. I. Stenberg and E. F. Travecedo, J . Org. Chem. 35, 4131 (1970). 48. F. R. Stermitz, R. P. Seiber, and D. E. Micodem, J . Org. Chem. 33, 1136 (1968). 49. C. Kaneko, S. Yamada, and M. Ishikawa, 3rd, Int. Congr. Eeterocycl. Chem., 1971 Abstr., p. 211. 50. R. M. Pinder, i n “Medicinal Chemistry” (A. Burger, ed.), 3rd ed., Vol. 1, pp. 492-516. Wiley (Interscience), New York, 1970. 51. A. Brossi, M. Uskokovi6, J. Gutzwiller, A. U. Krettli, and Z . Brener, Experientk 27, 1100 (1970); A. Brossi, Pure Appl. Chem. 19, 171-185 (1969). 52. R. M. Pinder, Progr. Med. Chem. 8, 232-306 (1971). 53. D. F. Clyde, R. M. Miller, H. L. DuPont, and R. B. Hornick, J . Amer. Med. Ass. 213, 204 (1970). 54. L. S. Goodman and A. Gilman, eds., “The Pharmacological Basis of Therapeutics” 4th ed., pp. 711-719. Maemillan, New York, 1970.
18. 19. 20. 21. 22. 23. 24.
This Page Intentionally Left Blank
-CHAPTER
6-
THE OXOAPORPHINE ALKALOIDS MAURICESHAMMA AND R . L . CASTENSON Department of Chemistry The Pennsylvania State University University Park. Pennsylvania
. .
I Introduction ...................................................... I1 Oxoaporphines Isolated from Natural Sources ........................ A Liriodenine .................................................... 33. Lysicamine .................................................... C Atherospermidine .............................................. D . Moschatoline ................................................... E Lanuginosine .................................................. F. 1.2.9.1 0.Tetramethoxyoxoaporphine .............................. G Atheroline .................................................... H . Cassameridine .................................................. I Cassamedine .................................................. J . Imenine ...................................................... K Thalicminine .................................................. L Hernandonine .................................................. M Diccntrinone . . .......................................... N Oxopurpureine ................................................ 0. Alkaloid PO-3 ................................................. P Corunnine ...................... ............................ Q . Pontevedrine .................................................. I11. Some Oxoaporphines not Isolated from Natural Sources . . . . . . . . . . . . . . . . A . 1.2.10.1 1.Tetramethoxyoxoaporphine ................... B 2.9.1 0.Trimethoxyoxoaporphine .................................. C . 1.2.Metliylenediox y. 10-methoxyoxoaporphine ..................... D . 2.1 0.Dimethoxyoxoaporphine .................................... E . 1.2.1 0.Trimethoxyoxoaporphine .................................. F. 1.2.Methylenedioxy.10. I I-dimethoxyoxoaporphine . . . . . . . . . . . . . . . . . . IV . The Oxidation of phines to Dehydroaporphines and Oxoaporphines ... V . Biogenesis . . . . . . ............................................ VI . Pharmacology . . ........................................... VII . Ultraviolet Spectroscopy . . . . ................................ VIII . Nuclear Magnetic Resonance S copy ....................... I X Mass Spectroscopy . . . . . . . . . . . . . . . . . . ......................... X Addendum ........................................................ References ........................................................
. . .
.
. . . . . . .
. .
226 226 226 229 230 231 233 235 236 238 240 241 242 243 244 245 246 247 249 250 250 250 251 251 252 252 253 254 254 254 254 257 262 262
226
MAURICE SHAMMA A N D R. L. CASTENSON
I. Introduction Several naturally occurring oxoaporphines with the 7-keto-4Hdibenzo(de,g)quinoline skeleton are presently known. They are found in members of the Anonaceae, Araceae, Hernandiaceae, Lauraceae, Magnoliaceae, Menispermaceae, Monimiaceae, Papaveraceae, and Ranunculaceae. The oxoporphines can be divided into two distinct subgroups. The larger one is made up of weakly basic, nonphenolic compounds which are bright yellow or orange yellow in color. These are without exception high-melting and usually show a decomposition point rather than an actual melting point. Since they possess a conjugated carbonyl function they show an IR absorption band near 1650 cm-l. Additionally, these weakly basic, nonphenolic oxoaporphines turn red upon addition of acid, and their chloroform solutions show a greenish fluorescence. The smaller subgroup of oxoaporphines, which presently includes only the alkaloids PO-3 and corunnine, consists of high-melting, monophenolic, quaternary N-metho salts which are green in neutral or basic solution and red in acid. The oxoaporphine alkaloid pontevedrine stands apart from these two subgroups. Its unique feature is that it possesses an N-methyl pyridone moiety. The numbering system for the oxoaporphines follows that of the aporphines and is shown for liriodenine (1).
11. Oxoaporphines Isolated from Natural Sources A. LIRIODENINE 3
4
9
1
Liriodenine (1) [C,,H,O,N; mp 270-272" (dec) (CHCl,) ( I ) , 271-275" (dec) (CHC1,) (Z), 272" (dec) (CHC1,) (3), 272474" (dec) (CHC1,) (a),
6.
THE OXOAPORPHINE ALKALOIDS
227
275-277" (CHC1,) ( 5 ) , 282" (CHC1,) ( 6 ) , 285-286" (CHC1,) (7, 8), 289" (CHCl,) (9), 293-295" (CHCl, or CHC1,-C,H,OC,H,) (10);oxime, mp 265-267" (dec) (n-C,H,OH) (U), 271" (n-C,H,OH) ( 6 ) ; red picrate, mp 280" (dec) (CH,OH) ( 3 ) ;orange perchlorate, mp 308-310" (dec)(CH,OH) ( 3 ) ;orange-red hydrochloride, mp 263-265" (dec) ( 1 2 ) ] ,sometimes called spermatheridine and oxoushinsunine, was the first oxoaporphine to be characterized. Its isolation from the heartwood of Liriodendron tulipifera L. (Magno1iaceae)-the yellow poplar tree-was first reported in 1960 ( 6 ) .The following year, W. I. Taylor proposed the correct structure for this yellow alkaloid (9). Liriodenine exhibits one sharp conjugated carbonyl absorption in the I R spectrum and readily forms an oxime. No hydroxyl or methoxyl groups are present, but a methylenedioxy function was evident from the characteristic I R bands (KBr) at 1490, 1420, 1360, 1120, 1050, and 960 cm-l. The UV spectrum showed a complex pattern characteristic of a highly conjugated system. Oxidation of liriodenine with chromic acid gave l-azaanthraquinone4-carboxylic acid (la) which upon heating decarboxylated to the known azaanthraquinone l b (6, 9, 13).
These data, together with the observation that members of the Magnoliaceae are known to produce benzylisoquinoline alkaloids, were sufficient for Taylor to propose the now accepted structure for the alkaloid. As final confirmation Taylor synthesized liriodenine by an unambiguous route starting with the known dihydroisoquinoline lc, Scheme 1 (9). Liriodenine can also be prepared by oxidation of the aporphine unshinsunine (la) (14-16) or roemerine (le) with chromium trioxide in pyridine (14). Other oxidizing agents which afford liriodenine from ushinsunine are acidic potassium permanganate, selenium dioxide, and selenium (15). A superior method involves the air oxidation of a potassium tertiary butoxide in t-butyl alcohol solution of anonaine (If) (17). Clemmensen reduction of liriodenine yielded ( & )-anonaine (If) and
228
MAURICE SHAMMA A N D R. L. CASTENSON
similar reduction of liriodenine methiodide supplied ( +_ )-roemerine ( l e ) (13).
280" (CHC1,) (dec) (C,H,OH) (47), 300" (dec) (CHC1,-C,H,OH) (27a); oxime, mp 264-265" (dec) (C,H,OH) (47)l was by Ito and Furukawa who obtained the orange-yellow crystals from the trunk and bark of Hernandia ovigera L. (Hernandiaceae). Hernandonine shows a conjugated carbonyl group in the I R spectrum (Nujol) a t 1650 em-l, and the NMR spectrum in deuterochloroform possesses two methylenedioxy groups at 6 6.10 and 6.20. I n the aromatic proton region there is a C-3 proton singlet a t 6 7.07 and two AB-type aromatic quartets are centered at 6 6.98 and 8.21 (J = 8.5 Hz) and a t 6 7.05 and 8.80 (J = 5.0 Hz), thus accounting for all nine hydrogens in the molecule. These data were suggestive of a 1,2:10,ll-bismethylenedioxyoxoaporphine structure. Chemical proof was obtained by oxidation of the aporphine ( + )-N-methylovigerine (12a) with chromium trioxide in pyridine which afforded hernandonine (46).
(as),298-300"
12a
12b
R = CH, R =H
Hernandonine (12) has also been found in H . papuana C. T. White as bright yellow needles and it was then characterized independently (47). Zinc in sulfuric acid reduction of the alkaloid led to the racemic form of the aporphine ovigerine (12b) isolated as the hydrochloride. Yet another independent investigation of hernandonine followed its isolation as bright yellow needles from H . jamaicensis Brjtton & Harris.
244
MAURICE SHAMMA AND R. L. CASTENSON
Light-induced oxidation of ovigerine (12b)in t-butyl alcohol solution containing some potassium t-butoxide using a stream of oxygen gas gave a good yield (24y0)of the oxoaporphine (48). Treatment of ovigerine (12b)with iodine in refluxing ethanol also affords hernandonine (27a).
M. DICENTRINONE
CH30 OCH, 13
Dicentrinone (13) [CI9Hl3O3N; mp 300' (dec) (CHC1,-C,H,OH) (27a, 48)] was isolated from Ocotea macropoda Mez (Lauraceae) by Cava and Venkateswarlu as small, bright yellow needles (48).The I R spectrum (KBr)showed a conjugated carbonyl absorption at 1650 cm-l. The NMR spectrum in trifluoroacetic acid revealed all thirteen protons as follows: two methoxyl singlets at 6 4.30 and 4.33, a methylenedioxy singlet at 6 6.85, three unsplit aromatic protons at 6 7.75, 8.28, and 8.58, and two adjacent aromatic protons at 6 8.67 and 9.00 (J = 7 Hz). These data together with the occurrence of the aporphine (+)-dieentrine (13a)as one of the companion alkaloids suggested that the new base was the oxoaporphine corresponding to dicentrine. Oxidation of nordicentrine (13b)by chromium trioxide then gave dicentrinone (13) (48). (0
/ \
CHBO
\
'H
OCH, 13a R = CH, 13b R = H
C
F/ \
CH30
\ OCH, 130
C
H
3
6.
THE OXOAPORPHINE
ALKALOIDS
245
Dicentrinone has also been prepared in 477, yield by treating nordicentrine (13b) with iodine in refluxing ethanol. Alternatively, passing oxygen through a solution of dehydrodicentrine (13c) in a mixture (at pH 6) of buffer and dioxane also led to dicentrinone, but in 3007, yield
(27a).
N. OXOPURPUREINE
cH30GN 9CH3
CH30
CH,O OCH, 14
The orange-colored oxopurpureine (14) [C,,H,,O,N.+C,H,; mp 198202" (dec) (toluene) (36)] was isolated from the stems and leaves of Anona purpurea where it is accompanied by the yellow 1,2,9,10-tetramethoxyoxoaporphine (6).The IR spectrum of oxopurpureine showed a conjugated carbonyl peak a t 1640cm-l. The NMR spectrum in trifluoroacetic acid included five methoxyl singlets at 6 4.18, 4.26, 4.34, 4.38, and 4.43. Two aromatic singlets were present at 6 8.08 and 8.98 with the latter chemical shift characteristic of a C-11 hydrogen. The C-4 and C-5 aromatic protons were present as two doublets at 6 8.87 and 9.01 (J4,5= 6.3 Hz). Finally, chromium trioxide in pyridine oxidation of the aporphine purpureine (14a), found in the same plant, furnished oxopurpureine (14) thus settling the positions of the methoxyl substituents (36).
cCH3H 0*3 0
N,CH3
6CH3 14a
246
MAURICE SHAMMA A N D R. L. CASTENSON
0. ALKALOID PO-3
CH30
15
Alkaloid PO-3 (15) [C,,HIGNO~C10~; perchlorate, mp 253-255' (dec) (as)]the first naturally occurring quaternary oxoaporphine to be reported, was isolated as a green crystalline salt from Papaver orientale L. (Papaveraceae) (50).The I R spectra (CHCl,, KBr, and Nujol) show a carbonyl band between 1650 and 1700 cm-l. I n acid solution, alkaloid PO-3 is red; in neutral or basic solution it is green. The spectrophotometrically determined pK, is 3.88 .02 in 50% ethanol. The NMR spectrum of alkaloid PO-3 in DMSO-d, has a one-proton singlet a t 6 7.14 (C-3), a one-proton doublet at 6 8.40 (C-5), a two-proton multiplet around 6 7.93 (C-4, C-S), and a multiplet between 6 7.2 and 7.5 (C-9, C-10). The chemical shift of the N-methyl group is 6 4.65, while the shifts of the two methoxyl groups are about 6 4.0 (49). Light-catalyzed air oxidation of isothebaine (15a), also isolated from P. orientale (50), was reported to give 6a77-didehydroisothebaine(15b) and alkaloid PO-3. Alkaloid PO-3 has the following resonance structures in the protonated and unprotonated forms:
It
I
6.
THE OXOAPORPHINE
247
ALKALOIDS
Reduction of alkaloid PO-3 with either zinc in acid solution or hydrogen over a platinum catalyst yielded racemic isothebaine (15a) and 7-hydroxyisothebaine (15c) (49).
15a
15b
15c
P. CORUNNINE
16
Corunnine (16) [C,,H,,O,N; mp 255-257" (C,H,OH) (51);perchlorate, mp 293-295" (51) (C,H,OH and aq. HClO,] is a minor alkaloid isolated from Glauciumjlavum Cr. var. vestitum (Papaveraceae). It was obtained as violet needles but is green in neutral or basic solution and reddish in acid solution. The UV spectrum of corunnine in acid solution is close to that of 1,2,9,1O-tetramethoxyoxoaporphine(6); but there is a distinct bathochromic shift when the spectrum is taken in basic solution, a behavior reminiscent of the phenolic oxoaporphine PO-3 (15). The NMR spectrum of corunnine in trifluoroacetic acid revealed three aromatic methoxyls (6 4.55, 4.55, and 4.80), a quaternary N methyl singlet ( 6 5.36), an aromatic AB system assigned to the C-4 and C-5 protons (6 8.75d and 8.95d; J,,, = 6Hz), and three aryl proton singlets (6 7.93, 8.33, and 9.30). Since there is a claim that oxidation products derived from aporphines carrying a phenolic function a t C-1 or C-11 are green (as),the phenolic function in corunnine was placed at C-1. The three methoxyl groups were assigned the C-2, C-9, and C-10 positions on NMR spectral grounds, as well as from the fact that 1,2,9,10-tetramethoxyoxoaporphine(6) is found in the same
248
MAURICE SHAMMA A N D R. L. CASTENSON
plant. Corunnine is therefore represented by the following resonance structures in the protonated and unprotonated forms (51). CH30
CH3 OH CH,O
-
CH3
OHOL H@
OQ
CH30 OCH3
OCH,
I
CH30 HO
CH30
CH30 bCH,
OCH,
I n an attempt to quaternize 1,2,9,1O-tetramethoxyoxoaporphine (6) with methyl iodide in dry benzene it was found that the almost exclusive product was corunnine:
CH.0
CH3
CH30 OCH,
OCH,
I
JCorunnine (16)
Corunnine was also obtained as a minor product when glaucine ( L e . , 1,2,9,10-tetramethoxyaporphine)was oxidized with the chromium trioxide-pyridine complex in dichloromethane (51).
ZFIH ::::l$yH , 6.
249
THE OXOAPORPHINE ALKALOIDS
Q . PONTEVEDRINE
t---f
CH,O
\
CH,O
OCH,
\ OCH,
17
Pontevedrine (17)[C,,H,,O,N; mp 269-271" (C,H,OH-CHC1,) (51)] was isolated as a minor alkaloid from Glaucium jlavum var. vestitum where it is accompanied by corunnine (16) and 1,2,9,10-tetramethoxyoxoaporphine (6). It was obtained as red needles which were insoluble in aqueous alkali but showed an apparently positive ferric chloride test. The I R spectrum (KBr) of the alkaloid showed a strong peak at l66Ocm-1 due to a conjugated carbonyl. The UV spectrum was unchanged upon the addition of acid or base. The NMR spectrum in CDC1, revealed four aromatic methoxyl groups at 6 3.96 (3H), 4.00 (3H), and 4.10 (6H), an N-methyl group at 6 3.50, and four aromatic one-proton singlets at 6 6.96, 7.00, 7.70, and 8.80. A way of interpreting these data was to place the four methoxyl groups at C-l,C-2,C-9,C-l0on an oxoaporphine skeleton together with an oxide function at C-5, thus assigning the resonating structure 17 to pontevedrine (51).
1
Pontevedrine (17)
SCHEME 5
250
MAURICE SHAMMA A N D R. L. CASTENSON
It has been observed that, when 1,2,9,10-tetramethoxyoxoaporphine (6)is treated with excess methyl iodide in refluxing commercial acetone, corunnine (16) and a small amount of pontevedrine are obtained (Scheme 5) (51). Alternatively, treatment of the aporphine glaucine with a large excess of chromium trioxide-pyridine complex in dichloromethane led in a low yield to a mixture of dehydroglaucine, 1,2,9,10-tetramethoxyoxoaporphine (6), corunnine (16), and pontevedrine (17) (51). 111. Some Oxoaporphines not Isolated from Natural Sources
A. 1,2,10,1l-TETRAMETHOXYOXOAPORPHINE
cH30 CH30
1,2,10,11-Tetrarnethoxyoxoaporphine (18) [C,,H,,O,N; mp 225-227" (dec) (C,H,OH) ( I d ) ] ,vmaX 1643 cm-l(Nujol), was prepared via oxidation of the corresponding aporphine 0,O-dimethylcorytuberine by chromium trioxide in pyridine (14).
B. 2,9,10-TRIMETHOXYOXOAPORPHINE
bCH, I9
2,9,10-Trimethoxyoxoaporphine (19) [C,,H,,O,N; mp 264" (dec) (CHCl,) (52);oxime, mp 220-221" ( 5 2 ) ] ,vmax 1640 em-,, was the unexpected product from the catalytic hydrogenation of 1,2,9,10-tetra-
9 cH30 cH 6.
251
THE OXOAPORPHINE ALKALOIDS
methoxyoxoaporphine (6) using Adams catalyst in acetic acid. The structure was confirmed by a total synthesis (Scheme 6) (52).
CH,O
CH,O
NO2
\
Na2Crz0,, HOAc
,
CH,O
OCH, 1. Ha, PdlC 2. NaN02, H2S04
3. A
/N
NO2
/N
\
NO2
cn30H KOH, Air
CH,O
OCH,
\ OCHB
2,9,10-Trimethoxyoxoaporphine(19)
SCHEME 6
c. 1,2-METHYLENEDIOXY-~o-METHOXYOXOAPORPHINE
Oxidation of the aporphine laureline (i.e.7 172-methylenedioxy-10methoxyaporphine) by chromium trioxide in pyridine generated the yellow 1,2-methylenedioxy-lO-rnethoxyoxoaporphine (20)[Cl8Hl1O4N. H,O; mp 268" (ethyl acetate) (34)l.This material proved to be different from the alkaloid lanuginosine which is 1,2-methylenedioxy-9-methoxyoxoaporphine ( 5 ) (34). D. 2,10-D1METH0XY0X0AP0RPH1NE Sodium-liquid ammonia cleavage of the dimeric base dehydrothalicarpine (21a)yielded 2,1O-dimethoxyoxoaporphine (21)[C18H1,03N; mp 218-220" (CH,COCH3) (53)] as a minor product (53). The IR spectrum (Nujol) of 21a shows a conjugated carbonyl peak at 1661 cm-l and the NMR spectrum (CDC1,) shows two methoxyl groups superimposed at 6 3.96.
252
MAURICE SHAMMA A N D R . L. CASTENSON
A qualitative TLC comparison also indicated that manganese dioxide oxidation of 2,lO-dimethoxydehydroaporphinegives some of the oxoaporphine 21 (53).
cH30
E. 1,2,10-TRIMETHOXYOXOAPORPHINE CH,O
CH30
\ 22
1,2,1O-Trimethoxyoxoaporphine (22) [C,,H,,O,N; mp 256-258" (CH,COCH,-C,H,OH) (53)] was a minor product isolated from the sodium-liquid ammonia cleavage of dehydrothalicarpine (21a). This red base showed a conjugated carbonyl peak at 1669 omT1 in its I R spectrum (KBr), and two methoxyl singlets at 6 3.73 (3H) and 4.03 (6H) in its NMR spectrum (CDC1,) (53).
F.
??
~,2-METHYLENEDIOXY-10,~1-DIMETHOXYOXOAPORPHINE
CH30
CH30 \
23
1,2-Methylenedioxy-10,1l-dimethoxyoxoaporphine (23)[C,,H,,O,N; mp 240-241" (CHC1,-C,H,OH) (27a)l was prepared by treating an ethanol solution of the corresponding noraporphine with iodine (27a).
6.
253
THE OXOAPORPHINE ALKALOIDS
I n addition to the preceding five oxoaporphines, l-ethoxy-2,9,10trimethoxyoxoaporphine and 10-ethoxy-1,2,9-trimethoxyoxoaporphine have also been prepared (31).
IV. The Oxidation of Aporphines to Dehydroaporphines and Oxoaporphinea The reagent that had originally been used commonly for the oxidation of aporphines to oxoaporphines was chromium trioxide in pyridine (14-16). A recent study by Cava and co-workers of the oxidation of aporphines and dehydroaporphines has led to the development of superior methods of oxidation which may be summarized as follows (era). (a) Oxidation of nonphenolic aporphines by iodine in dioxane affords the corresponding dehydroaporphines. (b) Iodine in ethanol oxidation of nonphenolic noraporphines proceeds all the way to the oxoaporphine stage. (c) Dehydroaporphines such as dehydronuciferine and dehydrodicentrine can be efficiently oxidized by oxygen at pH 6 McIlvain buffer to give the corresponding oxoaporphines. Dehydronuciferine is also rapidly oxidized in good yield to lysicamine (2) by peracetic acid or by benzoyl peroxide; a benzoate ester being an intermediate in the latter reaction. CH@
/
CH,O
' /
\
CH30 +
I
0-C-Ph
II
0
Dehydronuciferine
2
254
MAURICE SHAMMA A N D R. L. CASTENSON
V. Biogenesis It has been pointed out that oxoaporphines are probably formed in nature by the oxidation of aporphines. Substantial support for this hypothesis comes from the fact that in several instances the corresponding aporphine or noraporphine base is found in the same plant (39). No investigations with labeled precursors have been reported.
VI. Pharmacology Liriodenine (1) has significant in vitro inhibitory activity against the 9-KB tumor test system ( 5 ) , while oxopurpureine (14) and 1,2,9,10tetramethoxyoxoaporphine (6) show only borderline activity (36).
VII. Ultraviolet Spectroscopy There are slight differences for the UV spectrum for the same oxoaporphine from one laboratory to another. The spectra show a complex pattern (Table 11).Six bands may be observed in some cases, and these bands have the following ranges: 206-226, 235-256, 264-282, 292-324, 347-390, and near and above 400nm. A seventh absorption peak is present around 450 nm. A peak at 281-282 nm is characteristic of a 1,2-methylenedioxy3-methoxy or a 1,2,3-trimethoxyoxoaporphineunsubstituted at C-4. 1,2,10,1l-Tetrasubstituted oxoaporphines show a characteristic peak around 222-226 nm. The presence of a 1,2-methylenedioxy group results in a bathochromic shift of the 235-256 nm band by comparison with the spectrum of the corresponding 1,2-dimethoxy analog. To cite one example, liriodenine (1) has a peak at 247.5nm but lysicamine (2) shows an absorption maximum at 235 nm.
VIII. Nuclear Magnetic Resonance Spectroscopy Most of the NMR spectral data that have been reported for the oxoaporphines are summarized in Table 111. The solvent was not indicated in all cases but was usually trifluoroacetic acid. I n the aromatic region, the C-3 proton resonates at high field while the C-5 and C-11 protons are farthest downfield. A C-1 methoxyl
6.
THE OXOAPORPHINE ALKALOIDS
255
TABLE I1 UV SPECTRA OF OXOAPORFHINES WITH Liriodenine (1)
Lysicamine (2)
Atherospermidine (3)
Moschatoline (4)
Lanuginosine ( 5 )
LOG e IN
PARENTHESES
247.4,268.2,309.2,and 413 nm (4.22,4.13, 3.62,and 3.82)( 6 ) 257.9,291.9,and 340 nm (4.08,3.51,and 3.16) ( 6 ) 256.7,277.3,329,392,and 455 nm (4.33, 4.26,3.67,3.69,and 3.58)( 6 ) 268.7,307,362,and 426 nm (4.20,3.53, 3.55,and 3.52)( 6 ) 247.5,269,and 302 nm (4.23,4.16,and 3.70)( 2 6 ) 256.5,280,and 334 nm (4.33,4.25,and 3.70) ( 2 6 ) 248,267,and 305 nm (4.18,4.05,and 3.59) ( 5 ) 235,270,307,and 400 nm (4.47,4.41,3.76, and 3.94)( 1 9 ) 249,276,306,and 453 nm (4.33,4.44,3.82, and 3.58)( 1 9 ) 247 and 281 nm (4.38and 4.52)( 2 6 ) 262.2 and 283 nm (4.24and 4.16) ( 2 6 ) 247,281,316sh,383,and 440 nm (4.39, 4.53,3,80,3.71,and 3.92)( 2 9 ) 263,283,410,and 505 nm (4.46,4.36,3.78, and 3.58)(29) 237,272,315sh,374,and 440 nm (4.47, 4.41,4.10,3.55,and 3.67)( 3 0 ) 246,281,390,and 496 nm (4.37,4.40,3.63, and 3.36)( 3 0 ) 247,283,310,407,and 517 nm (4.42,4.31, 4.25.3.99,and 3.33) ( 3 0 ) 246,271,and 315 nm (4.54,4.44,and 3.89) (32)
258,283,and 334 nm (4.57,4.47,and 3.83) (32)
247,273,315,390,and 440 nm (4.32,4.21, 3.61,3.45,and 3.65)( 3 4 ) 246,271,and 314 nm (4.46,4.34,and 3.78) (33)
1,2,9,1O-Tetramethoxyoxoaporphine ( 6 )
257 and 284 nm (4.31and 4.19)( 3 3 ) 242,272,355,and 376-382 nm (4.52,4.53, 3.99,and 3.90)( 3 9 ) 246,277,and 363 nm (4.59,4.58,and 4.16) (36)
243.5,273,356,and 423-433 nm (4.46, 4.47,4.04,and 3.87)( 1 4 ) 230,258,and 323 nm (4.33,4.31,and 3.82) (14)
256
MAURICE SHAMMA AND R. L. CASTENSON
TABLE I1 (conti.nued)
UV SPECTRAOF OXOAPORPHINES WITH Atheroline (7)
: : t :x
hEtOH.H+
max
h:BO,H.OH-
Cassameridine (8)
: : t :x hEtOH.H+
max
XEtOH
max
hEtOH.H+
max
Cassamedine (9)
hEtOH
max
hEt0H.H +
max
Imenine (10)
hgtg
Thalicminine (11)
hEtOH-CHC13
max
h Emax tOH
Hernandonine (12)
::%A ,)EtOH max
X max EtOH
Dicentrinone (13)
XEtOH
max
XEtOH max
h%t:LH
Oxopurpureine (14)
XEtOH
Alkaloid PO-3 (15)
XEtOH
Corunnine (16)
hEtOH
rnax
max max
Elt Pontevedrine (17)
XEmH
max
+
LOG E IN
PARENTHESES
244, 273, 292sh, 355, 380sh, and 435 nm (4.09, 4.17, 3.96, 3.90, 3.83, and 3.62) ( 4 0 ) 257, 282, 385, and 500 n m (4.12, 4.12, 4.05, and 3.38) ( 4 0 ) 252, 294, 320, 390, and 535 n m (4.04, 3.99, 3.98, 3.74, and 3.46) ( 4 0 ) 251, 274, 323, 353, 388, and 440 n m (4.46, 4.40, 4.08, 3.91, 3.85, and 3.73) ( 4 1 ) 261, 290, 385, and 500 n m (4.62, 4.59, 4.31, and 3.62) ( 4 1 ) 249, 272, 320, 350, 388, and 434 nm (4.55, 4.45, 4.11, 4.00, 3.93, and 3.79) ( 4 2 ) 261, 290, 381, and 499 nm (4.74, 4.68, 4.37, and 3.97) (42) 252, 281, 324, 364, and 460 n m (4.47, 4.53, 4.12, 3.97, and 3.76) ( 4 1 ) 272, 286, 408, and 534 nm (4.49, 4.50, 4.10, and 3.40) ( 4 1 ) 240, 275, 345, and 438 nm (4.15, 4.38, 3.58, and 3.42) ( 4 3 ) 252, 282, 364, and 456 n m (4.29, 4.43, 3.91, and 3.72) (44) 214, 252, 282, 324sh, 360, and 460 nm (4.48 4.38, 4.46, 3.83, 3.89, and 3.68) ( 5 4 ) 222, 265, 364, and 426 n m (4.55, 4.37, 4.03, and 3.99) ( 4 6 ) 226, 256sh, 264, 365, and 430 nm (4.58, 4.45, 4.46, 4.12, and 4.07) ( 4 7 ) 226, 255sh, 267, 300sh, 368, and 433 n m (4.65, 4.51, 4.52, 4.08, 4.16, and 4.13) (48) 213, 250, 272, 310sh, 352, 396, and 433 n m (4.57, 4.54, 4.45, 4.05, 4.07, 3.62, and 3.60) ( 4 8 ) 250, 272, 313sh, 351, 392, and 438 n m (4.69, 4.62, 4.17, 4.22, 4.39, and 4.29) ( 4 1 ) 260, 292, 382, and 506 n m (4.69, 4.62, 4.30, and 3.64) ( 4 1 ) 251, 282, 354, 392, and 456 n m (4.37, 4.54, 3.86, 3.94, and 3.78) (36) 225, 310, 430, and 645 n m (4.45, 4.50, 3.70, and 3.70)a ( 4 9 ) 258, 325, 400, 440sh, and 630 nm (4.13, 4.32, 3.54, 3.42, and 3.35) ( 5 1 ) 256, 295, and 385 n m (4.23, 4.14, and 3.75) (54 245, 312, 325, and 470 n m (4.59, 4.28, 4.39, and 4.01) ( 5 1 )
6.
THE OXOAPORPHINE
ALKALOIDS
257
TABLE I1 (continued) UV SPECTRA OF OXOAPORPHINESWITH 1,2,10,11-Tetramethoxyoxoaporphine (18)
A :g : AEtOH min
B,g,lO-Trimethoxyoxoaporphine (19) 1.2-Methylenedioxy10-methoxyoxoaporphine (20) 2,1O-Dimethoxyoxo aporphine (21) 1,2,10-Trimethoxyoxoaporphine (22) 1,2-Methylenedioxy10,ll-dimethoxyoxo aporphine (23) a
hgt:: AEtOH max
xgp
A;:y
LOG e IN
PARENTHESES
222, 275, 360, and, 405 nm (4.42, 4.23, 3.82, and 3.79) ( 1 4 ) 263, 325, and 383 (4.15, 3.52, and 3.74) (14) 238, 270, 292, 359, and 430 nm (4.50, 3.58, 4.40, 4.00, and 3.61) (52) 249, 309, 347, and 398 n m (4.27, 3.85, 3.96, and 3.91) (34) 236, 266, 273sh, 284, 312, 345, and 376 nm (4.41, 4.41, 4.35, 4.27, 3.81, 4.01, and 3.95) (53) 234, 246.5, 322, and 470 n m (4.52, 4.61, 3.87, and 3.77) (53) 223, 255, 272sh, 360, and 410 n m (4.52, 4.31, 4.25, 4.29, and 4.25) (27a)
Approximated from graph.
is usually at slightly higher field, in the range 6 4.0-4.2, than the other methoxyls, by analogy with the aporphine alkaloids. A tentative generalization concerns the C-11 proton which appears farther downfield than the C-3, C-8, C-9, or C-10 proton. Its chemical shift appears to depend upon the presence or absence of a C-3 substituent. If a methoxyl is present at C-3, as in cassamedine (9) and oxopurpureine (14), the C-11 proton signal appears in the range 6 8.85-9.0 but the same proton is found between 6 8.29 and 8.8 when C-3 is unsubstituted. Additional examples are needed before this generalization can be accepted. A 1,2-methylenedioxy group resonates at lower field (6 6.6-6.85) than if located at C-9,10 ( - 6 6.2) (41-42). A C-3 methoxyl appears between 6 4.43 and 4.55, i e . , at lower field than C-1, C-2, C-9, or C-10 methoxyl groups (30).
IX. Mass Spectroscopy The mass spectral fragmentations of some oxoaporphines were studied in detail by Bick and co-workers (31). They proposed that atherospermidine (3), liriodenine ( l ) , and 0-methylmoschatoline (23a)lose A ring substituents through conjugative elimination involv-
TABLE I11
NMR DATAFOR Oxoaporphine Liriodenine (1)
Lysicamine ( 2 ) b Atherospermidine (3) Lanuginosine (5)
1,2,9,10-Tetramethoxyoxoaporphine(6) 00
Cassameridine (8) Cassamedine (9)b Imenine (10) Hernandonine (12) Dicentrinone (13) Oxopurpureine (14)
C-1
THE
WEAKLYBASICOXOAPORPHINES~
C-2
C-3
0-CHZ-0 H 6.72 s 7.63 s 6.65 s 7.53 s OCH, OCH, H 4.00 s and 4.02 s 7.12 s O-CH,-O OCH, 4.55 s 6.72 s 0-CH2-0 H 6.65 s 7.53 s OCH, OCH, H 3.95s 4.03 s 7.08s 0-CHZ-0 H 7.57 s 6.66 s 0-CH,-0 OCH, 6.62 s 4.48 s OCH, OCH, OCH, 4.05 s, 4.10 s, 4.15 s 0-CHZ-0 H 6.58 s 7.6 s 0-CH2-0 H 6.85 s 7.75 s OCH, OCH, OCH, 4.18 s 4.26 s 4.43 or 4.34 s or 4.38 s
C-4
C-5
C-8
C-9
(2-10
C-11
Refs.
H
H
H
H
H
H
26
9 H
H
H
H
H
H
19
H
H
H
H
26
H
33
8.75 d
H H 8.45 d H 7.63 d H 8.46dg
H
H 8.78 d H 8.76 d H 8.76 d g H H 8.72 d 8.83 d OCH, H and 4.25 s H H 8.5dC 8.75 dC H H 8.67 dC 9.00 dC H H 8.87 df 9.01 df
H 8.07 d
H 7.93 s H 7.90 s H 7.83 s
H
OCH, H 4.12 7.67 dd OCH3 OCH, 4.03 s 4.03 s 0-CH2-0 6.25 s 0-CHZ-0 6.23 s H H
8.78 d
H 8.65 s
H
30, 40 42
8.29 s
H 8.19 s H
H 0-CHZ-0 H 8.38 dd 7.24 dd 6.36 s H OCH, OCH, H 4.30 and 4.33 s 8.58 s 8.28 s H OCH, OCH, H 4.26 s or 4.34 s 8.98 s 8.08 s or 4.38 s
41, 54 43 48 48 36
TABLE I11 (Continued) ~~
Oxoaporphine Alkaloid PO-3 (15)*
c-1 OH
C-2
C-3
OCH,
H 7.14 s
H 7.93 s
[N+-CH34.65 Corunnine (16)
t s ur
OH
C-5
C-8
C-9
C-10
H
H 8.40 de
H
H H 7.2-7.5 m
H 8.75d‘
H 8.95 di
H 8.33 s
C-11
Refs.
OCH,
49
H 9.30s
51
H 8.80 s
51
S]
OCH,
[N+-CH35.36
C-4
OCH, 4.55 s
OCH, 4.55s
S]
CD
Pontevedrine (17)’
OCH3 OCH, 3.96 s or 4.00 s or 4.10 s
H H 6.96 s or 7.00 s or 7.70 s
[N-CH,3.50] 4 Solvent is trifluoroacetic acid unless specified otherwise. CJ,,, = 7 Hz. g J 4 , 5 = 6.5 Hz. Solvent is DMSO-d6 * J 8 , s = 8.5 Hz. e J4,5 = 5.5 Hz. ‘JqSs = 6 Hz. j Solvent is CDCl,. f J4,5= 6.3 Hz.
Solvent not indicated.
OH
H 6.96 s or 7.00 s or 7.70 s
OCH3 OCH, 3.96 s or 4.00 s or 4.10 s
260
MAURICE SHAMMA AND R . L. CASTENSON
ing the 7-keto group. The proposed elimination pattern of atherospermidine is given in Scheme 7.
m/e 305
m/e 290
m/e 262
m/e 206
m/e 262
m/e 176
SCHEME7
Liriodenine (1) is thought to cleave initially via resonance form l g since the elimination sequence for 1 is: M-CO-CH,O-CO or M-CO-CO-CHZO .
23a
1
0-Methylmoschatoline (23a) alternatively loses three methyl radicals and three carbon monoxide molecules starting with the C-1 or C-3 methoxyl group. The position of the hydroxyl group in moschatoline (4) was determined from the fragmentation pattern of 0-acetylmoschatoline. After
6.
261
THE OXOAPORPHINE ALKALOIDS
initial loss of the acetyl C,H,O, the sequence is: M-Me-CO-MeCO-CO-CO. This elimination sequence is indicative of a C-2 hydroxyl group because a large M-H peak would be expected if the hydroxyl group were at C-1 or C-3 (31). This substitution arrangement for moschatoline agrees with that proposed from UV spectral data (30).
Atheroline (7)
F
0
-Me +
- CH,OK
CH3
m/e 322 SCHEME 8
I
0
I
m/e 290
D ring substituents may also cleave with the aid of the C-7 keto group. The concerted loss of CH,OH (or CH,OD) from atheroline (7) is diagrammed in Scheme 8. C CH,OH
CH30
, / ,
O
F
'
C
~~~~~
Cz&O
OCZH, 24
\
CH,O
z
I
p
\
OCH,
OCH,
25
26
A study of several ethoxyl-trimethoxyl substituted 1,2,9,10-0xoaporphines (24-26) showed that loss of a C-1 alkyl radical was greater than loss of a C-9 or C-10 alkyl radical (Table IV) (31). TABLE IV
RELATIVE ABUNDANCES~ O F 8f-R IONS IN MASS SPECTRA O F 24, 25, AND 26 M-R
.
M-Me M-Et * a
Percent of base peak.
THE
24
25
26
26 13
22 11
4 70
262
MAURICE SHAMMA A N D R. L. CASTENSON
X. Addendum A new oxoaporphine alkaloid, found in Abuta imene Eichl. (Menispermaceae), is O-methylmoschatoline (27;C,,H,,O,N) (54).
cH30mN
CH,O
27
An unusual base obtained from Glaucium Jlavum (Papaveraceae) is glauvine (28; C2,H,,0,N) which furnished 1,2,9-trimethoxy-lO-hydroxynoraporphine upon reduction with zinc in hydrochloric acid (55).
OCH, 28
REFERENCES 1. S.-T. Lu, S.-J. Wang, and F.-S. Lin, J . Pharm. SOC. Jap. 89, 1313 (1969). 2. I. R. C. Bick, G. K. Douglas, and W. I. Taylor, J . Chem. SOC., C 1627 (1969). 3. P. L. Majumder and A. Chatterjee, J. Indian Chem. SOC.40, 929 (1963). 4. M. Tomita and H. Furukawa, J . Pharm. SOC. Jap. 82, 1199 (1962). 5. D. Warthen, E. L. Gooden, and M. Jacobson, J . Pharm. Sci. 58, 637 (1969). 6. M. A. Buchanan and E. E. Dickey, J . Org. Chem. 25, 1389 (1960). 7. N. K. Hart, S. R. Johns, J. A. Lamberton, J. W. Loder, A. Moorhouse, A. A. Sioumis, and T. K. Smith, Aust. J . Chem. 22, 2259 (1969). 8. S. R. Johns, J. A. Lamberton, C. S. Li, and A. A. Sioumis, Aust. J . Chem. 23, 423 (1970). 9. W. I. Taylor, Tetrahedron 14, 42 (1961).
6.
THE OXOAPORPHINE ALKALOIDS
263
10. S. A. Gharbo, J. L. Beal, R. H. Schlassinger, M. P. Cava, and G. H. Svoboda, Lloydia 28, 237 (1965). 11. M. S. Yunusov, S. T. Akramov, and S. Yu. Yunusov, Dokl. Akad. Nauk Uzb. S S R 23, 38 (1966); C A 65, 13781a (1966). 12. S. K. Banerjee, R. N. Chakravarti, and H. M. Fales, BUZZ. Calcutta Sch. Trop. Med. 12, 23 (1964); C A 61, 12323c (1964). 13. T.-H. Yang, J. Pharm. Soc. J a p . 82, 804 (1962). J a p . 82, 14. M. Tomita, T.-H. Yang, H. Furukawa, and H.-M. Yang, J . Pharm. SOC. 1574 (1962). 15. S . 3 . Yang, W.-Y. Huang, L.-C. Lin, and P.-Y. Yeh, Chemistry ( T a i p e i ) 144 (1961); CA 56, 1489c (1962). 16. T.-H. Yang, J . Pharm. SOC.J a p . 82, 798 (1962). 17. M. P. Cava and D. R. Dalton, J . Org. Chem. 31, 1281 (1966). Jap. 85, 77 (1965). 18. M. Tomita and M. Kozuka, J . Pharm. SOC. 19. N. Katsui, K. Sato, S. Tobinaga, and N. Takeuchi, Tet. Lett., 6257 (1966). 20. T. Nakasato, S. Asada, and Y. Koezuka, J . Pharm. SOC.Jap. 86, 129 (1966). 21. T.-H. Yang, J . Pharm.Soc. Jap. 82, 794 (1962). 22. M. Tomita and H. Furukawa, J . Pharm. SOC.Jap. 82, 925 (1962). 23. T.-H. Yang, J . P h a r m . 8 0 ~ .J a p . 82, 811 (1962). 24. T.-H. Yang, S.-T. Lu, and C.-A. Hsiao, J . Pharm. SOC.Jap. 82, 816 (1962). 25. M. Tomita and M. Kozuka, J . Pharm. SOC.J a p . 87, 1134 (1967). 26. I. R. C. Bick and G. K. Douglas, Tet. Lett. 1629 (1964). 27. I. R. C. Bick, P. S. Clezy, and W. D. Crow, Aust. J . Chem. 9, 111 (1956). 27a. M. P. Cava, A. Venkateswarlu, M. Srinivasan, and D. L. Edie, Tetrahedron, 28, 4299 (1972). 28. B. R. Pai and G. Shanmugasundaram, Tetrahedron 21, 2579 (1965). 29. W. M. Harris and T. A. Geissman, J . Org. Chem. 30, 432 (1965). 30. I. R. C. Bick and G. K. Douglas, Tet. Lett. 4655 (1965). 31. I. R. C. Bick, J. H. Bowie, and G. K. Douglas, Aust. J . Chem. 20, 1403 (1967). 32. S. K. Talapatra, A. Patra, and B. Talapatra, Chem. Ind. (London) 1056 (1969). 33. S. M. Kupchan, M. I. Suffness, and E. M. Gordon, J . Org. Chem. 35, 1682 (1970). 34. T. R. Govindachari and N. Viswanathan, Indian J . Chem. 8, 475 (1970). 35. C. Casagrande and G . Merotti, Parmaco, E d . Sci., 25, 799 (1970). 36. P. E. Sonnet and M. Jacobson, J . Pharm. Sci. 60, 1254 (1971). 37. Kh.G. Kiryakov and P. Panov, Dokl. Bolg. Akad. Nauk 22, 1019 (1969); C A 72, 5177613 (1970). 38. M. Tomita, S.-T. Lu, S.-J. Wang, C.-H. Lee, and H.-T. Shih, J . Pharm. SOC. Jap. 88, 1143 (1968). 39. J. Cohen, W. von Langenthal, and W. I. Taylor, J . Org. Chem. 26,4143 (1961). 40. I. R. C. Bick and G. K. Douglas, Tet. Lett. 2399 (1965). 40a. M. P. Cava and I. Noguchi, J. Org. Chem. 37, 2936 (1972). 41. M. P. Cava, K. V. Rao, B. Douglas, and J. A. Weisbach, J . Org. Chem. 33, 2443 (1968). 41a. M. P. Cava, P. Stern, and J. Wakisaka, Tetrahedron, 0000 (1973) 42. F. N. Lahey and K. F. Mak, Tet. Lett. 4511 (1970). 42a. M. P. Cava and S. Libsch, unpublished results (1972). 43. M. D. Glick, R. E. Cook, M. P. Cava, M. Srinivasan, J. Kunitomo, and A. I. daRocha, Chem. Commun. 1217 (1969). 44. Kh. G. Pulatova, Z. F. Ismailov, and S. Yu. Yunnsov, Khim. Prir. Soedin. 2, 426 (1966); Chem. Natur. Compounds 2, 349 (1966).
264
MAURICE SHAMMA A N D R . L. CASTENSON
45. Kh. S. Umarov, M. V. Telezhenetskaya, 2. F. Ismailov, and S. Yu. Yunusov, Khim. Prir. Soedin. 6 , 224 (1970); C A 73, 63193t (1970). 46. K. I t o and H. Furukawa, Tet. Lett. 3023 (1970). 47. F. N. Lahey and K. F. Mak, Aust. J . Chem. 24, 671 (1971). 48. M. P. Cava and A. Venkateswarlu, Tetrahedron 27, 2639 (1971). 49. V. Preininger. J. Hrbek, Jr., 2. Samek, and F. Santavf, Arch. P h r m . ( Weinheim) 302, 808 (1969). 50. V. Preininger and F. 9antav9, Acta Ulziv. Pulacki. Olomuc., Fuc. Med., 43, 5 (1966). 51. I. Ribas, J. Sueiras, and L. Castedo, Tet. Lett. 3093 (1971); H. Furukawa, F. Ueda, M. Ito, K. Ito, H. Ishii, and J. Haginiwa, J . Pharm. SOC.Jup. 92, 150 (1972). 52. J. Cohen and W. I. Taylor, J . Org. Chem. 28, 3567 (1963). 53. S. M. Kupchan, T.-H. Yang, M. L. King, and R. T. Borchardt, J. Org. Chem. 33, 1052 (1968). 54. M. P. Cava, private communication (1972). 55. L. D. Yakhontova, V. I. Sheichenko, and 0. N. Tolkachev, Khim. Prir. Soedin, 214 (1972); C A 77, 48675r (1972).
-CHAPTER
7-
PHENETHYLISOQUINOLINE ALKALOIDS TETSUJIKAMETANI AND MASUO KOIZUMI Pharmaceutical Institute. Tohoku University Aobayama. Sendai. Japan
I. Introduction ....................................................... I1. Structural Elucidation. Chemical Reactions. and Stereochemistry ......... A . Homomorphinandienone and its Analogs ............................ B . Bisphenethylisoquinoline.......................................... C Homoproaporphine .............................................. D Homoaporphine .................................................. E Homoerythrina Alkaloids ......................................... I11 Biosynthesis ....................................................... A Androcymbine (Formation of Colchicine) ............................ B Melanthioidine .................................................. C Homoproaporphine .............................................. D Homoaporphine .................................................. E . Homoerythrina Alkaloids ......................................... IV . Synthesis .......................................................... A Phenol Oxidation ................................................ B. Ullmann Reaction ................................................ C Modified Pschorr Reaction ....................................... D . Photo-Pschorr Reaction ........................................... E Photolytic Cyclodehydrobromination ............................... V . The Hypot.hetica1 Alkaloids (New Phenethylisoquinoline Skeletons) ....... V I. Spectroscopy ....................................................... V I I . Addendum ......................................................... References .........................................................
. . . . . . . . . . .
265 277 277 279 279 281 282 286 286 288 289 289 289 290 290 296 299 304 308 310 314 319 320
.
I Introduction
Phenethylisoquinoline alkaloids are classified into six major alkaloid groups based on structural differences. namely. simple l-phenethylisoquinoline (1). homomorphinandienone (2). bisphenethylisoquinoline (3). homoproaporphine (4). homoaporphine (5). and homoerythrina alkaloids (6). These alkaloids are related to the benzylisoquinoline alkaloids such as morphinandienone. bisbenzylisoquinoline. proaporphine. aporphine. and erythrina alkaloids . Although colchicine and its derivatives also belong to the phenethylisoquinoline alkaloids group. these alkaloids are not included in this review as they have been reviewed earlier (1) .
266
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART1
Rz R1T\ N
R3
a -
M
\
e
R,
R4
1
4
2
3
5
6
Although the phenethylisoquinoline alkaloids represent a wide diversity of chemical types, it appears nevertheless that they share a common origin from the 1-phenethylisoquinoline precursor, and that their biosyntheses parallel the formation of analogous alkaloids from 1-benzylisoquinoline. Among these, the notable alkaloids are the simple 1-phenethylisoquinoline and homomorphinandienones, which are key intermediates in the intriguing problem of the biosynthesis of colchicine. The other phenethylisoquinolines, however, which are of considerable biosynthetic interest, do not have a close structural resemblance to cholchicine. Phenethylisoquinoline alkaloids have been isolated from six genera: Androcymbium, Colchicum, Kreysigia, Bulbocodium, Schelhammera, and Phelline. Except for Phelline, whose family affiliation is still in question, these genera are all Liliaceae. These alkaloids are listed in Table I along with their physical properties.
TABLE I PHYSICAL PROPERTIES AND PLANTSOURCES
Compound Simple 1-Phenethylisoquinoline Autumnaline Cz1HzvN05
166-168
OMe Homomorphinandienone Androcymbine C ~ I H ~ ~ N O E 199-201
uo -
Me0 0-Methylandrocymbine
MW e0
Optical rotation (deg)
Mp of derivatives ("C)
154-155.5;C methiodide, 230C
uv (nm, log E)
[ a ] b - 5 f 3 (CHCld : : ? A
[a]:'
[a],,
-260 (CHCld
- 295 (CHC13)
206 (4.82) 225 (4.25) 285 (3.62)
-
vmax 1665
239 (4.21) 277 (3.67)
1635 1615
282 (3.69)
Plant source
Colchicum cornigerum
Amax 211 (4.56)
Agz2H238 (4.28P
NMR
Ir (cm-l)
vmax 1663
1638 1613
S
Refs.
2
CDClaa 2.36 (NMe) 3.63 (OMe) 3.82 (OMe) 4.02 (CB-H) 6.27 (CI-H) 6.83 (CB-H)
Androcymbium melanthioides 2C, 4
CDCl3W 2.38 (NYe) 3.62 (OMe) 3.81 (2 x OMe) 4.01 (OM@ 6.25 (Cs-H) 6.28 (CI-H) 6.78 (Cs-H)
Colchicum autumnale
S
L
t
F 3, 8, 56, 61
r s Q,
O
continued
a
Table I-wnlinued t 3 Dfp of
Compound
derivatives ("C)
Kreysiginine Cz1HZ,NO5 -4
Me0
149; HBr salt, 142-143
Q,
Optical rotation (deg)
+ 89 (EtOH)
00
Uv (nm, log E )
Ir (cm-1)
218 (4.95) 274 (3.35)
vmsx 1667
Amax
212 (4.60) 213 (4.02) 275 (3.07)
-
A,,
200 (4.36) 283 (3.34)
-
A,,
0
H j
---OH
H
Me0
Alkaloid CC-21 enantiomeric with kreysiginine Bisphenethylisoquinoline Melanthioidine C38H42N20e
- 100
k 5 (EtOH)
151-154
[ ~ i ] : '
142-144
[ a ] n - 63 (CHCls)
6 CDCl3'J
2.58 (NMe) 3.28, q, J5.e = 9.0 HZ (C8-H) 3.53 (OMe) 3.53, q, J = 1.5, 6.0 HZ ('20-H) 3.81 (OMe) 3.91 (OMe) 4.28, 9. Je,, = 4.0 HZ (C-H) 4.64, d, J5.B= 9.0 HZ (C5-H) 5.70, d, J,,8 = 6.0 HZ (Ca-H)
I&
\
NMR
6 2.44 (2 x NMe)
3.79 (2 x OMe) 6.5 6.9 Aromatic 10 H
Plant source
Refs.
Kreysigia muuiflora
6, 8
Colchieum eornigerum
2e, 7
Androcymbiurn 2, 13 melanthioides
Homoproaporphine Kreysiginone CZoHz3N04
214 (4.54) 243 (4.15) 287 (3.78)
1550
YZ:$''
1659 1633 1614
6 CDC4
1678 1635 1610
6 CDC13
0
OMe
Dihydrokreysiginone CzoHasNO4
217-222
iPMe
AEy.!
220 269
vg:!13
2.45 (NMe) 3.54 (OMe) 3.76 (OMe) 5.95, d, J = 3 HZ (C13-H) 6.28, d, J = 10 Hz (C1o-H) 6.52 (C3-H) 6.83, q, J = 3, 10 HZ (Go-H)
2.57 (NMe) 3.54 (OMe) 3.84 (OMe) 5-74 (c13-H) 6.54 (C3-H)
Kreysigia multiflcra
2a
Kreysigia multiflora
2a
Bulbocodium vernum
16
M0e 0 /
Bulbocodine ClsH23N04
220-222
r a g +111
A,,
221 (4.65) 260 (4.02) 293 (3.82)
-
tQ Q,
continued
Table I--eontinued t.3
Mp of derivatives ("C)
Compound Homoaporphine Ereysigine CzzHz7N05
Me0
188
-J
Optical rotation (deg)
[.ID 0
Uv (nm, log E )
-
Ir (em-l)
-
NMR
8 CDC13
7.60 (NMe) 3.59(0Me)' 3.83 (OMe) 3.86 (2 x OMe) 6.54, 6.59 (Cs-H, CS-H)
8
Me0 \ OMe ( - )-Kreysigine CzzHmN05
- 70 i 4 (CHCl3)
123-125
[alg2
230
[alD - 77 (CHC13)
A:?.
218 (4.62) 257 (4.10) 293 (3.67)
-
Amax
220 (4.65) 259 (4.13) 293 (3.81)
-
Plant source
Refs.
Kreysigia multitlora
6, 20
Colchium eornigerum
2
Kr~y8igia multiflora
6, 20
Me
OMe Floramultine CziHzsNOs
OH
8 3.55 (OMe)
3.84 (OMe) 3.89 (OMe) 6.54, 6.59 (C3-H, Ce-H)
0
209-212
La]=
- 108 (CHC1d
A,,
216 (4.66P 257 (4.06) 293 (3.86)
6 CDCl3Q.C
2.40 (NMe) 3.58 (OMe) 3.92 (2 x OMe) 6.65, 6.70 (Ca-H, Cs-W
Kreysigia multiflora
20
m
0 Homoerythrina alkaloids Schelhammerine C 1 H a 3 N 04
OH
173-174; 0-acetate, 143-144; methiodide, 210-212
[a]=
+ 186 (CHCL)
9 3 236 (3.68) 289 (3.60)
6 CDCVJ
Sehelhammera 22-24
2.06, q, J4ax,3ax peduneulata = 3.2 Hz, (C4ax-H) 2.60, q, J4ax.ees = 13.9 HI, Jreq.aeq = 5.0 Hz (C4eq--H) 2.77 (OMe) 3.50, m (Caeq-H) 4.06, m, Ja,o = 3 Hz (Ca-H) 5.62, d, Jl.a = 2.8 HZ (CI-H) 5.82 (OCHaO) 6.52 (GI,-H) 6.71 (CIS-H)
8 E 3
2L 8m
continued
2 w
p.3
Table I-continued
Compound Alkaloid H (3-Epischelhammerine) CioH23N04
MeO.
Mp of derivatives ("C)
182-185
4 N
Optical rotation Uv (nm, loge)
(deg) [ a ] +167 ~
(CHCl3)
A=:!
238 (3.70)
Ir (cm-l)
NMR 6
290 (3.63)
=u OH
76-77
Plant source
CDC1,b Schelhammera 22-25 peduneulata, 1.85, t, J 4 & X 9 4 0 q = 12.0 HI, Phelline J3.4ax = 12.0 Hz comosa (C4ay-H) 2-47. 4, J4eq,sax = 3.5 H I , J4ax.qeq = 12.0 HZ (C4eq-H) 3.25, m (Caax-H) 3.28 (OMe) 4.34, m (C,-H) 5.73, d, J i , a = 5 H Z (Ci-H) 5.88 ( O C H ~ O ) 6.61 (Cis-H) 6.63 (Cis-H)
CDC1,b Schelhammera 22-24 1.78, q. J4ax.389 = peduneulata 3.5 Hz (Qax-H) 2.38, m (C,-H) 2.74 (OMe) 2.90, q, J4es,ses = 5.0 Hz, J4ax,4eq = 14.0 H Z (C4eq--H) 3.66, m (C3eq-H) 5.54, m (Cl-H) 5.85, 5.87, each d, J = 1.5 Hz (OCHzO) 6.56 (Cis-H) 6.86 (Cis-H)
6
Refs.
r3
M I+
rn
Alkaloid E 3-Epischelhammericine
169-172
[a]=
+ 123 (CHC4)
A:?!
237 (3.59) 290 (3.58)
6 CDC13b
1.52, t, J4ax,res= 11 Hz, J3.4ax = 11 HZ (C4ax-H) 2.70, 4, J4ax.489 = 11 HZ (Cleq-H) 3.10, m, (Csax-H) 3.17 (OMe) 5.47, m, (Ci-H) 5.84 (OCH,O)
Schelhammera 22-25 pedunculata
4
6.58 (Cia-H) 6.69 (Cie-H) Schelhammeridine CisHziN03
Me0
118; methiodide, 215-216; picrate, 202-207
[aID - 108
(CHC13)
234 (4.24) 287 (3.60) 290 (3.61)
6 CDC13b 1.87, q, J4Px.3eq =
z z
M
Schelhammera 22-24 pedunculata
4.5 Ha (C4ax-H) 3.02 (OMe) 3.03, 4. J,.eax = 1.0 Hz (CsarH) 3.33, 9. J4e4,4ax = 13.0 Hz, J4eq.aeq = 1.5 HZ ('2489-H) 3.62, q, Jseq.aax = 15.0 Hz, J,,eeq = 2.5 Hz (C6es-H) 3.74, m, (Caes-H) 5.81, 5.84, each d, J = 1.5 Hz (OCH20) 6.39 (Cis-H) 6.53 (Cia-H) 6.53, d, Jl.a = 9.5 Ha (4-H)
k i
E m 0
Q
z
3tc
i
k%
8m E3
continued
4
w
Table I-continued
Compound Alkaloid G (3-Epischelhammeridine) C19HalN03
MeO.
Mp of derivatives ("C) 131-133
Optical rotation (deg)
[.In
+ 24 (CHCl3)
Uv (nm, log Amax
E)
228 (4.22) 289 (3.63)
Ir (cm-l)
NMR
Plant source
6 CDC13b Schelhammera 1.83, t., J4ax,3ax = pedunculata
Refs. 22-24
11.0 He, J4ax.4eq = 11.0 HZ (C4ax-H) 3.23 (OMe) 3.38, m (Caax-H) 5.83 (OCH20) 6.38, q, J1.a = 9.5
.-u
HZ
J1.3ax = 2.5 H Z (C1-H) 6.43 (CIS-H) 6.59 (C1a-H) Alkaloid B
152-153
[a]=
+ 111(CHC13)
Amax
235 (3.90) 283 (3.57) 289 (3.52)
Schelhamrnera 22-24 1.56, t (C4ax-H) pedunculata 2.19 (OMe) 2-71>4,J4es.aax = 3.0 Hz J4ax,4eq 11.0 HZ (C4eq-H) 3.22, m (C3ax-H) 5.51, m (Cl-H) 6.62 (Cia-H) 6.76 (Cm-EI)
6 CDC13'J
Alkaloid A
Picrate, 188-189
[a]= -100 (CHC4)
A",",","
6 CDC13b
236 (3.63) 289 (3.59)
1.96, q, J,,x,aeq 7.5 H z
=
Schelhammera 22-24 gedunculata
(C4ax-H)
2.44, q,J4es,ses = 5.0 Hz J4ax.4eq = 13.5 H z (Caw-H) 3.23 (OMe) 3.82, m (Caes-H) 5.83 (OCHaO) 6.50 (Cis-H) 6.71 (Cia-H) 150-153
[or],
-47 (CHC13)
,422: 232 (4.49) vg:: 277 (3.66) . , 313 (3.69)
1665
6 CDClSb 1.96, q9J4ax,seq =
Schelhammera 22-24 pedunculata
7.5 Hz (Caax-H) 2.65, q, Jiax,res = 15.0 Hz (Cies-H) 2.87 (OMe) 3.17 (C~ax-H) 3.64, m (Cses-H) 3.80, q, Jcaax,cses = 16 Hz, J8eq.7 = 3.0 (C8es-H) 5.82, q, J2.389 = 5.0 HZ
(Cz-H) 5.94, 5.96, each d, J = 1.5 HZ (OCHaO) 6.00, m (C7-H) 6.42 (Cis-H) 6.51,d, J1.z = 10.0 HZ (C1-H) 7.05 (Cin-H) . . continued
cn
Table I - c d i n u e d Optical rotation (de@
Mp of derivatives ("C)
Compound Alkaloid 11
170-171
[a]=
+ 35 (CHCl,)
' :A?
241 (4.25) 285 (3.77)
u
Me0
Ir (cm-l)
Uv (nm, log E )
~;2:
NMR 6
CDC1,'J 1.67,q. J4ax.3eq = 5.0 H z (Gall-H) 3.05 (OMe) 3.38, bd,J4ax,res = 14.0 H z (C4eq-H) 4.00, m (CW,-H) 5.82, 5.86, each d, J = 1.5 Hz (OCHzO) 6.01 (C-H) 6.14, a, J z m s = 5.0 H z (Cz-H) 6.46 (Cis-H) 6.56 (Cie-H) 6.85, d, J3.z = 10.0 HZ
60 MHz.
* 100 MHz.
C
Synthetic.
Refs.
M 1685
(C1-H) a
Plant source
Schelhammera 22-24 peduneulata
2
9 H
w
h
W H
2 E
7. PHENETHYLISOQUINOLINE ALKALOIDS
277
11. Structural Elucidation, Chemical Reaction, and Stereochemistry
Chemical reactions and the stereochemistry of individual phenethylisoquinoline alkaloids are considered in this section. The simple phenethylisoquinoline alkaloid autumnaline (68), isolated from Colchicum cornigerum (Z), has the basic skeleton of several phenethylisoquinoline alkaloids described later. The structure of 68 was arrived at through comparison with a synthetic sample (Zu, Zb). A. HOMOMORPHINANDIENONE AND ITS ANALOGS 1. Androcymbine and 0-Methylandrocymbine
Androcymbine (7) and 0-methylandrocymbine (8) were isolated from the leaves of Androcymbium melanthioides (2c) and Colchicum uutumnale (3). Oxidation of 8, derived from 7,gave 3,4,5-trimethoxyphthalic anhydride (lo), and reduction with sodium in liquid ammonia afforded the phenethyltetrahydroisoquinoline derivative (11), the structure of which was confirmed by its synthesis ( 4 ) . Compound 11
CHART 2
,---: -Me
RO \ OMe
OMe 0 7 R = H 8 R=Me
Y'.oH
Meoq dMe 9
/--: -Me
Me0
\
\
OMe
---- O H OMe
0 10
11
12
278
TETSUJI KAMETANI AND MASUO KOIZUMI
showed a positive Cotton effect in the 278-265 nm region proving ( 5 ) that it has the S-configuration. Moreover, androcymbine and salutaridine (12)have a mirror-image optical rotatory curve. The position of the phenolic hydroxy group was assigned by analogy with 3-demethylcolchicine. The absolute configuration of androcymbine must therefore be represented as shown in Chart 2. 2. Kreysiginine
Kreysiginine (9) ( 6 ) , which is enantiomeric with alkaloid CC-21 (7), is related as a ring A homolog of the morphine group of alkaloids such as thebaine (15). CHART 3
Hi) 14
13
-Me
15
Mild Jones oxidation of kreysiginine afforded an enone 13, which was treated with a base to give a dienone 14. O-Methylation gave the dienone 8 ( 8 ) , which was identical with O-methylandrocymbine of rigorously established structure and absolute configuration 8. The configuration between C,-H and C,-H of kreysiginine was determined to be of trans diaxial relationship by the NMR spectrum (5, 9 ) , and the hydroxy group must then be axial. Moreover, the absolute chirality of kreysiginine, defined by X-ray analysis (10,11),is the same as that of androcymbine.
7.
279
PHENETHYLISOQUINOLINE ALKALOIDS
B. BISPHENETHYLISOQUINOLINE The only alkaloid of this group is melanthioidine (IS),which was isolated from Androcymbium melanthioides (2,13)along with androcymbine. CHART4
0 OMe
16
R = H
18
17 R = Me
The symmetry of the bisphenethylisoquinoline molecule is such that reductive cleavage of 0,O-dimethylmelanthioidine(17) with sodium in liquid ammonia afforded almost exclusively the one phenolic isoquinoline 18 (12, 13) which showed a negative first Cotton effect. Previous knowledge (14, 15) of ORD measurement on tetrahydroisoquinoline chromophores established the illustrated R-configuration and indicated that the molecule is in a head-to-tail arrangement.
C. HOMOPROAPORPHINE Of the homoproaporphine alkaloids kreysiginone (19), dihydrokreysiginone (21), and bulbocodine (22), the former two (19 and 21) were isolated from Kreysigia multiflora (Za). The last was isolated from Bulbocodium vernum (16) and its structure has been determined recently by fiantavg (17). The configurations of the spiro centers of dienones 19 and 20 were determined by chemical reactions and by NMR spectra (18).Kreysiginone was subjected to dienone-phenol rearrangement with concentrated
280
T E T S U J I KAMETANI AND MASUO KOIZUMI
CHART 5
MHO e\ p
-
M
Z P - M e
e
M!p-Me
/ 0
OMe
0
OMe
0
20
19
21
r:g ::g ~9 CHART6
MHeO0 /
HO \ OMe 23
-Me
-Me
-Me
Me0 \
\
OH
OMe
24
25
-Me
,I
OMe
OH 26
27 28
R = Me R = H
7.
281
PHENETHYLISOQUINOLINE ALKALOIDS
hydrochloric acid in glacial acetic acid to give a homoaporphine (23) and the same reaction of 20 afforded the three compounds 25,27,and 28. On the other hand, reduction of 19 with sodium borohydride afforded dienol 26, which, under dienol-benzene rearrangement with concentrated hydrochloric acid, gave another homoaporphine (24). Recently, photolysis of dienone 20 afforded compound 30 via 29, the mechanism of which is outlined in Chart 7 (19). CHART 7
Me0 / H 20
hu
P
N
g \-
Meo
-
M M
e e
-
-
\ /
-0
29
N-Me
Me0
30
D. HOMOAPORPHINE Some years ago, three alkaloids, namely, kreysigine (31a),floramultine (32),and multifloramine (33),were isolated from Kreysigia mu& Jlora (6, 20). Recently, a fourth alkaloid, ( - )-kreysigine (31b)was isolated from Bulbocodium vernum (17). The chemical behavior of this alkaloid has not been described. CHART 8
31a
R =-H
31b R = + H
32
33
282
TETSUJI KAMETANI AND MASUO KOIZUMI
The assignment of S-configuration to multifloramine was accomplished by comparison with the synthetic sample (21).
E. HOMOERYTHRINA ALKALOIDS Schelhammerine (Alkaloid D) (34), schelhammeridine (Alkaloid C) (38), and Alkaloids A (41) and E (36) as the major homoerythrina, and schelhamrnericine (Alkaloid F) (35) and Alkaloids B (40),G (39),H (37), J (42), and K (43) as the minor homoerythrina were recently isolated from Xchelhammera pedunculata (22-24). Alkaloids 36 and 37 were more recently isolated from Phelline comosa (25). CHART 9
MeO”
It, = R, = 36 It, = 37 R, =
34 35
---OH, R, = i O M e H, R, = -0Me H, R, = ---OMe ---OH, R, = ---0Me
?!+
38 R = i O M e 39 R = - - - 0 M e
Me0
41
40
(9 Me0
42
43
The structure of these alkaloids and the relative stereochemistry at all the centers other than C-2 were determino,d by NMR spectral assignment (22-24) and the complete structure and absolute configurations (2S,3S,5S) of 34 were confirmed by X-ray analysis of schelhammerine hydrobromide (26). I n the course of the structural investigation of these alkaloids Johns and his co-workers (27) examined various reactions on schelhammeridine (38) which was the most readily available of the Schelhammera alkaloids.
7.
283
PHENETHYLISOQUINOLINE ALKALOIDS
The treatment of schelhammeridine (38)with methanesulfonyl chloride in pyridine gave schelhammerine (34) which has the same [.ID as the natural alkaloid. Both alkaloids should have the same absolute Sconfiguration a t C-3 and C-5. Catalytic hydrogenation of 38 in acetic acid, two moles of hydrogen being absorbed, gave the following four compounds. CHART 10
44
46
45
J 48
47
The first compound, in approximately 4% yield, was regarded as demethoxydihydroschelhammeridine (44) which is presumably formed by hydrogenolysis of the allylic methoxy group at C-3 of 38 followed by 1,4 addition of hydrogen to the dienone system. The second product was obtained in 30y0 yield and has been shown to be 1,2,6.,7-tetrahydroschelhammerine (45). The stereochemistry shown at C-6 of 45 cannot be deduced from spectral data but inspection of molecular models indicates that the attack from the /3 side of the molecule is hindered by the bulky aromatic ring. The third compound, obtained in 30% yield, was postulated to be dihydroschelhammeridine (35), which was identical with schelhammericine, a natural product. The formation of 35 can be readily explained by 1,4 addition to the diene system. Furkher attempts to reduce it under the same conditions have been unsuccessful. The fourth minor product has been shown to be the
54
55
53
ro
0
+N-
H.,
OH -COMe
LI,. 56
/
El
N
7.
285
PHENETHPLISOQUINOLINE ALKALOIDS
cyclic amide 46, the acetylation of which afforded the N-acetyl derivative 47. The formation of 46 can be explained by reduction of the C-l=C-2 double bond in 38 to give, under acidic conditions, the protonated form of the dihydro compound 48 and cleavage of the C-5-C-9 bond with migration of the C-6-(2-7 bond to C-5-(2-6, followed by hydride addition at C-7. Alkaloids G (39) and A (41) were treated by the same method to give Alkaloid E (36) and schelhammericine (35)) respectively. Oxidation of 38 gave Alkaloid K, which was identical with the natural moduct. Heating of 38 with hydrochloric acid gave alcohol 49, in 70y0 yield, with the configuration at C-3 opposite to that in schelhammeridine, and alcohol 50 in 10% yield. Furthermore, two amino alcohols, 51 and 52, obtained in 307, and 10% yield, respectively, have a biphenyl ring system formed by the aromatization of ring A. The compounds 51 and 52 have been shown to be diastereoisomers with the same configuration of the biphenyl system and opposite configurations at C-7. They have been characterized as N-acetyl derivatives 54 and 55, which have been assigned the respective configurations shown in 56 and 57. Oxidation of compounds 54 and 55 afforded the ketone 53 ([a],,Oo), the identity of which indicated that compounds 54 and 55 were epimeric at C-7. The formation of compounds 49 and 50 suggests a mechanism in which protonation at the methoxy oxygen atom of 38, followed by elimination of methanol, gives the carbonium ion 58. This is then attacked by the CHART 12
58
59
60
hydroxyl ion from the a and p sides of the molecule. The greater yield of the a-isomer can be explained by a study of molecular models which shows that the /3 side is more hindered than the a side. On the other hand, the formation of compounds 51 and 52 can be represented by protonation against the tertiary nitrogen followed by elimination of methanol and electron transfer as shown in 59. Since the attack by the hydroxy ion could occur from either side of 60 a mixture of epimeric alcohols at C-7 was obtained.
286
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART13
,COMe
61 62
63
R = COMe R = H
64
COMe
Acetylation of 38 with acetic anhydride afforded only the N,Odiacetyl compound 63 which on hydrolysis gave compound 62, the optical antipode of 54. Although the formation of the two C-7 epimeric alcohols in the reaction of 59 with hydrochloric acid supports an attack on a hydroxyl anion of a C-7 carbonium ion-the formation of a single stereoisomer 63 by the action of acetic anhydride may be more satisfactorily explained if the reaction proceeds by way of cyclic intermediate 64 such as the acetyl cation and an acetoxy anion which are derived from the same molecule of acetic anhydride. 111. Biosynthesis
Although the biosynthesis of all the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbine and homoaporphine has been examined by tracer work. I n this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. A. ANDROCYMBINE (FORMATION OF COLCHICINE) Androcymbine may be derived from phenethylisoquinoline 68 by phenol oxidation. The derivation of colchicine from phenethylisoquinoline precursors 67 and 68, which were formed from 65 and 66,
J I
i
T I
7.
9
T
IW
J
gg
T T
\ /"
-
287
tco
gJ
PHENETHYLISOQUINOLINE ALKALOIDS
g\\
&.aw 0
x x
0
288
T E T S U J I KAMETANI AND MASUO KOIZUMI
(28-31) and its relationship to the androcymbine skeleton (8, 69) have been demonstrated by a series of tracer experiments with doubly labeled compounds. Of particular significance was the finding that the 14C/15N ratio of colchicine (6), isolated by a feeding experiment with the phenethylisoquinoline 68 doubly labeled as shown, matched that of the precursor. The formation of the tropolone ring in colchicine was confirmed by tracer work (31)using tyrosine. Furthermore, the formation from phenylalanine of the A ring of colchicine was proved by tracer work (31).The results of these experiments provide strong evidence for several of the postulated steps of the biosynthesis of colchicine, shown in Chart 14. The sequence involves introduction of a hydroxy or related group into dienone 8, the elimination of which in a subsequent step provides the driving force for ring expansion 70 -+ 71 -+72 -+ 73.
B. MELANTHIOIDINE The biosynthesis of ( - )-melanthioidine (16) (12, 13) almost certainly involves phenol oxidation, and diphenolic isoquinoline 74 is the required substrate; R is probably methyl, but the presence of a secondary
&
\ OH
RN
/ OMe
CHART 15
-
&6M:xI$ \
/
RN
/ OMe 75
74
Y
H N
O
I
16
nitrogen is also possible with methylation at a later stage. Biological oxidation could generate the radical 75 which is shown in the appropriate canonical forms for pairing to construct melanthioidine. The formation of the diary1 ether links is not necessarily simultaneous.
7.
PHENETHYLISOQUINOLINE ALKALOIDS
289
C. HOMOPROAPORPHINE Although the biosynthesis of the homoproaporphines has not yet been elucidated, these alkaloids could be biosynthesized by phenolic oxidative coupling of the diphenolic isoquinoline 76. CHART 16
OH 76
D. HOMOAPORPHINE (32) By analogy with the biosynthesis of several aporphine alkaloids (33-35) the homoaporphines could arise naturally by way of homoproaporphines 78a and 78b or by direct coupling of the diphenolic isoquinoline 77a. In order to distinguish between these possibilities, the [3-14C] diphenolic isoquinolines 77a,b,c were administered to Kreysigia multijlora shoots which converted the homoaporphines 79a,b,c,d into O-methylkreysigine (80). The good incorporation (1.670) of 77a, compared with the very low efficiency ( < 0.01470)of 77c, is in accord with the mechanism involving direct coupling. These results imply that floramultine (79a) is the first homoaporphine alkaloid to be formed. The incorporation (0.21Y0)of 77b is presumably by conversion into 77a.
E. HOMOERYTHRINA ALKALOIDS(23) It seems likely that the ring system of the homoerythrina alkaloids is derived by a route analogous to that involved in the formation of the erythrina alkaloids for which a l-benzyl- 1,2,3,4-tetrahydroisoquinoline precursor has been established ( 3 6 , 3 7 ) .On the basis of this analogy the homoerythrina skeleton could be formed from a sequence of an oxidative coupling reaction through a l-phenethyl-l,2,3,4-tetrahydroisoquinoline derivative, as shown in Chart 18.
290
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 17
R, 78a R = H 78b R = OMe
t
79a R, = OMe, R, = O H 79b R, = OH, R, = H 790 R, = R, = OMe 79d R, = OH, R, = OMe
OMe 80
Rl 77a 77b 77c
R, = OMe, R, = OH R, = OH, R, = H R, = OH, R, = OMe
IV. Synthesis This section describes various synthetic methods, each of which gives rise to a different type of phenethylisoquinoline alkaloid, depending upon reactivity and reaction conditions.
A. PHENOL OXIDATION There are many reports on the biogenetic synthesis of these alkaloids by phenol oxidation. These reactions were carried out using a diphenolic isoquinoline with one-electron oxidizing reagents : ferric chloride, potassium ferricyanide, manganese dioxide, and so on. I n order to obtain the androcymbine-type compound 82 the diphenolic isoquinoline 81 was subjected to phenol oxidation with potassium ferricyanide (Za) and with ferric chloride ( Z b ) , respectively, but instead the homoaporphine 83 (Za) coupled at the ortho-ortho position to the hydroxy groups.
7. PHENETHYLISOQUINOLINE ALKALOIDS
291
+ (34-43)
CHART 19
MHe 0 / O
T --Me
/ M e 0 \OMe 81
82
'
F
-
HO
/'
M
Me0 \ OMe 83
e
292
TETSUJI KAMETANI AND MASUO KOIZUMI
However, the synthesis of homomorphinandienone 85 was accomplished by phenol oxidation of diphenolic isoquinoline 84 with potassium ferricyanide (38, 39). CHART 20
K3Fe(CNb
F
OMe
85
84
Before kreysiginone was isolated from a natural source diphenolic isoquinoline 76 had been oxidized with ferric chloride to yield homoproaporphines 19 and 20 ( 4 0 ) )one of which, dienone 19, was isolated from Kreysigia multijlora by Battersby (Za).Battersby also synthesized both dienones 19 and 20 by the same reaction of 76 with potassium ferricyanide. In this reaction he examined the phenol oxidation of the diphenolic isoquinoline 86 and obtained product 87 containing an CHART 21
HoTe
Me0 /
N-Me
-
76 OH
OMe 86
OMe 87
1s
+
20
7.
293
PHENETHYLISOQUINOLINE ALKALOIDS
ether linkage which underwent rearrangement with isopropenyl acetate-p-toluenesulfonic acid to yield the diacetate of 83. Total syntheses of multifloramine (94) were achieved as follows. The diphenolic isoquinoline 88 was subjected to phenol oxidation with CHART22
OMe 88 R = - H 89 R = + H 90 R = - - - H
ferric chloride (40, 41) and potassium ferricyanide ( I @ , and the resulting homoproaporphine 91 underwent dienone-phenol rearrangement in concentrated sulfuric acid (42) to give multifloramine (94). Recently Brossi (21) oxidized R-( - )-(89)and S-( + )-diphenolie isoquinolines 90 with ferric chloride and obtained R-( - )-(92) and S-( + )-homoproaporphines 93, respectively, both of which were rearranged to afford natural ( - )-multifloramine (33) and its enantiomeric ( + )-multifloramine (95). Methylation of ( k )-multifloramine with diazomethane gave kreysigine (31a) (20). I n an attempt to synthesize melanthioidine (16) from diphenolic isoquinoline 96, which is thought to be the biosynthetic precursor of 16, the compound 96 was oxidized with several one-electron inorganic oxidizing reagents, but there was obtained the homoproaporphine 97 (2b, 40). Further, enzymic phenol oxidation of the above phenolic base 96, a reaction which is more nearly biogenetic, with homogenized potato peelings (43) and with homogenized Wasabia japonica Matsumura ( 4 4 ) in the presence of hydrogen peroxide at room temperature gave the head-to-tail coupled product, promelanthioidine (98), and the head-to-head coupled one, bisphenethylisoquinoline 99. Since oxidation of 96 did not give the expected product 16, the Ullmann reaction was applied to the synthesis of 16, which will be described later.
294
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 23 16
v
\
\
96
VH
0
97
OH
OH 99
98
Diphenolic isoquinolines 100 and 101 were oxidized with ferric chloride to homoproaporphines 104 (45) and 105 (as),respectively, while 102 and 103 afforded the ortho dienones 106 and 107 (47), respectively . The possibility that homoerythrina alkaloids exist has been anticipated from biosynthetic consideration. Homoerythrinadienones 110 and 111 were synthesized by phenol oxidation with potassium ferricyanide (48)of secondary amines 108 and 109, a homolog of erythrina dienone. This compound 110 is believed to be involved in the biogenesis of the homoerythrina alkaloids. On the other hand, Barton (49) has elucidated the biogenesis of erythrina alkaloids by tracer work as follows. Norprotosinomenine (112) was oxidized to dienone 113, which was cleaved reductively. Phenolic oxidative coupling of 114 then gave the erythrinadienone 115, which was modified to give several erythrina alkaloids, such as erysodine (116).
7. PHENETHYLISOQUINOLINE ALKALOIDS
101
MHe 0 O /T
105
-
; M e
M
:
g
-
M
e
-
\ R, 102 103
Rz
R1
R, = OMe, R, = H R, = H, R, = OMe
106 107
RI R, = OMe, R, = H R, = H, R, = OMe
CHART25
OMe 108 109
R
=H R = OMe
110 R = H 111 R = OMe
295
296
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 26
-
Me0
OH
OH 112
OH 113
114
0 115
116
I n attempts to understand the biogenesis of the “prohomoerythrinadienone” of the type of compound 118, which has the same skeleton as the key intermediate 119 used in the biogenesis of the homoerythrina alkaloids, the diphenolic isoquinoline 117 was subjected to oxidation with potassium ferricyanide. However, this reaction gave unexpectedly the abnormal products phenylpropionaldehyde 120, seco-dehydrohomerythrinadienone (121), seco-homoerythrinadienone (122), and a quinoline derivative 123 (50). A mechanism which would reasonably explain the formation of 122 would involve the initial ring opening of the oxidation product 118, followed by hydrolysis, to give biphenyl derivative 125 via 124, which would then be reoxidized. Moreover, the formation of quinoline derivative 123 involves oxidative coupling of imine 126, derived from ammonia and propionaldehyde (120), the latter of which could be formed by direct oxidation of starting material 117, followed by dehydrogenation of 127.
B. ULLMANN REACTION Total synthesis of ( & )- and ( - )-melanthioidine (16)was accomplished by Battersby’s double Ullmann reaction (13) which is a useful method
7. PHENETHYLISOQUINOLINE ALKALOIDS
0
& \ /
g zs
El du 3
297
298
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 28
Me
Me0
+ LN-Me
\
118
124
CHO
-122
121
OH 125
120
-
CHART 29
NHIOH
phc&T
K3Fe(CN)e
Me0 \
H 126
127
CHART 30
MHe 0 / O
T -Me
Br \ OCHzPh 128
__f
Me0 /
\ o \
MeN
I
/OMe 129
16
--Me
OCH,Ph
7.
PHENETHYLISOQUINOLINE ALKALOIDS
299
for syntheses of various bisbenzylisoquinoline alkaloids. Thus alkaloid 16 was synthesized from phenolic bromoisoquinoline 128 with copper and sodium carbonate in pyridine at 140-150". Catalytic debenzylation of the resulting ( - )-0,O-dibenzylmelanthioidine (129) gave natural ( - )-melanthioidine (16). At the same time, melanthioidine (51) also was synthesized by the method described above.
C. MODIPIED PSCHORR REACTION Some years ago a general synthetic method (52) for the morphinandienone-type alkaloids was discovered by modifying the Pschorr reaction which had been used widely for the synthesis of the aporphine alkaloids and this method was applied to a synthesis of the homomorphinandienone-type compounds. Diazotization of 2'-aminophenethylisoquinoline 130 with a slight excess of sodium nitrite in 1N sulfuric acid, followed by thermal decomposition of the diazonium salt at 70" for 1 hr, gave homomorphinandienone 132 (53).Although structure 133 was also thought probable, it was ruled out by spectral consideration and by the alternative synthesis which follows. CHART31
M i : T - M e
Z q H M e
--4d HNO heat
OMe 0
'
Me0 \ ITHZ OMe 130 R = Me 131 R = CHzPh
133
RF-M 0
Me0 \OMe
133 R = Me 134 R = CHzPh
300
TETSUJI KAMETANI AND MASUO KOIZUMI
If the structure of the dienone above were 133, the product 134 from 2’-aminoisoquinoline 131 should be different. However, the products obtained by diazotization of the two aminoisoquinolines 130 and 131, followed by decomposition, were proved to be identical by extensive spectral data. The modified Pschorr reaction was applied to the 2’-aminoisoquinolines 135 and 136 in order to obtain androcymbine (139) and O-methylandrocymbine (137), but the abnormal products, spiroisoquinolines 140 and 141, were obtained and their structures were determined in the following way (54). CHART 32
MeoF:
300 mp) originates from transannular interaction of the nitrogen lone pair with the conjugated system of rings C and D and is no doubt responsible for the yellow color. That such interaction exists is clear from examination of the UV spectra of the alkaloids in acidic media (Table IV; see also Section 11, A, 4). Parello and co-workers used the difference in the UV spectra of securinine and allosecurinine as evidence for the assignment of conformations 103 and 108b, respectively, for the two alkaloids (16). Nakano questioned these assignments by first noting that no transannular interaction is possible in conformation 108b and therefore no long-wavelength absorption should be evident if this configuration is indeed correct for allosecurinine. Nakano recorded the UV spectra of allosecurinine and virosecurinine in various solvents and observed that as the polarity of the solvent increases the high-wavelength band undergoes a hypsochromic shift. Thus this absorption could be assigned with some confidence to an n +n-* transition due to overlap of the nonbonded N-lone pair with the .rr-orbitals of the a,P,y,&unsaturated lactone system. Further evidence to support this conclusion was obtained from ORD and CD measurements. Both allosecurinine and virosecurinine exhibit strong Cotton effects which are absent in the respective protonated forms. That the origin of these Cotton effects could be attributed to n + T* transitions was confirmed by CD studies. Also consistent with these observations is the fact that virosecurinine methiodide shows only a plain ORD curve. [See also discussion of a similar independent study on securinine (Section 11, A, 4) and securinine and allosecurinine by Parello (41a).] Since neither of the two conformations, 108b nor 104, fits the requirement for transannular interaction it was concluded that 108a and 103 are the preferred conformations for virosecurinine and allosecurinine, respectively (35). The UV spectral study of Nakano (35)also offers a possible explanation for the puzzling 26 times slower rate of methiodide formation for securinine compared with that for allosecurinine observed by Parello (16) (vide supra). It will be noted (Table IV) that the change from carbon tetrachloride to ethanol produces a rather large shift ( A h = 36 mp) in the high-wavelength maximum of allosecurinine but only a minimal effect ( A h = 2 mp) on that of virosecurinine. Since in virosecurinine (108a) and therefore in the enantiomeric securinine the A/B ring junction is cis, the nitrogen lone pair is somewhat more
TABLE IV UV SPECTRA OF ALLOSECURININE, VIROSECURININE, AND SECURININE Virosecurinine
Allosecurinine Solvent
UV(max)
log
e
UV(max)
log
332
255 325 257.5 300b 257.5 300b
3.30 4.22 3.35 4.23 3.44 4.25 3.46
256.5
4.26
Securinine E
m(max)
log
c
Refs.
~
Hexane cc1,a Dioxane MeOH a 95xEtOH
5
507, EtOH
HZO EtOH, H + HZO, H + a
342 342 345 300 256.5 304 259 29gb 259 29gb 256 256.5
3.17 3.17 3.22 3.26 4.19 3.36 4.20 3.37 4.24 3.39 4.22 4.26
Lower absorption maximum cannot be measured because of interference of solvent. Shoulder.
328
3.11
333 325 256 330(325)
3.35 3.23 4.15(4.27) 3.30(3.23)
32 35 32 32 16, 30, 35 35
256 -
35 16, 30 35
11.
THE SECURINEGA ALKALOIDS
477
hindered than in allosecurinine (103) whose A/B ring junction is trans. This may account for the spectral and chemical observations above in that the more highly exposed nitrogen lone pair in allosecurinine should be both more strongly hydrogen-bonded and undergo faster methiodide formation, whereas in virosecurinine (and therefore in securinine) the lone pair is buried under ring C and therefore would be much less available for interaction with protic solvent or methyl iodide. Consistent with this explanation was the observation of a similar large solvent shift for allosecurinine but not for securinine recorded independently by Horii and co-workers (32).Further investigations by this group also culminated in the assignment of the absolute configuration and preferred conformation for securinine (Section 11, A, 4).
H. VIROALLOSECURIMINE Viroallosecurinine was isolated together with virosecurinine from the leaves of Securinega virosa Pax. et Hoffm. (52, 53). It was shown to possess the same molecular formula and IR spectrum as allosecurinine but depressed the melting point in admixture with the latter alkaloid. Viroallosecurinine exhibits an optical rotation almost identical in magnitude with, but opposite in sign to, allosecurinine and the ORD curves of the two alkaloids are exact mirror images (53).Thus viroallosecurinine must be antipodal with allosecurinine and may be assigned structure and absolute stereochemistry 136. This discovery completed the set of four theoretically possible isomers of the basic securinine structure. The fact that they all occur naturally and in the same genus is, of course, a relatively rare phenomenon in alkaloid chemistry. (cf. Vol. XII, p. 396). 0
b0 N H 136
I. SECURITININE Preliminary physical and spectroscopic data on securitinine indicated that it possessed all the basic features of securinine and, in
47 8
V. SNIECKUS
addition, a methoxyl group (NMR, T 6.75, singlet, 3 H) (54, 55). The high-resolution mass spectrum of securitinine compared with that of securinine (Section 11,C) gave valuable information about the location of this methoxyl group. Two prominent peaks were observed at m/e 114 and m/e 82, the former corresponding to a 30 higher mass unit increment compared with a similarly prominent peak in securinine. These could be assigned to fragments 138 and 139 and thus strongly suggest that the methoxyl group is part of ring A of securitinine (137) (Scheme 22). Furthermore, the fragment ion (79) a t m/e 56, also observed in securinine (Scheme 12), may be assumed to arise from the m/e 114 ion; this
137
138 m/e 114
139 m/e 82
I 79 m/e 56
SCHEME 22. Key mass spectral fragmentations of securitinine (137)(55).
suggests that the methoxyl group is not located a t C-3 or C-6. Additionally it could be reasoned that, if the methoxyl group were located a t C-3 or C-5, fragmentation would be expected by a-cleavage next to the oxygen function as observed in securinol A (Section 11,K, 1) and tropane alkaloids. Since such fragmentations were not observed it could be reasonably proposed that the methoxyl group in securitine is located a t C-4 as in structure 137. This proposal received confirmation from NMR and degradation studies. Comparison of the NMR spectra of securitinine with that of allosecurinine led to the assignment of a multiplet a t T 6.16 (2H) to C-7-H and C-2-H and a symmetrical multiplet a t
\
T
6.46 (1H) to CHOCH, in
/
the former alkaloid. Double irradiation at T 6.41 and near 6.16 showed that a multiplet a t T 8.84 (1H) assignable to one of the methylene
11.
479
THE SECURINEGA ALKALOIDS
protons a t C-3 is coupled both to C-2-H and to the proton attached to the carbon bearing a methoxyl group. Hence the methoxyl group could be located at C-4 in agreement with the mass spectral evidence. It may be noted in passing that confidence may be placed in the NMR assignments (in particular for C-2-H) both as a result of the decoupling experiments and of the fact that comparison is made with the NMR spectrum of allosecurinine which had been also interpreted with the aid of double irradiation studies (Section 11, E). I . CH,=CHCN, EtOH 2. HClgas, EtOH
COzEt
'
q\
1. NaH, PhH 2. 10% HCl
C0,Et COzEt
140
141
Y
ly3
HO
0
143
142
I
1. Zn, H2S04
EtOH 2. LiAIHa
H OH
H
144 1. (CH&S04, KOH
2. KI
I
3 CH,O' 145
H
H OCH, 146
SCHEME 23. Assignment of relative stereochemistry of securitinine ( 1 3 7 4 (55).
The highly useful zinc-sulfuric acid degradation was applied to securitinine and gave, after an additional metal hydride reduction step, an oily base, 145 ([.ID -89.5"), characterized as its methiodide (mp 242-243"). Racemic 145 was synthesized as outlined in Scheme 23 thus proving the structure of the degradation product and firmly
480
V. SNIECKUS
establishing both the position of the methoxyl group a t C-4 and its cis stereochemical relationship to C-2-H. The benzoquinolizinine 142 was obtained in four steps and overall 30y0 yield from 140 via compounds 141 and 142. Reduction of the ketone 142 with sodium borohydride (thermodynamic control) gave the epimeric alcohols 144 and 143 in 89:ll ratio; on the other hand, treatment of 142 with aluminum isopropoxide (partial kinetic control) produced these two compounds in a 52:41 ratio. The configurational assignments of the epimeric alcohols rest on NMR data: one showed a heptet a t T 6.21 (lH, J = 10 and 5 Hz) clearly due to C-2-H in the equatorial alcohol (144) while the other exhibited a quintet a t r 5.78 (lH, J = 3 Hz) compatible with the assignment for the corresponding proton in the axial alcohol (143) on the basis of a typical A,B,X ( X = C-2-H) analysis. This assignment also makes it obligatory that the alcohols 143 and 144 possess trans ring fusion since a cis fusion would permit a stable conformation with an equatorial C-2-OH for each epimer. The presence of Bohlmann bands in both 143 and 144 confirmed the trans-quinolizidine ring fusion. The two alcohols 143 and 144 were readily converted into the methoxybenzoquinolizidines 145 and 146, respectively. The methiodide of compound 145 showed the identical I R spectrum with that of the methiodide of the product from the zinc-sulfuric acid degradation of securitinine (137a), thus confirming the location of the methoxyl group and establishing the cis-C-&-OCH3-C-2-H relationship in the alkaloid. The relative configuration a t C-2 and C-9 was deduced from the following observations. Firstly, the high-wavelength absorption in the UV spectrum of securitinine due to transannular interaction between the nitrogen lone pair and the conjugated system in rings C and D was observed a t UV max 308 (log E 3.33) mp in ethanol and UV max 341 (log E 3.21) mp in dioxane solution. This is reminiscent of the behavior of allosecurinine but not of securinine (Section 11,G and Table IV) and therefore implies the allosecurinine C-2-C-9 stereochemistry for securitinine. Secondly, as already shown, the C-2 proton appears a t unusually low field ( 6.16) in the NMR spectrum of securitinine, suggesting lack of shielding by the conjugated system and leading to the same conclusion as deduced from the UV spectral information. Thus securitinine must be represented by complete stereochemistry 137a or its antipode. This structure is further supported by a more detailed analysis of the NMR spectrum (55).Finally, the ORD curve of securitinine shows a strong negative Cotton effect classifying it as a securinine or allosecurinine type but not as a virosecurinine type alkaloid. This information coupled with the UV, NMR, and chemical
11.
481
THE SECURINEGA ALKALOIDS
observations lead to 137a as the absolute stereochemical formulation for securitinine.
J. PHYLLANTHINE Prior to the report of Horii and associates on securitinine (54), Parello and Munavelli announced the isolation of an alkaloid, phyllanthine from Phyllanthus discoides, which possessed the same molecular formula as securitinine (Section I) and showed most of the typical spectral features of Securinega alkaloids (41a, 56). Thus the I R and UV spectra were fully reminiscent of the behavior of securinine. Furthermore, the mass spectrum showed major peaks at m/e 247 (M+), 216, 134, 114, 106, 82, 78, and 56 indicating a similarity to the fragmentation pattern of securinine (Scheme 12) and, even without this comparison, locating the methoxyl group in ring A on the basis of the m/e 114 and 82 fragments. Although it received no comment initially (41a, 56), the fact that a fragment ion at m/e 56 is observed as in securitinine, indicating that the methoxyl group is not located a t C-3 or C-6, was subsequently noted (36). Detailed analysis of the NMR spectrum of phyllanthine in comparison with those of securinine and allosecurinine (Section 11, E) provided evidence for the gross structure 148 (Scheme 24) for the former alkaloid. It showed a typical AB part ( T 3.45, lH, d, C-14-H; 3.65, l H , q, C-15-H) of an ABX pattern (J14,15 = 9.3, J,,,, = 5.5, J,,,, 0.7 H z ) ; a singlet at r 4.45, lH, C-12-H; a triplet a t r 6.18, lH, C-7-H; a complex multiplet in the region r 7.0-7.7 (4H) in which could be discerned (reference to structure 147) C-Sa-H a t r 7.52, l H , g, J8a,8B= 9.5,
-
147
JBcr,,= 4.5 Hz; another complex multiplet a t r 8.0-8.5 (5H) in which appeared the C-SP-H at r 8.25, l H , d, J8a,8B= 9.5Hz; and finally a singlet at r 6.77 representing the OCH, function. Importantly, a quintuplet at r 6.38 was recognized as the X portion of an A,B,X system (JAB J B x )and therefore assigned to a proton in the environment -CH,-CH(0-)CH,-. On this basis the methoxyl group N
482
V. SNIECKUS
could be assigned the C-4 or C-5 location in phyllanthine 148. Double irradiation studies provided some evidence for the C,-OCH, assignment. Reference to the NMR spectra of securinine and allosecurinine (Section 11, E) led to the distinction of two broad zones at T 7.1-7.6 for the three protons (C-6-H,, C-2-H) next to nitrogen and at T 8.0-8.5
D CH,O
H
H
CH,O
149 Cm=C13 150
148
I
151
I
LiAIH4
Zn, HaS04
q
L
i
A
CH,O
l
'H
H
4
&
q
fI
$
/
C H 3 0 'H
H
CH,O
H 152
153
154
SCHEME 24. Assignment of relative configuration of phyllanthine (148) (4lo).
for the remaining protons in the piperidine ring. If in fact this analysis is correct and the methoxyl group is located at C-4, then irradiation at T 6.38 should simplify the T 8.0-8.5 region. This was observed and thus phyllanthine could be assigned structure 148 without stereochemical implications ( H a ) . The assignment of the relative stereochemistry of phyllanthine was effected by first noting that this alkaloid undergoes with equal facility degradation reactions already applied to securinine (Section 11, A, 1) and allosecurinine (Section 11,D, 1). Thus catalytic hydrogenation of phyllanthine gave besides the dihydro (149) and tetrahydro (150) derivatives, a 2207, yield of a lactam-carbinol (151) (mp 197-198"; [a],,+32") (Scheme 24). Metal hydride reduction of compound 151 gave the quinolizidine 154 which showed in its I R spectrum a strong absorption at 3503 cm-l but no bands in the 2800-2600 cm-l region.
11. THE SECURINEQA ALKALOIDS
483
By reference to degradative work of Horii and collaborators (Section 11, A, 2) these spectral data were only compatible with a cis C-lla-HC-llb-OH structure, 154. On this basis phyllanthine should possess a securinine-type (trans C-2-H-C-9-lactone oxygen) arrangement as indicated and not the allosecurinine (cis C-2-H-C-9 lactone oxygen) structure. It was also observed that the relative rate of methiodide formation of allosecurinine is about 8 times faster than that for phyllanthine ( H a ) but previous discussion (Section 11,G) deems tenuous any stereochemical significance which would be placed on this result. Zinc-sulfuric acid treatment of phyllanthine gave the oily lactam 152 which could be reduced to the methoxybenzoquinolizidine 153 ([a]=+110"; picrate, mp 189-190"). Since the configuration of C-2 in
155
II
156
0 142
LiAlH4 (or LiAl(tBuO),H)
or Al(iPrO),, iPrOH Cf. Scheme 23
f
143
+
I --
1. CHJ, Ag,O, DMF 2. H o c H a c H a m z
Phyllanthine 148
cf. Scheme 23
144
145
I
146
SCHEME 25. Synthesis of racemic diasteriomeric methoxybenzoquinolizidines 145 and 146 by Parello (41a).
both 152 and 153 could not be established by NMR because of poorly resolved peaks, synthesis of the diasteriomeric compounds 145 and 146 was undertaken for possible direct comparison (Scheme 25). This work overlaps in part that carried out by Horii and associates in conjunction with determination of relative configuration of securitinine (Scheme 23). The benzoquinolizidine 142 was synthesized in four steps via compound 156 from isoquinoline (155) by a known procedure. In agreement with the results of Horii and Saito (Scheme 23) metal hydride reduction of 142 gave almost exclusively the equatorial amino alcohol 144 while Meerwein-Ponndorf-Verley reduction produced a mixture of the equatorial (144) and axial (143) amino alcohols. Parello established the configurations of the two racemic alcohols by application of I R and NMR spectroscopy in the manner already discussed in
484
V. SNIECKUS
connection with the work of Horii and Saito on securitinine (Section 11,I). Moreover, there was good agreement in the physical and spectral data on compounds 143 and 144 synthesized in the two laboratories. Finally, methylation of 143 and 144 gave quaternary ammonium derivatives but these, when refluxed in ethanolamine, produced the diasteriomeric methoxybenzoquinolizidines 145 and 146, respectively. Racemic 145 was found to be identical by I R spectral comparison with optically active 153 obtained from phyllanthine (148, Scheme 24) thus establishing unambiguously the position of the methoxyl group at C-4 and the cis-C-4-OCH3-C-2-H stereochemistry in the alkaloid. Since, as will be shown, the methoxybenzoquinolizidines 153 and 145 (Section 11, I) should be related as enantiomers, it is interesting to compare molecular rotation values for the two compounds: 153, [.ID + 110"; 145, [elD- 89.5". The lower value for 145 may indicate that the zinc-sulfuric acid degradation reaction does not proceed without some racemization. Information on the absolute configuration of phyllanthine was obtained by comparison of CD curves of phyllanthine and its hydrochloride with those of securinine and securinine hydrochloride. Like securinine (Section 11,A, 4), phyllanthine showed a negative rotation ([a]gO- 898") and Cotton effect [d324-3,, - 13.6 (dioxane)]. Likewise, its hydrochloride exhibited a strong negative Cotton effect (A€,,, - 25.0). Making the reasonable assumption that the C-4-0CH3 does not contribute significantly to the CD absorption, these results permit the conclusion that phyllanthine possesses the same absolute configuration at C-2, C-7, and C-9 as does securinine. Taking into account the cis C-4-OCH3-C-2-H relationship, phyllanthine may thus be represented by the 2R,,7S,9S absolute configuration (148, Scheme 24), showing that it is a diasteriomer of securitinine (137a, Scheme 23) (41~).
K. SECURINOL A, B, AND C Trimethylsilylation of the mother liquor from the securinine crystallization obtained from Securinegu suffruticosu followed by gas-liquid chromotography (GLC)revealed, aside from peaks due to allosecurinine and dihydrosecurinine, a new peak which was not observed in the GLC of the original mother liquor and which thus suggested the presence of hydroxylated alkaloids ( 5 7 ) .Further separation led to the isolation of three alkaloids, securinol A, B, and C, whose structures were elucidated by combination spectral and degradative methods (57, 58). These alkaloids turn out to be ring C hydroxylated derivatives of the securin-
11.
485
THE SECURINEGA ALKALOIDS
ine type and, as such, may be suspected of being artifacts. Whether or not this is the case has not been conclusively established. 1. Securinol A
Securinol A showed IR, UV, and NMR spectral features which suggested that it possesses a dihydrosecurinine skeleton (57). I n addition, a broad peak at 3625 cm-l in its I R spectrum measured in dilute carbon tetrachloride solution together with a multiplet at T 5.75
\
(lH, CEO-)
and an exchangeable proton at T 7.14 in its NMR spectrum
/ was evidence that the additional oxygen in securinol A was present as a secondary hydroxyl function. Treatment of securinol A with methanesulfonyl chloride in pyridine gave viroallosecurinine (Section 11,H) which was shown by direct comparison to be identical with the natural product. This information established that securinol A possesses a dihydrosecurinine-type structure and absolute stereochemistry containing a hydroxyl group at C-14 or C-15. 0 \\
m/e 191
H H 157
158
159
Further interpretation of the NMR and mass spectra coupled with the preceding information led to the assignment of structure and stereochemistry 157 for securinol A. The signal at T 5.75 in securinol A, predictably shifted to T 4.39 in its 3,5-dinitrobenzoate derivative, could be analyzed as two triplets representing a proton within the \
\
CHCEJ (OR)CH2-
system, thus suggesting the location of the
/ hydroxyl group at C-15 in the alkaloid. On the basis of a first-order analysis, J14a,15 J,,,, 3 H z and J144,15 = 8 Hz, thus suggesting that the hydroxyl group is equatorially oriented. Application of Brewster's benzoate rule to securinol A and its 3,fi-dinitrobenzoate indicated the S-configuration a t C-15, thus supporting the assignment of an equatorial hydroxyl function. N
N
486
V. SNIECKUS
Comparison of the mass spectrum of securinol A with that of securinine (Section 11,C) showed the presence of a common peak a t mle 84 as expected for a bare tetrahydropyridinium ion. The most important peak in securinol A was observed a t m/e 191 (m* 155.2) assignable to the ion 159 formed by loss of CH,=CHOH. The presence of an m/e 44 peak in securinol A and its absence in securinine and dihydrosecurinine gave assurance that the ion a t m/e 191 was not due to loss of CO,. Reference to literature examples leads to the most reasonable interpretation of this fragmentation as shown (158 +-159) and thus fully supports the assignment of a C-15-OH function in securinol A (157) which may now be named 14,15-dihydroviroallosecurinin-15a-o1. 2. Securinol B
Securinol B showed IR,NMR, and mass spectral data essentially identical with those of securinol A, thus suggesting that the two alkaloids are stereoisomers of one another (57).Furthermore, the NMR spectrum of securinol B showed a one-proton triplet a t T 4.34 ( J 1.5 Hz) attributable to the olefinic (3-12 proton coupled to the two allylic (3-14 protons. Treatment of securinol B with methanesulfonyl chloride in pyridine solution provided a mesylate derivative which upon refluxing in collidine gave viroallosecurinine (Section 11, H). These results indicate that securinol B is an C-15-OH epimer of securinol A (157) and may be represented as 14,15-dihydroviroallosecurinin-15~01 (160) (58). N
&
0
H,
H H
OS0,CH3
------L
Hd 160
161
162
Detailed examination of the NMR spectrum of securinol B (160) and its mesylate led t o the conformational assignment for the alkaloid (58). The proton at C-15 in the mesylate derivative appeared as an octet ( J = 9.5, 5 , and 2 Hz). The small J ( = 2 Hz) could be ascribed t o a long-range " W-type" coupling between the C-15 and C-Sex, protons similar to the one observed in dihydrosecurinine (Section 11,E). Two possible conformations of ring C, 161 and 162, can be constructed for securinol B mesylate both of which could be expected to exhibit this
11.
THE SECURINEGA ALKALOIDS
487
" W-type " coupling. However, conformation 161 does-not explain the observed large diaxial coupling (J = 9 . 5 H z ) whereas the semiboat ring C conformation 162 satisfies both this diaxial coupling ( J 1 5 , 1 4 4 9.5 H z ) as well as the smaller couplings (J15,,,, = 5 and J 1 5 . 7 = 2 Hz). Since the signal a t T 6.20 in the NMR spectrum of securinol B (160) assigned to C-15-H appeared as a broad multiplet ( w ~ >, ~15 Hz) it is reasonably concluded that the C- 15-OH group is equatorially oriented in the alkaloid.
3. Securinol C
Securinol C, isomeric with both securinol A and B (57), exhibited
IR,UV, and NMR spectra consistent with a hydroxylated dihydrosecurinine formulation (58). Treatment of securinol C with methanesulfonyl chloride in pyridine gave allosecurinine (Section 11, D). Thus securinol C is a 14,15-dihydroallosecurinine-typealkaloid with a hydroxyl group located at C-14 or C-15. The latter possibility (C-15OH) was excluded by showing that securinol C was not enantiomeric with either of the two possible 14,15-dihydroviroallosecurininealkaloids, securinol A and B. Further examination of the NMR and mass spectra of securinol C provided evidence for the assignment of structure and partial stereochemistry 163 to securinol C. 0
H 163
Comparison of the mass spectra of securinols A (Section 11, K, 1) and B with securinol C revealed that the very prominent m/e 191 peak due to CH,=CHOH loss from ring C in the former alkaloids is present to an insignificant extent in the case of securinol C. This observation constitutes additional evidence against locating the hydroxyl group at C-15 in securinol C. Furthermore, the NMR signal at 7 4.27 (lH), assigned to C-12-H, appears as a broad singlet supporting the expected allylic coupling with C-14-H in structure 163. Finally, the larger coupling constants (J = 9.5, 4 Hz) within the quartet at T 5.55 ( l H ,
\
CBO-)
/
demonstrates that the C- 1&OH function is equatorially
488
V. SNIECKUS
oriented. Thus the structure and stereochemistry expressed by 163 may be written for securinol C, the remaining uncertainty being the configuration of the C-14-OH group which can be a or p depending on whether ring C exists as a chair or boat conformation. It may be noted that the rates of loss of methanesulfonic acid from securinols A, B, and C appear to be different, being more facile for securinols A and C (pyridine, steam bath) than for securinol B (collidine, reflux) (57, 58). However, without quantitative data it is difficult to offer an explanation for these differences based on stereochemical arguments.
L. ALKALOIDS OF UNDETERMINED STRUCTURE 1. Phyllanthidine
Phyllanthidine, together with phyllanthine (Section 11, J),represents the minor alkaloid constituents isolated from Phyllanthus discoides (56). Phyllantidine is a colorless compound which shows no OH absorption but bands a t 1825, 1785, and 1775 cm-l in its I R spectrum, thus indicating the presence of a a,/?-unsaturated lactone system. Its UV spectrum [258 (log E 4.20) mp, unaffected by acid or base] and its NMR spectrum point to the presence of a O=&-CH=C(R,)CH= CH-C(H)R,R, unit while its mass spectrum shows close similarity to those of securinine and allosecurinine. The absence of high-wavelength absorption in the UV spectrum may indicate that phyllanthidine does not possess a tertiary nitrogen function in close proximity to the conjugated system. Subsequent to the isolation work (56), it was briefly reported ( 4 l a )that phyllanthidine appears to be identical with a compound obtained by hydrogen peroxide oxidation of allosecurinine. This leads one to suspect that phyllanthidine may possess a 1,2oxazolactone-type structure analogous to one obtained from the peracid oxidation of virosecurinine (Section 11,F, 3) and therefore that it may be an artifact formed during alkaloid isolation.* 2 . Suffruticodine
Treatment of the mother liquor from securinine crystallization from Securinega suflruticosa with 10% sulfuric acid followed by ether extrac*This suspicion has been confirmed in so far as the structure is concerned: Z. Horii, T. Imanishi, M. Yarnauchi, M. Hanaoka, J. Parello, and S. Munavalli, Tett. Lett. 1877 (1972).
11. THE
SECURINEGA ALKALOIDS
489
tion gave suffruticodine (59). It was shown t o be optically inactive and to possess I R absorption bands at 3048, 1756, and 1636 cm-l assigned to OH or NH, C=O, and C=C functions, respectively. A very unlikely structure was proposed (37) for suffruticodine by a different group of workers on the basis of biogenetic considerations. 3. Suffruticonine Basification (pH 8.5) of the acid mother liquor from the suffruticodine isolation above gave suffruticonine (59). Like suffruticodine, it was also found to be optically inactive and to exhibit bands at 3050 (OH or NH), 1773 (C=O), and 1655 (C=C) cm-l in its I R spectrum. 111. Norsecurinine-Type Alkaloids
A. NORSECURININE 1. Skeletal Structure
Iketubosin and Mathiesen isolated an alkaloid (Cl2H,,NO2) from
Securinega virosa Baill. of Nigerian origin which they brilliantly elucidated to be a lower ring A homolog of securinine represented by structure 164 (Scheme 26) solely on the basis of spectral evidence. The name norsecurinine was thus given to the alkaloid (60). Somewhat later, Saito and co-workers isolated (61)the same alkaloid from S. virosa Pax. et Hoffm. native to Formosa and by chemical degradation as well as ORD studies established (62) the absolute configuration of norsecurinine , I n contrast to the securinine-type alkaloids, which were stable highly crystalline compounds, norsecurinine polymerized readily upon removal of solvent from chromatographic separation (62). It could, however, be purified as its stable hydrochloride from which the free base could be regenerated and handled for short periods of time. Norsecurinine showed I R absorption at 1802, 1770, and 1640 cm-l and features in the NMR spectrum which were fully compatible with an a,jI,y,&unsaturated y-lactone unit. Interestingly, the UV spectrum showed maxima at 255.5 (log E 4.42) and 256.5 (log E 4.42) mp in ethanol solution and no long-wavelength absorption of the type associated with the securinine alkaloids (Table IV). However, a long-wavelength, low-extinction absorption was observed in hexane and dioxane solutions 2.59) mp (60, 62). Iketubosin and Mathieson recorded at 308 (log E - 19.5" in ethanol (60), whereas the Japanese group observed N
490
V. SNIECKUS
166
165
164
I
I
ichromatog.
dZ
Zn, H2S04, EtOH
168
j.
170
169
171
SCHEME 26. Determination of the skeletal structure of norsecurinine (164) by Saito et al. (62).
in the same solvent (62).The low molecular rotation value observed by Iketubosin and Mathieson is undoubtedly due to polymerization of the sample occurring under the conditions of the measurement. The mass spectrum of norsecurinine showed peaks at m/e 203 (M+), 157, 134, 106, 78, 70, and 69 (60). By high resolution, the exact mass of the peaks at m/e 134 (C,H,O,+), 106 (C,H,O+), 78 (C6H6+), and 70 (C4H,N+) was determined. These results in conjunction with reasonable fragmentation modes could be taken as evidence for a structure possessing a pyrrolidine but not a piperidine ring. Although two structures (164 and 164 with N, and Cz interchanged) are possible, the NMR spectrum of norsecurinine could be interpreted only in terms of structure 164. Aside from a singlet at T 4.3 (lH, H-12), a sextet at T 3-3.6 (2H, H-14, H-15) and a triplet at 7 6.37 ( l H , H-7, J7,14 0.5, J,,,, 6 Hz) could be interpreted as a typical ABX pattern. Furthermore, part of a multiplet at 7 7.2-7.8 (2H) could be assigned to H-8a (J8a,, 0.5, J8a,84 11 Hz). The geminal coupling, J8a,84, could be extracted from the high-field multiplet at T 7.8-8.6 which also contain [a]gO- 272"
-
-
N
11.
THE SECURINEGA ALKALOIDS
491
absorption due to the C-3 and C-4 methylene protons. On the basis of expected shielding, one of the protons in the C-5 methylene was thought to absorb in the r 7.2-7.8 region while C-2-H and the other C-5 proton were assigned to a multiplet at r 6.6-7.1 (60). Using degradative and synthetic sequences which had served so admirably in the structural elucidation of securinine, the Japanese workers were able to confirm fully (Scheme 26) (62) the basic skeletal structure proposed by Iketubosin and Mathieson. Reduction with sodium borohydride gave dihydronorsecurinine ( 165) whose structure was evident from the I R (1820, 1750, 1640 cm-l) and UV [214 (log E 4.16) mp] spectra. Furthermore, this compound was also isolated from the plant (Section 111, C). Catalytic hydrogenation of 164 gave a mixture of the hydroxy ester 166 and the saturated lactone 167. The structure of compound 166 was assigned on the basis of spectral data. The presence of compound 167 was noted by an I R absorption at 1790 cm-l, but this compound could not be isolated since it was transformed upon chromatography into the hydroxy amino acid 168. Reduction of norsecurinine with zinc and sulfuric acid gave the oily lactam 169 which was extremely unstable and thus was immediately converted into the hexahydropyrrolo[2, l-alisoquinoline 170. This rearrangement was predicted from the previous results of the same reaction effected on securinine and related alkaloids (e.g., Section 11, A, 1) and was confirmed by synthesis of compound 170 from the pyrrolidinone 171 in two steps. Thus the skeletal structure 164 of norsecurinine as originally proposed (60) was fully confirmed (62). 2. Relative and Absolute Configuration Extensive degradative work culminated in the assignment of absolute configuration 164a t.0 norsecurinine (Scheme 27) (62, 63). The initial attempt to correlate the stereochemistry of norsecurinine with that of securinine or its stereoisomeric alkaloids by attempting to effect a ring expansion of ring A failed. Thus von Braun reaction of dihydronorsecurinine 165a resulted in ring B rather than the desired ring A cleavage to give the bromocyanide 172 in high yield. The structure of 172 was supported by its NMR spectrum which showed a multiplet at r 5.9 (1H) due t o the a-bromo (C-7) proton. The undesired result notwithstanding, compound 172 was converted into lactam 173 in four steps. Lactam 132 was found to be different from the compound produced by hydrogenation of lactam 67 (Scheme 11) obtained from securinine. Fortunately, von Braun degradation of pyrroloisoquinoline 170a
1. NaCN, DMSO, 75-80"
1. LiA1H4, THB 2.
H 175
03,
2. 12% HCI 3. HC1 gas, EtOH 4. 190-200"
10% HC1
t
aH 0
H 172
165a
173
NaBH,
4
&
c
0
1. Zn, H,S04
BrCN CHCI,
___+
N , '
2. LiAlH,
__j
\
NCN
\
H
H
170a
174
H 164a
Br
I
1. NaCN, DMSO 2. Conc. HC1, dioxane 3. HC1 gas, CH,OH 4. 150-160° 5. LiAIH,, EtaO
SCHEME 27. Determination of the absolute configuration of norsecurinine (164a) (62).
57
11.
THE SECURINEUA ALKALOIDS
493
obtained from norsecurinine (Scheme 26) gave the bromocyanide 174 which was readily transformed to the benzoquinolizidine 57. This compound was found to be identical with an authentic sample of R-( + )-1,3,4,6,7,1lb-hexahydro-2H-benzo[a]quinolizidineobtained from securinine (Scheme 10) by comparison of I R and ORD spectra of the bases as well as by mixture melting point determination of their perchlorates. Clearly, the absolute configuration at C-2 of norsecurinine corresponds to the R-form, the same as that at C-2 of securinine. ORD studies on norsecurinine and the a-ketol 175 derived for dihydronorsecurinine (165a) as shown in Scheme 27 established the S absolute configuration at C-9 for the alkaloid. I n studies of securinine alkaloids it was observed that the sign of the Cotton effects as well as the CD maxima near 250-255 mp depends on the skewness of the transoid diene with respect to the lactone function, and it was concluded that a negative Cotton effect and CD maximum near 250 mp indicates S absolute configuration for C-9 (Section 11, A, 4). Norsecurinine shows a strong negative Cotton effect and CD maximum at 255 mp which indicates that it also possesses S absolute configuration at C-9. Confirmation for this assignment was obtained by observing that the ORD curves of the a-ketol from securinine (17a, Scheme 10) showed negative Cotton effects. Application of the octant rule to 175 led to the same conclusion, and thus it was fully established that the absolute stereochemistry of norsecurinine is represented by structure 164a. The results above readily lent themselves to interpreting the stereochemical consequences of a further degradative scheme carried out on norsecurinine (Scheme 28) (62). This sequence was again based on a study effected on securinine (Schemes 1 and 3) and yielded analogous results. Reduction of norsecurinine (164a) with aluminum amalgam gave the unconjugated amine 176 which upon hydrogenation under two different conditions produced the pyrroloisoquinoline-lactams A (177) and B (178). Reference to results obtained with securinine (Section 11,A, 2) led to the conclusion that these two lactams are epimeric a t C-6a. Upon metal hydride reduction they yielded compounds designated as pyrroloisoquinoline A (179) and B (180), respectively. The I R spectrum of pyrroloisoquinoline A (179) showed Bohlmann bands at 2778 and 2715 cm-l but no band due to intramolecularly hydrogen-bonded hydroxyl group, while the I R spectrum of pyrroloisoquinoline B (180)showed no Bohlmann bands but a band at 3560 em-' due to intramolecular hydrogen bonding. Of the four theoretically possible diasteriomers of the dodecahydropyrrolo[2,l-a]isoquinolin10a-ol system only two possibilities will explain these I R data: either pyrroloisoquinoline A is represented by structure 179a and B by 180a or pyrroloisoquinoline A possesses structure 179b and B has structure
C F p /
LiAlH A
Raney Ni, HZ.
,:i3
THF
0
*
177
179
178
180
H 164a
176 0.
I
H cis-syn-trans 179a
trans-syn-cis 180a
trans-syn-trans 179b
SCHEME 28. Degradative proof of relative configuration of norsecurinine (164a)(62).
I
\
cis-syn-cis 180b
11.
THE SEGURINEGA ALKALOIDS
495
180b. The former combination is more reasonable because conformation 179b has a central boat form which would make it of lower thermodynamic stability than conformation 1179a. This analysis leads to the conclusion that the relative configuration of the C-lOa-OH and C-lob-H in pyrroloisoquinoline A and B is cis and therefore that the relative configuration of the C-2-H and C-9 lactone oxygen in norsecurinine is trans, in full agreement with the previously assigned absolute configuration 164a. Although the conformation of ring A was not determined, the previously recorded UV evidence indicates very weak if any transannular interaction between the nitrogen lone pair and the ring C/D conjugated system. Examination of models shows that a trans arrangement is quite prohibitive owing to strain, and yet it is not obvious in the corresponding cis arrangement why long-wavelength absorption should not be observed. Thus this point requires further investigation.
B. ANTIPODAL NORSECURININE Rouffiac and Parello (64) isolated from Phyllanthus niruri L. an alkaloid as yet unnamed whose NMR and mass spectra are identical with those of norsecurinine (Section 111,A) and to which solely on the basis of physical and spectral data has been assigned the optical antipode structure of norsecurinine (164a).
C. DIHYDRONORSECURININE Saito and co-workers isolated an alkaloid from the roots of Securinega wirosa which they originally called virosine (53).It was later renamed dihydronorsecurinine to avoid confusion (see footnote e, in Table I) (61). Dihydronorsecurinine was shown to be identical with the sodium borohydride reduction product of norsecurinine (Section 111,A). Since the absolute configuration of the latter has been established, the structure and absolute stereochemistry of dihydronorsecurinine is fully represented by formula 165a (Scheme 27) (62).
IV. Synthesis* The necessity to establish structures of key products by synthesis in the early degradation studies on securinine (Section 11, A, 1) provided a large part of the stimulus and direction in the planning of a *A synthesis of 2-episecuritinine has been reported recently: Z. Horii, T. Imanishi, M. Hanaoke, and C. Iwata, Chem. Pharm. Bull. 20, 1774 (1972)
496
V. SNIECKUS
total synthesis of the alkaloid. The additional impetus for developing a total synthesis came from the early observation that securinine possesses a clinically useful strychnine-like activity (Section V). Thus in 1963, only one year after the structure elucidation was announced by Horii and co-workers, a partial synthesis of securinine in which the reconstitution of the 6-azabicyclo[3,2,l]octaneskeleton (bridging of rings A and B) was announced by the same group (65).This was followed in short order by reports on the synthesis of tricyclic degradation products of securinine possessing the full skeleton of the natural product but lacking the ring A to B bridge (27, 66). Finally, the Japanese workers climaxed their intense efforts in a total synthesis of racemic securinine (67, 68). A unique aspect and a welcome side benefit of this work, which is available in detail (69),is that resolution of the racemic product provided not only securinine but obviously also its antipode which happens to be virosecurinine! A partial synthesis of dihydrosecurinine using previously developed methods for fused butenolide ring formation has been described (70). Undoubtedly owing to the potentially beneficial biological activity of the securinine alkaloids (Section V) most of the synthetic work has been covered by patents (71, 72).
A. TOTALSYNTHESIS OF SECURININE AND VIROSECURININE The total synthesis of securinine (and virosecurinine) formally involved the following stages; (a) formation of the ring A/C unit 181; (b) transformation of 181 into the tricyclic lactone 182; and (c) ring closure of 182 to the racemic alkaloid 183 (69).
A C
181
182
H
183
Treatment of the monoketal of cyclohexan-1,2-dione 36 with 2pyridyllithium, a reaction used previously in conjunction with the synthesis of a degradation product (Scheme 5), gave in 66y0yield the alcohol 37 which upon hydrogenation followed by hydrolysis and acetylation yielded the two diasteriomeric a-ketols 184 and 185
11. THE SEGURINEGA ALKALOIDS
497
(Scheme 29). The a-ketol 184 was found to be identical by I R spectral comparison with a degradation product of securinine. Attempts to effect condensation of 184 with diketene, ethyl acetoacetate, ethyl cyanoacetate, diethyl malonate, and triethyl phosphonoacetate failed. However, treatment with lithium ethoxyacetylene proceeded smoothly to give the diol 186 which was not isolated but subjected to the acidic conditions known to effect the rearrangement of the newly added function to an a$-unsaturated ester. This reaction gave the butenolide 187 and the hydroxylactone 188 in 50y0and 217, yields, respectively. The yield of the butenolide 187 could be augmented by its synthesis from 188. Compound 187 was found to be identical with another degradation product of securinine (13; N-acetate, Scheme 1) by comparison of their I R spectra. Incidentally, a similar reaction sequence on 185 provided the C-2 epimeric butenolide and hydroxylactone corresponding to structures 187 and 188, respectively, the former of which proved to be identical by I R spectral comparison with a degradation product (99, Scheme 15) of allosecurinine. Allylic functionalization of 187 could not be effected under a variety of conditions (e.g., N-bromosuccinimide, lead tetraacetate, selenium dioxide), nor could an additional double bond be introduced under dehydrogenation conditions (e.g., chloranil). Osmium tetroxide was ineffective in hydroxylation of 187; however, potassium permanganate treatment gave the diol 189 although in only 5.5y0 yield [originally reported as 33y0 (@')I. Compound 189 could be converted into 190 again in low yield (4.507,). The latter was shown to be identical with yet another degradation product (68, Scheme 11) of securinine by comparison of IR spectra and GLC behavior. The sequence 187 + 189 -+190 was obviously unsatisfactory and a more efficient method for the preparation of 190 was sought. Bromination of 184 gave the a-bromoketone 191 which upon dehydrobromination under standard conditions gave the a,P-unsaturated ketone 192 whose structure was assigned on the basis of I R and NMR spectral data. The previously developed efficient butenolide synthesis was applied to 192 to yield the desired unsaturated butenolide 190 and the hydroxylactone 193 in 37Y0 and 4y0 overall yield, respectively, from 184. With compound 190 in hand in reasonable amount the stage was set for attempting to effect the construction of ring B of securinine. Deacetylation of 190 followed by formylation and allylic bromination gave the N-formyl bromide 194 in moderate overall yield. Compound 194 upon acid hydrolysis followed by base treatment gave dl-securinine (27), the last step unfortunately proceeding in only 7.5y0 yield. The
36
37
AC
A0
184
185
I. LiC=COEt. EtlO, -30’ 2 . 15% HzSO., HsO-THF
194
190
193
195
12
20% HCI 1 2 . K,COo 1.
27
SCHEME 29. Total synthesis of securinine (27) by Horii et al. (69).
498
11.
THE SECURINEGA ALKALOIDS
499
identity of the synthetic material and natural securinine was established by comparison of their I R and UV spectra. Resolution of the racemic product with d-camphor-10-sulfonic acid gave natural l-securinine and virosecurinine (d-securinine), thus completing the total synthesis of both alkaloids. An alternative partial synthesis of securinine was also developed by Horii and co-workers (65, 69). The unconjugated lactone 12 available from a key degradation of the alkaloid (Scheme 1) gave upon bromination a 7101, yield of the dibromide 195 which upon basic treatment yielded natural securinine (27)in 15% yield. It may be envisaged that this short route could provide a new relay stage for the total synthesis of the alkaloid. The synthetic work above on the securinine-type alkaloids carried out to date has been directed mainly along one particular avenue of approach. I n view of the intrinsically interesting structure and potentially useful biological activity of these alkaloids other synthetic attacks are to be expected particularly since new and intriguing methods for construction of the 6-azabicyclo[3,2,lloctane skeleton are being rapidly developed (73, 74). Synthetic work on the corresponding norsecurinine alkaloids has not as yet appeared.
B. PARTIAL SYNTHESIS OF DIHYDROSECURININE The two-step preparation of fused butenolides used in the synthesis of securinine (Scheme 29) was generalized and further applied to the partial synthesis of dihydrosecurinine (70).The a-ketol17a (Scheme 10) obtained from degradation of dihydrosecurinine was treated with lithium ethoxyacetylide and the resulting crude product refluxed with sulfuric acid to give, in 25y0 overall yield, dihydrosecurinine (70) shown to be identical with the natural product (Section 11,B) by IR spectral and GLC comparison.
V. Biological Activity The first biological screening of securinine and its derivatives was carried out in Russia soon after the discovery of the alkaloid. Turova and Aleshkina reported that securinine nitrate is a central nervous system (CNS) stimulant similar to strychnine but possessing lower toxicity (75). They found that this derivative when administered in
500
V. SNIECKUS
nontoxic doses raises muscle tonus, stimulates respiration, strengthens cardiac contraction, and raises blood pressure (75), and they stated that it is useful in the treatment of paresis, paralysis following infectious disease, and psychical disorders (76). Almost simultaneously, similar results were reported by Bobokhodzhaev (77). There followed experiments designed to test the effectiveness of securinine as an antiradiation agent (78),inhibitor of the acetyl CoA-acetylcholinesterase system ( 7 9 ) ,and for some miscellaneous purposes (80, 81) mainly but not exclusively carried out on pure alkaloid samples from Securinega species. Comparison of the CNS activity of securinine and allosecurinine has shown that the latter alkaloid possesses a lower toxicity (82).Finally, securitinine has been tested as an anticancer agent (83). Most of these results appear to be of a preliminary nature and require confirmation and extension in order to develop these alkaloids for beneficial purposes.
VI. Analytical Methods The potential pharmacological properties of securinine alkaloids (Section V) no doubt are responsible for the development of techniques suitable for both rapid and exact analysis of these alkaloids (Table V) (84-94). A number of other papers have dealt with determination of the most effective methods for alkaloid extraction (86, 95, 96).
VII. Biosynthesis Since no experiments with labeled precursors have been carried out the biosynthetic routes traveled by the Securinega alkaloids are unknown. On the other hand, a substantial amount of work has been expended in determining the effects of factors such as age, climatic conditions, and geographic location on the growth rate and localization of these alkaloids. Thus fifty species of the genus Securinega have been screened for securinine content, and from these it was found that S. durissima, S. obovata, and S. suffruticosa contain 0.0i’-0.2270 of securinine and are most suitable for growing purposes (21). Studies on S. suffruticosa grown in Poland have shown that the highest securinine content (0.26%) is found in the flowering plant, the lowest (0.0870) during fruit formation, and that it increases again after the latter stage at which time the plant may be conveniently harvested (97, 98). It was also discovered that sex and age of this species have no effect on
TABLE V
ANALYTICALMETHODSFOR SECTJRININE DETERMINATION Method Colorimetric m 0
F
Spectrophotometric Microcrystalline reactions (qualitative) Polarimetric Titrimetry Thin-layer chromatography Hydroxylamine-sulfanilic acid Not available
Sample Pure alkaloid Securinine nitrate in medicinal preparations Raw plant material Securinine nitrate in medicinal preparations, tablets Securinine nitrate Raw plant material Raw plant material Biological material Raw plant material S. suffruticosa tablets
Refs. 84
85 86 85,87 88, 89 90 91 92 93 94
502
V. SNIECKUS
the alkaloid content (97). I n contradication to one of these results (98),other workers have stated that securinine content in S. suffruticosa grown in Tashkent is maximized (0.58-0.8470 of dry weight of leaves) in the flowering and fruit-bearing stages (6).It should be noted, however, that the studies were carried out in two different regions. Two other miscellaneous but related reports may be noted (99, 100). The only investigations which have some bearing, however slight, on the question of biosynthesis have been concerned with the effects of amino acids added to S. suffruticosa plants grown in a sterile agar nutrient medium (101, 102). Feeding of trytophan, phenylalanine, tyrosine, and methionine resulted in an increased crop yield. The conclusion (101) that these amino acids are involved in the biosynthesis of Securinega alkaloids is obviously unjustified without labeled precursor studies. I n the other investigation (108), arginine, lysine, and nicotinic acid were administered to S. suffruticosa. It was found that securinine content was highest (a) in leaves in the experiments with arginine; (b) in the roots with lysine; and (c) in stems when nicotinic acid was administered. I n spite of the intriguing skeletal structure of the Securinega alkaloids chemists have not yielded, with one exception (37), to the temptation of biogenetic speculation in the literature. Perhaps this speaks for the inability to write any one entirely convincing biogenetic scheme for this group or the increased awareness of the literature pollution problem. REFERENCES 1. J. J. Willaman and H.-L. Li, Lloydia 33, No. 3A, Suppl. (1970). 2. R. A. Raffauf, “A Handbook of Alkaloids and Alkaloid-Containing Plants.” Wiley (Interscience), New York, 1970. 3. V. A. Snieckus, in “Specialist Periodical Reports on Alkaloids” (J. E. Saxton, ed.), Vol. 1, p. 456. Chemical Society, London, 1971. 4. 0. E. Edwards, in “Specialist Periodical Reports on Alkaloids” (J.E. Saxton, ed.), Vol. 1, p. 343. Chemical Society, London, 1971. 5. T. R. Govindachari, S. J. Jadhav, B. S. Joshi, V. N. Kamat, P. A. Mohamed, P. C. Parthasarathy, S. J. Patankar, D. Prakash, D. F. Rane, and N. Viswanathan, Indian J . Chem. 7,308 (1969). 6. S. V. Teslov and M. Mukhitdinov, T r . Tashkent. Farm. Inst. 3, 52 (1962); C A 60, 11050c (1964). 7. B. Anjaneyulu, Indian J . Chem. 3, 237 (1965). 8. S. K. Moitra, A. N. Ganguly, N. N. Chakravarti, and R. N. Adhya, Bull. Calcutta Bch. Trop. Med. 17, 80 (1969); C A 74, 997h (1971). 9. V. A. Snieckus, in “Specialist Periodical Reports on Alkaloids” (J. E. Saxton, ed.), Vol. 1, p. 457. Chemical Society, London, 1971; Vol. 2. p. 275, 1972. 10. V. I. Murav’eva and A. I. Ban’kovskii, Dokl. Akud. Nauk SSSR 110, 998 (1956); C A 51, 8121a (1957); Proc. Acad. Sci. USSR, Chem. Sect. 110, 631 (1956); C A 52, 5441e (1958).
11.
THE SECURINEGA ALKALOIDS
503
11. V. I. Murav’eva and A. I. Ban’kovskii, Med. Prom. SSSR 10, 27 (1956); C A 50, 17335e (1956). 12. V. I. Murav’eva and A. I. Ban’kovskii, T r . Vses. Nauch.-Issled. Inst. Lek. Aromat. Rast. 12, 16 (1959); C A 55, 176788 (1961). 13. Z. Horii, T. Tanaka, Y. Tamura, S. Saito, C. Matsumura, and N. Sugimoto, J . Pharm. Soc. J a p . 83. 602 (1963); C A 59, 9087c (1963). 14. I. Satoda, M. Murayama, Y. Tsuji, and E. Yoshii, Tet. Lett. 1199 (1962). 15. R. Mukherjee, B. Das, V. P. Arya, and A. Chatterjee, Naturwiss. 50, 155 (1963). 16. J. Parello, A. Melera, and R. Goutarel, Bull. SOC.Chim. Pr. [5] 898 (1963). 17. C. W. L. Bevan, M. B. Patel, A. H. Rees, and D. A. H. Taylor, Chem. Ind. (London) 838 (1964). 18. S.-F. Chen, C.-H. Hsieh, and H.-T. Liang, Y a o Hsueh Hsueh Pao 10, 225 (1963); C A 59, 14039a (1963). 19. B. Borkowski, I. Frencel, and M. Niemczycka, Poznan. Tow. Przyj. N a u k , Wydz. Lek., Pr. Kom. Farm. 3, 115 (1965); C A 63, 7349f (1965). 20. 0. Clauder, G. Bojthe, I. Mathe, P. Sandor, and J. Varga, Acta Pharm. Hung. 38, 126 (1968); C A 69, 54266j (1968). 21. Z. Kowalewski, I. Frencel, I. Urszulak, and A. Filarowska, Ann. Pharm. (Poznan) 7, 99 (1969); C A 72, 63580w (1970). 22. Institut des Plantes MBdicinales et Aromatiques de l’U.R.S.S., F r . Pat. 291,526 (1962);C A 58, P416d (1963);B. K. Rostotskii, A. D. Kuzovkov, and 0. E. Lasskaya, U.S.S.R. Pat. 168,300 (1965); C A 62, P14427e (1965). 23. Z. Horii, Y. Tamura, N. Sugimoto, S. Saito, and K. Kodera, Jap. Pat. 24,861 (1963); C A 60, 42038 (1964). 24. Z. Horii, H. Hano, Y. Tamura, S. Saito, T. Iwamoto, and N. Sugimoto, J a p . Pat. 119 (1965); C A 62, P11869d (1965). 25. S. Saito, K. Kodera, N. Sugimoto, Z. Horii, and Y . Tamura, Chem. I n d . (London) 1652 (1962). 26. S. Saito, K. Kodera, N. Shigematsu, A. Ide, N. Sugimoto, Z. Horii, M. Hanaoka, Y. Yamawaki, and Y. Tamura, Tetrahedron 19, 2085 (1963). 27. Z. Horii, Y. Yamawaki, M. Hanaoka, Y. Tamura, S. Saito, and H. Yoshikawa, Chem. Pharm. Bull. 13, 22 (1965). 28. Z. Horii, M. Hanaoka, M. Ikeda, Y. Yamawaki, Y. Tamura, S. Saito, N. Shigematsu, and K. Kodera, Chem. Pharm. Bull. 13, 27 (1965). 29. Z. Horii, M. Ito, and M. Hanaoka, Chem. Pharm. Bull. 16, 1754 (1968). 30. Z. Horii, M. Ikeda, Y. Yamawaki, Y. Tamura, S. Saito, andK. Kodera, Tetrahedron 19, 2101 (1963). 31. Z. Horii, M. Ikeda, Y. Yamawaki, Y. Tamura, S. Saito, and K. Kodera, Chem. Pharm. Bull. 11, 817 (1963). 32. Z. Horii, M. Ikeda, Y. Tamura, S. Saito, M. Suzuki, and K. Kodera, Chem. Pharm. ’ Bull. 12, 1118 (1964). 33. S. Imado M. Shiro, and Z. Horii, Chem. Ind. (London) 1691 (1964); S. Imado, M. Shiro, and Z. Horii, Chem. Pharm. BuEl. 13, 643 (1965). 34. S. Saito, N. Shigematsu, and Z. Horii, J . Pharm. SOC. J a p . 83, 800 (1963);C A 59, 1553511 (1963). 35. T. Nakano, T. H. Yang, and S. Terao, J . Org. Chem. 29,3441 (1964). Chim. Pr. [5] 1552 (1968). 36. H.-E. Audier and J. Parello, Bull. SOC. 37. A. Chatterjee, R. Mukherjee, B. Das, and S. Ghosal, J . I n d i a n Chem. SOC.41, 163 (1964). 38. R. Mukherjee, B. Das, and A. Chatterjee, Indian J . Chem. 4, 459 (1966).
50 4
V. SNIECKUS
39. C. W. L. Bevan, M. B. Patel, and A. H. Rees, Chem. Ind. (London)2054 (1964). 40. Z. Horii, Y. Yamawaki, Y. Tamura, S. Saito, H. Yoshikawa, and K. Kodera, Chem. Pharm. Bull. 13, 1311 (1965). 41. C. Pascard-Billy, Bull. SOC. Chim. Fr. [5] 369 (1966). Chim. Fr. [5] 1117 (1968). 41%. J. Parello, Bull. SOC. 42. T. Nakano, T. H. Yang, and S. Terao, Chem. Ind. (London)1651 (1962). 43. T. Nakano, T. H. Yang, and S. Terao, Tetrahedron 19, 609 (1963). 44. T. Nakano, T. H. Yang, and S. Terao, Tet. Lett. 665 (1963). 45. T. Nakano, T. H. Yang, and S. Terao, J . Org. Chem. 28, 2619 (1963). 46. T. Nakano, S. Terao, K. H. Lee, Y. Saeki, and L. J. Durham, J . Org. Chem. 31, 2274 (1966). 47. A. C. Cope and E. R. Trumbull, Org. React. 11, 317 (1960). 48. S. Saito, K. Kodera, N. Shigematsu, A. Ide, Z. Horii, and Y. Tamura, Chem. Ind. (London)689 (1963). 49. P. Crabb6, “Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry.” pp. 282-283. Holden-Day, San Francisco, California, 1965. 50. T. Nakano, T. H. Yang, S. Terao, and L. J. Durham, Chem. Ind. (London) 1034 (1963). 51. T. Nakano, T. H. Yang, S. Terao, and L. J. Durham, Chem. Ind. (London) 1763 (1963). 52. S. Saito, T. Tanaka, T. Iwamoto, C. Matsumura, N. Sugimoto, Z. Horii, M. Makita, M. Ikeda, and Y. Tamura, J . Pharm. SOC.Jap. 84, 1126 (1964); C A 62, 5498d (1965). 53. S. Saito, T. Iwamoto, T. Tanaka, C. Matsumoto, N. Sugimoto, 2. Horii, and Y. Tamura, Chem. Ind. (London)1263 (1964). 54. Z. Horii, M. Ikeda. M. Hanaoka, M. Yamauchi, Y. Tamura, S Saito, T. Tanaka, K. Kodera, and N. Sugimoto, Chem. Pharm. Bull. 14, 917 (1966). 55. Z. Horii, M. Ikeda, M. Hanaoka, M. Yamauchi, Y. Tamura, S. Saito, T. Tanaka, K. Kodera, and N. Sugimoto, Chem. Pharm. Bull. 15, 1633 (1967). 56. J. Parello and S. Munavalli, C. R. Acad. Sci. 260, 337 (1965). 57. Z. Horii, M. Ikeda, Y. Tamura, S. Saito, K. Kodera, and T. Iwamoto, Chem. Pharm. Bull. 13, 1307 (1965). 58. Z. Horii, M. Yamauchi, M. Ikeda, and T. Momose, Chem. Pharm. Bull. 18, 2009 (1970). 59. V. I. Murav’eva and A. D. Kuzovkov, Zh. Obshch. Khim. 33, 693 (1963); C A 59, 2884h (1963). 60. G. 0. Iketubosin and D. W. Mathieson, J . Pharm. Pharmacol. 15, 810 (1963); C A 60, 4370d (1964). 61. S. Saito, T. Tanaka, K. Kodera, H. Nakai, N Sugimoto, Z. Horii, M. Ikeda, and Y. Tamura, Chem. Pharm. Bull. 12, 1520 (1964). 62. S. Saito. T. Tanaka, K. Kodera, H. Nakai, N. Sugimoto. Z. Horii, M. Ikeda, and Y. Tamura, Chem. Pharm. Bull. 13, 786 (1965). 63. S. Saito, T. Tanaka, K. Kodera, H. Nakai, N. Sugimoto, Z. Horii, M. Ikeda, and Y. Tamura, Chem. Pharm. Bull. 13, 614 (1965). 64. R. Rouffiac and J. Parello, Plant. Med. Phytother. 3, 220 (1969); C A 72, 32094m (1970). 65. S. Saito, N. Shigematsu, H. Yoshikawa, 2. Horii, and Y. Tamura, Chem. Pharm. Bull. 11, 1219 (1963). 66. Z. Horii, M. Hanaoka, Y. Tamura, S. Saito, and N. Sugimoto, Chem. Ind. (London) 664 (1964).
11. THE SECURINEGA
ALKALOIDS
505
67. S. Saito, H. Yoshikawa, Y. Sato, H. Nakai, N. Sugimoto, Z. Horii, M. Hanaoka, and Y. Tamura, Chem. Pharm. Bull. 14, 313 (1966). 68. Z. Horii, M. Hanaoka, Y. Tamura, S. Saito, and N. Sugimoto, Chem. Pharm. Bull. 14, 1059 (1966). 69. Z. Horii, M. Hanaoka, Y. Yamawaki, Y. Tamura. S. Saito, N. Shigematsu, K. Kodera, H. Yoshikawa, Y. Sato, H. Nakai, and N. Sugimoto, Tetrahedron 23, 1165 (1967). 70. Z. Horii, M. Ito, I. Minami, M. Yamauchi, M. Hanaoka, and T. Momose, Chem. Pharm. Bull. 18, 1967 (1970). 71. Z. Horii, Y. Tamura, S. Saito, N. Sugimoto, and N. Shigematsu, Jap. Pat. 5945 (1966); C A 65, P5502e (1966). 72. Z . Horii, Y. Tamura, S. Saito, N. Sugimoto, and N. Shigematsu, Jap. Pat. 2179 (1966); C A 64, PC15939d (1966). 73. R. Furstoss, P. Teissier, and B. Waegell, Chem. Commun. 384 (1970). 74. Y. L. Chow and R. A. Perry, Tet. Lett. 531 (1972);E. Flesia, A. Croatto, P. Tordo, and J.-M. Surzur, ibid. 535. 75. A. D. Turova and Ya. A. Aleshkina, Farmakol. Toksikol. (Moscow) 19, 11 (1956); C A 50, 17201a (1956). 76. A. D. Turova and Ya. A. Aleshkina, Med. Prom. SSSR 11, 54 (1957); C A 52, 6724a (1958). 77. I. Ya. Bobokhodzhaev, Parmakol. Toksikol. (Moscow) 19, Suppl., 3 (1956); C A 51, 10759c (1957). 78. V. D. Rogozkin and M. F. Sbitneva, Vop. Patog., Eksp. Ter. ProJil. Luchevoi Bolez. p. 147 (1960); C A 55, 202078 (1961). 79. S. L. Friess, R. C. Durant, E. R. Whitcomb, L. J. Reber, and W. C. Thommesen, Toxicol. Appl. Pharmacol. 3, 347 (1961); C A 55, 25053b (1961). 80. P. K. Dey, R. Roychoudhury, and M. Mukherjee, Naturwws. 52, 483 (1965). 81. N. Yoshii, K. Hano, and Y. Suzuki, Med. J . Osaka Univ. 15, 155 (1964); C A 65, 6138h (1966). 82. A. Quevauviller, 0. Foussard-Blanpin, and P. Bourrinet, Therapie 22, 302 (1967); C A 67, 102243. (1967). 83. E. M. Vermel and S. A. Kruglyak, Vop. Onkol. 8, 9 (1962);C A 58, 1824h (1963). 84. M. Aoki, Y. Ywayama, and T. Matsumura, Yakuzaigaku 25, 49 (1965); C A 65, 3671b (1966). 85. B. I. Shvydkii, R. M. Pinyazhko, and I. V. Borys, K h i m . Tekhnol. 88 (1969);from R e f . Zh., Khim. Abstr. No. 12G288 (1970); C A 75, 121447h (1971). 86. V. V. Mikhno, Farm. Zh. ( K i e v ) 20, 26 (1965); C A 64, 11029e (1966). 87. B. A. Krivut and M. E. Perel’son, Khim.-Farm. Zh. 1, 44 (1967); C A 67, 67617h (1967). 88. K. P. Lapina, Aptech. Delo 15, 47 (1966); C A 65, 12061d (1966). 89. V. T. Pozdnyakova and Yu. V. Onishchenko, Farm. Zh. (Kiev) 22, 23 (1967); C A 68, 53315s (1968). 90. B. K. Rostotskii, B. A. Krivut, and 0. E. Lasskaya, Med. Prom. SSSR 18,51 (1964); C A 61, 4155c (1964). 91. V. I. Murav’eva, T r . Vses. Nauch.-Issled. Inst. Lek. Aromat. Rast. 279 (1959); C A 56, 543f (1962). 92. K. Lapina, Parmatsiya (Moscow) 17, 54 (1968); C A 70, 14434b (1969). 93. V. V. Mikhno, Farm. Zh. (Kiev) 20, 45 (1965); C A 64, 140268 (1966). 94. A. P. Oboimakova and S. A. Malykhina, Aptech. Delo 5, 45 (1956); C A 51, 8373e (1957).
506 95. 96. 97. 98. 99. 100. 101. 102.
V. SNIECKUS V. V. Mikhno, Farm. Zh. (Kiev)21, 28 (1966); C A 66, 88625d (1966). V. V. Mikhno, Farm. Zh. (Kiev) 23, 28 (1968); CA 68, 9859713 (1968). S. V. Gritsenko, Farmatsiya (Moscow) 17, 39 (1968); C A 69, 57439d (1968). Z. Kowalewski, I. Frencel, and D. Pawluc, Diss. Pharm. Pharmacol. 20, 105 (1968); C A 68, 986672 (1968). N. A. Trofimova, Fiziol. Rast. 13, 307 (1966); CA 64, 20197a (1966). D. Karaguishieva, R. Z. Levina, and Sh. Alibekova, Izv. Akad. Nauk Kaz. SSR, Ser. Biol. 9, 8 (1971); C A 7 5 , 1 6 5 7 2 ~(1971). L. N. Bereznegovskaya and N. A. Trofimova, Fiziol. Rmt. 12, 708 (1965); C A 63, 13710d (1965). N. A. Trofimova, Mater. Gar. Nauch. Konf. Molodykh Uch.-Med., lst, 475 (1967); C A 76, 120372 (1972).
-CHAPTER
12-
ALKALOIDS UNCLASSIFIED AND OF UNKNOWN STRUCTURE R. H. F. MANSKE University of Waterloo Waterloo, Ontario, Canada
I. Introduction ........................................................ 11. Plants and Their Contained Alkaloids .................................. References ..........................................................
507 507 564
I. Introduction As more plants come under chemical scrutiny more alkaloids of hitherto unknown nuclear structure come to light. Furthermore, as the technique of isolation becomes more sophisticated well-known alkaloids are revealed in sources not hitherto suspected; the isolation of Cinchona alkaloids from the leaves of the olive tree can serve as an example. The listing of plants and the alkaloids isolated therefrom is the subject of this chapter. They are mostly of structural types not treated in separate chapters and are given with brief descriptions of their properties and of their structures where known. This chapter is supplementary to Volume XIII, Chapter 9, p. 397.
11. Plants and Their Contained Alkaloids 1. Adenocarpus mannii Hook. (Leguminosae) (VII, 256)*
+'-Dipiperidine, ( + )-adenocarpine, isoorensine, and santiaguine. Quinolizidine derivatives were not encountered ( I ) . 2. Adhatoda vasica Nees (Acanthaceae) (VII, 102)
In addition to the known peganine the following quinazoline alkaloids were revealed: vasicoline (C,,H,,N,; mp 135") (1; R = H,;
* The Roman numeral followed by an Arabic number refers to volume number and page where the subject of the heading has been treated in previous volumes.
508
R. H. F. MANSKE
R1 = NMe,; R2 = R3 = H); adhatodine (C20H2,0,N3; mp 183') (1; R = H,; R1 = H; R = C0,Me; R3 = NHMe); vasicolinone (C19H190N3;mp 152") (1; R = 0; R1 = NMe,; R2 = R3 = H); and anisotine (C20Hlg03N3;mp 186') (1; R = 0; R1 = H ; R2 = C0,Me; R3 = NHMe). The structures were determined almost exclusively by the use of exhaustive spectral methods (2). 0
1
3. Aegle marmelos Correa (Rutaceae) (IX, 227; X, 545, 565)
The minor alkaloid of this plant, provisionally named aegelenine, was shown to be identical with halfordinal previously obtained from Halfordia scleroxyla F. Muell. (3). 4. Abngium lamarckii Thw. (Alangiaceae) (X, 546); XII, 456; XIII, 190)
Alangiside (C2,H3,0,,N; [a],,- 105') was obtained from this plant, the greater amount being present in the unripe fruit. P-Glucosidase cleaved it t o d-glucose and the aglucone (C,,H,,O,N). The structure was largely arrived at by spectral methods and then confirmed by a variety of chemical reactions but a decision between 2 and 3 was not made (4). RO
OMe
2 3
R = H,R1 = M e R = Me,R1= H
4
12. UNCLASSIFIED ALKALOIDS
509
5. AlchorneaJloribunda Muell. Arg. (A.hirtella Benth.) (Eupborbiaceae)
Spectral examination of alchorneine confirms structure 4 for this alkaloid. Acid hydrolysis generated an imidazolidinone. The alkaloid showed strong vagolytic activity, inhibited intestinal peristalsis in dogs, and exhibited ganglioplegic parasympathy (5). 6. Alchornea javanensis (Bl.) Muel1.-Arg.
Alchornine (C11Hl,03N3; mp 134"; [.ID +74') (5) on reduction yields the dihydrobase (picrate, mp 263-267"); and alchornidine, (C16H2302N3;mp 95";DI.[ -18') (6 or 7), hydrolysis of which with alkali generates alchornine and 2,2-dimethylacrylicacid). However, mild hydrolysis with dilute acetic acid gives isoalchornine (mp 137; [.ID -84') (8) which, in turn, on treatment with alkali generates alchornine. Two new guanidine derivatives 9 (hydrochloride, mp 139") and 9a (mp 44-46") have also been isolated. The structures of the last two were confirmed by hydrogenation to the fully saturated guanidines and subsequent hydrolysis. The structures of the pyrimidine bases were largely determined by spectral methods ( 6 ) .
/=
/=
co
co
5
8
7
6
Me,C=CH. CH,.NH-C-NH.CH,.
II
-
CH=CMe2
N CH2.CH=CMe, 9a
7 . Ancistrocladus heyneanus Wall. (Ancistrocladaceae; Dipterocarpaceae)
Ancistrocladine (C2,H2,04N; mp 265-267'; hydrochloride, mp 220[.ID - 25.5"; ON-diacetyl-, amorphous; N-acetyl-, mp 277"; other derivatives) was shown to have structure 10. Exhaustive spectral 224';
510
R. H. F. MANSKE
data led to this structure. Oxidation of the alkaloid generated an acid which was shown to have structure 11 and which was synthesized by two methods. Comparison was with the methyl ester (mp 102-103") (7-9).
%r OMe
OMe
OMe
OMe
COzH
@Me
OMe
Me
10
11
8. Anisotes sessiZi$orus C.B.Cl. (Acanthaceae) (XII, 458)
The syntheses of several of the alkaloids from this botanical source have been reported. I n general, anthranilic acid or a nuclear derivative of it when heated in benzene solution with a slight excess of O-methylbutyrolactam (12) generates a compound (13)which on reaction with NBS gave 14. The latter when reached with ethyl anthranilate yielded anisessine (15). Similarly, other alkaloids of this type were synthesized and the structure of sessiflorine was revised to 16 (10). 0
12
0
13 R = H 14 R = Br
15
0
16
NHMe
12. 9. Annuloline
511
UNCLASSIFIED ALKALOIDS
(X,574)
Tracer studies with labeled phenylalanine and with tyrosine have shown that these are specifically incorporated. Intermediates in this biosynthesis are tryamine, cinnamic acid, p-coumaric acid, and caffeic acid (11). 10. Anodendron afine Druce (Apocynaceae)
Anodendrine (17)and alloanodendrine (18) are a pair of zwitterionic alkaloids whose structure was determined by a combination of physical and chemical methods. The synthesis of the former was achieved by treating the methyl ester of laburninic acid with isopentenyl bromide and hydrolysing the product. The allo base was similarly prepared from ( + )-isoretronecanolic acid (12).
17
18
19
11. Anonu squamosa L. (Anonaceae) (IX, 17; X, 419;XII, 489)
Anonaine, michelalbine, oxoushinsuine (liriodenine), L-( + )-reticuline, and anolobine (13). 12. Antirrhynum majus L. (Scrophulariaceae)
The first known natural occurrence of a 2,6-naphthyridine has been reported. Thin-layer chromatography of an alcoholic extract of the plant above gave a base (C,H,N,; mp 78') whose spectral examination indicated that it is 4-methyl-2,6-naphthyridine(19). Other possible isomers were excluded on the basis of the NMR spectral data (14, 15). The same base was also isolated from A. orontium L. (16). 13. Araliorhamnus vaginatus Perrier (Rhamnaceae)
+ 82') was obtained in Aralionine (C34H3,0,N4;mp 165-167'; 0.0670yield from the air dried leaves. Its structure (20) was determined by a combination of spectral methods and by chemical reactions,
512
R. H. F. MANSKE
especially by hydrolysis ( 1 7 ) . A minor constituent, aralionine B (C,,H,,O,N,; mp 103"; [a];0 -73") was similarly shown to have structure 21 (18).
Ph NHMe 20
21
14. Arcangelisia loureiri Diels (Anamirta loureiri Pierre) and Coscinium wallichianum Miers (C.fenestratum Colebr.) (Menispermaceae) (IVY86)
Palmatine , berberine, and jatrorrhizine were isolated as chlorides from the former and palmatine from the latter (19). 15. Argemone glauca (Prain) Degener & I. Degener var glauca (Papaveraceae) (IV, 79; X, 468;XII, 335;XIII, 398)
This plant collected from the island Lanai of the Hawaiian group contained protopine, allocryptopine, sanguinarine, berberine, and chelerytherine (20). 16. Argyreia nervosa Boj . (Convolvulaceae)
The seeds of this so-called wood rose were shown to contain lysergic and isolysergic acid amides (21). 17. Ariocarpus lcotschoubeyanus Hort. (Mammillaria sulcata SalmDyck) (Cactaceae)
Hordenine and N-methyltyramine (22). 18. Ariocarpus retusus Scheidw. (Mammillaria prismatica Hemsl.)
N-Methyl-3,4-dimethoxy-P-phenethylamineand N-methyl-4-methoxy-P-phenethylamine (23). 19. Aristotelia peduncularis (Labill.) Hook. f. (Elaeocarpaceae)
This plant, endemic to Tasmania, has yielded 0.003% of the alkaloid peduncularine (C20H24N2; mp 155-157"; [a]h9 - 24") Its UV spectrum
12.
513
UNCLASSIFIED ALKALOIDS
closely resembles that of indole and it gives a positive Ehrlich test. Other data, including mass and NMR spectra, point to structure 22 for this alkaloid (24).
H 22
20. Arundo donax L. (Graminae) (VIII, 4; XI, 11; XII, 460)
The flowers of this grass yielded gramine and its methohydroxide, N,N-dimethyltryptamine methohydroxide, 3,3'-bis(indolylmethyl)dimethylammonium hydroxide (22a)which had not been known previously, and eleagnine, the first report of a P-carboline alkaloid in grasses (25). 21. Atabntia monophylla Correa (Rutaceae) (XII, 500)
Atalaphylline (C,,H,,O,N; mp 246') and N-methylatalaphylline (C,,H,,O,N; mp 192') show UV and I R spectra consonant with 9acridones. Chemical and other spectral data point to structures 22b, 22c, respectively, for these alkaloids. Atalaphylline on treatment with diazomethane yields a dimethyl ether (mp 145") which still has a hydroxyl and under forcing conditions with methyl iodide and potassium carbonate generates an O,O,O-trimethyl-N-methyl derivative. Treatment with formic acid resulted in cyclization of both prenyl groups to give 23 (mp 251') (26).
I
OH
22b 220
.
R =H R = Me
23
2 2 . Banisteriopsis argentea Spring ex Juss. (Malpighiaceae) (X, 495; XI, 12)
The following alkaloids were isolated largely by chromatographic methods and were identified by spectral methods and mixed melting
514
R. H. F. MANSKE
points : ( + )-N,-methyltetrahydroharman, N,N-dimethyltryptamine and its N-oxide, harmine, ( + )-tetrahydroharmine, harmaline, choline, betaine, and the new compound, ( + )-5-methoxytetrahydroharman (CI3Hl60N2;[a]:5 + 34"). Dehydrogenation of the last gave 5-methoxyharman (27). 3. Bellendena montana R.Br. (Protoeaceae)
This is the first plant of the Proteacea which has been shown t o elaborate alkaloids. Bellendine (C,,H,,O,N; mp 162"; + 168" was isolated in 0.001370 yield. Traces of two other bases were also indicated. Bellendine is of some interest in that its structure was determined by X-ray methods without the incorporation of a heavy atom into a crystalline derivative. The absolute stereochemistry indicated in the structure (24) has not been determined but is discussed on the basis of analogy to that of ecgonidine (28).
OMe 24
CH,.OH 25
24. Bocconia cordata Willd. (Papaveraceae) (IV, 79; X, 468; XII, 335)
Bocconoline (C22H2105N; mp 232-233') is the name now given to base C (29). Chiefly on the basis of a spectral study, structure 25 was assigned to this base. On treatment with acetic anhydride the expected O-acetyl derivative (mp 189") is formed (30). 25. Bocconia microcarpa Maxim.
I n addition to several quaternary bases this plant was shown to contain prot opine, all0cryptopine, chelerythrine , sanguinarine, and several unidentified bases (31). 26. Bhesa archboldiana (Merrill & Perry) Ding Hou (Kurrimia archboldiana Merrill & Perry) (Celastraceae)
9-Angelylretronecine, its N-oxide, and calycanthine were isolated from this plant. The occurrence of the last is a phytogenetic anomaly (32).
12.
UNCLASSIFIED ALKALOIDS
515
27. Bolusanthus speciosus Harms (Lonchocarpus speciosus Bolus)
(Legominosae) Cytisine and N-methylcytisine (33). 28. Bryonia alba L. (Cucurbitaceae)
Thin-layer chromatography indicated the presence of five alkaloids in the roots of this plant (34). 29. Campanula medium L. (Campanulaceae)
This plant yielded (-)-lobeline and a new base, campedine (C,,H,,O,N), whose structure (26) is based on physical methods and diagnostic chemical tests for the methylenedioxy group (35).
30. Camptothecine (XII; 464)
A total synthesis of this alkaloid has been reported. The tricyclic quinoline acid (27; R = C0,Et; R1 = H) (36) was heated with 50y0 hydriodic acid for 14 hr to effect hydrolysis and decarboxylation and then esterified to yield 27 (R = H; R1 = Et). Compound 27 was condensed with the acid chloride of the half ester of malonic acid to generate 27 (R = CO.CH,.CO,Et; R1 = Et), and finally condensation to 28 (R = C0,Et) was achieved by heating with sodium ethoxide in ethanol-toluene (1:5). Hydrolysis and decarboxylation to 28 (R = H) occurred when 28 (R = C0,Et) was heated under reflux for 4 hr in 10% acetic acid. Reduction with sodium borohydride and dehydration then yielded 29. The anion of 30 prepared by reaction with lithium diisopropylamide in THF was unstable at room temperature but at dry ice-acetone temperature it reacted with 27 to give the pentacyclic lactone 31 (R = Et). Successive hydrolysis, reduction with sodium borohydride, reaction with acetic anhydride in pyridine, and dehydrogenation with dicyanodichloroquinone (DDQ) gave 32. The last was converted into dl-camptothecine (33) by hydrolysis, reduction again with sodium borohydride, and acidification (37).
516
R. H. F. MANSKE
CH,.CH, .CH.CO,Et
I
O*CO,Et
/
29
31
30
\
/ '
N
OAc 0
CO,H 32
31. Capaurimine
33
(IX,102;XII,464)
Degradation of capaurimine O-diethyl ether gave a mixture of acids from which 3-methoxy-4-ethoxyphthalicacid was isolated and characterized as its N-ethylimide (mp 83-84'), identical with a synthetic specimen. The isomer, 4-methoxy-3-ethoxyphthalicacid, was also characterized as its N-ethylimide which had the same melting point (38). 32. Capsella bursa-pastoris Medic. (Cruciferae)
Choline, histamine, and two alkaloids not characterized except that they were physiologically active on isolated rabbit uterus (39). 33. Carex brevicollis DC. (Cyperaceae) (X, 550; XI,10)
Brevicarine (C19H21N3;mp 112'; hydrate, mp 61'; dihydrochloride, mp 195'; picrate, mp 210'; monoacetyl, mp 154') was given structure
12.
UNCLASSIFIED ALKALOIDS
517
34 on the basis of spectral data and the preparation of a number of derivatives. N-Methylation with formaldehyde and formic acid gave N-methylbrevicarine (mp 128") (40, 41). In addition to the alkaloids previously reported this sedge yielded harman, harmol, harmine, and a base, CI5Hl8N2 (41).
34. Cassia occidentalis L. (
) (Leguminosae) (XI, 491)
N-Methylmorpholine was isolated (42). 35. Caulerpa Species (Caulerpaceae)
C. racemosa var. clavifera is one of the marine algae consumed as a salad delicacy in the Philippines and adjacent lands. Ether extraction of the dried plant yielded a red crystalline substance, caulerpin (C24H,,04N2;mp 317"), whose structure (35)was assigned on the basis of spectral evidence. Hydrolysis with alkali yields caulerpinic acid (mp 256") (43).The var. lamourouxii also yielded caulerpin (44). 36. Cestrum nocturnum L. and C. diurnum L. (Solanaceae)
Both plants yielded nicotine and nornicotine; the former yielded cotinine and myosmine as well (45). 37. dl-Chelidonine (IV, 253; IX, 44; X, 485)
The total synthesis of this alkaloid as well as its N-nor derivative by a novel route is detailed. The critical step was the rearrangement of compound 36 to 37 by heating in o-xylene at 120". The latter on hydroboration followed by hydrogen peroxide oxidation gave a mixture of the secondary carbinols one isomer of which on Jones oxidation gave the ketone 38. Stereospecific reduction of 38 was achieved by means of sodium borohydride in methanol-dioxane and hydrogenolysis of the benzyloxycarbonyl group generated dl-norchelidonine. The synthesis of the intermediate 37 involved a series of reactions which, however, were not without analogy (46).
518
R. H. F. MANSKE
L
O 38
38. Chelidonium mujus L. (Papaveraceae) (IV, 79; X, 423; XII, 335) The first isolation of d-tetrahydrocoptisine (mp 203"; [a],,+ 310") from this plant is claimed (47). 39. Choriluenu quercifolia Endl. (Rutaceae) Dictamnine was isolated (48).
40. Cinnumomum spp. The major alkaloids of the bark of species T.G.H., 13077, were 1,2,3,4-tetidentified as ( + )- 1-( 4-hydroxylbenzyl)-6,7-methylenedioxyrahydroisoquinoline (norcinnamolaurine), ( - )-cinnamolaurine, ( + )reticuline, and ( + )-corydine. The structure of norcinnamolaurine was elucidated by spectroscopic methods and confirmed by conversion into cinnamolaurine and by a synthesis of its racemate (49). The structure of cinnamolaurine (mp 212"; hydrochloride, mp 230"; - 100') (39) was confirmed by a synthesis starting with 4-benzyloxyphenacetyl-~-3,4-methylenedioxyphenethylamide followed by the well-known cyclization, quaternization, and reduction sequence (50). 4 1. Coccinella septempunctuta The alkaloid in the defensive exudate of this beetle, named coccinellin (C,,H,,ON), was given either of two structures (40 or 41) based largely on NMR studies (51).
12.
519
UNCLASSIFIED ALKALOIDS
42. Codonocarpus australis A. Cunn. (Phytolaccaceae)
Codonocarpine (C26H310,N3;mp 187") is a new alkaloid structurally related to lunarine. Hydrolysis generated spermidine, [H,N(CH,)3NH(CH,),NH,]. Spectral analysis indicated that its structure is 42 and chemical degradation was consistent therewith. Hydrolysis of the tetrahydro derivative of the 0-methyl derivative gave an acid whose properties were consistent with structure 43 (52).
39
40
41
43. Codompsis clematideu C. B. Clarke (C. ovatu Benth.) (Campanulaceae) (XIII, 402)
The alkaloid codonopsine (C14H2104N;mp 150'; [w]EO - IS0) from this plant was given a structure which was later revised to 44 on the basis of spectral studies and on Hofmann degradation (53-55). A small amount of another alkaloid, codonopsinine (C,,H,,O,N; mp 169"; [w]zO - 8.8") of structure 45 was also reported (56).
44
45
520
R. H. F. MANSKE
44. Colchicum kesselringii Rgl. (Liliaceae) (XI, 410) I n addition to the already known 2-dimethylcolchicine and 3dimethyl-/3-lumicolchicine previously isolated from this plant there was obtained 2-dimethyl-/3-lumicolchicine(57). 45. Colchicum spp. (11, 261; XI, 407) Colchicine was found in alcoholic extracts of C. chalcedonicum Aznav., C. micranthum Boiss., C. szovitzii Fisch. & Mey., and C. turcicum Janka. All, except C. micranthum, also contained demecolcine (58). 46. Colubrina asiatica Brongn. (Rhamnaceae) The bark contained O-methyldauricine (59). 47. Colubrina faralaotra (H. Perrier) R. Capuron (Macrorhamnus faraZaotra H. Perrier) The main alkaloid proved to be nuciferine (60). 48. Coptis groenlandica Pernald (Ranunculaceae) Berberine, isocoptisine (46), and a methoxyhydroxy derivative [C,,H,,O,NCl (?), mp 270'1 of coptisine were isolated. 49. Corydalis campulicarpa Hayata (Papaveraceae) (XII, 424; XIII,
402)
Of the seven alkaloids isolated from this plant four were identified as protopine, ophiocarpine, a-allocryptopine, and berberine (62). 50. Corydalis Jimbrillifera Korsh. and C. stricta Steph.
P-Hydrastine and protopine were isolated from these plants as well as a number not identified. The rootstocks of C. stricta also yielded sanguinarine (63, 64). 5 1. Corydalis gortschakovii Schrenk.
The alkaloid corgoine (Cl7H,,O,N) isolated from this plant was shown to be an N-benzylisoquinoline of structure 47. It is the second known base of this type, the first being sendaverine into which it was converted by reaction with diazomethane (65).
12. UNCLASSIFIED ALKALOIDS
521
41
52. Corydalis incisa (Thunb.) Pers. (X, 468; XII, 468)
A reexamination of this plant collected in Sendai gave the two morphinandienone alkaloids sinocutine and pallidine in addition to corynoline, acetylcorynoline, isocorynoline, corynoloxine, protopine, and corycavine (66). 53. Corydalis paczoskii N. Busch.
The alkaloid corydaine (C,,H,,O,N; mp 184") was given structure 48 or 49 (67). Corpaine also isolated from the same plant was given structure 50 (68).
48
50
49
54. Corydalis pallida (Thunb.) Pers. (IV, 81)
Two new alkaloids, pallidine (51)and cycemanine (52),were isolated (69).
Me0 0 51
52
/ '
OMe
\
OH
522
R. H. F. MANSKE
55. Corydalis pseudoadunca Popov and C. gortschakovii Schrenk
The former plant yielded d-bicuculline, d-p-hydrastine, I-adlumidine, I-scoulerine, coramine, and protopine. The latter yielded isocorydine, I-adlumine, sendaverine, d-bicuculline, and protopine (70). 56. Corydalis racemosa Pers. (IX, 41)
Protopine and dl-tetrahydropalmatine were isolated (71). 57. Crotalaria medicaginea Lam. (Leguminosae) (XII, 254)
The two pyrrolizedine bases (53, R = H, and 53, R = OH) were isolated from the seeds of this plant. Their structures were ascertained largely by spectral methods (72).
B
RmCH20
v 0
53
54
58. Croton sparsi$orus Morong (Euphorbiaceae) (X, 555; XIII, 403)
I n addition to the known crotspartine and its N-monomethyl and N,O-dimethyl derivatives and sparsiflorine, there were isolated crotsparinine (mp 184') (54, R = H) and N-methylcrotsparinine (mp 160') (54, R = Me) (73). 59. Cryptocarya pleurosperma C. T. White & Francis (Lauraceae) (X, 577; XIII, 403)
Cryptopleuridine (C,,H,,O,N; mp 196-197"; cryptopleurospermine (C,,N,,O,N; mp 188-190';
[..ID + 90") (55) and [..ID 0 ) (56) are two
56
OH
12. UNCLASSIFIED ALKALOIDS
523
new alkaloids from the bark. NMR spectroscopy of the former and of its 0-acetyl derivative (mp 268-269") point to the given structure. The structure of the latter as 2-dimethylaminoethyl-3'-hydroxy-4'methoxy-4,5-methylenedioxybenzi1 follows from spectroscopic and degradative evidence (74). 60. Cularine
(IV,249;X,463; XII,336; XIII,404)
The absolute configuration of cularine and its relatives has been determined by chemical correlation to L(S)-romneine (57) which had previously been related to L-(S)-laudanosine. The new configuration (58) is in contradiction to that previously assigned (75).
Me0
OMe
OMe
57
58
61. Cularine
A synthesis of ( f )-cularine (61)(mp 119") by oxidative coupling of the diphenolic benzylisoquinoline (59) has been achieved. The oxidant was potassium ferricyanide in a two-phase system (8y0 ammonium acetate-chloroform) and gave the phenolic product (60)(mp 1 26O) in 7% yield. Methylation with diazomethane completed the synthesis. The compound 59 was prepared as its dibenzyl derivative by a mild variant of the Pomerantz-Fritsch synthesis (76).
59
60
61
524
R. H. F. MANSKE
62. Cynanchum
vincetoxicum (L.) Pers. (Asclepiadaceae) (IX, 517;
XIII, 404) This plant yielded a mixture of two related bases which upon hydrogenolysis yielded 62 (R = H) (mp 212'). Similarly the acetate of the mixture on hydrogenolysis also yielded 62 (R = H). Spectral examination of the mixture indicated that it consisted of 62 (R = H) and 62 (R = OH). NMR spectra as well as mass spectra served to determine the position of the oxygen substituents. The acetate of 62 (R = OH) (mp 217') was separable by chromatography from the mixture after acetylation (77). OMe
62
63. Cypholophus friesianus
(K. Schum.) H. Winkl. (Urticaceae)
The major alkaloid in this plant proved to be a novel imidazole derivative. Cypholophine (C18H2603N2;mp 126'; [.ID -t 0 ) upon permanganate oxidation generated 3,4-dimethoxybenzoic acid in high yield and upon acetylation gave an 0-acetyl derivative which also occurs in the plant. Spectral examination indicated structure 63 for this alkaloid and a synthesis confirmed it. 7-(3,4-Dimethoxyphenyl)propionyl chloride reacted with diazoethane to generate an a-diazoketone which was converted into 64 by means of hydrogen bromide. The latter when heated in methanolic ammonia at 143" with compound 65 gave cypholopine in 6 yo overall yield (78).
@z:H@:: OMe OMe
63
OMe OMe
64
(-J
NH. HC1
65
12.
525
UNCLASSIFIED ALKALOIDS
64. Decatropis bicolor (Zucc.) Radlk. (Simaba bicolor Zucc.) (Rutaceae) Dictamnine and skimmianine (79). 65. Dehydrodecodine (X, 566) This alkaloid was isolated from Heimia salicifolia Link et Otto and its structure (66) was elucidated by spectral methods and by its reduction to decodine in which the cyclic double bond of 66 is reduced (80). 66. Dendrine (X, 558; XII, 475) When dendrobine immonium bromide, prepared by oxidizing dendrobine with N-bromosuccinimide, reacts with methyl bromoacetate under Reformatskii conditions, dendrine of the figured configuration (67) is generated (81). 67. Dendrobium Jindleyanum Par. and Reichb. (Orchidaceae) (XII, 475; XIII, 406) This plant yielded dendrobine, nobiline, and a new alkaloid, 2-hydroxydendrobine, whose structure (68) follows from a study of its spectra (82). 0 CH2.C02Me
;
y
Pr
OMe 66
67
68
68. Dendrobium friedricksianum Reichb. f. and D. hildebrandii Rolfe (XII, 475) The N-isopentenyl derivatives of dendroxine and of 6-hydroxydendroxine were isolated as chlorides from these plants. The latter was prepared by the reaction of l-bromo-3-methyl-2-butene with 6-hydroxydendroxine in acetone (83).
526
R. H. F. MANSKE
69. Dendrobium hildebrandii Rolfe (XII, 475) This plant yielded the known nobiline and dendramine together with the new 6-hydroxynobiline whose structure was assigned on the basis of its spectra and on its conversion into dendramine (83a). 70. Dolichothele sphaerica Britton & Rose (Cactaceae) Dolichotheline (CI0H1,0N3; mp 130-131') from this plant has been shown to be N-isovaleroylhistamine (69) and the structure was confirmed by a synthesis (84). The imidazole moiety was shown to be derived from histamine, and the isovaleryl fragment was derivable from leucine and less efficientlyfrom mevalonate (85). 71: (+)-Dubinidine (IX, 254; X, 565)
Platydesmine (70), by the use of the conventional reagents, was dehydrated to the thermodynamically more stable endoolifine. However, the action of triphenyl phosphate dibromide on 70 gave a mixture of olefins in which the exo isomer 71 predominated. Separation of the mixture was achieved by chromatography on neutral alumina, and the exo- isomer (71) was then allowed to react with osmium tetroxide in dioxane. The product was ( )-dubinidine (72)(86). CH,. CH,. N H .CO .CH, .CHMe2
LJf
ex%.,--OH
H
69
OMe
70
0H
OMe
Me 71
I2
73
72. Echinops commutatus Juuratska (Compositae) (XII, 475)
Echinorine was isolated (87). 73. Echinops ritro L. (Compositae) (XII, 475)
The seeds yielded an oily optically inactive base from which crystal-
12.
527
UNCLASSIFIED ALKALOIDS
line derivatives could not be prepared. Spectral studies showed it to have structure 73 (88). 74. EZeagnus commutata Bernh. (E. argentea Pursh) (Elaeagnaceae) (VIII, 48; XI, 10) The root bark yielded 1-isobutyl- 1,2,3,4-tetrahydro-p-carboline (B.HC1, mp 257-259"). A synthetic specimen prepared by the condensation of tryptamine with isovaleraldehyde was identical with the natural product (89). 75. Eria javensis Zoll. & Mor. (Orchidaceae) N-Methyl- and N,N-dimethylphenethylamine were detected by a combination of gas chromatography and mass spectra. The quaternary trimethyl derivative was isolated as iodide (90). 76. Erica lusitanica Rudolph (Ericaceae)
Traces of 4-methoxyphenethylamine were present in this plant. The base could not be detected in sixteen other species of Erica nor in twenty-eight other Ericaceous plants (91). 77. Erythrina Zithosperma Blume (Leguminosae) (VII, 201; IX, 485; XI, 11) Eight known bases were isolated from this plant, namely, erysopine, erythraline, erythramine, erysodine, erysotrine, erythratine, N , N dimethyltryptophan, and hypaphorine. In addition three alkaloids, not previously known to occur naturally, were isolated, namely, N norprotosinomenine (C1,H,,O,N; hydrochloride, mp 242-244"; + 18') (74), protosinomenine (picrolonate, mp 172-174") (75) which was methylated to laudanosine (mp 83-85"), and P-erythroidine (76) (92).
Me0
OMe
%Mz:
Me0 0
OH 74
75
R = H R = Me
76
528
R. H. F. MANSKE
78. Erythrophleum chlorostachys Baill. (E. Zaboucherii F. Muell.) (Leguminosae) (X, 561; XII, 533) The leaves of this plant grown at Mareeba, North Queensland, yielded P-dimethylaminoethyl cinnamate, N-2-hydroxyethyl-N-cinnamamide, N-2-hydroxyethyl-N-methyl-trans-p-hydroxycinnamamide, and 2-hydroxyethylcinnamamide. The structures were confirmed by syntheses. Though some of these may be artifacts, generated during the isolation, the same products were not found in leaves of the same plant grown at Darwin, N.T., or at Cooktown, North Queensland. The leaves of the latter two sources yielded the alkaloid esters of terpenoid acids as in other Erythrophleum species (93). 79. Erythrophleum ivorense A. Chevalier (IV, 265; X, 561; XII, 476)
~
I n addition to eight known compounds three new alkaloids were isolated from the bark of this tree. They are cassamide (77),erythro~phlamide . C O N (78), ( M and e ) . cassaide C H z . (79) C H (94). z O ~ ~ C H . C O z C H z . C H z .
Me
R R' H H
HH COzMe 77 R = H, R1 = COzMe R = OH, R' = COzMe R = OH, R' = Me
78 79
80 81
R = H R=OH
80. Erythrophleum ivorense A. Chevalier Of the seven alkaloids isolated from this plant, four, namely, cassamine, cassamidine, erythrophlamine, and erythrophleguine, had been obtained from E. guineense G. Den. In addition there were isolated three new ones, 80 and 81, of indicated structure and a third one (95). 81. Erythroxylum ellipticum R.Br. (Erythroxylaceae) (I, 296; XII, 476) Tropine 3,4,5-timethoxycinnamate (mp 165-166O) was isolated from the bark. It was identical with a synthetic specimen (96). 82. Eschscholtxia Species (Papaveraceae) (IV, 82; XII, 336) The roots of E. californica Cham., E. douglassi (Hook & Am.) Walp.,
N M e z
12.
UNCLASSIFIED ALKALOIDS
529
and E. glauca Greene yielded protopine, allocrytopine, benzophenanthridine bases, and ( - )-norargemonine and bisnorargemonine (97). 83. Euonymus europaeus L. (Celastraceae) (X, 561)
Alkaloid D isolated from this plant was shown to be R-( - )-armepavine (98). 84. Euonymus sieboldianus Blume (X, 561; XI, 489)
Exhaustive spectral investigations have shown that evonine (82) (C,,H,,O,,N; mp 184-190"; [..ID + 8.4"),neoevonine (83) (C34H4101,N; mp 264-265"; [aID + 24.9"), evonymine (84) (C,,H4,0,,N; mp (picrate) 142-146"; [..ID - 20"), and neo-evonymine (85) (C,,H,,O,N; mp 259262"; [.ID - 11") have the structures shown. A number of chemical operations carried out confirm the given structures (99-102).
82 83
R = Ac,X = 0 R = H , X = O
84
R = Ac, X = -
85
,
OAc
86 87 88
''H ,OAc R=H,X= ''.H
89
R1 = 89, R2 = H, R3 = COMe R1 = R2 = H, R3 = 89 R' = R2 = R3 = H
530
R. H. F. MANSKE
85. Euphorbia millii Ch. deMoulins (Euphorbiaceae) Two alkaloids of an essentially new type, namely, milliamine A (C4,H,,010N,; [a];, + 6"; hydrochloride, mp 167-170") (86) and milliamine B (C43H4,0,N3; - 14"; hydrochloride, mp ca. 140") (87). The structures were arrived at in part by exhaustive spectral studies and confirmed by chemical degradation. Both bases upon methanolysis yielded a diterpentetraol (ingenol) (88), thus accounting for the non-nitrogenous fragment. The structure of ingenol had previously been established (103).The structure of the nitrogen-containing fragment (89) was proved by further degradation and by a synthesis. Methanolysis of 87 generated the same fragments that; were obtained from 86 and the spectral data provided evidence for the siting of the substituents (104). 86. Fagara capensis Thunb. (Rutaceae) (XII, 478)
Skimmianine, chelerythrine, and nitidine (105). 87. Fagara macrophylla Engl. (Zanthoxylum macrophyllum Oliver) (XII, 478) Fagaramide, skimmianine, chelerythrine, and nitidine were isolated from stem and root barks of this plant (106). 88. Fagara Species (X, 423; XII, 478)
Fagara xanthoxyloides Lam. (Zanthoxylum senegalense DC.) was shown to contain skimmianine as well as chelerythrine and its dihydro derivative. The previously isolated fagaridine was shown to be a mixture. Fagara macrophylla Engl. was shown to contain chelerythrine and its dihydro derivative as well as the previously named xanthofagarine which, from mass spectral methods, appears to be C20H1504N (107).Nitidine was also reported as a constituent (108). 89. Pagonia Species (Zygophyllaceae) Six species of Fagonia were shown to contain alkaloids (0.03-0.1707,) and F . eretica L. contained harman (109). 90. Flindersia iflaiana F. Muell (Rutaceae) (IX, 234) The alkaloid ifflaiamine had been assigned structure 90 on the basis of spectral studies. Its synthesis, although in only By0 yield, followed an exhaustive study of the Claisen rearrangement of compound 91. When it was heated at 140-145" for 4+ hr in the presence of anhydrous
12.
53 1
UNCLASSIFIED ALKALOIDS
sodium carbonate there were formed at least three other products than that sought (90). A reexamination of a mixture of alkaloids from the plant above yielded infflaiamine { (mp 122-125'; [aID - 6.2" (MeOH), - 9.15' (CHCl,)} and a new base (mp 47-50') which was shown to have structure 92 and which was identical except for optical activity with one of the products obtained as above from 91 (110).
a. ~2 I
I
I
Me
Me
Me
90
91
92
91. Flindersine (VII, 230; XII, 480)
A one-step synthesis of this alkaloid is consequent upon the reaction of thallous salts of nonchelated P-diketones with alkyl halides. I n the present instance the thallous salt of 4-hydroxyquinolone (93) reacted with 3-chloro-3-methyl-1-butyne to generate flindersine (94) in 2 8 7 , yield (111).
'
N
H
O
H
93
0
94
95
0 Me0
96
97
532
R. H. F. MANSKE
92. Fumaria parvijiora Lam. (Papaveraceae) (XII, 337) Parflumine (C20H1905N;mp 111'; O-acetyl, mp 198; O-methyl, mp ISSO), an alkaloid from the named plant, was given structure 95 (112). 93. Galanthus caucasicus Baker (G. nivalish L.) (Amaryllidaceae) (XI, 313) The structure of galanthusine (96) was determined by spectrographic methods (113). 94. Genista angulata (Auth?)(Leguminosae) (XII, 479; XIII, 408)
Four alkaloids were detected by a variety of procedures. Three were identified as cytisine, anagyrine, and lupanine (114). 95. Genista cinerea DC. (XII, 479; XIII, 408) The branches of this plant served as a source for three different esters of 13-hydroxylupanine (97). They are cinegalleine (3-hydroxy4,5-dimethoxybenzoyl), cinegalline (3,5-dihydroxy-4-methoxybenzoyl), and cineverine (3,4-dimethoxybenzoyl) (115). 96. Gentiana asclepiadea L. (Gentianaceae) (XI, 487) Gentianine, gentianidine, gentiabutin, and gentiabetin were isolated from the roots (116). 97. Girinimbine (X, 573; XIII, 281) Of the two structures which had been indicated for this compound, that represented by 99 was considered the more probable. It has been (98) was prepared synthesized. l-Formyl-2-hydroxy-3-methylcarbazole in two stages from 2-methoxy-3-methylcarbazole. The hydroxyaldehyde was converted into the pyran derivative 99 by a procedure already recorded, and it proved to be identical with girinimbine. Mahanimbine for which structure 100 was suggested was also synthesized from the 2-hydroxy-3-methylcarbazole.Condensation with citral in a procedure similar to that used by Crombie gave the dlcompound identical with the racemized natural product (117). 98. Glaucium corniculatum Curt. (Papaveraceae) (IV, 83; X, 469; XII, 337) The main alkaloids were allocryptopine and protopine along with lesser amounts of d-corydine, heliotrine, and sanguinarine (118).
533
12. UNCLASSIFIED ALKALOIDS
99
98
100
R =Me R = -CH,.CH,.CH=CMe,
99. Glaucium Jlavum Cranz.
This much-investigated plant yielded glaucine, isocorydine, daurotensine, and a base (C20H1,05N;mp 213") of unknown identity. The alkaloid content was greatest during the flowering stage (119,120). 100. Glaucium flavum Cranz. var vestitum This plant, native to Spain, yielded the known glaucine and the related yellow base 101 along with two new alkaloids, namely, the violet corunnine (C,,Hl,05N; mp 255-257") (102) and the red pontevedrine (C,,H190,N; mp 269-27 1") (103) whose structures were determined largely by spectral methods. When glaucine was treated with a large excess of the chromium trioxide-pyridine complex in dichloromethane there was generated a mixture from which it was possible to isolate, by alumina chromatography, compounds 101, 102, and 103 as well as dehydroglaucine (121).
::pzg
Z F :
Me0
\
Me0
\
Me0
\
OMe
OMe
OMe
101
102
103
101. Griffonia simplicifolia Baill. (Bandeiraea simplicifolia Benth.) (Leguminosae) The mature seed of this plant contained 6-10y0 of 5-hydroxytryptophan. An enzyme system capable of hydroxylating tryptophan was identified in various tissues. 5-Hydroxytryptamine (up to 0.2y0) was found in the pods and in lesser amounts in other tissues. 5-Hydroxyindole-3-acetic acid and indole-3-acetylaspartic acid were also identified (182).
534
R. H. F. MANSKE
102. Halfordinol (X, 565; XI, 498)
A simple one-step synthesis of this oxazole type base has been devised. p-Hydroxymandelonitrile was first reacted with thionyl chloride in the presence of hydrogen chloride in ether. The addition of nicotine aldehyde was followed by saturation with hydrogen chloride. The reaction mixture was set aside for 2 days at room temperature after which it was possible to isolate halfordinol (104) in 1607, yield (123).
104
105
103. Helietta longifoliata Britton (Rutaceae) (XII, 408)
Five known furoquinoline alkaloids were isolated: dictamnine, 6methoxydictamnine, kokusaginine, flindersiamine, and skimmianine. A new base named isodictamnine was also reported (124). 104. Haloxylon articulatum Bunge (Chenopodiaceae) (XII, 480)
The main alkaloid proved to be carnegine (105; R amount of a new base, N-methylisosalsoline (105, R obtained (125).
= Me). A small = H), was also
105. Haplophyllum bucharicum Litwinow (Rutaceae) (XII, 480)
The new alkaloid bucharaine (C19H2504; mp 151') was given structure 106 (126). A Claisen rearrangement in tetralin (127) generated
.
YCH,.CH(OH)- CH(CMe,OH) CH,.CH:CHMe
106
H 107
12. UNCLASSIFIED ALKALOIDS
535
bucharidine (C19Hz504N;mp 152"), also isolated from the same plant. Functional group analysis and spectral data indicate structure 107. Kuhn-Roth oxidation gave acetone (128). 106. Haplophyllum suaveolens G. Don (X, 565)
Dictamnine and skimmianine (129). The name Haplophyblum is nomen conservandum for genera which had been Haplophyllum and in part Ruta. 107. Hernandia papuana C. T. White (Lauraceae) (Hernandiaceae)
Hernangerine, L-( + )-laudanidine, and hernandonine (ClSH1905N; mp 298-300") (108) which had been isolated earlier from H . ovigera (130, 131). 108. Hesperethusa (Rutaceae)
crenulata M. Roem (Lirnonia acidissima L.)
4-Methoxy-1-methyl-2-quinolone was isolated from the stem bark (132). 109. Ipalbidine (XIII, 410)
A synthesis of the dl and of the optically active forms of ipalbidine as well as of its glycoside, ipalbine, has been reported. When Z-methoxy1-pyrroline was condensed with methvl acetoacetate at 85" there was formed 109 which on reaction with p-methoxyphenacetyl chloride in COMe I
108
109
CO,H I
110
I
112
536
R. H. F. MANSKE
the presence of sodium hydride generated 110 and its methyl ester. Decarboxyalation and demethylation with hot hydrobromic acid and subsequent reduction with lithium aluminum hydride gave dl-ipalbidine (111) (mp 149-150"). Resolution was effected by means of the active di-0-p-toluoyltartrates of the 0-acetyl derivative (133). 110. Juglans regia L. (Juglandaceae)
Serotonin was synthesized in the embryo and in the cotyledons of the Persian walnut but not in the pericarp, seed coat, leaves, stems, or roots. Its source was shown to be tryptophan (134). 111. Kingiella taenialis Rolfe (Doritis taenialis Benth. & Hook. f.) (Orchidaceae)
The plant gave phalaenopsine (112) in 1% yield. Transesterification with methanol generated laburnine and dimethyl ( - )-2-benzylmalate
(135). 112. Lappula intermedia (Lebed.) Popov (Echinospermum intermedium Lebed.) (Boraginaceae)
Lasiocarpine (136). 113. Lemonia spectabilis Lindl. (Ravenia spectabilis Engl) (Rutaceae)
Lemobiline (113) (137), also isolated from Flindersia iflaiana 3'. Muell. (138),was obtained along with ( - )-ravenoline (114)and arborinine. When ( - )-ravenoline is treated with 48y0 hydrobromic acid or with hydrogen chloride in acetic acid at room temperature it generates ( - )-lemobiline in 6507, yield (139).
a&a c q Q I
Me 113
I
H
H
Me 114
115
114. Leontice albertii Regel (Berberidaceae) (VII, 258; X, 570; XII, 486)
The known alkaloids taspine, N-methylcytisine, anabasine, leontine, matrine, and leontalbine were identified. Additionally two new alka-
12.
UNCLASSIFIED ALKALOIDS
537
loids, albertidine (C,,H,,ON,; mp 70"; [a]A8+ 33.8") and d-isosophoridine (C,,H,,ON,; mp 108"; [a];2 + 59.3") were isolated (140). 115. Leontice leontopetalum L. (X, 416, 570; XII, 486) I n addition to the known alkaloids, plant material of Bulgarian origin yielded 1-stylopineand d-lupanine in addition to a new quinolizidine named leontiformine (C,,H,,ON,; mp 61-63"; [a]g2 + 51.9; hydrobromide, mp 275-276'; [a]g2 + 57.5") whose structure (115) was determined by spectral methods. Hydrolysis removed the N formyl group to generate the base (C,,H,,N,; mp 46") which upon heating with formic acid re-formed the natural substance. Its properties were identical with a base of the same structure previously prepared by t-butylhydroperoxide oxidation of the perchlorate of 5,6-dehydrosparticine (141). 116. Leontice smirnowii Trautv. (X, 570; XII, 398) D-Argemonine and 1-lupaninewere identified by their spectra and by the preparation of derivatives. A third base (C,,H,,O,N; mp 152-153"; [.ID + 218") of uncertain identity appeared to be related to the pavine group (142). 117. Ligularia Spp. (Compositae) (XII, 247)
These species of Ligularia, namely, L. macrophylla DC. (Xenecio ledebourii Sch. Bip.), L. brachyphylla Hand.-Mazz., and L. dentata A. Gray contained clivorine, ligularine (116), and ligudentine. The structure of 116 was proposed largely on the basis of NMR spectra, and a partial structure of ligudentine was suggested on the same evidence (143). 117 R = -CH,
' i ,
Me 116
U
538
R. H. F. MANSKE
118. Liparia parva (Walp.) Vog. and L. sphaerica L. (Leguminosae) Small amounts of ( - )-lupanine, ( )-sparteine, and ( + )-ammoden-
+
drine were identified by TLC (144). 119. Liparis loeselii (L.) L. C. Rich. and Hammarbya paludosa (L.) 0. K. (Orchidaceae)
The former plant yielded an amorphous base which upon alkaline hydrolysis generated nervogenic acid and laburnine while acid hydrolysis gave glucose as well. The structure (117) is identical with that given for auriculine. From H . paludosa it was possible to isolate two alkaloids, both amorphous, one of which (118) on alkaline hydrolysis gave nervogenic acid and lindelofidine ([a]:1 + 70") (145, 146). 120. Litsea xeylanica C. & T. Nees (Lauraceae) (IX, 17)
( + )-Reticuline, ( + )-isoboldine, and ( + )-norisoboldine were isolated (147). 121. Lobelia spp. (VI, 126; XI, 464)
Eleven Brazilian species of Lobelia were shown to have up to eight alkaloids which resembled those found in L. inJEata. One species, L. nummularioides Cham., had no alkaloids in the examined sample (148). 122. Lolium perenne L. (Gramineae) (XII, 322)
The new alkaloid, perlolyrine (C,,H,,O,N,; mp 183"; hydrochloride, mp 204-233") from this source has the structure 119 as determined by X-ray analysis of its hydrobromide. It has also been synthesized by the condensation of tryptamine with 5-acetoxymethyl-2-formylfuran followed by hydrolysis of the ester group and oxidation of the initial tetrahydro base (149).
12.
539
UNCLASSIFIED ALKALOIDS
123. Lunaria annua L. (L. biennis Moench.) (Cruciferae) (X, 572)
Three new alkaloids were isolated from the seeds of this plant. Their structures, largely derived from spectral studies, are given as 120, 121, and 122. The relation between 121 and lunarine (123) is a result of the insertion of a methylene group (150).
\
o(-II-
1 ' CH,
R R' 120 R = H, R' = OH 123 R R' = 0
+
121 R + R' = 0 122 R = H, R' = OH
124. Lupinus hispanicus Boiss. & Reut. var. bicolor (Leguminosae) (XII, 530)
The total alkaloid content of the aerial portion was approximately
2y0 from which the following were isolated: ( + )-epilupinine (65y0), ( - )-lupinhe (10yo),gramine ( 15y0), and an unidentified base (507,)
(151). 125. Lupinus paniculatus Desr. (IX, 175)
Sparteine and lupanine were isolated (152). 126. Lythrum anceps Makino (Lythraceae) (X, 566; XII, 488)
I n addition to the alkaloids previously isolated and characterized from Lythraceae plants the present species yielded ten new alkaloids whose structural elucidation had already been announced. The methods of separation and of characterization are detailed. The alkaloids are lythranine (124), lythranidine (125), lythramine (126), lythrancine-I (127), -11 (128), -111 (129), -1V (130), lythrancipine-I (131), -11, (132), and -111 (133) (153-156). 127. Mackinlaya macrosciadea F. Muell. and M . klossii Philipson (Araliaceae) (X, 572)
I n addition to the previously reported tetrahydropyridoquinazoline alkaloids and anabasine reported from these plants, the former yielded deoxyvasicinone and an unidentified base, Cl2H1,ON, (157).
540
R. H. F. MANSKE
124 R' = H, R2 = AC 125 R' = R2 = H
126
127 128 129 130 131 132 133
R'
= R2 = H, R3 = O H R' = Ac, R2 = H, R3 = O H R' = R2 = Ac, R3 = O H R' = R 2 = Ac, R3 = OAC R1 = R2 = R3 = H R' = Ac, R2 = R3 = H R' = R2 = Ac, R3 = H
128. Macrorungia Zongistrobus C.B.Cl. (Acanthaceae) (IX, 257) I n addition to the quinolylimidazole alkaloids previously isolated a reinvestigation served to reveal the presence of three new alkaloids of the same general type. Spectral methods were the source of most of the structural information of these bases but chemical transformat,ions and degradations proved decisive in distinguishing between alternatives. On the basis of the assumption that these bases are tetrahydro derivatives of macrorine (134) and isomacrorine (135), particularly since zinc-dust distillation of longistrobine (C,,H,,O,N,; mp 145-148") and of isolongistrobine (C17H1903N3;mp 132-134') generated the known 134 and 135, respectively, it was necessary to establish the site or sites of attachment of the C4H,0, moiety. Jones oxidation of isolongistrobine gave a dehydro base (C1.,K1,O3N3; mp 131') in quantitative yield, and hydrolysis of the latter by heating in acetic-hydrochloric acid generated isomacrorine and succinic acid. These results indicated that isolongistrobine and its dehydro derivative had structures 136 and 137, respectively. Analogously structure 138 was ascribed to longistrobine. Mass and other spectral data are consistent with these assignments (158).
12.
541
UNCLASSIFIED ALKALOIDS
Me 134
135
Me 136
137
138
129. Magnobia coco DC. ( M . pumila Andr.) (Magnoliaceae) (X, 407; XII, 489) Steparine, anolobine, and an unidentified base melting at 181" (159). 130. Mahonia aquifolium Nutt. (Berberis aquifolium Pursh) (Berberidaceae) (IV, 85) dl-Corypalmine and dl-canadine (160). 131. Malacocarpus crithmifolius Fisch. & Mey. (Peganum crithmifolium Auth?) (Rutaceae) Anabazine D (161). 132. Malaxis grandifolia Schlechter (Orchidaceae) (XII, 489) The glycosidic alkaloid grandifoline (amorphous) from this plant was shown to have structure 139 in which R is a 2-O-P-~-glucopyranosyl-L-arabinose residue. Acid methanalysis yielded laburnine and the disaccharide as well as the chroman derivatives of the presumed intermediate methyl ester of 3,5-diisopentenyl-4-hydroxybenzoicacid (162). 133. Maytenus ovatzcs Loes. (Celastraceae)
Two alkaloids, maytoline (C29H3,0,,N; amorphous) (140) and maytine (C,,H,,O,,N; amorphous) (lal), were isolated from this
542
R. R. F. MANSKE
\
co
U 139
ON I
140 141 142 143
R R R
= OH) =H
Rl =
= OH =H ) R ~ = H
plant. Hydrolysis of 140 and 141 yielded maytol(l42) and deoxymaytol (143), respectively. I n addition to exhaustive spectral analyses, the structure of the methiodide of 140 was determined by X-ray crystallography (163). 134. Melicope confusa (Merrill) Liu (Rutaceae) (IX, 229)
Skimmianine, kokusaginine, and a new alkaloid, confusameline (C,,H,O,N; mp 239-240"), were isolated. The last on methylation with diazomethane generates evolitrine and an NMR study of this and the corresponding 0-ethyl derivative point to 144 as the structure of the new alkaloid (164). 135. Melodinus scandens Forst. (Apocynaceae) (XI, 242; XII, 209; XIII, 413)
In addition to a number of already known indole alkaloids this plant yielded meloscandinone of unknown structure and epimeloscine 9-oxide (mp 203-207"; [a]& + 310") (145) (165). 0
144
145
12.
UNCLASSIFIED ALKALOIDS
543
136. Melodorum punctulatum Baill. (Anonaceae) Asimilobine, michelalbine, and liriodenine (166). 137. Menispermum dauricum DC. (Menispermaceae)(VII, 427; 444; IX, 141) Cheilanthifoline, stepholidine, and stephazine along with six yellow crystalline bases have been isolated (16'2'). 138. Merendera jolantae Czerniakowska (Liliaceae) (XI, 412)
Of the approximately 0.40% of total alkaloids in the dried leaves and stalks the main constituent was colchamine. Smaller amounts of colchicine, colchameine, 3-demethylcolchamine, and colchiceine were also isolated (168). 139. Merendera raddeana Regel (XI, 412) Colchicine and a number of known bases of related structure were identified. An apparently new base, merenderin (C21H,,-,0,N; mp 219-220"), was also obtained (169). 140. Mesembrine (IX, 467; XII, 490) By means of labeled tracers and chemical degradations it was shown that the aromatic ring in the Xceletium alkaloids is derived from the aromatic ring of phenylalanine but not of tyrosine and that the perhydroindole moiety is derived from tyrosine and not from phenylalanine. The S-methyl group of L-methionine provides the 0- and N-methyl groups (170). 141. ( + )-Mesembrine (XII, 490) A series of reactions, which ultimately led to a partially asymmetric molecule without intermediate resolution; has been recorded. The penultimate step was the conversion of the amide-aldehyde (146) into the cyclohexenone derivative (147) by heating first with L-proline pyrrolidide and then adding methyl vinyl ketone. Ring closure to 148 was finally achieved by means of ethanolic hydrogen chloride. The result,ing mesembrine (148) was partially optically active and the pure ( + )-base hydrochloride was obtained from it by fractional crystallization (171).
544
R. H. F. MANSKE
142. Mucuna mutisiana DC. (Leguminosae) (XI, 12) I n addition to L-dopa there was isolated ~-3-carboxy-6,7-dihydroxy1,2,3,4-tetrahydroisoquinoline(149) whose structure was confirmed by a synthesis (172). 143. Murraya koenigii Spreng. (Rutaceae) (X, 573; XII, 491; XIII, 281) Continued investigations of this plant uncover still more alkaloids. Mahanimbicine (150)and bicyclomahanimbicine (151)were isolated and their synthesis was achieved from 2-hydroxy-6-methylcarbazole (173). Isomahanimbine (C,,H,,ON; mp 142") (152)and koenimbidine (C,,H,,O,N; mp 225") (153)had their structures determined largely by NMR spectroscopy and by comparison with alkaloids of known structure (174). In the meantime the structure of girinimbine (154)has been confirmed (174) and a synthesis has been reported (175). l-Formyl-2hydroxy-3-methylcarbazole was prepared in two stages from 2-methoxy-3-methylcarbazole. The aldehyde was converted into the pyran derivative 154 by a procedure already known (176)and this compound proved to be identical with girinimbine. By a procedure similar to that used by Crombie (177))condensation of the above-mentioned aldehyde with citral gave the dl-compound 155,melting at 75-76', identical with the racemized natural product. 144. Nectandra pichurium (H.B. & K.) Mez (Lauraceae) (VII, 427; 516; I X , 151) Isoboldine (178). 145. Nelumbo nucifera Gaertn. (Nymphaeaceae) (X, 410)
The embryos of these plants were shown to contain O-methylcorypalline and neferine as well as the phenolic isoliensinine and lotusine (156)(179). 146. Nelumbo nucifera Gaertn. I n addition to the known remerine, nuciferine, O-nornuciferine, and dl-armepavine, there were isolated anonaine, pronuciferine, N-nornuciferine, liriodenine, and O-methylcoclaurine (180). 147. Nigella damascena L. (Ranunculaceae) I n addition to the known damascenine the seeds of this plant yielded damascinine (mp 75-79') whose structure (157)was determined by spectral methods (181).
12.
g;45
545
UNCLASSIFIED ALKALOIDS OMe
CHO
OMe
----_-
0
O
A
H I
Me CHO
146
Me
147
148
L4 149
150
151
153
152
154 155
R = Me R = -CH, .CH, .CH=CMe,
156
148. Nuphur Zuteum Sibth. et Sm. (Nymphaeaceae) (IX, 4 4 1 ) I I
I
I
The new alkaloid, 3-epinuphamine from var. varieguturn, was given the structure shown (158). More recently another pair of sulfurcontaining alkaloids have been isolated. They are glasslike solids6,6'-dihydroxythionuphlutine-A (C,,H,,N,O,S) and -B-whose structures are closely related to neothiobinupharidine (182, 183).
546
R. H. P. MANSKE
149. Ochrobirine (IV, 80; XII, 391) The synthesis, claimed to be stereospecific, was achieved by the method earlier achieved for the synthesis of a base like octobirine without one of the methylenedioxy groups (184). The intermediate diketone (159; R = H ) resulting from the Pictet-Spengler condensation of the appropriate arylethylamine and the ninhydrin was Nmethylated with formaldehyde and formic acid t o 159 (R = Me) (mp 118-122"). Reduction of the latter with sodium borohydride in methanol gave the corresponding dihydroxy compound (mp 185-1 87') which was identical in spectral properties with the natural base (185). 150. Ochrosia vieillardii Guillaumin (Apocynaceae) (XII, 491) Three alkaloids, ellipticine, isoreserpilline, and 1O-methoxydihydrocorynantheol, have been separated from the mixture of bases isolated from this plant (186). 151. Oncinotis inandensis Wood et Evans (Apocynaceae) Inandenine (C23H,,02N3) (amorphous; B .HCl, mp 150-151"; k 5") proved to be an equimolecular mixture of inandenine A and B which was not separated and whose structures are represented by 160 (R = H-2, R' = 0; or R = 0; R' = H-2). Spectral data are in conformity with these structures, and the fragents in the mass spectrograph clearly indicate the two (187). [a]=0
152. Orixajaponica Thunb. (Celastrus orixa Sieb. & Zucc.) (Celastraceae) (111, 69) I n addition to kokusagine which had been obtained from this plant previously there was isolated japonine (Cl,Hl,03N; mp 143") whose structure (161) was determined largely by spectral methods and confirmed by a synthesis (188). 153. Ottonia vahlii Kunth. (Piper oaatum Vahl) (Piperaceae) (I, 170)
Piperovatine was shown, by spectral methods and a Synthesis, to be N-isobutyl-6-p-methoxyphenylsorbamide, p-Me0 CGH, CH, CH: CH CH:CH.CONHBu-iso (189).
.
-
154. Palmeria Species (Monimiaceae) (XII, 492) Laurotetanine and its N-methyl derivative were isolated from P. arfalciana Becc. and P. NGF 24998. The latter also contained another
12.
547
UNCLASSIFIED ALKALOIDS
base whose R, valve coincided with that of laurolitsine. The two alkaloids are also those of P. gracilis Perkins, previously misnamed P. fengeriana Perkins ( 190). 155. Papaver somniferum L. (Papaveraceae) (IV, 112)
Coreximine was shown to be elaborated by this much investigated plant and it was shown to be derived from labeled (k)-reticuline (191). 156. Papaver somniferum L. (XII, 112)
Salutaridine and 13-oxycryptopine were isolated from opium (192). Me HO * CH,
NHMe
‘0) 157
158
159
157. Paracynoglossum imeretinum (Kusnez.) Popov (Cynoglossum imeretinum Kusnez.) (Boraginaceae) By means of thin-layer chromatography it was possible to identify heliosupine, echinatine, and their N-oxides (193). 158. Pauridiantha callicarpoides (Hiern.) Bremek. ( Urophyllum callicarpoides Hiern.) (Rubiaceae)
The two new alkaloids pauridianthine (162) and pauridianthinine (163) are the first known pyridine-harman alkaloids (194).
548
R. H. F. MANSKE
159. Pedicularis olgae Regel (Scrophulariaceae) (X, 575)
A second alkaloid (mp 208'; [a]zO- 15.3") from this plant was given structure 164 in which R + R' are Me and C0,H. Oxidation gave pyridine-3,4-dicarboxyllicacid (195).
OCoMe 162
163
164
160. Peganum harmala L. (Zygophyllaceae) (11,393;111, 102; VIII, 47;
XII, 528) The new alkaloid, peganidine (CI4Hl6O2N2;mp 189'; [.ID 0'; oxime, mp 85'; semicarbazone, mp 204') from this plant has structure 165. Spectral methods were employed in the structural elucidation (196). Also found were dioxypeganine (197) and a new alkaloid, pegamine, whose structure (166) was determined by spectral methods (198).
2N;
-
otg eTCH2)3.0H 0
MeCO CH,
OH
)&:
H
165
I
166
167
NH(CHZ)~-NHZ
I
HO
\
H 168
168a
12.
549
UNCLASSIFIED ALKALOIDS
161. Penecillium concavo-rugulosum Rugulovasine A and rugulovasine B of structure 167 were isolated from cultures of this fungus. Spectral data indicate the structure shown. Hydrogenation gave dihydrorugulovasine C (mp 149"; [a]:& - 2.2") and D (mp 222"; [a]:?, +2.3"), respectively. Base C is convertible, by treatment first with alkali and then with acid, to the cyclic anide 168 (mp 209"; [a]:& - l.Oo), a structure reminiscent of the ergot alkaloids
(199). 162. Pentaclethra macrophylla Benth. (Leguminosae) The alkaloid paucine was shown to have structure 168a on the evidence of mass spectroscopy and upon its degradation to catechol, caffeic acid, and putresine (200). 163. Peripentadenia mearsii (C. T. White) L. S. Smith (Euphorbiaceae) (IX, 269; XI, 486) Two new hydroxytropane alkaloids, ( + )-(3R,6R)-3a-acetoxy-6/3hydroxytropane (C,,H,,O,N; mp 105-106"; [.ID 16") and ( + ) - 2 a benzoyloxy-3/3-hydroxynortropane(C,,H,,O,N; mp 187-188"; [.ID + 68") were isolated. The known tropacocaine was also obtained (201).
+
164. Perriera madagascariensis Courchet (Simarubaceae)
4,7-Dimethoxy-1-vinyl-/3-carboline was isolated along with another basc which appears to be its dimer (202). 165. Phakellia jiabeblata This marine sponge was found to contain the weakly basic guanidine derivative, dibromophakellin (C,,H,,O,Br,; mp 237-245"; [a]g5 - 203") (168b). Its structure was determined by exhaustive spectral methods and the structure of its reduction product, phakellin (C,,H,,ON,; mp 285") was similarly revealed. A monobromo derivative (mp 170-180") was also isolated (203). 166. Phalaenopsis cornu-cervi Blume & Reichb. f. (Orchidaceae) The new alkaloid cornucervine (C,,H,90,N; oil; [a]g2- 4.3") from this plant has structure 169 determined from its spectrum and the products of its acid methanolysis (804).
550
R. H. F. MANSKE
167. Phallaris tuberosa L. (Gramineae) (X, 492; XI, 11; XII, 527)
A reexamination of various strains of this grass has shown that some contain, in addition to the known bases, S-methyl-1,2,3,4-tetrahydro-Pcarboline and its 6-methoxy derivative (205). 168. Phelline collzosc~Labill. (Rutaceae) The seven alkaloids isolated from this plant are homoerythranes and can serve in the study of the taxonomy of this genus (206). Hitherto, alkaloids of the type above had been isolated only from plants of the Leguminosae (Chapter 7 , this volume). The alkaloids of Ph. billardieri (Loes.) Panch. are of a different nuclear type, represented by 169a and 170 (207))and indeed the plant has been relegated to Aquifoliaceae.
& J
CH202C.C(OH)*CH, * CHMe2
H2N