THE ALKALOIDS Chemistry and Physiology
VOLUME XIV
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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.
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United Kingdom Edition published b y ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London N W l
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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
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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
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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
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123 127 134 135 145 146 148 154 154
Alkaloids of Picralirna and Alstonia Species
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J E SAXTON
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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
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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
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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
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I . Occurrence ..................................................... I1. The C16 Aromatic Alkaloids ...................................... I11. The Ct6 Dienone Alkaloids ....................................... IV . Ct2 Alkaloiils of Elaecarpus kaniensis .............................. V Elaeocarpidine ................................................. VI . Biosynthesis ................................................... References .....................................................
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326 327 331 338 343 346 346
CONTENTS Chapter 9
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The Lycopodium Alkaloids
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D B MACLEAN
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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 ....................................................
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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
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V SNIECKUS
I . Introduction and Occurrence ..................................... I1. Securinine-TypeAlkaloids ....................................... I11. Norsecurinine-Type Alkaloids .................................... IV . Synthesis ...................................................... V Biological Activity .............................................. VI . Analytical Methods ............................................. VII Biosynthesis ................................................... References .....................................................
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Chapter 12
425 427 489 495 499 500 500 502
Alkaloids Unclassified and of Unknown Structure
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R . H F MANSKE
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I Introduction ................................................... I1 Plants and Their Contained Alkaloids .............................
..................................................... AUTHORINDEX........................................................ References
SUBJECTINDEX ........................................................
508 508 564 575 598
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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
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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
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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 . . . . . . .
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Contents of Volume II
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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
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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
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1 65 101 119 201 247 313 339 363
Contents of Volume I V 25 . 26 . 27 28. 29
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The Biosynthesis of Isoquinolines BY R . H . F. MANSKE . . . . . Simple Isoquinoline Alkaloids BY L . RETI . . . . . . . . . Cactus Alkaloids BY L . RETI . . . . . . . . . . . . . The Benzylisoquinoline Alkaloids BY ALFREDBURGER . . . . . The Protoberberine Alkaloids BY R . H . F . MANSKE AND WALTER R ASH-
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The Aporphine Alkaloids
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1 7 23 29 77 119
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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 . . . .
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Contents of Volume 38 . 39 . 40 . 41 . 42 43. 44 45 . 46 . 47 . 48.
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1 79 109 141 163 211 229 243 265 295 301
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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
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Contents of Volume V I
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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. .
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Contents of Volume V I I
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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
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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
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Contents of Volume V I I I
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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
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Contents of Volume I X
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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
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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 . . . .
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467 483 517 529 545
Contents of Volume X
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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 . . . . . . . . .
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Contents of Volume X 1. 2. 3. 4. 5. 6. 7. 8.
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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
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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
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CONTENTS OF PREVIOUS VOLUMES
CHAPTER 3. 4. 5. 6. 7.
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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
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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
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-CHAPTER
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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
<
systems derived from
two tryptamine residues. On the basis-of these data structures 83 and 84 are possible ones for this product and, if it is assumed that no skeletal
rearrangement occurs during its formation, structure 80 (or 81) is indicated for roxburghine-D. Even if the remote possibility of rearrangement during the formation of 83 or 84 is allowed, it is still almost certain that roxburghine-D retains the two units, ArCH,CH,N/
\
derived from
tryptamine, from which it follows that the accompanying partial structures are certainly present in the alkaloid; thus accounting for 28
of the 32 hydrogen atoms. A complete and accurate analysis of the NMR spectrum of roxburghine-D, assisted by extensive double and triple resonance experiments, then gave the sequence of the remaining which were shown to be present in a piperidine ring protons (H,,,,) having the conformation 85. I n view of its position, H, can only be the C-3 equatorial hydrogen in a tetrahydro-P-carboline system and a combination of these data together with the partial structures postulated above leads to two possible expressions, 80 and 81, for roxburghine-D. These structures are completely consistent with all the spectrographic data, including the mass spectra, although even this combined information does not allow an unequivocal choice to be made between them. Of the two possibilities, 80 and 81, the former is preferred partly on biogenetic arguments and partly on the basis of the NMR spectra of roxburghine-D and the iodine-sodium acetate product (83 or 84) If vincoside (86) is postulated to be an intermediate in the biosynthesis of the roxburghines, subsequent unexceptional reactions could lead to the biochemical equivalents of 87 and 88; condensation of the last intermediate with tryptamine would then give a compound of structure 80. The NMR spectrum of the dehydrogenation product (83 or 84) indicates that the three protons a t C-14, -17, and -21 are deshielded to a significantly greater extent than the other eight aromatic protons.
152
J. E. SAXTON
The extended conjugated system in 83 is such that effective charge delocalization can occur (cf. arrows in 83) and thus the deshielding is explained. The relative positions of the two nitrogen atoms in 84 are such that in this structure effective charge delocalization is not possible.
86
Vincoside
80
87
Tryptamine
COMe MeO& *CHO 88
The double and triple resonance experiments with roxburghine-D establish that the hydrogen atom at C-15 (H,) is coupled to two hydrogens at C-14 and one at C-20 but there is also a small coupling between H, and the hydrogen atom (H,) at C-17 (J,,,,, = 0.6 Hz). Such an allylic coupling is reasonable on the basis of structure 80 but is much less easily rationalized on the basis of structure 81. Further, the chemical shifts observed for the protons at C-15 and C-20 (6 2.15 and 1.76, respectively) are consistent with an allylic position for the former and an attachment of C-20 to saturated carbon atoms only. The stereochemistry of roxurghine-D follows, in part, also from its NMR spectrum. The observed value of J15,20 is 11Hz which is consistent only with a trans-diaxial arrangement of these hydrogen atoms. Hence the D/E ring junction is trans. Since the hydrogen at C-3 is equatorial (see above), rings C, D, and E must adopt the pseudo conformation; if one then assumes the usual configuration a t (2-15 there are only two probable conformations (89 and 90) for roxburghine-D (strictly a second conformation is possible having the same configuration as 89 at C-19, but this has a cis C’/E ring junction and is probably not favored; similarly, conformation 90 is probably preferred to the alternative
3.
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
153
conformation in which the C'/E ring junction is trans but ring E has now become a boat). A clear decision between 89 and 90 is not possible at present although it should be noted that the chemical shifts of the two protons a t C-21 are very similar indeed ( - 3.0 ppm), whereas a difference of about 1 ppm is normally observed for axial and equatorial protons in this environment (i.e.,adjacent to N b ) .I n conformation90 but not in 89 this difference may be offset by the deshielding effect of the indole rings A'B' on the axial proton a t C-21, the bond to which is parallel to the aromatic plane, and the proton itself is very close to the indole NH group.
89
90
Whatever the correct structure of the dehydrogenation product (83 or 84) may prove to be it is almost certain that it retains only one asymmetric center (C-19). It is therefore of some interest to note that the product from roxburghine-D has [.ID - 520" whereas roxburghinesB, -C, and -E gave products under the same reaction conditions having [.ID + 580", - 670", and + 430", respectively. Owing to the difficulty of obtaining substantial supplies of material, particularly of isomer C,
154
J . E. SAXTON
these determinations were carried out on small amounts of admittedly impure material; furthermore, the products were only slightly soluble in methanol in which the rotations were measured. It is the view of Merlini et al. (14)that the differences in the optical rotations are due to impurities and that the dehydrogenation products from roxburghines-B and -E are identical and enantiomeric with the dehydroroxburghines-C and -D. This accords with the observation that roxburghine-E is converted into roxburghine-B by heating with zinc and acetic acid, conditions which are known to induce epimerization at C-3. Hence roxburghine-B and -E are regarded as C-3 epimers and would be expected to give the same dehydro derivative (14).
VIII. Addendum For a recent confirmation by synthesis of the structure (SO), conformation (89),for roxburghine-D, see H. Riesner and E. Winterfeldt, Chem. Commun. 786 (1972). Further evidence for t,he structures of roxburghine-E (90) ((2-19 epimer of roxburghine-D) and roxburghine-B (C-3 epimer of roxburghine-E) is given by C. Cistaro, L. Merlini, R. Mondelli, and G. Nasini, in Chem. Commun. 785 (1972). The only other major paper published recently in this field describes a stereoselective total synthesis of ( & )-rhynchophylline (1) and (k )-iso-rhynchophylline (2) Y. Ban, M. Set0 and T. Oishi, Tet. Lett. 2113 (1972). REFERENCES E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 16, 436 (1968). E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 16, 20 (1968). E. J. Shellard, Pharm. Weekbl. 106, 224 (1971). E. J. Shellard, J. D. Phillipson, and D. G. Gupta, Planta Med. 17, 146 (1969). E. J. Shellard, J. D. Phillipson, and D. G. Gupta, Planta Mod. 17, 51 (1969). E. J. Shellard and P. J. Houghton, Planta Med. 20, 82 (1971). E. J. Shellard and K. Sarpong, J . Pharm. Pharmacol. 22, 345 (1970). A. N. Tackie, Ph.D. Thesis, University of London (1963). E. J. Shellard and K. Sarpong, J . Pharm. Pharrnacol. 21, 1135 (1969). E. J. Shellard, P. Tantivatana, and A. H. Beckett, Planta Med. 15, 366 (1967). E. J. Shellard and P. Houghton, unpublished work, cited in Tackie (8). E. J. Shellard, J. D. Phillipson, and K. Sarpong, Phytochernistry 10, 2505 (1971). W. F. Trager, C . M. Lee, J. D. Phillipson, R. E. Haddock, D. Dwuma-Badu, and A. H. Beckett, Tetrahedron 24, 523 (1968). 13a. N. An Cu, R. Goutarel, and M. M. Janot, Bull. SOC.Chim. F r . [5] 1292 (1957). 14. L. Merlini, R.Mondelli, G. Nasini, and M. Hesse, Tetrahedron 26, 2259 (1970). 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
3.
ALKALOIDS O F M I T R A G Y N A AND RELATED GENERA
155
15. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 23, 1285 (1970). 16. E. J. Shellard and K. Sarpong, J . Pharm. Pharmacol 23, 559 (1971). 17. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, Planta Med. 14, 266, 277 (1966). 18. A. H. Beckett, E. J. Shellard, J. D. Phillipson, and C. M. Lee, Sci. Pharm. 1, 303 (1965); C A 69, 93665 (1968). 19. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, Pluntu Med. 15, 245 (1967). 20. K. C. Chan, Tet. Lett. 3403 (1968). 21. J. Haginawa, M. Taguchi, and S. Seo, Yakugaku Zasshi 91, 575 (1971). 22. K. C. Chan, Phytochemistry 8, 219 (1969). 23. E. J. Shellard and J. D. Phillipson, Planta Med. 12, 27 (1964). 24. J. Carrick, K. C. Chan, and H. T. Cheung, Chem. Pharm. Bull. 16, 2436 (1968). 25. E. J. Shellard and M. 2. Alam, Planta Med. 16, 127 (1968). 26. E. J. Shellard and M. Z. Alam, J . Chromatogr. 32, 472 (1968). 27. E. J. Shellard and M. Z. Alam, Planta Med. 16, 248 (1968). 28. E. J. Shellard and M. Z. Alam, J . Chromatogr. 32, 489 (1968). 29. E. J. Shellard and M. Z. Alam, J. Chromatogr. 33, 347 (1968). 30. E. J. Shellard and M. Z. Alam, J . Chromatogr. 35, 72 (1968). 31. J. D. Phillipson and E. J. Shellard, J . Chromatogr. 24, 84 (1966). 32. J. D. Phillipson and E. J. Shellard, J . Chromatogr. 31, 427 (1967); E. J. Shellard, J. D. Phillipson, and D. Gupta, ibid. 32, 704 (1968); J. D. Phillipson and E. J. Shellard, ibid. 692. 33. A. H. Beckett and D. Dwuma-Badu, J . Pharm. Pharmacol. 20, 745 (1968). 34. A. H. Beckett, D. Dwuma-Badu, and R. E. Haddock, Tetrahedron 25, 5961 (1969). 35. A. H. Beckett and D. Dwuma-Badu, J . Pharm. Pharmacol. 21, 162s (1969). 36. C. M. Lee, W. F. Trager, and A. H. Beckett, Tetrahedron 23, 375 (1967). 37. See J. E. Saxton, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 10, p. 521. Academic Press, New York, 1968. 38. J. Poisson and J. L. Pousset, Tet. Lett. 1919 (1967). 39. J. L. Pousset, J. Poisson, and M. Legrand, Tet. Lett. 6283 (1966). 40. C. M. Lee, W. F. Trager, and A. H. Beckett, Tetrahedron 23, 365 (1967). 41. A. H. Beckett and A. N. Tackie, Chem. l n d . (London)1122 (1963); J. B. Hendrickson and J. J. Sims, Tet. Lett. 929 (1963); A. H. Beckett, C. M. Lee, and A. N. Tackie, ibid. 1709. 42. N. Finch and W. I. Taylor, J . Amer. Chem. SOC.84, 3871 (1962) 43. E. E. van Tamelen, J. P. Yardley, and M. Miyano, Tet. Lett. 1011 (1963). 44. E. E. van Tamelen, J. P. Yardley, M. Miyano, and W. B. Hinshaw, J . Amer. Chem. Soc. 91, 7333 (1969). 45. W. F. Trager, J. D. Phillipson, and A. H. Beckett, Tetrahedron 24, 2681 (1968). 46. M. Shamma, R. J. Shine, I. KompiS, T. Sticzay, F. Morsingh, J. Poisson, and J. L. Pousset, J . Amer. Chem. SOC.89, 1739 (1967). 47. J. L. Pousset, J. Poisson, R. J. Shine, and M. Shamma, Bull. Soc. Chim. Fr. [5] 2766 (1967). 48. A. F. Beecham, N. K. Hart, S. R. Johns, and J. A. Lamberton, Aust. J . Chem. 21, 491 (1968). 48a. C. Kan-Fan, P. Boiteau, P. Potier, and J. Le Pousset, Phytochemistry, 11,435 (1972). 48b. S. C. Pakrashi and J. Bhattacharyya, Tet. Lett. 159 (1972). 49. A. F. Beecham, N. K. Hart, S. R. Johns, and J. A. Lamberton, Chem. Commun. 535 (1967).
156
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50. E. Winterfeldt, A. J. Gaskell, T. Korth, H. E. Radunz, and M. Walkowiak, Chem. Ber. 102, 3558 (1969). 51. E. J. Shellard, A. H. Beckett, P. Tantivatana, J. D. Phillipson, and C. M. Lee, J. Pharm. Pharmacol. 18, 553 (1966). 52. E. J. Shellard and K. Sarpong, Planta Med. 20, 167 (1971). 53. E. J. Shellard and K. Sarpong, Tetrahedron 27, 1725 (1971). 54. I. Ognyanov, B. Pyuskyulev, M. Shamma, J. A. Weiss, and R. J. Shine, Chem. Commun. 579 (1967). 55. I. Ognyanov, B. Pyuskyulev, I. KompiQ,T. Sticzay, G. Spiteller, M. Shamma, and R. J. Shine, Tetrahedron 24, 4641 (1968). 56. M. Shamma and K. F. Foley, J . Org. Chem. 32, 4141 (1967). 57. M. Plat, R. Lemay, J. Le Men, M. M. Janot, C. Djerassi, and H. Budzikiewicz, Bull. SOC.Chim. Pr. [5] 2497 (1965). 58. S. Z. Kasymov, P. K. Yuldashev, and S. Y. Yunusov, K h i m . Prir. Soedin. 2, 260 (1966); CA 66, 2673 (1967). 59. N. Abdurakhimova, S. Z. Kasymov, and S. Y. Yunusov, Khim. Prir. Soedin. 4, 135 (1968); CA 69, 67587 (1968). 60. E. Z. Dzhakeli and K. S. Mudzhiri, Soobshch. Akad. N a u k Gruz. SSR 57, 353 (1970); C A 73, 25723 (1970). 61. L. Merlini and G. Nasini, cfazz. Chim. Ital. 97, 1915 (1967). 62. E. Wenkert, K. G. Dave, C. T. Gnewuch, and P. W. Sprague, J . Amer. Chem. SOC. 90, 5251 (1968). 63. J. A. Beisler, Tetrahedron 26, 1961 (1970).
---CHAPTER
4--
ALKALOIDS OF PICRALIMA AND ALSTONIA SPECIES J. E. SAXTON Department of Organic Chemistry T h e University Leeds, England I. The Picralima Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Introduction . . . . . . . . . .
11. The Alstonia Alkaloids.
....
157
.............
B. Alstoniline and Alstonilidine . . . . . . . . .
.........................
................................. ...... ..................................
E. Alstonisidine . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Addendum ........... References .................................
170
173 173 177
I. The Picralima Alkaloids A. INTRODUCTION Since the last review on Picralima alkaloids was written (for Volume X) activity in this field has considerably abated and in consequence there is comparatively little new work to be reported. The main features of indole alkaloid biosynthesis have now been elucidated and the reader is referred to Battersby ( 1 )for an authoritative summary of this fascinating topic. Preakuammicine (1) appears to be involved in the direct pathway to the Strychnos, Aspidosperma, and Iboga alkaloids, and although it has not been isolated from Picralima it is appropriate to include it here, and to note that its presence in very young seedlings of Vinca rosea has been established ( 2 ) .Preakuammicine is almost certainly the precursor of akuammicine (2), a transformation which can also be achieved by treatment with base ( 2 ) . Noteworthy are the total syntheses of akuammigine and tetrahydroalstonine ( 3 ) which appeared too late for detailed discussion in Volume X. Subsequently the synthetic route was modified to include ajmalicine,
158
J . E. SAXTON
formosanine, and their epimers ( 4 ) . Some interesting new transformations in the akuammicine-geissoschizine series have been reported (5, 6 ) and the extensive rearrangement which occurs during the zincacid reduction of picraline has been unraveled (7).
C0,Me 1
Preakuammicine
2
Me I
Akuammicine
Me 3 4
Akuammiline; R = CH20Ac Deaoetyldeformoakuammiline;R = H
7a
5 Picraline; R = CH,OAc 6 Picrinine; R = H 7 Picralinal; R = CHO
Dimethoxypicraphylline
New occurrences of the Picraliima alkaloids and their derivatives are occasionally reported; they are summarized in Table I (2, 8-20a). AT,-Methylakuammicine has previously been isolated from the bark of Hunteria eburnea, and it is now shown to be present in the seeds. The occurrence of akuammigine in the leaves of Mitragyna parvifolia collected in the Maharashtra State of India, near Poona, and in Ceylon is of some interest, since it appears not to be present in plants grown
4. ALKALOIDS
159
O F P I C R A L I M A AND A L S T O N I A
TABLE I
Picralima ALKALOIDS REPORTED SINCE1967 Alkaloid Preakuammicine (1) Akuammicine (2) N,-Methyl-( - )-akuammicine (isolated as perchlorate) Sewarine (10-Hydroxyakuammicine) Akuammine Akuammigine
Source
Vinca rosea seedlings V . rosea L. V . herbacea Waldst. et Kit. Hunteria eburnea Pichon seeds Rhazya stricta Decaisne
V . rosea leaves Mitragyna parwifolia (Roxb.) Korth. leaves V . erecta Rgl. et Schmalh. Akuammidine (aerial parts) Voacanga chalotiana Pierre ex Stapf. Melodinus scandens Forst. Conopharyngia durissima Stapf. Akuammiline ( 3 ) Rauwolfia vomitoria Afz. leaves Deacetyldeformoakuammiline(4) Picraline ( 5 ) Aspidosperma rigidum Rusby bark ( sA . laxijhrum Kuhlm.) Deacetylpicraline A . rigidum Rusby Rhazya orientalis A.DC. Picrinine (6) Rauwolfia vomitoria leaves Picralinal (7) Rhazya orientalis Alstonia scholaris R.Br. 10,ll -Dimethoxypicraphylline ("a) Ochrosia balansae (Guillaumin) Baill. (Emxzwatia balalzsae Guillaumin)
Refs. 2 8 8a 9
10, 11, l l a
8 12,13 14 15 15a 16 17 18 18 19 17 19 20 20a
near Cochin in the Kerala State of India (81)or in plants grown in the States of Bihar, West Bengal, Uttar Pradesh (ZZ), Burma, or Cambodia (13).These regional variations in alkaloid content have been summarized twice (23, 24). I n this context it is relevant to note that picralinal and picrinine were isolated (19) from Rhazya orientalis grown in Britain rather than in its natural warm temperate habitat. B. RECENTCONTRIBUTIONSTO THE CHEMISTRYAND SYNTHESIS OF THE Picralima ALKALOIDS
THE
The reduction of akuammicine (2) under new reaction conditions has been investigated and a correlation with geissoschizine achieved ( 5 ) . With zinc and aqueous or methanolic sulfuric acid, akuammicine affords
160
J. E. SAXTON
mainly 2/3,16/3-dihydroakuammicine (25); however, in acetic acid and in the presence of copper sulfate the course of the reduction with zinc is radically altered and a mixture of four products is obtained. Two of these are indoline derivatives; the remaining two &reindoles. The minor indoline, obtained in only 4y0yield, is 2/3,16P-dihydroakuammicine and the major indoline ( 16y0yield) is a new compound, picramicine (8). The two indolic products are deformylgeissoschizine (9) and its C-3 epimer (10). The course of this reduction is best rationalized by assuming C-16 protonation of akuammicine (2) followed by migration of C-3 to C-2 with formation of the intermediate 11. Reduction of 11 with protonation at C-7 then affords picramicine (8) while reduction with simultaneous fission of the 2,16 bond (dotted arrows in 11) leads to deformylgeissoschizine (9). The presence among the reaction products of a very poor yield (1%)of deformyl-3-epigeissoschizine(10)is probably the result of C-3 epimerization of 9 in the acid reaction medium. This reaction course is consistent with the observation that neither 2/3,16/3dihydroakuammicine nor picramicine is further affected by the reaction conditions-hence neither of these compounds is an intermediate in the formation of deformylgeissoschizine and its epimer. However, as expected from the structure proposed, picramicine can be converted into deformylgeissoschizine (9) by treatment with strong base, e.g., potassium t-butoxide (5). The reduction under similar conditions of the indolenine 12, prepared by the action of hydrochloric acid on akuammicine (26), appears to follow an analogous course ( 6 ) .The products here are the 1,2-dihydro derivative of 12 and its N-acetyl derivative together with decarbomethoxypicramicine (13). The complex nature of the reductions that can occur with the Picralima alkaloids is clearly exemplified by the behavior of picraline ( 5 ) toward zinc and hydrochloric acid which results in a profound skeletal modification and formation of an indolic ester (C2,H2,N20,) formulated as 14 ( 7 ) .The ease with which this transformation is effected (optimum yield at - 30") is all the more surprising when it is realized that the overall reaction must involve three carbon-carbon bond cleavages and the formation of one new carbon-carbon bond and of these processes only one, the fission of the 7,16 bond, has a clear precedent. The mechanism tentatively proposed for this reaction involves acidcatalyzed reductive opening of the C-2 to oxygen linkage followed by fission of the 7,16 bond as illustrated in 15. The product (16) of this fragmentation can undergo an internal Michael addition with formation of the new 2,17 bond; reverse Mannich cleavage of the 2,3-bond (17 ---f 18) is not then unexpected. Reduction of 18 a t the 2,7 and 3,4
4. ALKALOIDS
161
O F P I C R A L I M A AND A L S T O N I A
+ayH
Me0,C
Zri
H
Me
//-
BuO MeO-C
H
H
Me
MeO-C
II
H
Me
-t‘
Ok
8
Picramicine
11
I Me 12 I
C0,Me
Deformylgeissoschizine; a-H at C-3 10 Deformyl-3-epigeissoschizine; p-H at C-3 9
QyN Me 13
162
c& :
J. E. SAXTON
Zii
Me
5
Me
15
t-
MeO-C
COzMe 17
16
COzMe 18
5,6
COzMe 14
20
4. ALKALOIDS O F P I C R A L I M A AND ALSSTONIA
163
positions then leads to 19 which, it is proposed, suffers cleavage of the 6,7 bond and simultaneous expulsion of the hydroxyl group with formation of the vinylamine 20. Finally, reduction of the vinylamine system affords the indolic amino ester 14 ( 7 ) . The essential starting material for the total synthesis of ( 5 )-akuammigine (21) and ( & )-tetrahydroalstonine (22) was the tetracyclic unsaturated ketone 23 ( 3 ) .This was prepared by condensation of tryptamine hydrochloride with oxalacetic acid monomethyl ester which gave the tetrahydro-P-carboline 24. Michael addition of methyl vinyl ketone to 24, followed by basecatalyzed cyclization, afforded the P-diketone 25. Reaction of 25 with phosphorus oxychloride in dimethylformamide gave the vinylogous acid chloride 26 which afforded the corresponding chloro alcohol on reduction with lithium aluminum tri-t-butoxyhydride. Hydrolysis and concomitant dehydration of this chloro alcohol then gave the desired unsaturated ketone (23). The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate; however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to N , bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum a t 410 nm presufnably due to the conjugated enone system present in 29. Sodium borohydride reduction of the keto ester 27 gave as the single product the hemiacetal30 via the intermediate &lactone. The fact that the methyl group at C-19 in 30 occupied the preferred equatorial configuration (see 31) was established by spin-decoupling experiments. Irradiation of the signal due to the methyl group resulted in the collapse of the multiplet due to the C-19 hydrogen atom to a doublet with J = 6 Hz which was interpreted as indicating diaxial coupling with the proton at C-20. Similarly the proton a t C-17 was observed as a doublet ( J = 6 Hz) due to diaxial coupling with the proton at C-16. Dehydration of 30 was achieved by means of polyphosphoric acid which gave ( 5 )-akuammigine (21). Dehydrogenation of 21 with lead tetraacetate gave the corresponding tetrahydro salt which, on reduction with sodium borohydride, afforded ( & )-tetrahydroalstonine (22).
164
J. E. SAXTON
0
24
25
I
POCI,IDMF
H y H“’COMe MeO,C/
CH ‘C0,Me
CH MeO,C/ ‘C0,Me
27
28
07%
’
COMe
29
( ~f:)-Akuammigine and ( )-tetrahydroalstonine have also been synthesized by a novel route as part of a large program of synthesis directed toward the Cinchona and heteroyohimbine alkaloids (27, 28). This synthesis is particularly noteworthy for the original method used for the construction of ring E. The first major objective in this approach
4.
165
ALKALOIDS O F P I C R A L I M A AND A L S T O N I A
,.Me 19
’
\
COzMe NH
\
OH 31
30
21
Akuammigine
22
Tetrahydroalstonine
was the cis-N-benzoylmeroquinene methyl ester 36.The starting material, P-collidine (32),was methoxycarbonylated by means of dimethyl carbonate and lithium diisopropylamide and the product hydrogenated to the cis-disubstituted piperidine ester 33.The corresponding N-chloro compound (34),prepared from 33 by reaction with N-chlorosuccinimide, afforded a method for the introduction of the double bond into the ethyl group by means of an ingenious application of the photolytic Loffler-Freytag reaction. Irradiation of 34 in trifluoroacetic acid solution with a medium-pressure mercury lamp gave the trifluoroacetate salt of the o-chloroamine 35,presumably via the radical ion 34a. NBenzoylation of 35 followed by saponification afforded the corresponding N-benzoyl acid which eliminated hydrogen chloride when treated with potassium t-butoxide in dimethyl sulfoxide-benzene. Esterification with diazomethane then gave cis-N-benzoylmeroquinene methyl ester (36)(27). The next stage involved introduction of the formyl group into the ester 36, which was achieved by reaction with bis(dimethylamin0)t-butoxymethane followed by acid-catalyzed hydrolysis of the intermediate vinylogous carbamates. The formyl ester 37 so produced was
166
J. E. SAXTON
subjected t o intramolecular oxymercuration with mercuric acetate in dimethylformamide a t 50°C; reduction with sodium borohydride then gave only the kinetically favored enol ether 38 which lost its N-benzoyl group when reacted with 1 molar equivalent of diisobutylaluminum hydride a t -78OC t o give the free amino ester 39. Alkylation of 39 with tryptophol bromide gave the crystalline 2,3-secoalkaloid 40 which was cyclized by oxidation with mercuric acetate-ethylenediamine tetraacetic acid disodio salt followed by reduction of the iminium c1
Et Me
CHzC02Me
32
33
34
H 35
348
B
COPh
I
CH=CH,
H *' Me02CAc/OH
I
H 37
36
H .*' MeOzC
\ o
38 R = COPh 39 R = H
H
4. ALKALOIDS
167
O F P I C R A L I M A AND A L S T O N I A
intermediates with sodium borohydride. The mixture of products obtained consisted of 43y0 of ( & )-tetrahydroalstonine (22) and lOyoof ( k )-akuammigine (21)which were separated by preparative thin-layer chromatography (28).
C. 10,l 1-DIMETHOXYPICRAPHYLLINE A new alkaloid, 10,ll-dimethoxypicraphylline(7a), has been isolated from the leaves of New Caledonian Ochrosia balansae (20a). I t s constitution was established by borohydride reduction followed by pyrolysis of the hydrochloride of the product which afforded 3-isoreserpiline (40a).The reverse sequence, i.e., the conversion of 3-isoreserpiline into dimethoxypicraphylline, proved not to be possible but it was achieved in low yield starting from the 3-epimer, reserpiline (40b). Oxidation of 40b with lead tetraacetate afforded the 7-acetoxy
1. KBH4/MeOH **
&fe
2 . Pyrolysisof hydrochloride
H-LJ
-*
"'LA
MeO& 7a
Dimethoxypicraphylline
.-Me
MeOzC 40a Isoreserpiline; a-H at C-3 40b Reserpiline; ,%H at C-3
I
T
Pb(OAc),
400
I
T
1. Me1 2. AcOH/NaOAc/H,O
xOAc
168
J. E. SAXTON
indolenine derivative 40c which was converted into its methiodide and heated in aqueous acetic acid containing sodium acetate; dimethoxypicraphylline (7a) was thus obtained in 4y0yield (20a). 11. The Alstonia Alkaloids
A. INTRODUCTION Table I1 (15a, 29-43) lists the Abtonict alkaloids that have been reported during the period under review; included in the table are TABLE I1
Alstonia ALKALOIDS REPORTED SINCE 1968 Alkaloid Alstonine Tetrahydroalstonine
Echitamine
Alstonerine (52) Demethoxyalstophylline ( =alstonerine?) Alstonidine (51) Alstonilidine (50) Veneserpine (45) Venalstonine
Venalstonidine Villalstonine Macralstonine Alstonisidine ( 5 6 ) (Alkaloid A) mp 196-197O Alkaloid C43H50N407, Rhazine (akuammidine) Pioralinal Vincamajine (41) 0-Benzoylvincamajine (42) 0-3,4,5-Trimethoxycinnamoyl vincamajine (43) 0-3,4,5-Trirnethoxybenzoylquebrachidine (44) Pleiocaraamine
Source
Vinca rosea roots V . rosea roots Mitragyna parvifolia Uncaria gambir (Hunt) Roxb. leaves Uncaria species (Herbarium No. P.C.S.M. 2475) Alstonia scholaris roots and root bark A . congemis Engl. bark A. muelleriana Domin A. macrophylla Wall. leaves A. comtricta F. Muell. root bark A . comtricta root bark A . venenata R.Br. stem bark Craspidospermumverticillatum Boj. ex DC. leaves and trunk bark Melodinus scandens Forst. M . scandens A. macrophylla leaves A . muelleriana A. muelleriana bark
Refs. 29 29 29a 29b 29c 30,31 32 33 34 35 35 36 37 15a 15a 34 38 39,40
A . comtricta A. scholaris fruits and trunk bark A. scholaris A . constricta A . macrophylla leaves A. comtricta
35 41 20 35 42 35
A. constricta
35
A . macrowhwlla leaves and fruits
43
4.
169
ALKALOIDS O F P I C R A L I M A AND A L S T O N I A
some new alkaloids together with some known alkaloids isolated for the first time from Alstonia species as well as some well-known alkaloids which have been isolated by modified procedures or from parts of the plant not previously examined. The most important developments in this group would appear to be the isolation and structure determination of alstonerine (33), alstonisidine (39)[the Alkaloid A of Elderfield (441, and alstonilidine (35). For the first time alkaloids related to ajmaline have been isolated from Alstonia species ; these include vincamajine (41) (35), its 0-benzoyl (42) and 0-3,4,5-trimethoxycinnamoyl(43)esters,
41 42 43
Vincamajine; R = Me, R' = H 0-Benzoylvincamajine; R = Me, R' = COPh
O-3,4,5-Trimethoxycinnamoylvincamajine; R = Me,
R1 = COCH=CH OMe
OMe 44
0-3,4,5-Trimethoxybenzoylquebrschidine; R = H, R' = CO A
58
Quebrschidine; R = R' = H
O
w
M
e
OMe
Me?
OH
OMe OMe 45
Veneserpine
46
( - )-Venenatine
170
J. E. SAXTON
and 0-3,4,5-trimethoxybenzoylquebrachidine(44). Little comment needs to be made on veneserpine; since it affords methyl reserpate and methyl myristicinate on methanolysis it must have the constitution 45 (36). I n passing it is worth noting that the absolute configuration of ( - )-venenatine (46) has been established by comparison of its ORD spectrum with those of yohimbinoid alkaloids known to possess /3 hydrogen at C-3 (44).The routes used in the total Synthesis of ( f )-tetrahydroalstonine (3, 28) have been described above.
B. ALSTONILINE AND ALSTONILIDINE A new synthesis of alstoniline (47) has been reported (45) which utilizes the ester 48 prepared earlier by Elderfield and Fischer in their synthesis of alstonilinol (46).I n this earlier work the reductive cyclization of 48 by LiAIH, was accompanied by reduction of the ester function with formation of tetrahydroalstonilinol. This difficulty has been circumvented by reducing the ester 48 with sodium borohydride in a mixture of ether, water, and methanol; the product, tetrahydroalstoniline (as), was then dehydrogenated t o alstoniline (47) by iodine and potassium acetate (45).
48
49
Tetrahydroalstoniline
47
Alstoniline hydroiodide
Is 50
Alstonilidine
4.
ALKALOIDS O F P I C R A L I M A AND A L S T O N I A
171
Alstonilidine (50) (C,3H,,N,06; mp 244-245') is a closely related alkaloid which has recently been isolated from the root bark of Alstonia constricta (35). I t s IR spectrum discloses the presence of NH, unsaturated carbonyl, and ester functions. The mass spectrum gives evidence for two ester groups, present as methoxycarbonyl groups, since important peaks at M f - 5 9 (m/e 359) and M + -118 (m/e 300) are observed. I n accordance with this, alstonilidine can be hydrolyzed t o a yellow acid (C21H,4N,06)whose NMR spectrum contains signals due to a n aromatic methoxyl group but none due to the methoxycarbonyl groups. Aside from these three methoxyl absorptions the NMR spectrum of alstonilidine itself exhibits signals due only to eight aromatic protons, analysis of which indicates the substitution pattern implied in structure 50. The aromatic constituents are thus fully defined and must be attached to each other a t C-3 and C-15, presumably via the carbonyl group observed at 1670 em-l in the I R spectrum (35).
C. ALSTONIDINE The gross structure (51) for alstonidine (no stereochemical detail implied) was proposed as long ago as 1957) ( 4 7 ) but until recently rigorous proof of the nature of the dihydropyran ring residue was lacking. Proof of the structure (51) has now been provided after a detailed examination of the 100 MHz NMR spectra of alstonidine and its 0-acetyl derivative (35). The aromatic signals in these spectra were fully analyzed and assignments were made with the aid of double resonance experiments. The signals due to the methyl groups were obvious as was the singlet due to the C-17 olefinic proton. The remaining nonaromatic signals were complex and, since less overlap of the multiplets was observed, the spectrum of 0-acetylalstonidine in benzene-d, was analyzed. I n this spectrum the protons of the methyl group attached to C-19 resonate as a doublet a t T 8.94 ( J = 6.2 Hz) coupled to an octet at T 5.72 ( J = 6.2, 10.0 Hz) due to the C-19 proton. The magnitude of this second coupling, which is the coupling of the C-19 proton with that a t C-20, is consistent only with a pseudo-transdiaxial arrangement of these protons. The acetoxymethyl group a t C-20 in acetylalstonidine thus occupies the equatorial configuration and it only remains to elucidate the relative configuration at C-15. This was rendered difficult by the fact that the C-15 proton signal is obscured by the methoxycarbonyl signal a t T 6.32, and it was therefore necessary to analyze the complex multiplet at T 8.12 due to the C-20 proton. This signal shows couplings with the nonequivalent
172
J. E . SAXTON
protons of the C-21 methylene group which themselves are observed as quartets centered on T 5.93 ( J = 11.7 and 5.8 Hz) and T 6.23 ( J = 11.7 and 8.5 Hz). The large coupling in these quartets is attributed to geminal coupling of the C-21 protons and thus the smaller couplings are the result of interaction with the C-20 proton. With these values known, a series of theoretical signals for the C-20 proton were calculated using different values for J,,,,, and the computed spectra were compared with the spectrum actually observed. By this means it was 4.2 Hz, a value which is consistent only with a shown that J,,,,, cis relationship of the protons a t positions 15 and 20. The complete relative stereochemistry of alstonidine is thus that shown in structure 51; the absolute configuration has not been formally determined but it
-
COMe
H 51
Alstonidine
52 Alstonerine; R = H 53 Alstophylline; R = OM0
H
Et
54
Alstonisine (Alkaloid C)
55
may be presumed to be that depicted in which the C-15 hydrogen is a, in common with virtually all the other indole alkaloids of the yohimbine and heteroyohimbine series. It is of some interest to note that the stereochemistry a t C-15, C-19, and C-20 in alstonidine is the same as that deduced for its congeners, alstonine and tetrahydroalstonine (35).
4. ALKALOIDS O F
P I C R A L I M A AND A L S T O N I A
173
D. ALSTONERINE mp 172-173"; [a]g5- 195" (EtOH)] Alstonerine (52) [C,,H,,N,O,; [Elderfield's Alkaloid D (all)],a constituent of Alstonia muelleriana, is a new member of the small group of indolohomotropane alkaloids which includes alstophylline (53) and the nonpleiocarpamine portion of villalstonine (33).An isomeric compound, simply referred t o as demethoxyalstophylline, which has recently been isolated from A . macrophylla (34), may be identical with alstonerine but full details of this work are not available. The presence in alstonerine of the ring E functions was deduced from the IR and NMR spectra, and on this basis a structural relationship with alstonisine (alkaloid C) (54) from the same plant or with alstophylline (53) was suspected. This was substantially supported by a comparison of the mass spectrum of alstonerine with that of the ajmaline degradation product 55; the two mass spectra were virtually identical except for the upward displacement by 14 mass units of the molecular ion of alstonerine (52) (M+ 336) and a small peak at m/e 267 derived from it compared with the molecular ion of 55 (M+ 322) and a fragment ion a t m/e 253. No stereochemical conclusions were reached but the similarity in optical rotations suggests that alstonerine may possibly have the same stereochemistry as alstophylline (33).
E. ALSTONISIDINE mp 325"; [.ID - 234" (EtOH)] Alstonisidine (alkaloid A) [C42H48N404; was first isolated by Elderfield and Gilman from the aerial bark of Alstonia muelleriana (48) but its structure (56) hms only recently been elucidated (39). The indoline portion of this structure resembles macroline (57) and may well be derived from it or from a common precursor; the second unit is related to quebrachidine (58) and the linkage between the two components is of a novel kind. The UV spectrum of alstonisidine resembles that of villalstonine and indicates the presence of isolated indole and indoline chromophores. Its IR spectrum contains absorptions due to an ester group and a hydrogen-bonded hydroxyl group but no imino groups. The NMR spectrum shows the presence of seven aromatic protons but no a or /3 indole protons. An ethylidene group is clearly present, together with indole and aliphatic N-Me groups, and a methoxycarbonyl group. One
174
J. E. SAXTON
more signal of importance, the highest, field signal in the spectrum, is a singlet (3H) at T 8.50 ascribed to an amino ketal quaternary methyl group. The majority of the evidence on which the structure of alstonisidine is based was derived from its mass spectrum. The molecular ion (M+ 672.366) establishes the molecular formula (C42H48N404), and the spectrum, in common with the spectra of other alkaloids containing a unit derived from macroline (e.g., villalstonine, macralstonidine), exhibits a base peak at m/e 197 due to the P-carbolinium ion 59 and ions at m/e 308 and 307 resulting from fragmentation t o 60 and 61. The ion 60 is presumably formed by retro Diels-Alder fission of the ring uniting the two monomeric alkaloidal units and 61 very probably by transfer of hydrogen from 60 to its complementary fragment giving also the quebrachidine-related ion 62. One of the two monomeric components in alstonisidine is therefore derived from macroline and, as in the case of villalstonine, it may be concluded that the relatively low-field quaternary methyl group is part of an amino ketal function which is involved in the union between the two halves of the molecule. The ester, hydroxyl, and ethylidene functions are then contained in the nonmacroline part. I n accordance with the presence of only one hydroxyl group, alstonisidine gives a mono-0-acetate devoid of hydroxyl groups and it is therefore reasonable to assume that the remaining oxygen atom is contained in the amino ketal function. This is confirmed by the lithium aluminum hydride reduction of alstonisidine which gives a triol analogous to the reduction of villalstonine to villalstonine triol (49). The nonmacroline component of the alstonisidine molecule gives rise in the mass spectrum to fragment ions at m/e 222, 221, and 220-ions which are characteristic of alkaloids belonging to the quebrachidine group. These ions are derived from rings C, D, and E; thus the peak at m/e 222 (CI2Hl6NO3)is attributed to the fragment 63 which is formed along with the complementary ion 64 by fragmentationrearrangement of ring C of the quebrachidine portion of the alstonisidine molecule. Other features of the mass spectra of alstonisidine and quebrachidine are similar. Thus neither alkaloid appears to lose water or OH on electron impact. Both spectra, however, show peaks at M-31 and M-32, the latter resulting from loss of methanol due to the proximity of the hydroxyl and methoxycarbonyl groups. The resulting ion 65 can further fragment at the 5,16 bond with subsequent loss of C2H0 to give an ion (66) responsible for a peak at m/e 599. Cleavage of the oxygen-containing ring (retro Diels-Alder?) and aromatization
4. ALKALOIDS
O F P I G R A L I M A AND A L S T O N I A
175
COaMe
C0Me
56 Alstonisidine
57
Macroline
-
Me
176
J. E. SAXTON
Me
65
QO,Me
Eq, Me
--.
Me
of the quebrachidine-derived fragment leads also to a peak at m/e 403 attributed to the ion 67. Both quebrachidine and alstonisidine decompose to give some formaldehyde when boiled with hydrochloric acid. This is presumably formed by acid-catalyzed reverse aldol fission of the P-hydroxyester system present in these alkaloids followed by elimination of formaldehyde from the indoline aldehyde (68) so produced (39). I n connection with the biogenetic origin of alstonisidine it is of interest to note that O-benzoylvincamajine (42) has been shown to occur in the closely related A . macrophylla ( 4 2 )and trimethoxybenzoylquebrachidine (44) in A . constricta (35).It is thus possible that alstonisidine arises by Mannich condensation of macroline (57) with quebrachidine t o give an intermediate similar to 69, which is then converted into alstonisidine by closure of the amino ketal function (39).
177
4. ALKALOIDS OF P I C R A L I M A AND A L S T O N I A
/
Me
MI3
58
68
57
56
III. Addendum Since the above account was written the following important papers have been published: Alkaloids of Alstoniu muelleriuna. R.C. Elderfield and R.E. Gilman, Phytochemistry, 11, 339 (1972). Biomimetic Synthesis of the Bisindole Alkaloid Villalstonine. D.E. Burke and P.W. Le Quesne, Chem. Commun. 678 (1972).
178
J . E. SAXTON
Biomimetic Synthesis and Structure of the Bisindole Alkaloid Alstonisidine, D.E. Burke, J.M. Cook, and P.W. Le Quesne, Chem. Commun. 697 (1972). REFERENCES 1. A. R. Battersby, in “The Alkaloids” (J.E. Saxton, ed.) Vol. 1, pp. 31-47. Chemical Society, London, 1971. 2. A. I. Scott and A. A. Qureshi, J . Amer. Chem. SOC.91, 5874 (1969). 3. E. Winterfeldt, H. Radunz, and T. Korth, Chem. Ber. 101, 3172 (1968). 4. E. Wintcrfeldt, A. J. Gaskell, T. Korth, H. Radunz, and M. Walkowiek, Chem. Ber. 102, 3558 (1969). 5. W. B. Hinshaw, J. LBvy, and J. Le Men, Tet. Lett. 995 (1971). 6. J. LBvy, P. MaupBrin, M. DO6 de Maindreville, and J. Le Men, Tet. Lett. 1003 (1971). 7. A. Z. Britten, J. A. Joule, and G. F. Smith, Tetrahedron 23, 1971 (1967). 8. S. Kohlmunzer and H. Tomczyk, Diss. Pharm. Pharmacol. 19, 213 (1967); C A 67, 29850 (1967). 8a. A. M. Aliev and N. A. Babaev, Farmatsiya (Moscow) 18, 28 (1969); C A 72, 15711 (1970). 9. L. Olivier, F. Quirin, B. C. Das, J. LBvy, and J. Le Men, Ann. Pharm. Fr. 26, 105 (1968). 10. S. Siddiqui, Y. Ahmad, and M. I. Baig, Pak. J . Sci. I n d . Res. 9, 97 (1966). 11. Y . Ahmad, P. W. Le Quesne, and N. Neuss, Chem. Commun. 538 (1970); J . Pharm. Sci. 60, 1581 (1971). l l a . J. R4. Karle and P. W. Le Quesne, Chem. Commun. 416 (1972). 12. E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 16, 20 (1968). 13. E. J. Shellard, J. D. Phillipson, and D. Gupta, Planta Med. 17, 51 (1969). 14. V. M. Malikov, P. K. Yuldashev, and S. Yu Yunusov, Khim. Prir. Soedin. 2, 338 (1966); C A 66, 65684 (1967). 15. J. C. Braekman, M. Tirions-Lampe, and J. Pecher, Bull. SOC.Chim. Belg. 7 8 , 523 (1969). 15a. H. Mehri, M. Plat, and P. Potier, Ann. Pharm. Fr. 29, 291 (1971). 16. J. J. Dugan, M. Hesse, U. Renner, and H. Schmid, Helv. Chim. Acta 52, 701 (1969). 17. J. L. Pousset, Trav. Lab. Matiere Med. Pharm. Galenique Fac. Pharm. Paris 52, Part 11, 13 (1967); C A 70, 88034 (1969). 18. R. R. Amdt, S. H. Brown, N. C. Ling, P. Roller, C. Djerassi, J. M. Ferreira, B. Gilbert, E. C. Miranda, S. E. Flores, A. P. Duarte, and E. P. Carrazzoni, Phytochemistry 6, 1653 (1967). 19. D. A. Evans, J. A. Joule, and G. F. Smith, Phytochemistry 7, 1429 (1968). 20. R. C. Restogi, R. S. Kapil, and S. P. Popli, Ezperientia 26, 1056 (1970). 20a. J. Bruneton, J. L. Pousset, and A. Cave, C . R. Acad. Sci., Ser. C 273, 442 (1971). 21. E. J. Shellard and J. D. Phillipson, Planta Med. 12, 160 (1964). 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, Planta Med. 17, 146 (1969). 24. E. J. Shcllard, Pharm. Weekbl. 106, 224 (1971). 25. P. N. Edwards and G. F. Smith, J . Chem. SOC.,London 152 (1961). 26. G. F. Smith and J. T. Wrbbel, J . Chem. Soc., London 792 (1960). 27. M. Uskokovic, C. Reese, H. L. Lee, G. Grethe, and J. Gutzwiller, J . Amer. Chem. SOC.93, 5902 (1971). 28. J. Gutzwiller, G. Pizzolato, and M. Uskokovic, J . Amer. Chem. SOC.93, 5908 (1971).
4. A L K A L O I D S
O F P I C R A L I M A A N D ALSTONIA
179
29. A. Bonati and E. Pesce, Pitoterapia 37, 98 (1966); C A 69, 65104 (1968). 29a. E. J. Shellard and P. Houghton, unpublished work, cited in Shellard (24). 29b. L. Merlini, R. Mondelli, G. Nasini and M. Hesse, Tetrahedron 26, 2259 (1970). 29c. K. C. Chan, Phytochemwtry 8, 219 (1969). 30. S. K. Talapatra and B. Talapatra, J . Indian Chem. SOC.44, 639 (1967). 31. R. N. Chakravarti, D. Chakravarti, and R. Sur, Bull. Calcutta Sch. Trop. Med. 16, 81 (1968); C A 71, 3529 (1969). 32. L. N. Prista, M. A. Ferreira, A. C. Alves, and A. S. Roque, Garcia de Orta 13, 571 (1965); C A 68, 46435 (1968). 33. J. M. Cook, P. W. Le Quesne, and R. C. Elderfield, Chem. Commun. 1306 (1969). 34. G. D. Manalo, Natur. A p p l . Sci. Bull. 20, 225 (1967); CA 71, 57585 (1969). 35. W. D. Crow, N. C. Hancox, S. R. Johns, and J. A. Lamberton, Aust. J . Chem. 23, 2489 (1970). 36. A. Chatterjee, P. L. Majumder, and B. C. Das, Chem. I n d . (London) 1388 (1969). 37. C. Kan Fan, B. C. Das, P. Potier, J. Le Men, and P. Boiteau, Ann. Pharm. Fr. 26, 577 (1968). 38. J. M. Cook and P. W. Le Quesne, Phytoehemistry 10, 437 (1971). 39. J. M. Cook and P. W. Le Quesne, J . Org. Chem. 36, 582 (1971). 40. R. C. Elderfield, Amer. Sci. 48, 193 (1960). 41. A. Chatterjee, B. Mukherjee, S. Ghosal, and P. K. Banerjee, J . Indian Chem. SOC. 46, 635 (1969). 42. B. Mukherjee, A. B. Ray, A. Chatterjee, and B. C. Das, Chem. I d . (London) 1387 (1969). 43. G. D. Manalo, Philipp. J . Sci. 97, 259 (1968); C A 74, 84010 (1971). 44. W. Klyne, R. J. Swan, N. J. Dastoor, A. A. Gorman, and H. Schmid, Helv. Chim. Acta 50, 115 (1967). 45. J. A. Beisler, Chem. Ber. 103, 3360 (1970). 46. R. C. Elderfield and B. A. Fischer, J . Org. Chem. 23, 332, 949 (1958). 47. H. Boaz, R. C. Elderfield, and E. Schenker, J . Amer. Pharm. Ass. 46, 510 (1957). 48. R. E. Gilman, Diss. Abstr. 20, 1578 (1959). 49. M. Hesse, F. Bodmer, C. W. Gemenden, B. S. Joshi, W. I. Taylor, and H. Schmid, Helv. Chim. Acta. 49, 1173 (1966).
This Page Intentionally Left Blank
-CHAPTER
5-
THE Cinchona ALKALOIDS M. R. USKOKOVI~ AND G . GRETHE Chemical Research Department Hoffmnn-La Roche Ino. Nutley, New Jersey
I. Introduction ...................................................... 11. Isolation .......................................................... 111. Syntheses ......................................................... A. Reinvestigation of the Rabe-Woodward Synthesis of Quinine ......... B. New Syntheses of Cinchona Alkaloids .............................. IV. Biosynt,hesis ....................................................... V. ConGguration of Cinchonamine at C-3 ................................. VI. Miscellaneous ...................................................... VII. Pharmacology of Cinchona Alkaloids.. ................................. References
........................................................
181 181 182 183 186 209 217 219 220 222
I. Introduction
Since the appearance of the last review on Cinchona alkaloids in Chapter 3 of Volume XI in this treatise, major progress has been made in the synthesis and biosynthesis of these alkaloids. This review will therefore focus the attention on these particular aspects of Cinchona alkaloid chemistry.
11. Isolation
Generally, the Cinchona alkaloids are found in the bark and leaves of Cinchona and Remijia species. Recently, however, small amounts of quinine and cinchonine have been isolated from the heartwood of Cinchona ledgeriana Linn ( 1 ) . From a chemotaxonomic point of view it is of interest to note that the distribution of the Cinchona alkaloids is not restricted to the aforementioned species. Quinidine has been isolated, although in small quantities, from the bark of two plants of the Anonaceae family,
182
M. R. USKOKOVIC AND G. GRETHE
Enantia polycarpa Engl. et Diels and E. pilosa Exell. (2, 3 ) ) which principally afford protoberberine alkaloids. Furthermore, cinchonidine and other Cinchona alkaloids have been extracted from the leaves of Olea europaea L ( 4 ) . One new alkaloid, dihydroquinamine (1))has recently been isolated from the leaves of Isertia hypoleuca Benth ( 5 ) . This is the first plant which contains a 2,2'-indolylquinuclidine alkaloid as the major alkaloid. The crystalline alkaloid C,,H,,O,N,; (mp 154-156') shows color reactions characteristic of indole alkaloids. The UV spectrum (CH,OH), 242 nm (e 8500) and 300 nm (c 2600), suggests a dihydroindole chromophore (6). Both the IR spectrum of 1 and the MS fragmentation pattern are closely related to those of quinamine. The molecular ion peak is
1
observed at m/e 314, and other characteristic peaks appear at m/e 297, 285, 138, 123 (base peak), and 110. The spectral evidence in support of structure 1 for the new alkaloid was corroborated chemically by methods paralleling those previously reported for the structure elucidation of quinamine. The most typical methods were the LiAlH, reduction ( 7 ) of 1 to dihydrocinchonamine and the reverse reaction with peracetic acid (8).
111. Syntheses
The classic work in the synthesis of Cinchona alkaloids, which was initiated in the 1920s by Rabe and his co-workers and completed in the 1940s by Woodward and Doering, is described fully in a previous chapter (9). After a dormant period of more than 20 years in this field, interest was renewed in these alkaloids because of their antimalarial properties. Shortages of the Cinchona alkaloids from natural sources led to new efforts at total synthesis.
5.
183
THE C I N C H O N A ALKALOIDS
A. REINVESTIGATION OP THE RABE-WOODWARD SYNTHESIS OF QUININE
I n the Rabe-Woodward synthesis (9) the intermediate quinotoxine (6) was obtained by a Claisen ester condensation with quininic acid ethyl ester and racemic N-benzoylhomomeroquinene ethyl ester (4) followed by resolution. A significant improvement (10)in the preparation of quinotoxine (6) was made possible by an efficient synthesis of the optically active ester 4 which is discussed later in this section. Furthermore, a variation in the formation of 6 avoided the loss of one carbon inherent in the original procedure. This was accomplished by condensation of the ester 4 with 6-methoxy-4-quinolyllithium (3)to give N-benzoylquinotoxine [5; mp 112-113"; [a]g5 + 40.59" (CH,OH); hydrochloride, mp 202-204"; + 45.38' (CH,OH)] which afforded 6 on hydrolysis. The formation of the quinuclidine moiety in the Rabe-Woodward synthesis was also reinvestigated (11).The presence of the vinyl group
2
R=Br
3 R=Li
4
J
cH3013fJ 5
6
184
z’cl M. R. U S K O K O V I ~AND G. GRETHE
CH30
‘
N
-
/
7
p
P
0
0
”
iI
8
H
cH30133
CH30
+
10
Quinine
11
Quinidine
HP cH3013f!J H
H
H
N
@ H N
+
12
9-epi-Quinine
13
SCHEME 1
9-epi-Quinidine
5.
185
THE CINCHONA ALKALOIDS
in quinotoxine (6) significantly limited the use of halogenating agents in the cyclization to quininone (8) and quinidinone (9) (Scheme 1). However, N-chloroquinotoxine (7)could be readily prepared by reaction of 6 with sodium hypochlorite. The cyclization of 7 to 8 and 9 was effected with 1 0 0 ~ ophosphoric acid followed by basic workup. This cyclization reaction presumably proceeds via intramolecular a-chlorination with the chloroaminium ion 14 acting as a source of C1+. The intermediacy of 2-chloroquinotoxine (15) is supported by effecting the cyclization to 8 and 9 with an external chloramine-N-chlorodiisopropylamine-in concentrated phosphoric acid.
14
15
A peculiar property of quininone (8) and quinidinone (9) is their easy epimerization which results in a characteristic mutarotation (9). I n equilibrated solutions 8 and 9 exist in an approximately 1:1 mixture. The half-life of the equilibration of the dihydro analog of 9 was determined in various solvents (11).It ranged from 24 min in ethanol to 24 hr in cyclohexane as determined by measuring the rate of mutarotation. However, essentially complete conversion of quininone (8) into the less soluble quinidinone (9) can be effected by careful crystallization. The configuration of two [i.e., the 3(R),4(S) centers] of the four asymmetric carbon atoms of quinine (10) and its diastereomers 11-13 is controlled by the configuration of the starting N-benzoylhomomeroquinene ethyl ester (4) and the configuration of the two remaining centers at C-8 and C-9 is fixed in the last step of this synthesis. Reduction of a mixture of ketones 8 and 9 with diisobutylaluminum hydride in benzene leads selectively to the C-8--C-9 erythro pair, quinine [lo; 8(S),9(R)]and quinidine [ll:8(R),9(S)],respectively. This reducing agent presumably acts first as a Lewis acid which complexes with the quinuclidine nitrogen. The resulting complexes 16 and 17 are probably responsible for the high stereoselectivity of the subsequent reduction step. Conversely, sodium borohydride reduction of the pure quinidinone
186
M. R. U S K O K O V I ~AND
a. GRETHE
(9) in ethanol gave stereoselectively the C-S-C-9 threo pair, 9-epiquinine [12;S(S),S(S)]and 9-epi-quinidine [13; S(R),9(R)]in high yield. This indicates that under these conditions the ketone 9 is first partially epimerized at C-S and then the ketone grouping is reduced by hydride attack from the less hindered side.
17
16
B. NEWSYNTHESES OF Cinchona ALKALOIDS Several new syntheses of quinoline and indole Cinchona alkaloids were reported in the last few years. I n these synthetic routes the quinuclidine moiety of the alkaloids was derived from various synthetic meroquinene derivatives 18. These new syntheses all proceed through intermediates of general formula 19 which are characterized by a properly positioned functional group (i.e., X) which facilitates the formation of quinuclidine ring 20.
/ 19
18
20
5.
187
THE C INC HONA ALKALOIDS
1. Synthesis of Meroquinene
Meroquinene (18; R, = H; R, = OH) was previously known only as a degradation product of Cinchona alkaloids (9). Recently N-benzoylmeroquinene (30) was synthesized by two methods (12, 13). One (12) of these methods (Scheme 2 ) employs the photolytic Loffler-Freytag
bCH3 COOCH,
(CH3O).CO,
21
k c H 3
I
H
22
A
COOCH,
H
k
C’H H
23
H
3
b H CH3 3
N
N
H
H
I
I
24
25
I
Hb;H3 c1
I
I
c1
h
27
/
26
H
.CF3 COOH
H
C
l
H
d
“.H b
“H
A
ACsH,
0 ’
28 29
0 ’
R = CH, R = H
30 31 SCHEDlE
2
CsH,
R = H R = CH,
188
M. R. USKOKOVIC
AND G . GRETHE
reaction in the formation of the vinyl side chain from an ethyl group. The saturated precursor, racemic cincholoipon methyl ester (23) obtained in high yield from P-collidine (21),was resolved with d- and I-tartaric acid into the pure 3(R),4(S)-enantiomer [24;hydrochloride, mp 174.5-175.5"; [a]g5 - 8.3" (CH,OH)] and the 3(S),4(R)-enantiomer [25;hydrochloride, [a];5 + 8.3" (CH,OH)]. An efficient rearrangement of the N-chloramine 26, which was obtained by chlorination of 24 with N-chlorosuccinimide, was effected by photolysis in trifluoracetic acid solution. Benzoylation of the resulting trifluoroacetate salt 27 led to the chloroethyl derivative 28 in 84y0 overall yield from 24.Elimination of hydrogen chloride from the corresponding acid (29)was porformed with potassium t-butoxide in DMSO-benzene at 70°C to give in high yield A?-benzoylmeroquinene [30; mp 115-117'; [a]g5 +49.77" (CH,OH)]. The methyl ester 31 was obtained on treatment with diazomethane. The natural enantiomer of N-b,enzoylhomomeroquinene [33;mp 132134"; [a]g5 +64.31" (CH,OH)] and its ethyl ester [a;[a]i5 +35.8" (CH,OH)] were synthesized by the same method starting from homocincholoipon ethyl ester (32)(10). COOC2H5
-
&CH3
H &
1
H I
'0 32
C6H5
33 R = H 4 R = CzH5
I n the second reported synthesis (13) (Scheme 3) racemic N-benzoylmeroquinene (42;R = H) was obtained from hexahydroisoquinolone 34.The cis vinyl and acetic acid side chains were formed by a sequence of reactions including stereoselective hydrogenation, Schmidt rearrangement, and pyrolytic N-nitrosolactam fragmentation. Hydrogenation of 34 in ethanolic hydrochloric acid over a rhodiumon-alumina catalyst afforded predominantly the cis-octahydroisoquinolone 35. Rearrangement of 35 with sodium azide in polyphosphoric acid gave rise to a 2:l mixture of the seven-membered lactams 36 and 37. The structure assignment for the lactam 36 emerged from
42
34
38
1
I
43
SCHEME 3
39
44
190
M. R. U S K O K O V I ~ AND G. GRETHE
an investigation of the Schmidt rearrangement of the unsaturated ketone 34 in which case the conjugated lactam 38 was obtained as a major product. The enamino lactam 39 was isolated as a minute byproduct. Hydrogenation of 38 over a rhodium-on-alumina catalyst gave exclusively the desired cis-lactam 36. Conversion of lactam 36 into racemic N-benzoylmeroquinene and its esters (42) was accomplished by two routes. Opening of the lactam ring with boiling ethanolic hydrogen chloride led to the amino ester 43 (R = CzH5; X = NH,) which was transformed by pyrolysis of the corresponding tertiary N-oxide into racemic N-benzoylmeroquinene ethyl ester [42; R = C,H5; rnp 67-68']. A more efficient conversion of the lactam 36 into racemic N-benzoylmeroquinene [42, R = HI was achieved via pyrolysis of the N-nitrosolactam 40. When heated at 125OC compound 40 rearranged to the diazolactone 41 which fragmented with extrusion of nitrogen to give a mixture of 42 (R = H) and the seven-membered lactone 44 in 50y0 and 307, yields, respectively. Hydrolysis of the lactone 44 gave the hydroxy carboxylic acid 43 (R = H; X = OH), which was converted into racemic N-benzoylmeroquinene methyl ester 142; R = CH,; mp 57-58'] by a sequence of reactions including esterification, tosylation, exchange of the tosyloxy group with iodine, and elimination. Although the synthesis of optically active N-benzoylmeroquinene (30) by t,he last route has not been performed, the intermediate cis-2benzoyloctahydro-6( 2H)-isoquinolone (35) has been resolved recently (14).This was accomplished by anaerobic reduction with Sporotrichum exile in which the 4a(S),Sa(R)-enantiomer51 is reduced six times more rapidly than the other enantiomer. This process in combination with chromic acid oxidation of the derived alcohol gave approximately 70% optically pure enantiomers. Resolution was completed by recrystallization from benzene in which the racemic form is significantly more soluble. The absolute configurations and optical purity of these enantiomeric ketones were confirmed by obtaining the 4a(S),Sa(R)enantiomer 51 from naturally occurring cinchonine (45) via meroquinene t-butyl ester (47) (15)by the following sequence of reactions which did not affect the configuration at the center corresponding to C-4a of 51 (Scheme 4). N-Benzoylmeroquinene (30), obtained from 47 by benzoylation and hydrolysis, was cyclized in polyphosphoric acid to give an equilibrium mixture (2:5) of cis and trans enones, 49 and 50. Catalytic hydrogenation of 49 gave the optically pure 4a(S),Sa(R)octahydroisoquinolone 5 1 which exhibited the same melting point and rotation as the specimen obtained by resolution.
5.
191
THE C I N C H O N A ALKALOIDS
__f
"H
I
H 47
45
COOH
'
AC,H,
0
48
30
;,:::-;:B -
*.
N
'
A
0
CBH5
'
49
'
ACBH5
0
50
ACsHs
0
51
SCHEME 4
192
M. R. USKOKOVI~! AND G. GRETHE
2. Formation of Meroquinene Derivatives
Meroquinene aldehyde and meroquinene alcohol, which were also employed in the synthesis of Cinchona alkaloids, were prepared as described below. Reduction of N-benzoylmeroquinene methyl ester (31) with diisobutylaluminum hydride in toluene at - 78OC (16) and subsequent benzoylation of the crude amino aldehyde 53 gave the liquid
I
H
OAR
53
54 55
H &
COOC2Hs
H
b
-
R = CsH5 R = CH3
H &
_3
I
I
I
H
H 52
COOC2H5 56
57
I
I
&
0 59
60
R = CsH5 R = CH,
I
COOC2H5 58
A'-benzoylmeroquinene aldehyde (54).Acetylation of 53 led to AT-acetyl aldehyde 55 (17).Reduction of 31 or 52 with an excess of diisobutylaluminum hydride or with lithium aluminum hydride (18) yielded meroquinene alcohol (56) from which the urethano alcohol 57 was formed. Oxidation with DMSO-DCC gave the urethano aldehyde 58. Benzoy-
5.
193
THE CINCHONA ALKALOIDS
lation and acetylation of 56 gave the N-benzoyl alcohol 59 and N acetyl alcohol 60, respectively. 3. Synthesis of Quinotoxine from Meroquinene Alcohol
The N-benzoylmeroquinene alcohol tosylate (61) was used in a new synthesis of quinotoxine (6) (Scheme 5) (19). The most interesting
A.C,H,
62
0’
R = H
63 R = Li
61
64 65
R = COC6H5 R = H
J HO
R = COC6H5 67 R = H
u
5
66
SCHEME 5
6
R = COCBH5 R = H
194
M. R. U S K O K O V I ~ AND G . GRETHE
aspect of this synthesis is the triplet oxygen hydroxylation of deoxyquinotoxine (65)obtained by condensation of 61 with B-methoxylepidyllithium (63) followed by hydrolysis (64 + 65). The epimeric amino alcohols 67 were oxidized further to quinotoxine (6) by a modified Oppenauer method. Analogously N-benzoyldeoxyquinotoxine (64) was converted into N-benzoylquinotoxine (5). 4. Quinuclidine Ring Formation via Vinylquinoline Intermediates
Several new synthetic approaches to the quinine system from meroquinene have a common quinuclidine ring-forming process (17, 20, 21). This process involves the intramolecular addition of the secondary amine function to the double bond conjugated to the quinoline ring
(e.g., 68) to form a mixture of deoxyquinine (69, 8P-H) and deoxyquinidine (69; 8a-H). Base-catalyzed oxygenation of 69 with molecular oxygen in the presence of potassium t-butoxide in DMSO/t-butyl alcohol (20) or in DMF/t-butyl alcohol containing triphenylphosphine (21) led to a readily separable mixture of the erythro isomers quinine (10) and quinidine (11). Only very small amounts of the threo compounds 9-epi-quinine (12) and 9-epi-quinidine (13) were found in these oxygenation reactions. The epimeric vinylquinolines 68 were obtained by several routes. I n the first route (20) (Scheme 6) N-benzoylmeroquinene methyl ester (31) was condensed with 6-methoxylepidyllithium (63) in tetrahydrofuran to give the N-benzoylketone 70 in high yield. Reduction of the ketone and the removal of the N-benzoyl group of 70 was effected with diisobutylaluminum hydride in toluene. This led to a 3 : 2 mixture of
5.
195
THE C I N C H O N A ALKALOIDS
the C-2 epimeric amino alcohols 71 which was also obtained by condensation of 63 with the N-benzoyl aldehyde 54 followed by hydrolysis. The epimeric ratio of 71 was determined by NMR analysis of the corresponding 0-acetates 72 obtained by exposure of 71 to acetic acid containing 10% boron trifluoride etherate. The alcohols 71 on heating in benzene-acetic acid underwent elimination to the epimeric vinylquinolines 68 which cyclized to a mixture of deoxyquinine and deoxyquinidine (69).Likewise, heating the acetate mixture 72 in boiling
“cCOOCH,
A
CBH5
31 1.63
4
6-:H cH30133 cH30a 7LH5 H
70
2
OH
71
/
F’H H
68
/\OAc
72
SCHEME 6
69
196
M. R. U S K O K O V I ~ AND G. GRETHE
benzene-acetic acid-sodium acetate also afforded the deoxyquininedeoxyquinidine mixture (69). I n two other synthetic approaches (Scheme 7) the vinylquinolines 68 were formed by a Wittig reaction. The Wittig reagent 74 (21) was
78
55
SCHEME I
obtained from the bromide 73 which in turn was derived from meroquinene alcohol (60). Condensation of 74 with quininaldehyde 75 formed a &,trans mixture of N-acetylvinylquinolines 78. This mixture was converted into the pure trans isomer by treatment with acetic acid. Conversely, the trans material can be converted largely into the cis isomer photochemically, The N-acetylvinylquinolines 78 were also obtained from meroquinene aldehyde (55) and the quinoline Wittig
5.
197
THE C I N C H O N A ALKALOIDS
reagent 77 which was preformed from 4-chloro-6-methoxyquinoline (76) and 2 moles of methylenetriphenylphosphorane ( 1 7 ) .The alkaline hydrolysis of 78 in aqueous alcohol led to amino olefin 68 which under these reaction conditions cyclized to a mixture of deoxyquinine and deoxyquinidine (69). 5. Quinuclidine Ring Formation via Aminoepoxides
This synthetic approach to quinine and its diastereomers is based on a simultaneous formation of a quinuclidine ring and a hydroxyl group by intramolecular epoxide opening with the piperidine nitrogen. This process results in an inversion a t (2-8.
9(R),S(R) 9(S),S(S) 81 9(S),S(R) 82 9(R),8(S)
79
80
-
9(R),S(S) = quinine(l0) quinidine (11) 9(S),8(S) = 9-epi-quinine (12) 9(R),S(R) = 9-epi-quinidine (13)
4 9(S),S(R)=
__f
__+
A mixture of all four aminoepoxides 79-81 was obtained in a nonselective fashion from the N-benzoyl ketone 70 (20).Conversion of this ketone into a mixture of diastereomeric N-benzoyl epoxides 84 was
cH30Q(3 83
84
198
M. R. U S K O K O V I ~AND G. GRETHE
J1\ 5
+yAc6H5
0
?2fCs
cH3073 86
H
+ CH30
CH30
R = COCsH, 81 R = H
90
82
R = COC,H, R = H
9-epi-quinine
13
9-epi-quinidine
89
12
SCHEME 8
5.
THE C I N C H O N A ALKALOIDS
CH=S(C,H5),
199
(CHO
I
93
OACH, 55
t
94 96
R = COCH, R = H
95
97
R=COCH, R = H
99
98
SCHEME 9
200
M. R. USKOKOVI~ AND G. GRETHE
effected by bromination with N-bromosuccinimide to a-bromoketones 83 followed by sodium borohydride reduction. Reductive debenzoylation with 1 molar equivalent of diisobutylaluminum hydride in toluene at - 78OC furnished the oily mixture of aminoepoxides 79-82. Heating of this mixture with toluene-ethanol (19:l) afforded 1307, of quinine (lo), 24y0 of quinidine (ll),18% of 9-epi-quinine (12), and 18% of 9-epi-quinidine (13). I n two separate routes the aminoepoxides were obtained by highly stereoselective methods. Chlorination of N-benzoylquinotoxine ( 5 ) with N-chlorodiisopropylamine in 1 0 0 ~ o phosphoric acid in the dark gave an amorphous mixture of the epimeric a-chloroketones 85 and 86 (Scheme 8) (10).Reduction with sodium borohydride or with lithium tri-t-butoxyaluminum hydride afforded stereoselectively a mixture of the threo chlorohydrins 87 and 88. Treatment of 87 and 88 with aqueous potassium hydroxide a t 20°C gave smoothly a mixture of the erythro N-benzoylepoxides 89 and 90. The benzoyl groups were removed reductively with diisobutylaluminum hydride to give the aminoepoxides 81 and 82 which were cyclized in refluxing toluene-methanol (100:1). This reaction yielded 9-epi-quinine (12) and 9-epi-quinidine (13) in a ratio of 2:l. The overall yield of 12 and 13 from 87 and 88 was 50y0.Only traces of the erythro products quinine and quinidine were observed. Conversely (Scheme 9), the threo aminoepoxides 96 and 97 were obtained from diphenylsulfoniumlepidylide (93) and N-acetylmeroquinene aldehyde (55) (17). The ylide was formed from 4-methylsulfonylquinoline (91) and methylenediphenylsulfurane (92) and was treated with aldehyde 55 to give a mixture of the threo N-acetyl epoxides 94 and 95. Removal of the N-acetyl group led to the aminoepoxides 96 and 97 which underwent intramolecular cyclization to give a mixture of the erythro alkaloids cinchonidine (98) and cinchonine (99). 6. Quinuclidine Ring Formation via Aminochloroepoxides
The base-initiated dichlorohydrin rearrangement 100 --f 101 + 102 constitutes another mode of quinuclidine formation employed in the synthesis of Cinchona alkaloids. The intermediate chloroepoxides 101 are transformed into the quinuclidine carbonyls 102 by intramolecular nucleophilic attack of the piperidino nitrogen (16). The 1,l-dichloro-3-piperidinylpropan-2-ols 106-109 were prepared by two complementary methods (Scheme 10). The first method was applicable only to the dihydro series (Le., R = ethyl). The condensation product 103 of P-collidine and chloral was resolved with 1- and
5 . THE
CINCHONA ALKALOIDS
201
I H
R
102
d-tartaric acids into the enantiomers 104 and 105. Stereospecific cis hydrogenation of the pyridine ring and removal of one chlorine atom from the side chain were performed in a single step utilizing a platinum catalyst in aqueous hydrochloric acid. Thus hydrogenation of 104 gave rise to the diastereomeric dichlorohydrins 106 and 107 and the enantiomer 105 yielded 108 and 109. The cis configuration of 106109 was confirmed by an X-ray analysis of the hydrobromide of 107 and by formation of the diastereomers 107 and 108 from cincholoipon methyl ester (24) via the N-benzoylaldehyde 112. Removal of the benzoyl group and the conversion of the aldehyde function of 112 into the dichlorohydrin moiety was efficiently effected with 2 equivalents of dichloromethyllithium at - 70°C to give 107 and 108 identical with specimens obtained by the previously described method. Under the same conditions, N-benzoylmeroquinene aldehyde (54) yielded a mixture of diastereomeric l,l-dichloro-3-[3(R)-vinyl-4(S)-piperidinyl]propan-2-01s 110 and 111. The configuration of 110 and 111 was established by catalytic hydrogenation of 110 which gave the dihydro derivative 107. The formation of the quinuclidine aldehydes 115 and 116 (Scheme 11) was achieved by treating the dichlorohydrins with methanolic potassium hydroxide or preferably with 2 N aqueous potassium hydroxide in a benzene suspension. Thus 107 and 108 or a mixture of both gave in 65y0 yield a mixture of the liquid epimeric carboxyaldehydes 115
202
M. R. USKOKOVI~!AND G . GRETHE
103
A
p 105
104
A H
& &: HCC1,
HCCl,
H.
H.
..
-.
%
‘H
H
N
I
H
*HC1 106
A
I
N
1
.HCl
H 107 R = ethyl 110 R = vinyl
.HCl
H 108 R = ethyl 111 R = vinyl
nl:lg I
N
112 R = ethyl 54 R = vinyl
SCHEME 10
HCCl, A Z H
Hby I
H
.HCl
109
HCCI,
g
HCCI,
H.
'H
I H 107 110
108 111
'
117 10
R = ethyl R = vinyl
-
113 114
R = ethyl R = vinyl-
J " 3
I
118 R = ethyl 11 R = vinyl
115 116
R = ethyl R = vinyl
119 R = ethyl 12 R = vinyl
SCHEME 11
120 13
R = ethyl R = vinyl
t.l
0
w
204
M. R. USKOKOVI~ AND G . GRETHE
[NMR (CDCI,), 6 9.78 (s, l H , CHO); m/e 167 (M+), m/e 138 (base peak)]. Similarly, a mixture of 110 and 111 yielded the liquid vinyl aldehydes 116 [NMR (CDCl,), 6 9.76 (9, l H , CHO); m/e 165 and 1361. Condensation of the epimeric dihydroaldehydes 115 at - 70°C with 6-methoxy-4-quinolyllithium (3) and separation of the reaction mixture by chromatography afforded 1307, of dihydroquinine (117)) 22y0 of dihydroquinidine (118), and 8% of a mixture of 9-epi-dihydroquinine (119) and 9-epi-dihydroquinidine (120). Under the same conditions, quinine (lo), quinidine (ll),and small quantities of their 9-epi analogs 12 and 13 were obtained from the vinyl aldehyde 116. Oxidation of the epimeric dihydro aldehydes 115 with freshly prepared silver oxide and esterification of the resulting epimeric acids 121 afforded the epimeric esters 123 [m/e 211 (M+), m/e 138 (base peak)]. I n the same manner the quinuclidinic vinyl esters 124 [m/e 209 (M+), m/e 136 (base peak)] were obtained from the vinyl aldehydes 116. Condensation of the esters 124 with 6-methoxy-4-quinolyllithium (3) gave a mixture of quininone (8) and quinidinone (9).
fl:
+ 3
RIOOC 121 122 123 124
N H R1 = H; R, = ethyl R1 = H; R, = vinyl R1 = ethyl; R, = ethyl R1 = ethyl; Rz = vinyl
Quininone ( 8 )
+
Quinidinone (9)
Another example of quinuclidine formation via dichlorohydrin rearrangement is the synthesis of quininone (8) and quinidinone (9) from the amino ketone 125 (Scheme 12) (22). Chlorination in the dark with an excess of N-chlorodiisopropylamine in 1 0 0 ~ phosphoric o acid led to the dichloro ketone 126 which was directly reduced with sodium borohydride to give the dichlorohydrin 127. The rearrangement in this case was effected with barium hydroxide in methanol to give 8 and 9 via the chloroepoxide intermediate 128. The overall yield of 8 and 9 from the starting ketone 125 was 34%.
5 . THE
205
CINCHONA ALKALOIDS
126
125
8
+
9
SCHEME 12
7. Quinuclidine Ring Formation by Other Methods
I n Augustine's recent synthesis (18) of ethyl 5(R)-vinyl-4(5)quinuclidine-2~-carboxylate (124)(Scheme 13) the quinuclidine ring was formed by an intramolecular displacement of a tosyloxy group with the piperidine nitrogen. Treatment of the urethano aldehyde 58 with sodium bisulfite in aqueous methanol followed by potassium cyanide led to the cyanohydrin 129. Quantitative preparation of the cyanotosylate 130 was accomplished by first treating an ether solution of 129 with thallous ethoxide and then adding solid p-toluenesulfonyl chloride to the mixture. Acid-catalyzed hydrolysis of the urethanocyano tosylate 130 afforded the amine 131 which cyclized in aqueous base to give the bicyclic acid 122.Esterification in ethanolic hydrogen chloride furnished the ester 124 in 35y0 overall yield from 130. The synthetic approach of Coffen (23) involving the preformed quinuclidine ring system has led thus far to an efficient stereospecific
206
M. R. USKOKOVI~!AND G . GRETHE
construction of the quinine skeleton. The pyridine lactone 132 (Scheme 14) was prepared, alkylated with methyl bromoacetate, and reduced to the piperidine lactone 133. Dieckmann cyclization of 133 gave 135. The stereochemistry of 135 follows from the conformational requirements (134) of the Dieckmann reaction, The piperidine ring must be in a boat conformation and the lactone ring must be cis-fused to it at the
H
C00C2H5
111
110
124
122
SCHEME 13
instant of C-C bond formation. Consequently the hydroxyethyl side chain must be syn to the ketone function in the resulting quinuclidinone 135. The aldol condensation with the quinoline aldehyde 75 gave enone 136 in which the quinine skeleton is complete. Several functional group transformations must be accomplished in order to achieve a total synthesis by this appealing approach.
5 . THE
207
C I N C H O N A ALKALOIDS
I
H ‘COOCH3 132
133
134
136 SCHEME14
8. Synthesis of Indole Cinchona Alkaloids
The synthetic preparation of ethyl 5(R)-vinyl-4(S)-quinuclidine-2fcarboxylate (124)meant also the formal completion of the first total synthesis of cinchonamine-the main representative of the indole cinchona alkaloids. Preobrazhenskii and co-workers had previously synthesized cinchonamine from 124 (24) which had been obtained by degradation (25). Renewed interest in these alkaloids has resulted for the time being only in the total synthesis of dihydrocinchonamine (143)(Scheme 15). This synthesis was carried out with racemic and optically active intermediates (26). Condensation of lithium o-toluidide (138)and the ester 123 in a 2 : l molar ratio afforded two epimeric amides (139 and 140)in 90% yield. The configurational assignment at C-3 was based on the different chemical shifts of the methyl protons of the ethyl group-
aCH3 '
208
M. R. U S K O K O V I ~AND G. GRETHE
+
137 138
NHR C,H,OOC R =€I R = Li
I
123
h 141
142
I
I
143
144
SCHEME15
0.90 and 0.81 ppm, respectively. An inspection of Dreiding models indicated that the shielding of the methyl protons of 140 was due to the anisotropic effect of the benzene ring. Cyclization of either 139,140, or a mixture of both with sodamide under the conditions of the Madelung indole synthesis afforded the epimeric 2,2'-indolquinuclidines 141 and 142 in excellent yield. The stereochemistry at the C-3 epimeric center was determined also by the chemical shifts of the terminal methyl
5.
209
THE C I N C H O N A ALKALOIDS
groups (0.93 and 0.75ppm), taking into account the shielding effect of the indole ring in this case. This assignment was corroborated by the corresponding chemical shifts reported for 10-methoxydihydrocinchonamine 3(S) and its epimer 3(R)-0.92 and 0.83 ppm, respectively (27)-and by the transformation of 141 into dihydrocinchonamine (143).Compound 141 was treated with a tenfold excess of methylmagnesium iodide followed by an ether solution of ethylene oxide. This gave dihydrocinchonamine [143;racemic, mp 177-178'; optically active, mp 162-163'; [a]$5 + 118.4' (EtOH)]. Under identical conditions 142 gave the epimeric compound 144 [racemic, mp 167-169'1.
IV. Biosynthesis I n recent years the understanding of the biosynthe3is of the Cinchona alkaloids has progressed to a point from which a fairly complete picture can be drawn. Very early Prelog and his co-workers (7), during their structural elucidation of cinchonamine (145)and quinamine (146), suggested that these indole Cinchona alkaloids might be biogenetic precursors of the major Cinchona alkaloids of the quinoline type [e.g., quinine (lo)]. Consequently d,Z-trypt0phan-2'-~~C (147)" was fed by the cotton wick technique to one-year-old C. succiruba Pav.
10
H
147
* For reasons of simplicity the carbon atoms in the precursors are numbered according t o the position they will occupy in the quinine molecule.
210
M. R. U S K O K O V I ~ AND G. GRETHE
plants (28). It had been shown previously (29) that radioactive alkaloids were produced when specimens of this species of similar age were allowed to grow in an atmosphere containing carbon dioxide-14C.After six weeks the plants were harvested and the radioactive cinchonamine (145) and quinine (10) were isolated (Table I).Degradation of the latter via the reaction sequence 148 -+ 149 --f 150 afforded radioactive benzoic acid (151) having the same specific activity as quinine. This result placed the radioactivity of the alkaloid at C-2'. Subsequent tracer experiments (30) with trytophan doubly labeled with 14C at C-9 and
-
H,CO 2'
10
149
n
151
150
with 15N at the indole nitrogen afforded quinine (10) which contained both 14C and 15N with identical specific incorporations (Table I). Oxidative degradation yielded quininic acid (148) which still contained all the as well as the I5N. Subsequent decarboxylation of 148 gave carbon dioxide having essentially the same specific activity as quinine (10).This result showed that, as expected, all the 15Nwas located at the quinoline nitrogen and all the 14C was present at C-9. Thus the two experiments present convincing evidence that quinine and its derivatives are derived from indole precursors.
0
n 10
148
-
5.
THE C I N C H O N A ALKALOIDS
211
Furthermore, the structural relationship of the C-9 unit of the quinuclidine part of quinine with the C-9, C-10 unit of the Corynanthe alkaloids [thickened bonds in 10 and 157, respectively] suggested that the quinoline bases are formed by modification of 156 or a similar substance (31). I n the indole alkaloid series the C-9, C-10 unit is derived from geraniol (152) by way of loganin (153), secologanin (154), and vincoside (156) (32) (Schemes 16 and 17). The same sequence should be observed for the biosynthesis of quinine if the Cinchona-Corynanthe relationship holds. The incorporation of geraniol (152) into quinine in the expected way was confirmed independently by two groups. The feeding of geraniol-10-14C (152) (30) to C . succiruba plants produced radioactive quinine (Table I) which contained all the activity at C-10 (30, 33) while administration of geraniol-3-I4C (152) to C. ledgeriana Moens plants afforded quinine radioactively labeled at C-3 (Table I) (34).The site of radioactive incorporation was established by a KuhnRoth oxidation of dihydroquinine (117) which yielded a mixture of radioactive acetic and propionic acids. Further degradation of the acetic acid by a Schmidt reaction gave in the first case (30, 33) carbon dioxide containing all the radioactivity. Administration of l~ganin-S-~H (153) (35) to C. Zedgeriana plants afforded inactive cinchonine (99) and radioactive quinine (10) (Table I) (36)which contained all the tritium at C-8. The site of radioactivity was secured by chemical means. A modified Oppenauer oxidation of the quinine and workup with D,O-DCl gave radioinactive quinidinone (9) 20-3070 deuterated at C-8. The loss of label in the isolated cinchonine (99) can be explained as a consequence of the inversion step (46 + 164) which generates the opposite configuration at C-8. Although the direct incorporation of secologanin (154) into the Cinchona alkaloids was not studied, an indication for the intermediacy of 154 was indirectly provided by the incorporation of sweroside-11-14C (155) into quinine (Table I) (37). It is assumed that this glucoside enters the direct biogenetic pathway by biological conversion into secologanin (154) (38). The specific incorporation of vin~oside-aryl-~H (156) (39)into the Cinchona alkaloids (Table I) (40)is another indication that secologanin is a direct precursor. In analogy to the biosynthesis of the indole alkaloids (36)one would assume that corynantheine aldehyde (157) is in the direct biogenetic pathway to the Cinchona alkaloids. But unexpectedly the administration of ~orynantheine-aryl-~H aldehyde (157) to C. ledgeriana shoots gave negative results. This observation implied that loss of the methoxycarbonyl group from 156 probably occurs at an early stage before, or concomitant with, formation of ring D of the Corynanthe skeleton.
Tryptophan (147)
I Loganin (153)
Geraniol (152)
Sweroside (155)
H3c0a H'T
8,
H,COZC'
v"
Vincoside (156)
0
+ *H
H#
1'
\
Cinchonidinone (46)
Cinchonamine (155)
\CHO Corynantheal (158)
SCHEME16
TABLE I
INCORPORATION OF RADIOACTIVE PRECURSORS INTO Cinchona ALKALOIDS Precursor
Plants
~ ~ - T r y p t o p h a n - 2 ’ (147) -~~C DL-Tryptophan-I’-l5N, 9-14C (147) Geraniol-10-14C(152) Geraniol-3-14C(152) L ~ g a n i n - S - ~(153) H
C. succiruba C. succiruba C . succiruba C . ledgeriana C. ledgeriana
Sweroside-11-14C(155)
C. succiruba
Vinco~ide-aryl-~H (156)
C. ledgeriana
Corynantheine a l d e h ~ d e - a r y l - ~(157) H
C . ledgeriana
Corynantheal-ar~l-~H (158)
C . ledgeriana
Cinchonidinone-11-3Hz(46)
C. ledgeriana
Cinchonidine-1l-3Hz(98) Cin~honamine-aryl-~H (145)
C. ledgeriana C . ledgeriana
Tryptamine-2’-3H,,2’-14C (163); ratio 3H:14C = 4.70
C. ledgeriana
Alkaloid Quinine Quinine Quinine Quinine Quinine Cinchonine Quinine, Quinidine Quinine Cinchonidine Cinchonine Quinine Cinchonidine Cinchonine Quinine Cinchonidine Cinchonine Quinine Cinchonidine Cinchonine Cinchonidinone Quinine Cinchonidine Cinchonine Cinchonidinone Quinine Cinchonidine Cinchonine
Incorporation
Refs.
0.7Y0 0.97y0 0.00670 0.001 yo 0.0 15yo None 0.2%
28 30 30,33 34 36
0.008yo 0.008 yo 0.0707, None
40
0.007y0 0.04Oj, 0.13y0 0.002 yo 0.03y0 0.14y0 0.06y0 0.0001 yo 0.0008yo 0.001 yo 0.47y0, ratio 2.28, 48y0 retention 3H 0.33y0, ratio 2.48, 53y0 retention 3H 0.12y0, ratio 2.45, 52y0 retention 3H 0.2070, ratio 2.33, 50y0 retention 3H
37
40
40
42
42 42
42
-
__f
____f
Tryptophan 147
H3C02C 152
153
154 156
c-
H H 159 160
R = CHO
CHO
R =COOH
OH 158
1
157
I/
k-
0
P;
\
I
\\
216
M. R. U S K O K O V I ~AND G. GRETHE
Accordingly, ~orynantheal-aryl-~H (158) was prepared and good incorporations into the Cinchona bases were observed (Table I) (40).
0 CH3COOH 10 -
+
-
m
CH,CH&OOH
117
It was suggested that the subsequent transformation of 158 into the quinoline bases proceeds by way of cinchonamine (145) or a close relative (7) and follows the reaction sequence 158 --f 159 --f 161 .+ 162 -+ 46 (31, 36)”. An understanding of these processes which start
10
9
with the opening of ring C of corynantheal (158) requires knowledge of the oxidation level a t C-2’ of 158. Therefore tr~ptamine-2’-~H, (163) in admixture with tryptamine-2’-14C (163) was fed to C. ledgeriana shoots (40). The results (Table I) indicated that oxidative attack at C-2’ of 158 is a stereospecific process since 50y0 of the tritium is lost, that the carboxylic acid 160 is an unlikely biosynthetic intermediate, and that cinchonidinone (46) is a natural product. As expected, the methoxylated ketones 8 and 9 also were shown to be present in the Cinchona plants by the isolation of radioactive quinidinone (9). Reduction of this compound gave quinine (10) and quinidine ( l l ) ,the latter showing an incorporation of 0.00270. The assumption that the ketone 46 leads to the four quinoline bases 10, 11, 98, and 99 was supported (46) into the main by the incorporation of cin~honidinone-ll-~H, Cinchona alkaloids (Table I) (42). The isolated radioactive cinchonine
* I n connection with this suggestion it is of interest to note that cinchonamine was found to be more abundant in young Chchona plants (41).
5.
217
THE CINCHONA ALKALOIDS
(99) was degraded with osmium tetroxide-sodium periodate to give formaldehyde which carried 105y0 of the original molar activity. The reversibility of the stages 46 -+98 was shown by feeding cinchonidine-11-3H, (98) to C. Zedgeriana plants and by isolating active cinchonidinone (46) (Table I) (42). The possibility that cinchonamine (145) is a direct precursor of the quinoline Cinchona alkaloids seems unlikely in view of the low incorporation of cin~honamine-aryl-~H (145) (Table I) ( 4 2 , 4 3 ) .One therefore has to assume that cinchonaminal (159) is the key intermediate between corynantheal (158) and the 9ketoquinoline bases 8, 9, 46, and 164. These results conclude a series of arduous tracer experiments all of which indicate that in all probability the biosynthesis of the Cinchona alkaloids follows the pathway outlined in Scheme 17.
V. Configuration of Cinchonamine at C-3 The a-configuration of the C-3 hydrogen of cinchonamine (145) was assigned by Wenkert and Bringi ( 4 4 ) who converted dihydrocinchonamine (143) and dihydrocorynantheol (165), which has an a-hydrogen a t C-3, into the same quaternary tosylate 166. This assign-
"R 143 145
J
R = ethyl R = vinyl
165
OH
166
ment of configuration was disputed by Augustine (45)but was confirmed recently by Sawa and Matsumura (27) on the basis of the following evidence.
218
M. R. U S K O K O V I ~AND G. GRETHE
i
10
H 167 normal C4,-Ha 168 a110 C4,-HB
PC N
H
0
cH30yJ3 H 1
0
169
C3-Ha
172
C3-Ha
171 C3-HB
173
C3-HF
174
C,-Ha
175
C8-Hj3
170
H
176
C3-Ha
177
C3-HB
OH
SCHEME18
5.
THE C I N C H O N A ALKALOIDS
219
Quinine (10) was converted into the epimeric ketones 169 via the normal and all0 2'-oxo-hexahydroquinines(167 and 168) (Scheme 18). Treatment of mixture 169 with ethanolic hydrochloric acid gave two isomeric indole esters, 170 and 171. It was evident that esters 170 and 171 are C-3 epimers because the CD curves of these compounds showed opposite Cotton effects and because acid-catalyzed epimerization of each isomer gave identical 1:1 mixtures. Reduction of the indole esters 170 and 171 with lithium aluminum hydride gave the corresponding indole alcohols, 172 and 173. When the indole alcohols were quaternized with p-toluenesulfonyl chloride, the corresponding quaternary salts, 174 and 175, were obtained in good yields. This showed that the quaternization reaction caused no epimerization at C-3 of the indole alcohols. I n the same manner, 10-methoxydihydrocorynantheol(176) gave the quaternary tosylate 174, and 3-epi-10-methoxydihydrocorynantheol (177)gave 175. Compound 172 was converted into dihydrocinchonamine (143) by demethylation followed by an Ullmann reaction. These results confirmed that the hydrogen at C-3 of cinchonamine (145) and dihydrocinchonamine (143) has the a-configuration.
VI. Miscellaneous A new type of photoreduction has been reported recently (46, 47). Irradiation of quinine, quinidine, cinchonine, and cinchonidine in aqueous acidic solution gave the corresponding 9-deoxy derivatives 182. The postulated mechanism of Stenberg (47) proceeds via the triplet state (TLn*)and in the initial stages is very similar to the mechanism proposed for the photochemical alkylation of aromatic nitrogen heterocycles in alcoholic solutions (48). The photochemical behavior of the N-oxides of the Cinchona alkaloids has been examined (49).Photolysis ( > 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).
SCHEME 1
le
If
Liriodenine has been reported in a variety of other plants, including Anona glabra L. ( 5 ) , Asimina triloba (L.) Dunal (18), Pseuduwaria sp. TGH 10530 (8), P. cf. grandifolia (Warb.) J. Sinclair (8), Polyalthia nitidissima Benth. (8), Schefferomitra subaequalis (Scheff.) Diels ( 8 ) (Anonaceae); Lysichiton camtschatcense Schott var. japonicum Makino (Araceae) (19),Dryadodaphne novoguineensis (Perkins) A. C. Smith ( 2 ) , Litsea glutinosu (Lour.) C. B. Rob. ( 7 ) , L. hayatae Kanehira ( I ) , Neolitsea sericea (Blume) Koidz. (20) (Lauraceae); Michelea compressa (Maxim) Sarg. (21-22), M . alba DC. (23),M . champaca L. ( 3 , 1 2 ) ,Mugnolia COCO DC. (24), M . grandi$ora L. (25) (Magnoliaceae); Atherosperma moschutum Labill (26-27), Doryphora sassafras Endl. (10) (Monimiaceae); and Roemeriu refracta DC. (Papaveraceae) (22).
6.
THE OXOAPORPHINE
ALKALOIDS
229
B. LYSICAMINE
CH30
2
Whereas the major alkaloid from Lysichiton camtschatcense var. japonicum is liriodenine, a minor yellow alkaloid from the same source is lysicamine ( 2 ) [CI8Hl3O3N;mp 210-211" (dec) (C,H,OH (19)](19). The UV spectra of the two alkaloids bear distinct similarities, and the IR spectrum of lysicamine shows a conjugated carbonyl absorption at 1675 cm-l. The lysicamine NMR spectrum was instructive because it showed methoxyl singlets at 6 4.00 and 4.02 as well as the absence of a methylenedioxy signal. Since all aporphines and oxoaporphines are substituted at C-1 and C-2, it was apparent that lysicamine must be 1,2-dimethoxyoxoaporphine.Conclusive proof of the structure was provided through a total synthesis (Scheme 2) (19).
SCHEME 2
Lysicamine (2) has also been prepared through oxidation of the corresponding aporphine nuciferine with chromium trioxide in pyridine
230
MAURICE SHAMMA A N D R. L. CASTENSON
( 1 4 ) )or better through oxidation of dehydronuciferine (2a) with either oxygen or benzoyl peroxide or peracetic acid (27a).
Za
C. ATHEROSPERMIDINE
3
A minor, nonphenolic, yellow or orange-yellow alkaloid found in the bark of Atherosperma moschatum was given the name atherospermidine (3) [CI8Hl1O4N;mp 275-276" (dec) (CHC1,) (as),275-276" (dec) (CHCl, -C,H,OH) (28), 276-278" (dec) (CHC1, or C,H,N) (27)) 282-285" (CHCI,) (29); scarlet hydrochloride, mp 256-258" (dec) (27); oxime, mp 247-250" (dec) (n-C,H,OH) (29)] by Bick and co-workers (27). The structure of atherospermidine was determined almost simultaneously in 1964 by Bick and Douglas (26) and by Harris and Geissman (29). The former group found IR spectral evidence for a methylenedioxy group as well as for a highly conjugated ketone (1657 em-l). The UV spectrum of the alkaloid resembles that of liriodenine (l), suggesting that atherospermidine is a methoxyliriodenine. The site of the methoxyl group was then determined by NMR spectroscopy. Liriodenine has a high-field C-3 aromatic proton singlet at 6 7.63 which is absent in atherospermidine, so that the methoxyl group in the latter alkaloid can be placed at C-3 (26). The team of Harris and Geissman isolated atherospermidine from
6.
THE OXOAPORPHINE ALKALOIDS
23 1
Guatteria psilopus Mart. (Anonaceae) along with the aporphine guatterine (3a). It was noted that atherospermidine (3) was formed from guatterine using chromium trioxide in pyridine. Further oxidation of atherospermidine by chromium trioxide in sulfuric acid yielded 1azaanthraquinone-4-carboxylic acid (la).
3a
The formation of the azaanthraquinone established the location of the methylenedioxy and methoxyl groups as C-1, C-2, C-3 with respect t o each other. The exact location of the methoxyl group was then determined from a consideration of the NMR spectrum of guatterine (3a). The methoxyl group of this aporphine base appears at 8 3.92. Since it was known that C-1 and C-11 methoxyls in aporphines appear relatively upfield between 8 3.55 and 3.72, while other methoxyl groups are found in the range 8 3.80-3.93, it followed that the methoxyl group of guatterine must be at C-3 rather than a t C-1. The methoxyl of the chemically related atherospermidine must, therefore, also be at C-3 (29). The synthesis of racemic 1,2-methylenedioxy-3-rnethoxyaporphine via a Pschorr cyclization and its oxidation to atherospermidine (3) by chromium trioxide in pyridine has been achieved (28). There is a possibility that atherospermidine may also be present in Anona glabra ( 5 ) .
D. MOSCHATOLINE Moschatoline (4)[C,,H,,O,N; amorphous; yellow O-acetylmoschatoline, mp 190-200" (30);pink hydrochloride (30)]is a yellow base isolated in very small amount from the phenolic alkaloidal fraction of Atherosperma moschatum (30).It is soluble in carbonate but not in bicarbonate solution and it gives a positive ferric chloride test. The yellow color together with the complex UV spectrum pointed to an oxoaporphine
232
MAURICE SHAMMA A N D R. L. CASTENSON
nucleus. 0-Acetylmoschatoline showed IR absorption peaks at 1775 cm-l (acetyl carbonyl) and at 1659 cm-l (conjugated ketone). C HOH
?CH3 , O
P
\ 4
Owing to its low solubility, the free base was not amenable to NMR spectroscopy, but its 0-acetyl derivative showed methoxyl singlets a t 6 3.91 and 4.11 and an acetyl methyl singlet a t 6 2.50. The absence of a one-proton singlet near 6 7.1 indicated that C-3 was substituted. Indeed, 0-methylation of moschatoline yielded 1,2,3-trimethoxyoxoaporphine, which showed NMR methoxyl peaks a t 6 4.06, 4.10, and 4.18, identical with authentic synthetic material. The determination of the position of the phenolic group in moschatoline is based mostly on UV data. Both rnoschatoline and the related alkaloid atheroline (7),obtained from the same source, show strong bathochromic shifts upon addition of base. The synthetic l-hydroxy2,9,10-trimethoxyoxoaporphine4a, on the other hand, exhibits an even stronger bathochromic shift. These results could possibly be OCH,
OCH,
*
CH,O
-
Ci:@
CH:@@
\
\ cH30F
OCH,
4
OHQ
/ CH30 \
/ CH,O
OH 7
/N
CH30
0
4b\
cH30pG
-
CH,O
\
cH30p
/N
\ OQ
-
CH,O
0
I
I
CH30 0 4C
0
6. CH,O H
O
P
:
cH:Ip cH -
233
THE OXOAPORPHINE ALKALOIDS
OHQ
__j
CH30
\
CH,O
OCH,
\
CH.0
OCH,
\ OCH, 4d
4a
explained by considering the resonating forms of the corresponding anions (30). One can draw canonical resonating forms 4b and 4c for the anions derived from moschatoline (4) and atheroline (7),respectively, in which the net charge is on the nitrogen atom. However, the charge is on the oxygen carbonyl atom in anion 4d derived from the synthetic oxoaporphine 4a.* Further data supporting structure 4 for moschatoline were derived from a study of the mass spectral fragmentation patterns of the alkaloid and some of its close analogs (31).
E. LANUGINOSINE
bCH, 5
Lanuginosine (5) [CI8Hl1O4N; mp 302-303" (dec) (CHC1,) (32), 319-321" (dec) (CHCl,) (33), 305" (dec) (ethyl acetate) (34), 310-312" (CHC1,-CH,OH) (35)] was first isolated from the trunk and bark of MicheZia Zunuginosu Wall. (Magnoliaceae). The free base was obtained as glistening orange needles which tarnished to orange-yellow in the course of time. The I R spectrum (Nujol) indicated a conjugated carbony1 (1655 cm-l) and ZL methylenedioxy group (1490, 1405, 1360, 1254, 1125, 1040, 960, and 940 cm-l) but showed no N-H or 0-H
* The explanation offered here is somewhat different from that presented by the onginal workers.
234
MAURICE SHAMMA A N D R. L. CASTENSON
absorption. The absence of a phenolic function was confirmed by the lack of a bathochromic shift in the UV spectrum upon addition of base. Because the fourth oxygen in lanuginosine was in the form of a methoxyl group (Zeisel-Viebock), the alkaloid is a monomethoxyl monomethylenedioxy oxoaporphine. The most salient feature of the NMR spectrum in trifluoroacetic acid, besides the methoxyl and methylenedioxy singlets, was a C-11 proton doublet ( J l o , l l = 10 Hz) indicating that the methoxyl group is at C-9 (32). About a year after these findings, an orange-colored oxoaporphine was obtained from Xtephania abyssinica Walp. (Menispermaceae); it was at first believed that this compound was not lanuginosine since the NMR spectrum, appeared to be different (33). The structure of the S. abyssinica base was proved conclusively to correspond to 1,2-methylenedioxy-9-methoxyoxoaporphinenot only by a detailed analysis of its NMR spectrum, but also through its reduction with zinc in hydrochloric acid to ( )-xylopine, i.e., ( f )-1,2-methylenedioxy-9-methoxynoraporphine, which was further acetylated to ( & )-N-acetylxylopine (33). The apparent anomaly concerning the structure of the M . Zanuginosa alkaloid was partially removed by total synthesis (Scheme 3). Condensation of hydrastinium iodide (5a) with 5-methoxy-%nitrotoluene (5b)followed by reduction and Pschorr closure gave ( f )-isolaureline
*
1. H2, Pt 2. NaN02, H2S0. +
o\
/
+
v
CH, bCH,
OCH3
OCH,
OCH,
50
5
SCHEME 3
6.
THE OXOAPORPHINE ALKALOIDS
235
(5c) which upon oxidation by chromium trioxide in pyridine furnished
1,2-methylenedioxy-9-rnethoxyoxoaporphine,identical (mmp, UV, IR, and TLC) with the alkaloid lanuginosine obtained from M . Zanuginosa (34). Final clarification concerning the structure of lanuginosine was derived from the isolation of the same alkaloid from Xylopia brasiliensis St. Hil. (Anonaceae) (35). Oxidation of synthetic ( & )-N-benzylxylopine, i.e., 1,2-methylenedioxy-6-benzyl-9-methoxyaporphine, gave lanuginosine, identical with material from X . brasiliensis and M . lanuginosa. A significant observation was that the NMR spectrum of lanuginosine as originally reported should be changed in some of its details (32).A new spectrum of lanuginosine from M . Zanuginosa then proved to be in complete agreement with that recorded for the alkaloid from S. abyssinica (35).
F. ~,~,~,~~-TETRAMETHOXYOXOAPORPHINE (O-METHYLATHEROLINE)
CH30
bCH3 6
A yellow base extracted from Liriodendron tulipifera together with liriodenine (1)( 6 )was shown to be 1,2,9,10-tetramethoxyoxoaporphine (6) [C,,H,,O,N; mp 220-226" (36), 223-224" (37), 225-226" (dec) (C,H,OH) (38), 225-227' (C,H,OH) ( l a ) , 227-229" (CHC1, then CH,OH) (39)]through synthesis (Scheme 4)( 9 , 3 9 ) .Nitropapaveraldine (6a), prepared either by a total synthesis or in two steps from papaverine (6b), was reduced to the amine stage and the diazonium derivative subjected to Pschorr ring closure. The resulting yellow base was identical with the natural product (39). Alternatively, 1,2,9,10-tetramethoxyoxoaporphine (6) has been prepared by chomium trioxide in pyridine oxidation of glaucine-the corresponding aporphine (14). It has also been found as a natural product in Anona purpurea L. (Anonaceae) (36) and in Glaucium Jlavum var. Zeocarpum Crantz (Papaveraceae) (37).
236
CH,O
MAURICE SHAMMA AND R. L. CASTENSON
q
\
\Conc.
HNO.;
OCH, 6b
0 cC H 3 H
a
o
3
OCH,
CH,O
7
CRa0H
CH30
\
6a
bCH3
I
1. H2, Ni(R) 2. NaN02, Haso. 3. Pschorr
CH,O OCH,
bCH,
1,2,9,10-Tetramethoxyoxoaporphine (6)
SCHEME 4
When Magnolia kachirachirai Dandy (Magnoliaceae) is extracted immediately after collection, the main base isolated is ( + )-glaucine ( i e . , 1,2,9,10-tetramethoxyaporphine).However, the main base obtained from a sample of M . kachirachirai seven years after collection was 1,2,9,10-tetramethoxyoxoaporphine(6) (38).
G. ATHEROLINE
CH,O OH 7
Atheroline (7)[C,,H,,O,N; mp 250-260" (dec) ( d o ) , 250-260" (dec) (CHC1,-C,H,OH) ( Z ) , 252" (dec) (40a); O-acetylatheroline, mp 190-195" (pyridine) (do), 216-218" (CHC1,-C,H,OC,H,) (doa)],is a yellow phenol-
6.
237
THE OXOAPORPHINE ALKALOIDS
ic alkaloid obtained from Atherosperma moschatum. The I R spectrum shows a conjugated carbonyl absorption at 1639 cm-l and a phenolic hydroxyl a t 3250 cm-l. The presence of the phenolic function was further indicated by a positive ferric chloride test and formation of a mono-0-acetyl derivative upon treatment with acetic anhydride in pyridine. Mono-0-methylation of atheroline (7) using methyl iodide and methanolic sodium methoxide provided the known alkaloid 1,2,9,10tetramethoxyoxoaporphine (6), thus confirming the skeleton of atheroline and the location of the oxygenated substituents at positions 1, 2, 9, and 10 (40). It had been previously established that election-withdrawing groups (e.g., acetoxyl but not methoxyl) attached to an aromatic ring produce downfield shifts of the resonance positions of protons attached to the CH,O
CH,O
CH30 CH,O
CH,O
\ OCH,Ph
CH,O
7s DMF
CH30
CH30 OCH,Ph
OCH,Ph SCHEME 4a
same ring, particularly those in ortho positions. I n the case of atheroline, the aromatic proton resonances for the C-3, C-4, and C-5 hydrogens were found at approximately the same positions for both the 0methyl and the 0-acetyl derivatives; but the C-S and C-11 proton resonances of 0-acetylatheroline were depressed to lower fields as compared to those for 0-methylatheroline (6), (Table I).This seemed to
238
MAURICE SHAMMA A T D R. L. CASTENSON
TABLE I AROMATIC PROTON RESONANCES (6) FOR ATHEROLINE DERIVATIVES Derivative O-Methylatheroline O-Acetylatheroline
H-3 7.08 (s) 7.11
(8)
H-4
H-5
7.63 (d) 7.65 (d)
8.76 (d) 8.80 (d)
H-8
H-11
7.93 (8) 8.20 ( s )
8.56
(8)
8.80 (s)
indicate that the acetoxyl group was located in ring D, either a t C-9 or at C-10. Total synthesis of 1,2-10-trimethoxy-4ethoxyoxoaporphine and 1,2,9-trimethoxy-10-ethoxyoxoaporphine then showed that the former compound is identical with O-ethylatheroline. The phenolic function in atheroline (7)must therefore be located at C-9 (30). The alkaloid has recently been synthesized by Cava and Noguchi (40a.).The important intermediate 7a could be prepared by any of the three routes indicated in Scheme 4a. Catalytic hydrogenation of 7a in the presence of Raney nickel followed by Pschorr cyclization, gave mainly the desired oxoaporphine 7b. Debenzylation was achieved in hydrochloric acid and tetrahydrofuran to afford atheroline in good yield.
3
CH,O
7a Ha,NKR)
__f
CH30
NHz
/
CH.0
' OCH,Ph
cu
P 2. 1. NaNOa,HaS04
HsO@,
~~~~~
Atheroline
/ CH30 \ OCH,Ph 7b
H. CASSAMERIDINE Cassameridine (8) [C,,H,O,N; mp 300" (C,H,OH) ( a l ) , 301-302" (CHC1,-CH,OH) (4la)was detected as a very minor yellow alkaloidal component in the extracts of Cassytha americuna Nees. (C.Jiliformis L.) (Lauraceae) from which the oxoaporphine cassamedine (9) had already been obtained. The mass spectrum showed a molecular weight of 319 corresponding to a demethoxycassamedine. Chromium trioxide in pyridine oxidation of the available aporphine
6. THE
OXOAPORPHINE
239
ALKALOIDS
0-methylactinodaphnine (8a) yielded the oxoaporphine 8b whose
UV spectrum was very similar to that of cassameridine (8). It was therefore suggested that cassameridine (8) is probably 1,2:9,lO-bismethylenedioxyoxoaporphine (41).
p
0 \ L
O 8
This suggestion received support through a total synthesis of cassameridine via Pschorr cyclization of the amino ketone 8c (42).A direct comparison of the two materials was not possible, but the UV spectra of the samples were found to be very similar. Cassameridine has also been efficiently synthesized by peracetic acid oxidation of dehydroneolitsine (8d) and by iodine oxidation of norneolitsine (8e) (41a).
80
8a
q oq
0 \ L
O 8d
\
L
O 8e
240
MAURICE SHAMMA AND
R.
L. CASTENSON
I. CASSAMEDINE OCH3 I
9
Cassamedine (9) [Cl9H1,O,N; mp 278" (CHC1,-C,H,OH) (a)]is an orange oxoaporphine found in Cassytha americana. The IR spectrum showed a highly conjugated carbonyl band at 1650cm-I but no N-H or 0-H absorption. The NMR spectrum in trifluoroacetic acid pointed to the presence of two methylenedioxy groups and one methoxyl, and by comparison with the NMR spectra of 1,2,9,10-tetramethoxyoxoaporphine (6) and atherospermidine (3) the assignments indicated in 9a were made (41). 4.48(s) OCH,
0
H
8.85(s)H
CH30
0 L
OCH,
O
6.23(s) 9,
9b
Additionally, it was pointed out that the UV spectrum of cassamedine (9) is very close to that of 1,2-methylenedioxy-3,9,lO-trimethoxyoxoaporphine [thalicminine (ll)]derived from oxidation of the corresponding noraporphine O-methylcassyfiline (9b) using chromium trioxide in pyridine (41).The structure of cassamedine (9) has recently been confirmed by synthesis (42a).
6. THE
OXOAPORPHINE ALKALOIDS
241
J. IMENINE
0"" 10
The woody climbing stems of the Amazonian vine Abuta imene Eichl. (Menispermaceae)have been found to contain a complex mixture of highly colored, weakly basic alkaloids. The most abundant of these is the yellow nonphenolic base imenine (10) [C20H,,0,N; mp 206-207" ( 4 3 ) ;dihydroimenine, mp 205" (43)]which is the first ring B substituted oxoaporphine. This interesting alkaloid showed a conjugated carbonyl group in the I R spectrum at 165Ocm-l, while the NMR spectrum revealed a complex multiplet of five aromatic protons and four clearly resolved aromatic methoxyl singlets at 6 4.05, 4.10, 4.15, and 4.25. Reduction of imenine (10) with Adams catalyst gave an initially colorless solution which became orange on contact with air t o afford the yellow-orange dihydroimenine (10a). The NMR spectrum of
CH30
10a
dihydroimenine showed, in addition to three aromatic methoxyl singlets a t S 4.09,4.13, and 4.22, an aliphatic methoxyl singlet at 6 2.04. The structure of imenine was then completely clarified by X-ray analysis-the first crystallographic determination of an oxoaporphine structure. Imenine crystallizes in space group P i with lattice parameters a = 9.087, b = 8.539, c = 11.660A, a = 111.68", p = 91.41", and y = 101.17" (43).The analysis was carried out on the free base.
242
MAURICE SHAMMA AND R. L. CASTENSON
K. THALICMININE
CH30 0CH3 11
Thalicminine (11) [C,,H,,O,N; mp 263-265" (CHCl,) (44),274-275" (CHC1,-C,H,OH) (41)]was isolated from the roots of Thalictrum minus L. (Ranunculaceae). This orange alkaloid possesses three methoxyl groups and a methylenedioxy as well as a conjugated carbonyl (1650 cm-I). Since another alkaloid found in T . minus is the aporphine ( + )-thalicmine ( l l a ) it was suspected that thalicminine incorporates a similar arrangement of the oxygenated substituents. Indeed, oxidation of the aporphine either with potassium permanganate in acetone or with chromium trioxide in pyridine gave rise to thalicminine (11). Conversely, reduction of thalicminine with zinc in sulfuric acid followed by Eschweiler-Clarke N-methylation yielded ( & )-thalicmine (44). OCH3 I
I
OCH3
lla
I n a separate study it was found that oxidation of O-methylcassyfiline (9b) using chromium trioxide in pyridine gave an orange oxoaporphine (mp 274-275") which should correspond to thalicminine (11) (41). Thalicminine has also been found in T . simplex DC. (Ranunculaceae) (45).
6.
THE OXOAPORPHINE
ALKALOIDS
243
L. HERNANDONINE
12
The first report of hernandonine (12)[C1,H,O,N; mp > 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
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6.
THE OXOAPORPHINE ALKALOIDS
263
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264
MAURICE SHAMMA A N D R . L. CASTENSON
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-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: <
Me0 /
NNO.
MeO\
OMe
:
heat
137 R = Me I38 R = CHzPh 139 R = H
Me0 /
OR 135 R = Me
136 R = CHzPh
/ OMe 140 141
R =Me
R
= CH,Ph
Product 140 had the molecular formula C2,H,,N0, and its UV spectrum showed the presence of a 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline system. The NMR spectrum revealed signals for three aromatic protons and one N-methyl and five methoxy groups among which N- and 0-methyl resonances were at abnormally high field (2.15 and 3.24ppm in CDCl,), probably because of the existence of several groups on the same ring. According to the data, the structures possible for this compound could be limited to the following five formulas: 142, 143, 140, 144, and 145. All but 140 were ruled out as follows.
7.
301
PHENETHYLISOQUINOLINE ALKALOIDS
CHART 33
142
143
144
145
Hofmann degradation gave a niethine base, which had only one olefinic proton, and its mass spectrum showed a strong fragment ion [M+-CH,NMe,]. The methine base must then be either 146 or 147. A second Hofmann degradation product was shown by its NMR spectrum to be 1-(2-~inylphenyl)indenederivative 149 but not 148, which implies that the modified Pschorr reaction product has structure 140. CHART34
143
Me0 OMe I46
140
148
__+
147
149
302
T E T S U J I KAMETANI AND MASUO KOIZUMI
A mechanism for the formation of compound 140 could be the following. An aromatic radical 151 formed by thermal decomposition from the diazonium salt 150 abstracts a hydrogen radical from the C-1 position of the isoquinoline skeleton, and the resulting aliphatic radical 152 is attacked by the hydroxy radical to give alcohol 153. The radical at the C-1 position in the 3,4-dihydroisoquinoline ring system 154, which formed from 153, is attacked by the radical formed in the phenyl group to give spiroisoquinoline 140. CHART 35
Me0 / e
135
0
9 --Me
-
__f
OMe 150
Me0
/’
N-Me
m6
Me0 \
Me
__f
-Meo% Me0 \ OMe OMe
L
151
Me0 \ M :e 6Me 152
OMe 153
OMe 154
1
Moreover, in order to obtain homoaporphine 157 or homoproaporphine 156, an extension of the above reaction was attempted. Thermal decomposition of the diazonium salt from the S-amino-l-phenethylisoquinoline 155 gave the unexpected anisaldehyde (158)) 1,2,3,4-tetrahydro - 6,7 -dimethoxy - 1-[P-hydroxy-P- (4- methoxyphenyl)ethyl]-2-
303
7. PHENETHYLISOQUINOLINE ALKALOIDS
methylisoquinoline (160a), and its diastereoisomer (160b). On the other hand, the treatment of the diazonium salt with hypophosphorous acid afforded 4-methoxystyrene (161), 160a, 160b, and the deamination product 159 (55). i
P
- CHART - 36 M
e
or E
:
F
-
M
e
Me0 \
0
157
156
I
Me0
,-’
Me0
OMe 155
CHO
0
+
OMe
158
6Me
R =H 160a R = 4 O H 160b R = - - - O H 159
Oxidation of both carbinols 160a and 160b with manganese dioxide afforded the ketone 162 which was reduced with sodium borohydride to give a mixture of compounds 160a and 160b, thus proving that they are stereoisomers. The formation of these products is rationalized in terms of a radical intermediate as shown in Chart 37. Furthermore, the Pschorr reaction of the aminoisoquinoline 163 gave no expected product 164 but only the abnormal products isovanillin (165) and the isocarbostyril derivative 166, the mechanism of the
304
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 37
155
formation of which was anticipated to proceed along the same route as in the case of 135 and 155 (55a).
D. PHOTO-PSCHORR REACTION If the Pschorr reaction above proceeded through a radical intermediate formed by homolysis of the carbon-nitrogen bond, photolysis of the diazonium salt would be a more efficient way of effecting homolysis. I n accordance with this view several phenethylisoquinoline alkaloids were synthesized in the following way.
7.
305
PHENETHYLISOQUINOLINE ALKALOIDS CHART38
-Me
164
0 165
166
Diazotization of the 2'-aminophenethylisoquinoline (133) in the usual way, followed by photolysis with a Hanovia 450 W mercury lamp using a Pyrex filter a t 5-10", gave four compounds, namely, the carbostyril 170, isocarbostyril 166, phenolic compound 172, and the expected O-methylandrocymbine (137) (56). The mechanism for the formation of 170 remained unclear. Although compound 137 could be thought to have structure 168 as in the case of 130, this was ruled out by the following evidence : the diazotization of 167, followed by photolysis of the diazonium salt in a manner similar to that above, gave the same dienone 137 together with compounds 171 and 173, but not the dienone (169). Thus it was apparent that in both cases an intramolecular reaction had occurred between the 2' and 4a -positions of the isoquinoline skeleton. Furthermore, homomorphinandienone (137) and kreysigine (31a) were synthesized from their phenolic aminoisoquinoline 174 under the same conditions as above (57'). An application of the photo-Pschorr reaction to the S-aminoisoquinolines 134 and 175 gave O-benzylandrocymbine 138 which on debenzylation afforded ( f )-androcymbine (139) (58). The same reaction of diphenolic aminoisoquinoline 176, however, gave the abnormal product, homoproaporphine 93 (58), which would have been formed via the radical intermediates 178, 179, and 180, derived from the diazonium salt (177). Moreover, the diazonium salt of 163 was photolyzed to homosalutaridine (164) (59) via its O-benzyl derivative 181.
306
TETSUJI KAMETANI AND MASUO KOIZUMI CHART 39
MeomN-Me 0%
Me0
168 169
R =Me R =CH,Ph
\
-
-Me
OMe 133
OMe 167
137
c74
+ OMe
H
170
+
c
166 171
Me0
0 R = Me R = CH,Ph
0." \
OMe
OMe 172 173
R = Me
R = CH,Ph
307
7. PHENETHYLISOQUINOLINE ALKALOIDS CHART40
OMe
OMe 174
137
31a
CHART41
134 175
R, = Me, Rz = CH,Ph R, = Rz = C H z P h
138
MI e 0i / I O T - M e
-
o#-Me
Me0 /'
/
NH,
Me0 \ OMe OH 176
93
308
T E T S U J I KAMETANI AND MASUO KOIZUMI
CHART42
-
176
-
-Me
OH
Abstraction
T
-
Me0 \
?
M
e
z:T‘ OH
L
177
MH Oe \ o
-
hu __f
Tautomerization
I OMe
178
N-Me
Me0
-
Homolytio J 93 coup1ing
‘OMe
0
_1
179
180
CHART43
163
181
164
E. PHOTOLYTIC CYCLODEHYDROBROMINATION Since Kupchan (60) accomplished the synthesis of nornuciferine (184) and nuciferine (185) from the corresponding 2’-iodoisoquinolines
7.
309
PHENETHYLISOQUINOLINE ALKALOIDS
182 and 183 by photolytic intramolecular cyclization many alkaloids have been synthesized by application of this reaction. CHART44
-R
182 183
R
=
H
184 185
R = Me
R =H R = Me
Recently, the reaction was applied to the syntheses of morphinandienone-, homomorphinandienone-, and homoaporphine-type compounds. Irradiation of l-(2-bromophenyl)-7-hydroxyisoquinolines187 and 186 with a Hanovia 450 W or a Riko 400 W mercury lamp using a Pyrex filter in the presence of an excess of sodium hydroxide gave the homomorphinandienones [0-methylandrocymbine (137) and 1321 and CHART 45
R2
186 187 188
R, = H, R, = R, = OMe R, = R, = R, = OMe
R, = R,
'lq
= OMe, R, = O H
-Me
+
OMe 0
189 31 94
R, = H, R,
= R, = OMe R, = R, = R, = OMe R, = R, = OMe, R, = O H
310
T E T S U J I KAMETANI AND MASUO KOIZUMI
homoaporphines [kreysigine (31a) and 1891 ( 6 4 , respectively. I n this reaction the starting materials must have a phenolic hydroxy group at the C-7 position in the isoquinoline ring and the reaction must be carried out in alkaline solution. Moreover, photolysis of 188 in aqueous ethanol in the presence of sodium hydroxide and sodium iodide gave androcymbine (139) (62). On the other hand, when the above photolysis was done without sodium iodide it afforded only multifloramine (94) (62). CHART 46
OMe
OH 190
191
Furthermore, 0-methylkreysiginone (191) was synthesized from its 8-bromo analog 190 under the same conditions as above (63). Recently, the same reaction of 192 to obtain homosalutaridine (164) gave unexpectedly enones 193 but not 194, the structures of which could be defined by the spectroscopic method (64). CHART 47
EiMe 192
193
194
V. The Hypothetical Alkaloids (New Phenethylisoquinoline Skeletons) Several possible alkaloids have been synthesized with the expectation that they might yet be isolated from plants. Battersby (13) anticipated the existence of homoprotoberberine
7.
311
PHENETHYLISOQUINOLINE ALKALOIDS
alkaloids when he studied the structural elucidation of melanthioidine (16). Although these alkaloids have not yet been isolated from natural sources their syntheses were achieved in the following way. CHART 48
’-
’.
\OMe
OMe 195
R =H
196
R = Me
‘OMe
Br
197
198
T
Me
Me0
Me0
\
/
OMe
OR 200
R
201
R = Me
=H
199
Tetrahydroisoquinolines 195 and 196 were subjected to the Mannich reaction with formaldehyde in the presence of acid to give homoprotoberberines 200 and 201 (65-67‘). Of these compounds the phenolic cyclization was examined on phenolic isoquinoline 195 which, however, gave the 9-hydroxyhomoprotoberberine 197. I n this case, cyclization had taken place at the ortho position to the phenolic hydroxy group of 195. I n order to confirm the structure of 197 the Mannich reaction of bromoisoquinoline 199 afforded the 12-bromo-9-hydroxyhomoprotoberberine (198) which on debromination with lithium aluminum hydride gave the expected compound 197. Spectral data of compound 197 were identical with those of the product prepared by phenolic cyclization of 195. Since the direction of cyclization by Mannich reaction for the formation of the so-called berberine bridge is para to the phenolic hydroxy group it is interesting that phenolic cyclization occurs selectively a t the ortho position to the phenolic hydroxy group in the ring homologs.
312
TETSUJI KAMETANI A N D MASUO KOIZUMI CHART49
204
205
J
207
/
J
209
Meo ME
208
210
Moreover, Shamma (67)achieved the synthesis of this compound by the following two methods. When lactones 202 and 203 were treated with methanolic potassium hydroxide a diastereoisomeric mixture of tetracyclic lactams 204 and 205 was obtained. The structures of 204 and 205 were indicated because of their R, values on thin-layer chroma-
7.
313
PHENETHYLISOQUINOLINE ALKALOIDS
CHART50
211
212
Me0
\
213
tography. The keto lactam 206 could be readily obtained through Sarett oxidation of the mixture of lactam alcohols 204 and 205. Reduction of this keto lactam with sodium borohydride or with hydrogen over Adams catalyst gave lactam alcohol 205 preferentially over 204. Lactam alcohols 204 and 205 were then reduced individually with lithium aluminum hydride to form homoprotoberberines 207 and 208, respectively. To obtain lactam 209 a mixture of lactam alcohols 204 and 205 was hydrogenolyzed in ethanol with hydrogen in the presence of perchloric acid on Pd-C. Reduction of lactam 209 to the homoprotoberberine 210 was achieved by refluxing with lithium aluminum hydride in tetrahydrofuran. Secondly, Dieckmann condensation of diester 211 with sodium hydride in benzene, followed by hydrolysis and decarboxylation,
Meo"3'r CHART 51
Me0 /
-Me
-Me
OMe
OMe 214
215
314
TETSUJI KAMETANI AND MASUO KOIZUMI
afforded ketone 212. Reduction with Adams catalyst then gave the 14-hydroxyhomoprotoberberine 213. On the other hand, an intramolecular Ullmann reaction of bromophenethylisoquinoline 214 gave a homocularine-type compound 215 (69) which could be a possible alkaloid belonging to the phenethylisoquinoline series.
VI. Spectroscopy Although the use of spectroscopic methods can be of great value in the identification and structural elucidation of these alkaloids, IR, UV, and NMR spectra are not discussed in this section as these data are similar to those of the benzylisoquinoline alkaloids (see Table I). Therefore only mass spectra are described here. Mass spectra of melanthioidine (16) (13)revealed major fragment ions at m/e 312 and 310 which correspond to the favored cleavage at b and b' in structure 16. Hydrogen transfer from one half of the molecule to the other occurs in this process. Another important fragment at m/e 485 corresponds t o the loss of C,H,O, from the parent ion. This fragment shows that the hydroxy groups must be located on rings C and C', since the fragmentation can then be explained by fission at a and b or at the equivalent bonds a' and b'. Then hydrogen transfer occurs. Additional evidence came from the mass spectra of 0 , O dimethyl (17) and O,O-diacety1216 derivatives of melanthioidine; they showed peaks at m/e 499 and 527, respectively, which correspond to loss of the 0-methyl and 0-acetyl derivatives of the ion C,H,O, arising again from fission at a and b. CHART52
16 17 216
R = H R = Me R = COMe
7. PHENETHYLISOQUINOLINE ALKALOIDS
315
Mass spectra of kreysiginone (19) and dienone 20 (40)showed strong peaks a t the following positions: m/e 341 (M+), 340 (M+ - l ) , 324 (M+ -17), 313 (M+ -28), 312 (M+ -29), and 298 (M+ -43). The (M+ - 1) peak is attributed to the fragment ion 221 which is formed by the loss of a hydrogen atom from the carbon adjacent to the nitrogen atom. I n this case the positive charge is stabilized by conjugation with the aromatic ring. Further loss of carbon monoxide from the molecular ions 217 and 221 gives rise to the fragment ions 219 (M+ - 28) and 222 (M+ - 29), respectively. The peak (M+ - 17) is probably ion 218, formed by the loss of the methoxy group and two hydrogens from the molecular ion 217. The second mode of stabilization which seems to lead to a characteristic fragmentation for homoproaporphines is a retro-Diels-Alder reaction of the tetrahydroisoquinoline ring. This CHART53
218
//
219
0 217
(M+)
OMe 220
I
P
0
221
& OMe 222
316
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART54 , & b
-CH.OCH=CII.
Me0 224 (a) m/e 298 (b) m/e 299 ( c ) m/e 340
(a) m/e 271 (b) m/e 272 ( c ) m/e 313
226
Me0
0 m/e 270
(a) m/e 270 (b) m/e 271
Me0
OR 228 (a) m/e 194 (b) m/e 195 ( c ) m/e 236
OR 221
OR 229 (a) m/e 181 (b) m/e 182 (c)
m/e 223
230
m/e 162
fragmentation would give ion 220 a t m/e 298 (M+ -43) by loss of CH,=NMe from the molecular ion 217. The mass spectra of schelhammerine (34), 0-deuteroschelhammerine, and 0-acetylschelhammerine are consistent with the proposed structures (23). According to Chart 54 the loss of a methoxy group from the respective parent ions 223a-c gives the ions 224a-c, while fission of the bond between C-2 and C-3 of ions 223a-c affords ions 225a-c. The ion at m/e 270, postulated to be 226, is obtained by loss of a n acetyl radical from ion 225c, but the corresponding ion at m/e 270 obtained by loss of a
317
7. PHENETHYLISOQUINOLINE ALKALOIDS
hydrogen radical from 225a is formulated as 227a, and it can be shown that the hydrogen which is lost must have been attached to a carbon atom (C-7, C-8, or C-10). The need for an alternative pathway is clear from the spectrum of deuteroschelhammerine in which the corresponding ion 227b appears at m/e 271 and shows that the deuterium atom has been retained. A major peak in the three spectra corresponds to fragmentation a and subsequent loss of a hydrogen radical to give ion 228a-c. Corresponding fragmentation 13 affords ions 22%-c which on loss of ROH and a hydrogen radical give stable ion 230. Peaks a t m/e 281 in all three spectra are consistent with the loss of neutral fragments CH,O and ROH to give ion 231. This elimination requires a hydrogen rearrangement to C-3, and a mechanism involving transfer of a methoxy hydrogen can be postulated. Subsequent loss of a hydrogen radical from 231 affords ion 232 while elimination of acetylene from 231 affords ion 233 which appears as a strong peak at m/e 255 in all spectra. The loss of a hydrogen radical from 233 gives ion 234 at m/e 254. CHART55
223
231
m/e281
232 m / e 280
--CHECH
233 m / e 255
234 m / e 254
The mass spectrum of schelhammeridine (38) (23) is much less complicated and has only four major ions, the formation of which is postulated to occur as shown in Chart 56. The molecular ion 235 cleaved with loss of a methyl radical to give ion 236; with loss of a
318
TETSUJI KAMETANI AND MASUO KOIZUMI
methoxy radical to give base peak ion 237; with hydrogen rearrangement and loss of formaldehyde to give ion 238; and with loss of methanol and a hydrogen radical t o give ion 239. CHART56
235
m/e 311
237
m/e 280
J
--CH,O
& 238
Me0
m/e 281
m/e 278
239
CHART57
" : q - M e
N-Me
Me0
0
OH 240 241 242
R, = Me, R,, R3 = -CH,R3 = H, R, = R, = Me R, = H, R, = R, = Me
243
@ : HO
Meo
---
\
I
OMe 244
245
-Me
7.
319
PHENETHYLISOQUINOLINE ALKALOIDS
VII. Addendum Recently, the structures of five alkaloids, namely alkaloid CC-2 (240), alkaloid CC-3b (241or 242),alkaloid CC-10 (243),alkaloid CC-20 (244), and alkaloid Cc-24 (245),isolated from Colchicum cornigerum, have been determined by a combination of spectroscopic methods, X-ray analysis, and chemical modifications (70). New homoerythrina alkaloids, alkaloid I1 (246),I11 (247),and VI (248),were more recently isolated from Cephulotuxus harringtoniu (71). CHART 58
246 247
R, + R, = OMe R, = R, = OMe
+ OH
248
( - )-0-Methylandrocymbine (8) was obtained from ( - )-2’-bromophenethylisoquinoline (249a)by irradiation. The corresponding ( )isomer (249b)gave alkaloid CC-lo methyl ether (250)and ( - )-kreysigine (31b)(72).
+
CHART 59 249tt, X = 4 H 1 - 8
Me
v
24913, X = ---H --f 31b --f
+ M e 0 \, Me6
-
M
e
c7
Me( 250
The isoquinoline (251)was subjected to the Dryden modification of the Birch reduction (73) to afford the enol ether (252),which was treated with hot phosphoric acid t o give tetrahydrohomoglaxiovine (253)(7’4).
320
TETSUJI KAMETANI AND MASUO KOIZUMI
CHART 60
251
252
253
Photolysis of the diazonium salt derived from 254 gave the homoaporphine (23)(75). CHART 61
1. HNOa 2. hu
254
REFERENCES 1. R. H. F. Manske and H. L. Holmes, eds., “The Alkaloids,” Vol. 2, Chapter X. Academic Press, New York, 1952; Vol. 11, Chapter XI, 1968. 2. H. PotBHilovA, J. Santavf, A. El-Hamidi, and F. santavy, Collect. Czech. Chem. Commun. No. 34, 3540 (1969). 2a. A. R. Battersby, E. McDonald, M. H. G. Munro, and R. Ramage, Chem. Commun. 934 (1967). 2b. T. Kametani, H. Yagi, F. Satoh, and K. Fukumoto, J . Chem. Soc. C 271 (1968). 2c. J. Hrbek Jr. and F. Santavy, Collect. Czech. Chem. Commun. N o . 27, 255 (1962). 3. R. Ramage, Annu. Rep. Progr. Chem. B64, 515 (1967).
7. PHENETHYLISOQUINOLINE ALKALOIDS
321
4. A. R. Battersby, R. B. Herbert, L. Pijewska, and F. Santavf, Chem. Commun. 228 (1965). 5. A. R. Battersby, I. R. C. Bick, W. Klyne, J. P. Jennings, P. M. Scopes, and M. J. Vernengo, J . Chem. SOC.London 2239 (1965). 6. G. M. Badger and R. B. Bradbury, J . Chem. SOC.London 445 (1960). 7. M. Salch, S. El-Gangihi, A. El-Hamidi, and F. Santavf, Collect. Czech. Chem. Commun. No. 28, 3412 (1963); see also H. PotiiBilovB, J. Hrbek Jr., and F. Santavf, ibid. No. 32, 141 (1967). 8. A. R. Battersby, M. H. G. Munro, R. B. Bradbury, and F. Santavf, Chem. Commun. 695 (1968). 9. N. K. Hart, S. R. Johns, J. A. Lamberton, and J. K. Saunders, Tet. Lett. 2891 (1968). 10. J. Fridrichsons, A. M. Mathieson, and M. F. Mackay, Tetrahedron 26, 1869 (1970). 11. J. Fridrichsons, M. F. Mackay, and A. M. Mathieson, Tet. Lett. 2887 (1968). 12. A. R. Battersby, R. B. Herbert, and F. Santavf, Chem. Commun. 415 (1965). 13. A. R. Battersby, R. B. Herbert, L. Mo, andF. Santavf, J . Chem. SOC.C 1739 (1967). 14. A. Brossi and F. Burkhardt, Helw. Chim. Acta 44, 1558 (1961). 15. A. Rheiner and A. Brossi, Ezpevientia 20, 488 (1964). 16. T. Reichstein, G. Snatzke, and F. Santav$, Planta Med. 16, 357 (1968). 17. F. Santavf, P. Sedmera, G. Snatzke, and T. Reichstein, Helw. Chim. Acta 54, 1085 (1971). 18. T. Kametani, F. Satoh, H. Yagi, and K. Fukumoto, J . Chem. Soc. C 382 (1970). 19. R. E. Harmon and B. L. Jensen, J . Heterocycl. Chem. 7, 1077 (1970). 20. A. R. Battersby, R. B. Bradbury, R. B. Herbert, M. H. G. Munro, and R. Ramage, Chem. Commun. 450 (1967). 21. A. Brossi, J. O’Brien, and S. Teitel, Helw. Chim. Acta 52, 678 (1969). 22. S. R. Johns, C. Kowala, J. A. Lamberton, A. A. Sioumis, and J. A. Wunderlich, Chem. Commun. 1102 (1968). 23. J. S. Fitzgerald, S. R. Johns, J. A. Lamberton, and A. A. Sioumis, A w t . J . Chem. 22, 2187 (1969). 24. S . R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 22, 2219 (1969). 25. N. Langlois, B. C. Das, and P. Potier, C. R. Acad. Sci., Ser. C 269, 639 (1969). 26. C. Kowala and J. A. Wunderlich, 2. Kristallogr., Kriatallgeometrie, Kristallphys., Kriatallchem. 130, 121 (1969). 27. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and H. Suares, Chem. Commun. 646 (1969); Aust. J . Chem. 22, 2203 (1969). 28. A. R. Battersby, R. B. Herbert, E. McDonald, R. Ramage, and J. H. Clements, Chem. Commun. 603 (1966). 29. A. C. Barker, A. R. Battersby, E. McDonald, R. Ramage, and J. H. Clements, Chem. Commun. 390 (1967). 30. A. R. Battersby and R. B. Herbert, Proc. Chem. SOC.London 260 (1964). 31. E. Leete, Tet. Lett. 333 (1965); J . Am. Chem. SOC.85, 3666 (1963). 32. A. R. Battersby, P. Bohler, M. H. G. Munro, and R. Ramage, Chem. Commun. 1066 (1969). 33. D. H. R. Barton, D. S. Bhakuni, G. M. Chapman, and G. W. Kirby, J . Chem. SOC. C 2134 (1967). 34. A. R. Battersby, T. J. Brockson, and R. Ramage, Chem. Commun. 464 (1969). 35. G. Blaschke, Arch. Pharm. (Weinheim) 301, 432 (1968). 36. D. H. R. Barton, R. James, G. W. Kirby, D. W. Turner, and D. A. Widdowson, Chem. Commun. 294 (1966).
322
TETSUJI KAMETANI AND MASUO KOIZUMI
37. D. H. R. Barton, Chem. Brit. 3, 330 (1967). 38. T. Kametani, K. Fukumoto, M. Koizumi, and A. Kozuka, Chem. Commun. 1605 (1968). 39. T. Kametani, K. Fukumoto, M. Koizumi, and A. Kozuka, J . Chem. SOC.C 1295 (1969). 40. T. Kametani, F. Satoh, H. Yagi, and K. Fukumoto, Chem. Commun. 818 (1967); J. Org. Chem. 33, 690 (1968). 41. T. Kametani, F. Satoh, H. Yagi, and K. Fukumoto, Chem. Commun. 1103 (1967); J. Chem. SOC.,C 1003 (1968). 42. T. Kametani, H. Yagi, K. Fukumoto, and F. Satoh, Chem. Pharm. Bull. 16, 2297 (1968). 0 9 (1969). 43. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC. 44. T. Kametani, S. Takano, and T. Kobari, J . Chem. SOC.C 2770 (1969). 45. T. Kametani and F. Satoh, Chem. Phurm. BUZZ. 17, 814 (1969). 46. T. Kametani and M. Mizushima, J . Phurm. SOC.Jap. 90, 696 (1970). 47. T. Kametani, K. Fukumoto, T. Hayasaka, F. Satoh, and K. Kigasawa, J . Chem.SOC. C 4 (1969). 48. T. Kametani and K. Fukumoto, Chem. Commun. 26 (1968); J. Chem. SOC. C 2156 (1968). 49. D. H. R. Barton, R. James, G . W. Kirby, D. W. Turner, and D. A. Widdowson, J . Chem. SOC.C 1529 (1968). 50. T. Kametani, K. Fukumoto, M. Kawazu, and M. Fujihara, J . Chem. SOC.C 922 (1970). 51. T. Kametani and S. Takano, Tet. Lett. 121 (1968); T. Kametani, S. Takano, and S. Haga, Chem. Phurm. Bull. 16, 663 (1968). 52. T. Kametani, K. Fukumoto, F. Satoh, and H. Yagi, Chem. Commun. 1398 (1968); J. Chem. SOC.C 520 (1969). 53. T. Kametani, K. Fukumoto, F. Satoh, and H. Yagi, Chem. Commun. 1001 (1968); J. Chem. SOC. C 3084 (1968). 54. T. Kametani, K. Takahashi, T. Sugahara, M. Koizumi, and K. Fukumoto, J. Chem. SOC.C 1032 (1971). 55. T. Kametani, K. Fukumoto, M. Kawazu, and M. Fujihara, J . Chem. SOC.C 2209 (1970). Jap. 90, 1331 (1970). 55a. T. Kametani, M. Koizumi, and K. Fukumoto, J . Phurm. SOC. 56. T. Kametani, M. Koizumi, and K. Fukumoto, Chern. Commun. 1157 (1970); J . Chem. SOC.C 1792 (1971). 57. T. Kametani, M. Koizumi, K. Shishido, and K. Fukumoto, J . Chem. SOC.C 1923 (1971). 58. T. Kametani, M. Koizumi, and K. Fukumoto, J . Org. Chem. 36, 3729 (1971). 59. T. Kametani, M. Koizumi, C. Seino, and T. Nakano, Chem. Pharm. BUZZ. 20, 295 (1972). 60. S. M. Kupohan and R. M. Konojia, Tet. Lett. 5353 (1966). 61. T. Kametani, Y. Satoh, S. Shibuya, M. Koizumi, and K. Fukumoto, J. Org. Chem. 36, 3733 (1971). 62. T. Kametani and M. Koizumi, J . Chem. SOC.C 3976 (1971). 63. T. Kametani, T. Sugahara, H. Sugi, S. Shibuya, and K. Fukumoto, Chem. Commun. 724 (1971). 64. T. Kametani, T. Kohno, R. Charubala, and K. Fukumoto, Tetrahedron 28, 3227 (1972). 65. T. Kametani, T. Terui, T. Ogino, and K. Fukumoto, J . Chem. SOC.C 874 (1969).
7. PHENETHYLISOQUINOLINE ALKALOIDS
323
66. A. Brossi, A. J. Rachlin, S. Teitel, M. Shamma, and M. J. Hillmann, E q e r i e n t i a 24, 766 (1968); A. Brossi and S. Teitel, Helv. Chim. Acta 52, 1228 (1969). 67. M. Shamma and M. J. Hillman, Tetrahedyon 27, 1363 (1971). 68. T. Kametani, K. Fukumoto, H. Agui, H. Yagi, K. Kigasawa, H. Sugahara, M. Hiiragi, and H. Ishimaru, J. Chem. SOC.C 112 (1968). 69. T. Kametani and T. Terui, J . Heterocycl. Chem. 7, 55 (1970). 70. A. R. Battersby, R. Ramage, A. F. Cameron, C. Hannaway, and F. Santavf, J . Chem. SOC.C 3514 (1971). 71. R . G. Powell, Phytochemistry 11, 1467 (1972). 72. T. Kametani, Y. Satoh, and K. Fukumoto, Tetrahedron, in press. 73. H. L. Dryden, Jr., G . M. Webber, R. R. Burtner, and J. A. Lella, J . Org. Chem. 26, 3237 (1961). 74. W. V. Curran, Chem. Commun. 478 (1971). 75. T. Kametani, T. Nakano, C. Seino, S. Shibuya, K. Fukumoto, T. R. Govindachari, K. Nagarajon, B. R. Pai, and P. S. Subramaniani, Chem. Pharm. Bull. 20, 1507 (1972).
This Page Intentionally Left Blank
-CHAPTER
8-
ELAEOCARPUS ALKALOIDS S. R. JOHNS AND J. A. LAMBERTON Division of Applied Chemistry, C.S.I.R.O. Melbourne, Australia
I. Occurrence ........................................................ 11. The C16Aromatic Alkaloids. . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Structures of ( If: )-Elaeocarpine and ( If: )-Isoelaeocarpine . . . . . . . . . . . . . . B. Syntheses of ( )-Elaeocarpine and ( )-Isoelaeocarpine . . . . . . . . . . . . . . C. (+)-Isoelaeocarpicine ............................................. 111. The C16 Dienone Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Structures of the Dienone Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Products from Reduction with Sodium Borohydride . . . . . . . . . . . . . . . . . . IV. The Cla Alkaloids of Elaeocarpus kaniensis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Elaeokanines A, B, C, D, and E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Synthesis of ( & )-Elaeokanine C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. ElaeokanidinesA,B,andC ...................................... V. Elaeocarpidine ..................................................... A. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Syntheses ....................................................... VI. Biosynthesis ....................................................... References .........................................................
.
.
.
.
.
. .
.
.. .
. .
.
.
325 327 327 329 330 331 331 337 338 338 341 342 343 343 344 346 346
I. Occurrence The genus Elaeocarpus of the family Elaeocarpaceae comprises some two hundred species which occur mainly in tropical regions and, of twenty-nine species identified and tested in the course of an extensive screening program in New Guinea, seven alkaloid-positive species were detected. Chemical examination of these species has revealed a new group of indolizidine alkaloids. No alkaloid-positive species were detected among members of other genera of the ElaeocarpaceaeSloanea, Aceratium, Sericolea-tested in this progam ( 1 ) . The leaf alkaloids from the New Guinea species Elaeocarpus polydactylus Schltr., E . dolichostylis Schltr., E . sphaericus (Gaertn.) K. Schum., E. kaniensis Schltr., E . densiJorus Knuth (syn. E . archboldianus A.C.Sm.), and E . altisectus Schltr. , which are all large rain-forest trees, have been
326
S. R. JOHNS AND J. A. LAMBERTON
TABLE I
BOTANICAL DISTRIBUTION Plant
E. altisectus Schltr. E. densifirus Knuth E . dolichostylw Schltr.
E. kaniensis Schltr.
E. polydactylus Schltr.
E. sphaericus (Gaertn.) E. Schum.
Alkaloid ( - )-Isoelaeocarpiline Elaeocarpidine Elaeocarpidine ( + )-Elaeocarpiline Elaeocarpinea ( - )-Isoelaeocarpiline Isoelaeocarpinea Elaeokanidine A Elaeokanidine B Elaeokanidine C Elaeokanine A Elaeokanine B Elaeokanine C Elaeokanine D Elaeokanine E Elaeocarpidine ( f )-Elaeocarpine ( + )-Isoelaeocarpicine ( f )-Isoelaeocarpine (- )-Alloelaeocarpiline Elaeocarpidine ( )-Elaeocarpiline ( f )-Elaeocarpine ( + ) -Epialloelaeocarpiline ( - )-Epielaeocarpiline ( )-Epi-isoelaeocarpiline ( - )-Isoelaeocarpiline ( f )-Isoelaeocarpine ( + ) -Pseudoepi-isoelaeocarpiline Unidentified base, C1BH24N202
+
+
a
Refs. 5 14,15 10 9 , 10 10 9,10 10 12,13 12,13 12,13 12,13 12,13 12,13 12,13 12,13 4 3, 4, 6 4,g 3, 4 5, 11 5 5, 11 5 5,11 5,11 5,11 5,11 5 5,11
5
Optical rotations not determined.
examined, and distinctive differences in the alkaloid content of these species were found, as shown in Table I. Elaeocarpus densijiorus is exceptional in having only one major alkaloid, the indolic base elaeocarpidine; E . altisectus, which yields a complex mixture of alkaloids, has not been studied in detail but preliminary examination has shown that, like E . dolichostylis and E . sphaericus, it contains predominantly C-16 dienone alkaloids. The leaves of one other species, E . trichophyllus A.C.Sm., gave a positive field test for alkaloids ( I ) , but laboratory extraction failed to give significant amounts of alkaloid.
8.
327
ELAEOCARPUS ALKALOIDS
With the exception of the recent isolation ( 2 ) of the unusual indolepyrrolizidine base, peduncularine, from Aristotelia peduncularis (Labill.) Hook.€., alkaloids have not yet been reported from other genera of the Elaeocarpaceae.
11. The C16 Aromatic Alkaloids
A. STRUCTURES OF ( & )-ELAEOCARPINE AND ( & )-ISOELAEOCARPINE The alkaloids ( )-elaeocarpine (1) (mp 81-82'; vmsx 1694 cm-l in CC1,; hydrobromide, mp 303-305') and ( & )-isoelaeocarpine (2) [dimorphic forms, mp 51-52' (3, 4) and 74-75' (5);vmsx 1680 em-l in CCl,; picrate, mp 245-247'1, are easily interconverted isomers of molecular formula C1,Hl,NO2 ( 3 , 4). Both bases as they occur naturally have a slight degree of optical activity, much less than 1% of that of the
1
2
optically pure forms, and are therefore virtually racemic. Structures 1 and 2 represent only one of the enantiomers of each alkaloid and are intended to depict relative and not absolute configurations. When each alkaloid is dissolved in methanolic potassium hydroxide solution it is converted into the other alkaloid, and at equilibrium an approximately 1 : l mixture results from either base. This interconversion can be followed by observing characteristic changes in the NMR spectrum when the reaction with potassium hydroxide is carried out in CD,OD solution. The complete stereochemistry of ( 5 )-elaeocarpine hydrobromide was established by X-ray crystal structure analysis ( 3 , 6 ) and the structure of ( & )-isoelaeocarpine was established by a detailed comparison (3, 4 ) of the NMR spectra of 1 and 2. The respective C-7-H signals, a broad multiplet in the NMR spectrum of ( k )-elaeocarpine and a narrow multiplet in the spectrum of ( f )-isoelaeocarpine, provide the key to the stereochemistry at the C-7, C-8 ring junctions. The C-7-H multiplet of ( 5 )-elaeocarpine at 6 4.15 (CDC1, solution) is complicated by virtual coupling from the
328
S. R. JOHNS AND J. A. LAMBERTON
C-5 axial proton, which coincides in chemical shift with the C-6 methylene group protons, but the C-7-H signal is simplified in CD,CO,D solution because the axial C-5-H signal is shifted to lower field and no longer has the same chemical shift as the C-6 protons. In CD,CO,D solution the C-7-H signal can be analyzed from double resonance + J 7 , 6 b )= studies as a six-line multiplet [J7,8= 11.8 Hz; &(J7,6a 7.8 Hz], and in CDC1, solution the C-8-H proton of ( )-elaeocarpine resonates as a quartet at 6 2.51 (J7,8= 11.8 Hz; J8,9 = 10.0 Hz), consistent with the trans diaxial conformation for C-7-H, C-8-H, and C-8-H, C-9-H. The C-7-H signal of ( f )-isoelaeocarpine at 6 4.64 in CDC1, solution is a deceptively simple quartet, and from double resonance studies the couplings J7,8 = 2.1 Hz and &(J,,,, + J7,6b)= 2.8 Hz could be determined. The small mean value for the couplings between C-7-H and the C-6 methylene group protons is consistent only with an equatorial configuration for C-7-H. Analysis of the C-8-H signal, a quartet a t 6 2.42 (J7,8= 2.1 Hz; J8,9 = 10.0 Hz), shows that C-8-H and C-9-H are trans diaxial, as in ( k )-elaeocarpine, and as C-8-H is axial ( i- )-elaeocarpine and ( i- )-isoelaeocarpine therefore have the same configuration at C-8 and are epimeric only at C-7. It has been suggested that the base-catalyzed epimerization of 1 and 2 proceeds by enolization at C-8 followed by breaking of the C-7 to oxygen bond to give an intermediate which on recyclization affords both 1 and 2. No products other than 1 and 2 were detected and it was argued from conformational considerations that the formation of stereoisomers resulting from epimerization at C-8 would be unlikely. CHART 1. MASS SPECTRAL FRAGMENTATION PATTERN SUGGESTED FOR ( k )-ELAEOCARPINE AND ( & )-ISOELAEOCARPINE
m/e 257
rnje 256
I m/e 240
mje 122
8.
329
ELAEOCARPUS ALKALOIDS
The indolizidine systems of the thermodynamically more stable isomers have a chair form for ring C with C-9-H axial and trans to the lone pair orbital on the nitrogen and at each C-S center C-8-H is axial and the bulky system linked through the carbonyl group is equatorial. The mass spectra of the Elaeocarpus alkaloids are simple and characteristic. They are typified by the spectra of ( & )-elaeocarpine and ( 5 )-isoelaeocarpine for which the major mass spectral fragmentation patterns are indicated in Chart 1.
B. SYNTHESES O F ( & )-ELAEOCARPINE AND ( f )-ISOELAEOCARPINE Independent syntheses of ( & )-elaeocarpine and ( f )-isoelaeocarpine have been reported by Tanaka and Iijima (7) and by Onaka (8).
3
4 5
R = H R = CHZCH2COOC2Hs
in t,oluene
H 11
10
330
S. R. JOHNS AND J. A. LAMBERTON
1. The diazoketone obtained by reaction of 6-methoxy-2-methylbenzoyl chloride was condensed with pyrrole in the presence of copper powder to give the ketone 3 which was then hydrogenated over platinum oxide in acetic acid to give the 2-pyrrolidyl methyl ketone 4. Reaction of 4 with ethyl acrylate gave the ester 5 which was then converted by a Dieckmann condensation into the diketoindolizidine 6. Demethylation of 6 with boron tribromide in dichloromethane at room temperature was accompanied by a spontaneous cyclization to give the chromanone 7 which with methanolic hydrogen chloride a t reflux temperature afforded the chromone 8. Reduction of 8 with sodium borohydride in ethanol at reflux temperature gave a mixture from which were isolated, in a ratio of 1 : 7, the isomeric alcohols 9 and 10, previously obtained ( 4 ) by reduction of ( & )-elaeocarpine and ( f )-isoelaeocarpine with sodium borohydride. Oxidation of the alcohols 9 and 10 with chromic acid in acetic acid afforded ( & )-elaeocarpine and ( k )-isoelaeocarpine, respectively ( 7 ) . 2. An interesting synthesis of 1 and 2 has been achieved (8) by condensation of 6-methylsalicylaldehyde with the dienamine generated from 2,3-dihydro-1H-indoliziniumbromide by the action of lithium aluminum hydride in anhydrous ether. The product 11, on oxidation of the benzylic hydroxyl group with Jones's reagent, underwent cyclization to give a mixture of ( k )-elaeocarpine and ( k )-isoelaeocarpine.
C. ( + )-ISOELAEOCARPICINE The phenolic alkaloid ( + )-isoelaeocarpicine (12) (mp 164-166"; + 29" in CHC1,; ,v 1670 cm-l) has the molecular composition CIGH,,NO3and it is readily converted into a mixture of near-racemic elaeocarpine and isoelaeocarpine on heating in methanolic sodium hydroxide solution ( 4 , 9). The low optical rotations of the products do not necessarily reflect the optical purity of ( + )-isoelaeocarpicine because racemization is known to occur under these conditions. The relative stereochemistry of ( + )-isoelaeocarpicine at the C-7, C-8, and C-9 centers was shown to resemble that of ( 5 )-isoelaeocarpine by analysis of the C-7-H and C-8-H signals in the NMR spectrum. The signal from the C-methyl group of ( + )-isoelaeocarpicine is 0.36 ppm upfield with respect to the C-methyl signal in the spectrum of ( f )isoelaeocarpine and indicates that the C-methyl group is well removed from the deshielding plane of the carbonyl group. A conformation with the carbonyl group and the aromatic ring noncoplanar may be favored [a],,
8.
331
ELAEOCARPUS ALKALOIDS
12
13
14
R = H R = COCH,
H
15
so as to relieve steric interaction between the C-methyl group and C-8-H. Comparison of the frequency of the carbonyl band in the I R spectrum (broad, 1665-1670 em-') with that of 2-hydroxy-6-methyl1630 cm- in CHC1,) supports this conclusion. acetophenone (v,, Reaction of 12 with diazomethane gives an O-methyl ether (mp 144-145') and acetylation of 12 in acetic anhydride-pyridine solution for a short time (5 min) gives the O-acetyl derivative 13 (mp 174-175"). Prolonged reaction of 12 with acetic anhydride-pyridine at room temperature, however, gives the N-acetyl compound 14 ( 4 ) .The formation of 14 can be explained by further acetylation of 13 to give the 7acetoxy compound followed by elimination of acetic acid to give an unsaturated ketone and finally cleavage of the C-9-N bond by the mechanism indicated in 15.
111. The C16 Dienone Alkaloids
A. STRUCTURES OF THE DIENONE ALKALOIDS Seven isomeric dienone alkaloids of molecular composition C16H,,N0, have been isolated and their structures and absolute configurations have been determined. 1. ( - )-Isoelaeocarpiline
(-)-Isoelaeocarpiline (16)(mp 146-147"; [.ID - 400" in CHCI,) shows bands in the I R spectrum at vmax 1657 cm-l and in the UV spectrum
332
S . R. JOHNS AND J. A. LAMBERTON
at, , ,A 224 and 323nm, typical of a conjugated dienone system ( 5 , 9-11). The NMR spectrum of (-)-isoelaeocarpiline has a threeproton doublet a t 6 0.85 (C-16 methyl group), a multiplet at 6 6.26 (C-14-H), and a well-defined doublet of doublets at 6 5.88 (C-13-H), which shows a large vicinal coupling (J13,14 = 10.0 Hz) and an allylic
16
17
coupling (J = 2.8 Hz). A narrow multiplet at 6 4.54 (C-7-H) resembles the signal for C-7-H in the spectrum of ( f )-isoelaeocarpine and indicates that the C-7,C-8 ring junction is cis. The relationship to ( * )isoelaeocarpine was firmly established by the formation, when ( - )isoelaeocarpiline was heated with palladium-charcoal in benzene, of ( - )-isoelaeocarpine (17)(colorless gum, [.ID - 120" in CHCl,, picrate, mp 260-263"), and ( - )-13,14-dihydroisoelaeocarpiline(mp 121-122'; [.ID - 219" in CHC1,). Attempts to reduce ( - )-isoelaeocarpiline with sodium borohydride gave quantitative yields of ( - )-13,14-dihydroisoelaeocarpiline but there was no reduction of the carbonyl group. Consideration of the steric requirements of the borohydride reduction (Section 111, B) enabled the relative configuration a t the C-16 center t o be assigned from this observation. The absolute configuration at C-16 was established by the isolation of S-(- )-methylsuccinic acid from the products of oxidation of ( - )-isoelaeocarpilinewith potassium permanganate and the absolute configuration of ( - )-isoelaeocarpiline could be given as 7R,8S,9S,16S, and of (-)-isoelaeocarpine (17)as 8S,9S,lSS. 2 . ( + )-Epi-isoelaeocarpiline
\ H 18
( + )-Epi-isoelaeocarpiline (18) (mp 98-100"; [.ID + 340" in CHC1,) also shows I R and UV spectra characteristic of a conjugated dienone.
8.
333
ELAEOCA R P US ALKALOIDS
The close relationship to ( - )-isoelaeocarpiline, indicated by their spectroscopic properties, was confirmed by the study of the reaction products formed on heating ( + )-epi-isoelaeocarpiline with palladiumcharcoal in benzene. ( + )-Epi-isoelaeocarpiline afforded a mixture of (+)-isoelaeocarpine (the optical enantiomer of 17) and (+)-13,14dihydroepi-isoelaeocarpiline. Apart from a difference in the chemical shift of the C-16 methyl group (at 8 0.99 in the spectrum of 18) the NMR spectra of ( - )-isoelaeocarpiline and ( + )-epi-isoelaeocarpiline were very closely similar and it was concluded that the alkaloids differ only in the relative configuration at C-16. As dehydrogenation of the two alkaloids gives the respective enantiomeric forms of isoelaeocarpine, it followed that the alkaloids have the same absolute configuration a t C-16 and the opposite absolute configurations a t C-7, C-8, and C-9. The absolute configuration of ( + )-epi-isoelaeocarpiline must therefore be 7S,8R,9R,16S. The stereochemical relationship between ( + )-epi-isoelaeocarpiline and ( - )-isoelaeocarpiline is reflected in their ORD spectra. Each spectrum shows two distinct Cotton effects the signs of which are considered to depend upon the configuration a t C-16 and C-8-the two asymmetric centers adjacent to the absorbing chromophores. A positive effect at 240nm in each spectrum was assigned to the C-16 center, while a negative effect a t 350 nm in the spectrum of (- )-isoelaeocarpiline and a corresponding positive effect a t 320 nm in the spectrum of ( + )-epi-isoelaeocarpiline were attributed to the C-8 configuration. 3. ( + )-Elaeocarpiline The alkaloid ( + )-elaeocarpiline (19) (mp 165-166", [a], + 395" in CHC1,) similarly has the spectroscopic properties of a conjugated
H 19
20
dienone (v,, 1657 cm-l in CC1,; A,, 221, 323 nm in ethanol). A complex multiplet a t 8 6.27 (C-14-H) and a doublet of doublets a t 8 5.85 (J,3,14 = 10.O;Jallylic = 2.9 Hz; C-13-H) were assigned to the double bond protons and a three-proton doublet a t 6 0.95 ( J = 6.7 Hz) to the C methyl group. A broad multiplet a t 8 4.06 (C-7-H), similar to that in the spectrum of ( f )-elaeocarpine, indicated a trans C-7,C-8 ring
334
S. R. JOHNS AND J. A. LAMBERTON
junction. Apart from the relative configuration a t the C-16 center, the structure of ( + )-elaeocarpiline was established by the formation of ( + )-elaeocarpine (20) (mp 104-106"; [aID + 206" in CHC1,) and ( )13,14-dihydroelaeocarpiline (mp 92-94'; [aID + 317' in CHC1,) when ( + )-elaeocarpiline was heated with palladium-charcoal in benzene. The ORD spectra of ( + )-elaeocarpiline (positive Cotton effects at 240 and 320 nm) and ( + )-13,14-dihydroelaeocarpilinewere found to be essentially the same, respectively, as those of ( + )-epi-isoelaeocarpiline and ( + )-13,14-dihydroepi-isoelaeocarpilineand it was therefore concluded that in these compounds the C-16 and C-8 centers, which are associated with the absorbing chromophores, have the same absolute configurations. As it was known from the relationship to ( + )-elaeocarpine that C-7-H,C-8-H and C-8-H,C-9-H are both trans diaxial, the absolute configuration of ( + )-elaeocarpiline could be represented as 7R,8R,9R,16S, and of ( + )-elaeocarpine as 7R,8R,9R.
+
4. ( - )-Epielaeocarpiline I n its spectroscopic properties, ( - )-epielaeocarpiline (21) (mp.70-74"; in CHC1,) is closely similar to ( + )-elaeocarpiline and the only significant difference between their NMR spectra is in the chemical [aID - 396"
21
shift of the (2-16 methyl group which is assigned to a three-proton doublet at 6 0.85 in the spectrum of ( - )-epielaeocarpiline.When heated with palladium-charcoal in benzene, ( - )-epielaeocarpiline gave a mixture of 7S,8S,9S-(-)-elaeocarpine (mp 104-107"; [.ID - 210" in CHCl,), enantiomeric with the product from ( + )-elaeocarpiline, and ( - )-13,14-dihydroepielaeocarpiline(mp 124-125"; [.ID - 318"in CHC1,). As ( + )-elaeocarpiline and ( - )-epielaeocarpiline differ only in their relative configuration at C-16 it is clear from their dehydrogenation products that they must have the same absolute configuration a t C-16 and the opposite absolute configuration at the C-7,C-8 and C-9 centers. The ORD spectrum of ( - )-epielaeocarpiline (positive Cotton effect at 240nm and negative effect at 350nm) is in accordance with this conclusion.
8.
ELAEOCARPUS ALKALOIDS
335
5. ( + )-Epialloelaeocarpiline
The amounts of this alkaloid and of ( - )-alloelaeocarpiline varied markedly in the crude alkaloids from different batches of plant material and it has been suggested that the amounts may depend upon small differences in the extraction and isolation procedures ( 5 ) . ( + )-Epialloelaeocarpiline (22) (mp 136-137"; [a]= + 139" in CHC1,) resembles CH3O H H
*--. \
':-I
.\
H 22
the other dienone alkaloids in IR, UV, and mass spectra, and in the presence of a C methyl doublet (60.94) in the NMR spectrum. From the mixture of products formed on heating ( + )-epialloelaeocarpiline with palladium-charcoal in benzene, only ( + )-isoelaeocarpine was isolated and the structure was assigned primarily from the observation that 22 is partly converted into 7S,SR,9R,lSS-(+ )-epi-isoelaeocarpiline when allowed to remain adsorbed on thin-layer plates of Kieselgel G. I n the NMR spectrum of 22 the signal assigned to C-7-H appears at 6 4.22 as an eight-line multiplet (J7,8= 14.0; J6,,= 5.5; J6,,= 9.5 Hz) and that from C-8-H as a doublet of doublets at 6 2.96 (J7,8= 14.01; J8,9= 5.5 Hz). The large (J = 14.0Hz) coupling indicates a truns diaxial conformation for C-7-H,C-S-H and the J = 5.5Hz coupling an axial-equatorial coupling for C-S-H,C-g-H. The apparently anomalous situation that ( + )-epialloelaeocarpiline,which has C-7-H,C-8H trans diaxial, is converted into ( + )-epi-isoelaeocarpiline with a cis B/C ring junction can be explained by the formulation of (+)-epialloelaeocarpiline as the c-8 epimer of ( + )-epi-isoelaeocarpiline. This explanation requires that ring C adopt a chair conformation with the indolizidine C/D ring junction cis (N-lone pair to C-9-H). Although indolizidines in general have a truns N-C-9 ring junction it has been observed that there is spectroscopic evidence for the presence in acid solution of the cis protonated form as well as the truns (4)and a cis formulation would be in accordance with the observed instability of ( )-epialloelaeocarpiline.
+
6. ( - )-Alloelaeocarpiline ( - )-Alloelaeocarpiline (23)(a colorless gum; [aID - 73" in CHC1,) has not been obtained entirely pure. Its spectroscopic properties are
336
S. R. JOHNS AND J. A. LAMBERTON
closely similar to those of ( + )-epialloelaeocarpiline except in the
H 23
chemical shift of the C-16 methyl group (6 0.89). Like (+)-epialloelaeocarpiline, it is unstable and is easily converted into ( - )-isoelaeocarpiline, presumably by a similar epimerization at €he C-8 center. ( - )-Alloelaeocarpiline is therefore formulated as the C-8 epimer of ( - )-isoelaeocarpilinewith a cis C/D junction for the indolizidine ring. 7. Pseudoepi-isoelaeocarpiline Pseudoepi-isoelaeocarpiline (24) (a colorless gum; [.ID + 222" in CHC1,; picrate, mp 230-235" dec) was shown to have the molecular formula C16H2,N02, isomeric with the conjugated dienone alkaloids. The I R (v,, 1665 ern-,) and UV (A, 275 nm, E 7600) spectra showed the presence of an .,Sunsaturated carbonyl group, and the close
I
I H 24
relationship to the conjugated dienone bases was established by the formation on catalytic hydrogenation of 7S,8R,9R, 16s ( + )-dihydroepiisoelaeocarpiline. The presence of a 14,15- rather than a 13,14-double bond was established from the NMR spectrum which showed a threeproton doublet at 6 1.13 (J = 6.5 Hz; C-16 methyl group), a narrow one-proton multiplet at 6 4.55 (C-7-H), and multiplets at 6 5.53 and 6 5.74 which have been analyzed by double resonance studies and assigned, respectively, to C-14-H and C-15-H (vicinal coupling, J,,,,, = 10.0 Hz). The absolute configuration of ( + )-pseudoepi-isoelaeocarpiline as 7S,8R,9R,16S follows from its conversion on catalytic hydrogenation into ( + )-dihydroepi-isoelaeocarpiline.
8.
337
ELAEOCARPUS ALKALOIDS
B. PRODUCTS FROM REDUCTION WITH SODIUM BOROHYDRIDE Comparison of the reduction products formed from the CI6 aromatic alkaloids and the CI6 dienone alkaloids with sodium borohydride in ethanol provides evidence for the assignment of the relative stereochemistry at C-16 in ( - )-isoelaeocarpiline (4, 5, 9).
25
26
H @ CH3H y - OyH )H
' 0 2
0 :
H 27
H 28
Reduction of ( )-elaeocarpine (1) afforded an approximately 1:1 mixture of two alcohols which are epimeric at C-10. The higher-melting isomer (mp 197-198') was assigned the structure 9 from the C-8-H, C-10-H coupling constant (J = 7 . 5 Hz) which indicates a trans pseudodiaxial conformation for these protons. By comparison the other isomer (25) (mp 177-178') has a C-8-H,C-lO-H coupling of 3.5Hz consistent with a cis pseudo-axial-equatorial conformation for C-8-H and C-10-H. Reduction of ( & )-isoelaeocarpine ( 2 ) gives only the alcohol 10 [mp 202-202.5'; for synthetic 10, mp 168-169' was recorded (r)],the formation of which was explained, when the particular enantiomer depicted in 2 is considered, by severe hindrance to attack from the a-side of the carbonyl group by the C-9a and C-la hydrogens. Although indolizidines have a preferred conformation with the nitrogen lone pair trans to C-9-H, both cis and trans forms (NH to C-9-H) of protonated indolizidines can be detected spectroscopically. The complexity of the NMR spectrum of the alcohol 10 in CD,CO,D was explained by the presence of both the cis and trans forms of the indolizidinium salt and it was suggested that the steric interactions in the N-C-9 cis form were relieved by a "flip " of the C-7,C-8 cis ring junction to give an alternative chair form for ring C. The C-10 hydroxyl groups in 10,9, and 25 are
338
S. R. JOHNS AND J. A. LAMBERTON
extremely labile. When 10 is warmed at 50" in dilute hydrochloric acid solution the epimeric alcohol 26 is formed quantitatively. Reduction of ( - )-isoelaeocarpiline (16) gives a quantitative yield of the 13,14-dihydro derivative and there is no reduction of the carbonyl group. I n this case the carbonyl group must be hindered to attack from the @-sideby the C-9@and C-l@ hydrogens and on the a-side by the C-16 methyl group, and consequently the relative configuration at (2-16 could be assigned. Attempts to further reduce the 13,14-dihydro derivative of 16 were unsuccessful. Reduction of ( + )-elaeocarpiline gives a tetrahydro derivative which was considered to be 27 while reduction of ( + )-13,14-dihydroelaeocarpilinegives only one C-10 alcohol (28). IV. CI2 Alkaloids of Elaeocarpus kaniensis The alkaloids of Elueocurpus Icuniensis differ from the other known Elueocurpus alkaloids in having a C12 skeleton and they can be divided into two groups-the elaeokanines and the elaeokanidines which have, respectively, one and two nitrogen atoms. The alkaloids are closely interrelated and the structures assigned initially from spectroscopic study (18) have been confirmed by the synthesis of ( & )-elaeokanine C and thence of elaeokanines A and B (13). The structures depicted for the alkaloids of this group indicate relative configurations only and not absolute configurations. A. ELAEOKANINES A, B, C, D,
AND
E
1. Elaeokanine A
Elaeokanine A (C,,H,,NO; colorless oil; [aID +13O in CHC1,; picrate, mp 163-165') was shown to be 8-n-butyryl-7,S-dehydroindolizidine (29). The presence of an a,@-unsaturatedcarbonyl group was indicated by the I R spectrum (v,, 1667 em-l, strong, and 1630 229 nm in ethanol). An NMR cm-l, weak) and the UV spectrum (A, study established the presence of the n-butyryl group and by analysis
29
8. ELAEOCA RP US ALKALOIDS
339
of the signals from C-7-H (a multiplet at 6 6.82) and C-9-H (a multiplet a t 6 3.42) it was shown that both C-7-H and C-9-H are adjacent to methylene groups. Bohlmann bands in the 2600-2900 em-l region of the I R spectrum and the similarity of the mass spectrum to those of other indolizidines provided spectroscopic confirmation for the carbon skeleton. When synthetic ( f )-elaeokanine C was heated in ethanolic potassium hydroxide solution a product spectroscopically identical with elaeokanine A was isolated. 2. Elaeokanine B
Elaeokanine B (30) was obtained as a colorless gum (C,,H,,NO; CHC1,). The presence of an alcohol group was indicated by a band at 3210 em-l in the IR spectrum, and signals at 6 4.08 and 6 5.67 in the NMR spectrum were assigned to the CH.OH and the
[.ID - 76" in
30
double-bond protons, respectively. The relationship of elaeokanine B to elaeokanine A was established by the identification of elaeokanine B with a product formed by reduction of elaeokanine A with sodium borohydride. 3. Elaeokanine C
Elaeokanine C (31) was isolated as a colorless gum (C,,H,,NO,; methiodide, mp 203-205"; [.ID - 11' in methanol). Bands at 3550 cm-l and 1690 em-l in the I R spectrum indicated the
[.ID - 14"in CHCI,;
31
presence of hydroxyl and carbonyl groups, and the NMR spectrum showed the presence of an n-butyryl group. The stereochemistry was assigned from a double resonance study of the NMR spectrum which
340
S. R. JOHNS A N D J. A. LAMBERTON
shows a one-proton doublet of triplets at 6 4.16 (all couplings approximately 2.5 Hz) assigned to C-7-H. The small couplings between C-7-H and the adjacent C-6 methylene group protons indicate that C-7-H is equatorial and a large coupling (J = 9.5 H z ) between C-8-H and C-9-H indicates that these protons are trans diaxial. The C-7-H, C-8-H coupling ( J = 2.5 Hz) is consistent with the structure 31 in which the bulky n-butyryl group is equatorial. Further confirmation for the structure of elaeokanine C was obtained from comparison of the mass spectrum with that of ( + )-isoelaeocarpicine which has the same partial structure and stereochemistry for the indolizidine moiety, and proof of the structure was obtained by synthesis of 1& )-elaeokanine C (Section IV, C). 4. Elaeokanine
D
Elaeokanine D (32)(ClzHl,NOz; mp 76-78”; [.ID +51” in CHC1,) was shown to have a carbonyl group by the presence of a band at 1705 em-I in the I R spectrum, and as there was no hydroxyl band it seemed that the second oxygen atom was present in an ether linkage.
32
The structure was assigned from a study of the NMR spectrum and the similarity of the mass spectrum to those of other Ebeocarpus alkaloids. A three-proton doublet at 6 1.26 (J = 7.0 Hz) was assigned to the C-12 methyl substituent, and the signal from C-12-H at 6 4.62 was analyzed as a quintet of doublets (J,,,,, = 7.0; J,,,,, = 2.0; J1z,CH8 7.0 Hz). It was concluded that C-12-H is not axial from comparison with the NMR spectrum of the stereoisomer elaeokanine E which shows a large trans quasi-diaxial coupling (J12,11ax = 14.0 Hz) and it has been suggested that in elaeokanine D there is probably a departure from the chair form for ring A to a “twist” conformation. This would relieve steric interactions by allowing the C-12 methyl group (which would be axial in the chair form for ring A) to assume a more equatoriallike conformation. A multiplet at 6 3.65, which was assigned to C-7-H, can be analyzed as a doublet of triplets and shows that there is a large trans diaxial coupling to C-8-H (J7,8= 10.0 Hz) and averaged couplings (&[J7,6ax + J7,6eq] = 8.0 Hz) to the C-6 protons. This high mean
8. ELAEOCA RP US ALKALOIDS
34 1
value for the C-7-H,C-6-H couplings confirms that C-7-H is axial. The C-8 axial proton was assigned to a triplet a t 6 2.34 (Je,, = 10.0; J8,9 = 10.0 Hz), an indication that C-8-H and C-9-H are also trans diaxial. 5. Elaeokanine E
Elaeokanine E (33)(C,,H19N0,; mp 57-58.5"; [a], +35" in CHC1,) is isomeric with elaeokanine D, similarly shows a carbonyl band at
33
1705cm-l, and no hydroxyl band in the IR spectrum. The mass spectra of the two alkaloids are very closely similar. I n the NMR spectrum of elaeokanine E (CDC1, solution) the signals assigned to C-12-H and C-7-H partially overlap. A doublet at 6 1.34 (J = 7.0 Hz) was assigned to the C-12 methyl group and a multiplet at 6 3.76 (J1P,CH3 = 7.0; J12,11ax = 14.0; Jlz,lles = 1.0 Hz) to C-12-H. The large coupling (J = 14.0Hz) between C-12-H and one of the C-11 protons was considered to indicate a quasi-axial conformation for C-12-H. A narrow multiplet a t 6 3.85 was assigned to C-7-H and, on the basis of the arguments presented in the discussion of other Elaeocarpus alkaloids, indicates that the C-7,C-8 ring junction is cis.
B. SYNTHESIS OF ( f )-ELAEOKANINE C ( & )-Elaeokanine C has been synthesized by Hart and co-workers (13) by a route similar to that used by Tanaka and Iijima for the synthesis of ( f )-elaeocarpine and ( 5 )-isoelaeocarpine. The diazoketone formed by reaction of n-butyryl chloride with diazomethane was allowed to react with pyrrole in the presence of copper powder t o give 2-(2-oxopenty1)pyrrole(34). Catalytic hydrogenation to 2-(2-oxopentyl)pyrrolidine (35) followed by condensation with ethyl acrylate gave the ester (36) which underwent a Dieckmann condensation with sodium (37)(mp 52-54"). hydride in toluene to give 8-n-butyryl-7-oxindolizidine Catalytic hydrogenation of the acetic acid salt of 37 in ethanol solution over platinum oxide then afforded ( f )-elaeokanine C in 30%
342
S. R. JOHNS AND J. A. LAMBERTON
n-Pr.CO CH,
H
R R = H 36 R = CH,CH,COOC,H,
35
38
t 0 37
31
39
yield. The major product (C,,H,,NO,; mp 77-79') formed under these conditions was shown to be 8,9-dehydro-8-n-butyryl-7-oxoindolizidine (38) produced by abstraction of hydrogen from 37. The formation of ( k )-elaeokanine C, which presumably occurs by addition of hydrogen to the double bond of the P-diketone in the enolic form 39, provided proof for the cis C-7-H,C-8-H stereochemistry assigned to elaeokanine C from spectroscopic evidence (12, 13).
C. ELAEOKANIDINES A, B, AND C Elaeokanidines A, B, and C are closely related stereoisomers of molecular formula C,,H,,N,O. A structure has been assigned to elaeokanidine A but structural assignments for elaeokanidines B and C have not been possible. 1. Elaeokanidine A
Elaeokanidine A (40) (mp 38-38.5'; [aID +9' in CHC1,; dipicrate, mp 153-155') shows bands in the IR spectrum at 1705cm-l (CO)
8.
ELAEOCARPUS ALKALOIDS
343
40
and 3440 cm-l (NH) and the structure of elaeokanidine A was assigned from the resemblance of its NMR spectrum (CDC1, solution) to that of elaeokanine D. The spectrum showed a C methyl doublet a t 6 1.16 (J = 7.0Hz) and a quintet of doublets a t 6 3.73 (J,,,,,, = 7.0; J,,,,, = 7.0; J,,,,, = 2.0Hz) assigned to C-12-H. It was therefore considered that elaeokanidine A has a flexible conformation for ring A with the C-12 methyl group twisted away from the C-T-H, as in elaeokanine D. From double resonance studies a triplet at 6 2.15 (J8,9= 11.0; J8,7= 11.0 Hz) was assigned to C-8-H, and the large C-7-H,C-8-H and C-8-H7C-9-H couplings are in accord with those determined for elaeokanine D and indicate that elaeokanidine A has the same relative stereochemistry as elaeokanine D. 2. Elaeokanidines B and C
Elaeokanidine B (mp 93-94'; [.ID k 0 " in CHC1,; dipicrate, mp 144-146") and elaeokanidine C (mp 56-58"; [.ID + 1" in CHC1,; dipicrate, mp 212-215") closely resemble elaeokanidine A in their mass spectra and both show I R bands at 1705cm-l (CO) and 3440cm-l (NH). Their NMR spectra confirmed this close relationship and elaeokanidine B and elaeokanidine C show C-methyl doublets a t 6 1.17 and 6 1.18, respectively. Detailed analysis of the NMR spectra was precluded, however, by the overlapping of multiplets, and the stereochemistry of elaeokanidines B and C could not be determined.
V. Elaeocarpidine A. STRUCTURE DETERMINATION Elaeocarpidine (41) (mp 229-230"; [.ID + O " in CHC1,) is the only indole alkaloid isolated from Elaeocarpus species. The structure of the carbon skeleton of elaeocarpidine was established from degradative and spectroscopic studies (14, 15). Selenium dehydrogenation afforded 1-ethyl-P-carboline and, on catalytic hydrogenation in acetic acid,
344
S. R. JOHNS AND J. A. LAMBERTON
Qyq N
42 43
41
9
R = H R=COCH,
dihydroelaeocarpidine (42) (mp 123-125") was formed by hydrogenolysis of the N-C-N linkage. N-Acetyldihydroelaeocarpidine (43) (hemihydrate, mp 107-109") was converted into a methiodide which was shown to give N-methylpyrrolidine on Hofmann degradation and thereby proof of the presence of the five-membered ring was obtained. Elaeocarpidine shows intense Bohlmann bands in the 2700-2800 em-' region of the IR spectrum and was rapidly oxidized by mercuric acetate in acetic acid solution. The structure as shown with each nitrogen lone pair trans diaxial to the hydrogen at the respective adjacent ring junction was favored on conformational grounds (15) and has been supported by additional spectroscopic studies (16). An alkaloid, tarennine, which was isolated from Tarenna bipindensis (K. Schum.) Bremerkamp (Family Rubiaceae), has been shown to be identical with dihydroelaeocarpidine 42 (17).
B. SYNTHESES Two syntheses of elaeocarpidine have been reported (16, 18). I n a simple three-stage synthesis (18) the amide 44, prepared from tryptamine and 3-N-succinimidopropionic acid, was converted by reaction with phosphorus oxychloride into the dihydrocarboline 45. Reduction with lithium aluminum hydride in tetrahydrofuran then gave elaeocarpidine (41) and dihydroelaeocarpidine (42). I n a somewhat similar synthesis (16) the lactam 46 which was prepared by two distinct routes was shown to undergo reductive cyclization to give elaeocarpidine and dihydroelaeocarpidine. When this reduction step was carried out with lithium aluminum hydride in tetrahydrofuran a 1 :2 mixture of elaeocarpidine and dihydroelaeocarpidine was obtained but reduction with lithium aluminum hydride in pyrrolidine-tetrahydrofuran (1:l) at 0" gave a 5207, yield of elaeocarpidine along with unchanged lactam (46).
8.
345
ELAEOCA R P US ALKALOIDS
0
0 45
44
46 CHART
2.
BIOSYNTHETIC ROUTES TO Elaeocarpw ALKALOIDS
POSTULATED
THE
346
S. R. J O H N S AND J. A. LAMBERTON
VI. Biosynthesis
It has been suggested (10, 13) that the aromatic and dienone alkaloids having the C16 elaeocarpine-isoelaeocarpine ring skeleton can be formally derived from appropriate condensations of an ornithine unit and a C12 polyketide chain (Chart 2a) and the CI2 alkaloids of Elaeocarpus could similarly be derived from ornithine and a C8 polyketide (Chart 2b). Elaeocarpidine was considered to be derived from condensation of tryptamine, ornithine, and a C3 unit as indicated in Chart 2c (15). Onaka ( 8 )has drawn attention to the possibility that, by analogy with elaeocarpidine, elaeocarpine could be derived as shown in Chart 2d and he has noted that elaeocarpidine and 2-methyl-6hydroxyacetophenone have both been isolated from the same plant as ( f )-elaeocarpine and ( & )-isoelaeocarpine ( 4 ) . This alternative biosynthetic route seems less attractive, however, when the C16 dienone alkaloids are taken into account. REFERENCES 1. T. 0 . Hartley, E. A. Dunstone, J. S. Fitzgerald, S. R. Johns, and J. A. Lamberton, Lloydia (1973) (in press). 2. I. R. C. Bick, J. B. Bremner, and N. W. Preston, Chem. Commun. 1155 (1971). 3. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and J. A. Wunderlich, Chem. Commun.
290 (1968). 4. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and R. I. Willing, Aust. J. Chem. 22, 775 (1969). 5. S. R. Johns, J. A. Lamberton, A. A. Sioumis, H. Suares, and R. I. Willing, Aust. J. Chem. 24, 1679 (1971). 6. J. A. Wunderlich, Acta Crystalogr., Sect. B 25, 1436 (1969). 7. T. Tanaka and I. Iijima, Tet. Lett. 3963 (1970). 8. T. Onaka, Tet. Lett. 4395 (1971). 9. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Chem. Commun. 1324 (1968). 10. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 22, 793 (1969). 11. S. R. Johns, J. A. Lamberton, A. A. Sioumis, H. Suares, and R. I. Willing, Chem. Commun. 804 (1970). 12. N. K. Hart, S. R. Johns, and J. A. Lamberton, Chem. Commun. 460 (1971). 13. N. K. Hart, S. R. Johns, and J. A. Lamberton, Aust. J . Chem. 25, 817 (1972). 14. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Chem. Commun. 410 (1968). 15. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J. Chem. 22, 801 (1969). 16. G. W. Gribble, J . Org. Chem. 35, 1944 (1970). 17. J. R. Boissier, G . Combes, A. H. Effler, K. Klinga, and E. Schlittler, Ezperientia 27, 677 (1971). 18. J. Harley-Mason and C. G . Taylor, Chem. Commun. 281 (1969).
-CHAPTER
9-
THE LYCOPODIUM ALKALOIDS D . B . MACLEAN Department of Chemistry McMaster University Hamilton. Ontario
. .
I Introduction ...................................................... I1 The Alkaloids and their Occurrence .................................. I11. Annotinine ....................................................... IV Lycopodine and Related Alkaloids .................................. A. Conformational and Configurational Studies ........................ B Lycopodine .................................................... C Serratidine ..................................................... D . Lucidioline .................................................... E 12-Epilycodoline................................................ V Alopecurine and Related Alkaloids .................................. A Alopecurine, Debenzoylalopecurine.and Acetyldebenzoylalopecurine . . B Lycopecurine and Dehydrolycopecurine ........................... C. Inundatine and Isoinundatine ................................... VI Annopodine ...................................................... VII Serratinine and Related Alkaloids ................................... A Serratinine. Serratine. Serratanidine. and 8-Deoxyserratinine ........ B . Serratinidine. Fawcettidine. Fawcettimine. and Alolycopine ......... V I I I Luciduline ....................................................... I X . Cernuine and Related Alkaloids ..................................... A. Cernuine. Lycocernuine. and Anhydrolycocernuine .................. B Carolinianine .................................................. X Selagine .......................................................... X I . Synthesis of the Alkaloids .......................................... A. Introduction ................................................... B . Annotinine .................................................... C. Approaches t o the Lycopodine Skeleton ............. ............. D . 12-Epilycopodine ............................................... E . Lycopodine .................................................... XI1. Biogenesis and Biosynthesis of the Alkaloids .......................... A. Biogenesis ..................................................... B Biosynthesis ofLycopodine ...................................... C. Biosynthesis ofcernuine ........................................ References .......................................................
.
. . . . . . . . . . .
.
.
348 348 353 354 354 355 356 358 359 360 360 362 363 364 365 365 366 370 372 372 378 380 380 380 381 384 387 390 394 394 396 401 403
348
D. B. MACLEAN
I. Introduction I n the chapter on the Lycopodium alkaloids that appeared earlier in “The Alkaloids” ( 1 )the literature was reviewed until the middle of 1966. I n the succeeding five and one-half years covered in this review significant advances have been made in all aspects of the study of this family of alkaloids. New plant species have been examined and new ring systems have been discovered. The intensive investigations of L. serratum, L. alopecuroides, and L. lucidulum have been particularly rewarding in this respect. Preliminary studies directed toward the synthesis of the alkaloids were reported before. These studies have now reached fruition in the total synthesis of annotinine and of lycopodine. A new synthesis of lycopodine has been developed and a promising route to alkaloids of the lycopodine and serratinine systems appears to be nearing completion. The biosynthesis of the alkaloids has also been investigated. The notion that the carbon skeleton of these alkaloids is derived solely from acetate units has been disproved. It has been shown that two molecules of lysine as well as acetate are incorporated into the ring system of lycopodine. Examples of the ring systems found in this family of alkaloids are given in Chart 1. The new structural types encountered since the last review are marked with an asterisk. The numbering system employed is identical with that used before.* This chapter is organized in much the same manner as its predecessor with the alkaloids grouped according to their structural type. Some sections that were prominent in the last review are absent or receive scant attention because little or nothing of interest has appeared whereas new sections have been added and others expanded whenever warranted. The synthesis and the biosynthesis of the alkaloids are discussed in separate sections rather than under the individual alkaloids. This arrangement is desirable since some of the synthetic approaches are applicable to more than one ring system and the biosynthetic pathways to the alkaloids appear to have much in common.
11. The Alkaloids and Their Occurrence
A number of new species of Lycopodium have been investigated and other species reinvestigated since the last review. The alkaloids and the species in which they have been found are listed in Tables I and I1 *The numbering system used for luciduline is that introduced by W. A. Ayer.
0yo 9.
9
9@ H
N
l3
349
THE LYCOPODIUM ALKALOIDS
'%,,H
0 8
N
"o,
OH
13
1
Annotinine
Lycopodine
(JJj Lyconnotine
9
3 15
9
1
3 2
Annotine
6COC,H, Alopecurine*
Serretinine
Fawcettidine"
AnnoPodine"
Luciddine"
H
H 8
H 9
1
Lycodine
L
A
Selegine
O
10
Cernuine
which supplement the corresponding tables of the earlier review ( 1 ) .The alkaloids are listed in order of increasing carbon number and alkaloids of the same carbon and oxygen number in order of increasing hydrogen content. Some duplication of the previous tables occurs in the case of alkaloids of L. alopecuroides and L. serratum because a complete listing
TABLE I
-oms Alkaloid Formula
Name
WITH
ONE NITROGEN
Melting point ("C)
Serratanine Lueiduline (L21) Anhydrolycodoline Fawcettidine Dehydrolycopecurine Lycopodine
Lycopecurine Dihydrolycopodine Alolycopine Acrifoline Lycothunine Serratidine Inundatine Isoinundatine Clavolonine Dehenzoyl alopecurine Flabelliformine
239-24 1 53-56 178-179 143-144 174-177 255
Derivatives-melting point ("C) or rotation
Occurrence (ref.)
L. $erratum" (7) L. lucidulum Michx. ( 8 ) L. alopecuroides L. ( 9 ) L. alopecuroides (10) L. inulzdatum L. ( 5 ) L. selago L. ( 4 ) ;L. volubile Forst. ( 1 1 ) ; L. alopecuroides ( 9 ) ;L. inundatum ( 5 , 6);L. alpinum (12); L. serrmmb (7); L. serratumC(7) L. alopecuroides (10) L. volubile ( 1 1 ) L. alopecuroides ( 1 0 ) L. selago ( 4 ) L. serratumC(7) L. serra&nab (7') L. inundatum ( 5 ) L. inundatum ( 5 ) L. serratum" (7); L. alopecuroides ( 9 ) ;L. alpinum ( 1 2 ) L. alopecuroides ( 9 ) L. lucidulum ( 2 )
Lycodoline
Pseudoselagine, L23, isolycodoline, 12-epilycodoline L20 Lucidiolined
Lycoserramine Lycobergine 8-Deoxyserratinine Serratinine Serratine Alopecuridine Serratanidine Annopodine Acetyldebenzoylalopecurine Lycoclavine Alopecurine Isolycopodine,e molecular complex of lycopodine and acrifoline Clavatoxine,e molecular complex of clavatine and lycodoline ~~
a
~
230-233
128-130 224-225 242-243
-
210-211 211-212 238-240
-
L. serratumbPc(7); L. alopecuroidea ( 9 ) ;L. selago ( 4 ) ; L. inundatum (5) L. selago ( 4 ) ; L. lucidulum ( 2 ) L. selago ( 4 ) HC104; 238-240 L. lucidulum ( 2 ) ; L. clavatum var. megastachyon (2) [aID-46.2 (C = 0.56, CH,OH) L. serratumC (7) L. serratumC ( 7 ) L. serratumC (7) L. clavatum ( 4 ) ; L. selago ( 4 ) L. serratumb*c(7) L. serratumbrC(7) L. alopecuroides ( 9 ) L. serratumb (7) L. annotinum L. ( 1 3 ) L. alopecuroides (10) L. alpirtum ( 1 2 ) L. alopecuroides ( 9 ) L. annotinum ( 3 )
~~
L. clavatum ( 3 ) ~
~~
Alkaloids recorded in the previous review. This refers to L. serratum Thunb. var. serratum form. serratum = (Lycopodium serratum Thunb. var. Thunbergii Makino). This refers to L. serratum Thunb. var. serratum form. intermedium Nakai. This alkaloid was reported previously t o melt at 261-283'. Formula revised since last review.
TABLE I1
ALKALOIDS WITH Two NITROUENS Alkaloid Formula
Name Selagine Lycodine Lycoserine Des-N-methyl-a-obscurine Anhydrolycocernuine
a
C
Melting point ("C)
99-100 137-138
Carolinianine Cernuine Lycocernuine
198.5-201.5 -
,Fl-Obscurine a-Obscurine Serratinidine
232-234
Derivatives-melting point ("C) or rotation
Occurrence (ref.)
L. selago ( 4 ) L. serratumb (7); L. lucidulum (2) L. 8erratumb*c(7) L. alpinum (12) L. carolinianum L. v m . afine (14); L. inundatum ( 6 ) L. carolinianum (14) L. cernuum L. ( 6 ) L. carolinianum (14); L. cernum ( 6 ) ; L. inundatum ( 6 ) L. selago ( 4 ) L. selago ( 4 ) L. serratumb (7)
Alkaloids recorded in the previous review. This refers to L. serratum Thunb. var. serratum form. serratum = (Lycopodiumserratum Thunb. var. Thunbergii Makino). This refers to L. serratum Thunb. var. serratum form. intermedium Nakai.
9.
THE LYCOPODIUM ALKALOIDS
353
in one table was considered desirable (only preliminary accounts had appeared when the previous tables were prepared). Other items that deserve comment here since they will not be dealt with elsewhere are the following. The alkaloid previously denoted L13 has been shown to be identical with lycopodine ( Z ) , isolycopodine to be a molecular complex of acrifoline and lycopodine ( 3 ) ,clavatoxine, previously assigned the formula C1,H2,N02, to be a molecular complex of lycodoline and clavatine (flabelliformine) (3), and pseudoselagine and alkaloid L23 to be identical (2, 4 ) . An anomaly appears in the reports of the alkaloids of L. inundatum. The L. inundatum of European origin yielded lycodoline, lycopodine, and alkaloids related in structure to alopecurine ( 5 ) . Lycopodium inundatum and L. alopecuroides are apparently closely related taxonomically and the common ring systems found in the two species were not unexpected. In contrast, L. inundatum of Asian origin was reported to yield anhydrolycocernuine, lycocernuine, and lycopodine (6). This finding is remarkable not only because it differs so greatly from the previous result but also because it is the first report of the occurrence of alkaloids of the cernuine and lycopodine systems in the same plant.
111. Annotinine
Annotinine ( 1 )was assigned its structure (1) on the basis of extensive degradative studies, an X-ray analysis of annotinine bromohydrin, and an unambiguous synthesis (Section XI, B). The configuration of the methyl a t C-15 was the only structural feature which was not rigorously established in the degradative work. Now it has been shown that the configuration a t this center is resolvable by NMR as well as X-ray analysis (15).Thus the C-methyl group of diphenylannotinine appears at 6 0.20 in its NMR spectrum in contrast to the C-methyl of annotinine
354
D. B. MACLEAN
which appears at 6 1.26 when its spectrum is recorded under similar conditions. Arguments based on model studies are presented that the shielding caused by one of the aromatic rings of 2 is possible only when the methyl group is pointing toward ring B.
IV. Lycopodine and Related Alkaloids A. CONFORMATIONAL AND CONFIGURATIONAL STUDIES Lycopodine (3)lacks Bohlmann bands (16) in its IR spectrum but they are present in 12-epilycopodine (4). These observations indicate that 3 has a cis- and 4 a trans-quinolizidine system as shown in the formulas. Ayer et al. (2) have shown that UV spectroscopy provides another probe for the investigation of the P-aminoketone system found in alkaloids of the lycopodine structure. Thus lycopodine and alkaloids that have the same configuration, such as lycodoline ( 5 ) and clavolonine (6),show an absorption of medium intensity in the 220 mp region that is absent in their salts and is absent in 12-epilycopodine and in 12epilycodoline (7) (Section IV, E). The absorption is attributed to a sigma coupled interaction between the lone pair on nitrogen and the n- system of the carbonyl and occurs when all three of these orbitals are parallel.
Lycopodine; R, = R2 = R3 = H Lycodoline; R, = O H ; R, = R3 = H Clavolonine; R, = R 2 = H; R, = O H 6 8a Flabelliformine; R, = R, = H; R, = OH 3
4
5
7
12-Epilycopodine; R = H 12-Epilycodoline; R = O H
Circular dichroism studies (2) on the same systems show that lycopodine and related alkaloids display two Cotton effects. In the case of lycopodine a positive effect is observed at 288 mp and a negative effect a t 223 mp, the latter associated with the chromophore discussed in the
9.
355
THE LYCOPODIUM ALKALOIDS
previous paragraph. Protonation removed that a t shorter wavelength and reversed the sign of that a t longer wavelength. 12-Epilycopodine, on the other hand, shows only one negative Cotton effect centered at 287 mp. Thus CD can be used as well as UV and I R to gain insight into the conformation of the quinolizidine system present in these alkaloids. It was also pointed out that ORD results in this series should be interpreted with caution. 12-Epilycodoline (7) has been shown to belong to the same enantiomeric series as lycopodine by conversion of 7 to 3, yet 7 shows a negative Cotton effect and 3 a positive Cotton effect in their ORD curves. The octant rule predicts a positive Cotton effect for 7 if one accepts the configuration previously assigned to 3. The possibility that the configuration assigned to lycopodine on the basis of ORD results was incorrect was therefore explored. The accumulated evidence, however, favored the original assignment. An explanation of the anomalous ORD results is still missing. Plabelliformine has been postulated to exist in conformation 8b because the I R spectrum suggested that the hydroxyl was hydrogen bonded to nitrogen (1).It has now been shown ( 2 )that flabelliformine has a UV absorption a t 228mp and has ORD and CD curves very similar to lycopodine. Thus in solution in protic solvents conformation 8a seems to make a major contribution.
8b
9a
9b
Anhydrolycodoline represents a case similar to flabelliformine ( 2 ) . It was assigned conformation 9a because of the presence of Bohlmann bands in its I R spectrum. Like lycopodine, however, anhydrolycodoline shows a strong positive Cotton effect and Conformation 9b must be a contributing structure at least in solution in protic solvents.
B. LYCOPODINE The structure of the Hofmann base derived from lycopodine methiodide has been clarified (17’).This compound, originally thought (18)
356
D. B. MACLEAN
to have structure 10, has been shown through a chemical and an X-ray study to be 11. It has been postulated to form through the sequence 12 + 13 + 14 +-11. The enolate 12, formed from lycopodine methiodide in the basic medium, undergoes solvolytic fission of the
CH3 13
N-(3-13 bond to give the dipolar species 13. The latter stabilizes itself by hydride transfer from C-9 to C-13 yielding the immonium ion 14 which then undergoes intramolecular cyclization to 11. The structure was deduced from a study of the NMR and mass spectra of deuteriumlabeled derivatives of 11 and verified by an X-ray crystallographic study of the hydrobromide of 11.
C. SERRATIDINE Lycopodium serratum has been a rich source of alkaloids of this family, and serratidine (15;C,6H,3N0,) is another interesting compound
9.
357
THE LYCOPODIUM ALKALOIDS
found in this species ( 7 , 19). Spectroscopic examination revealed the presence of a CH(CH,) group, a carbonyl group, a trisubstituted double bond, and a tertiary hydroxyl function. Since there are no other functions, serratidine must be tetracyclic. Reduction of the carbonyl gave the alcohol 16 that dehydrated in pyridine-SOC1, to an anhydro compound (17).The NMR spectrum of 17 has a new vinyl proton appearing as a multiplet a t S 5.37 along with the original vinyl proton a t S 5.72. Acetylation of the hydroxyl function still present in 17 gave the 0acetate (18) which lacked a signal in its NMR spectrum for a proton geminal to an acetoxy group; therefore the hydroxyl must be tertiary. An examination of the mass spectrum and the ORD spectrum of 15 and comparison with the spectra of known alkaloids of this family indicated that serratidine belonged to the lycopodine group and that structure 15 accounts for its properties and 16, 17, and 18 for the structures of its derivatives.
@ ROO,,
17
R = H
18
R
20 24
=
CH3C0
R=OH R = H
The structure assigned to serratidine was confirmed in the following way. Reduction of 16 over platinum gave the isomeric compounds 19 and 20 but only 19 had Bohlmann bands in its I R spectrum. Compounds
358
D. B. MACLEAN
epimeric at C-12 are also formed on similar treatment of acrifoline and anhydrolycodoline; thus it seems likely that serratidine has a double bond at C-11-C-12 like those alkaloids and that 19 and 20 have the structures shown. Acetylation of 19 to a monoacetate (21) took place at the secondary hydroxyl function and treatment of this product with PC1, gave the chloride 22. Hydrogenolysis of the chloride with sodium in liquid ammonia gave 23 which on oxidation was converted into 12epilycopodine (4). The epimeric diol 20 was converted in a similar series of reactions into dihydrolycopodine (24). To date this is the only alkaloid of established structure bearing a hydroxy group at the bridgehead position. On the basis of current ideas of the biogenesis of these alkaloids C-7 is an expected site of oxygenation.
D. LUCIDIOLINE The alkaloid (20) has been assigned structure 25. Spectroscopic examination revealed the presence of two hydroxyl functions, a trisubstituted double bond, a secondary C methyl group, and a tertiary nitrogen, and since these were the only functions present the alkaloid must be tetracyclic in nature. From the mass spectrum of the alkaloid it was inferred that the hydroxyl functions were present on adjacent carbon atoms because of the presence of an intense ion at m/e 203 (M-C,H,O,) and the fact that its formation apparently occurred in a single step (metastable peak at m/e 156.8). The absence of an intense ion at m/e 206 (M-C,H,) [characteristic of alkaloids like lycopodine which have an H a t C-12 (Sl)]implied that the double bond of lucidioline might be at C-11-(3-12 if the alkaloid has the lycopodine skeleton. Structure 25 was considered a plausible structure on the basis of the CH,
CH3
OH
25
26
27
9. THE
LYCOPODIUM ALKALOIDS
359
mass spectral and other evidence. The substitution pattern, oxygenation at C-5 and C-6, is similar to that of desacetyllycoclavine 26 (22) and accordingly an attempt was made to correlate lucidioline with this compound of known structure. Hydrogenation of 25 over Pt in methanol in the presence of HC10, gave two products (26 and 27) in the approximate ratio 1:1. The faster-moving component on TLC was found to be identical with desacetyllycoclavine and the slower-moving component to be an isomer. This experiment proved that lucidioline was dehydrodesacetyllycoclavine but it did not establish unequivocally the site of the double bond. When it was found that Bohlmann bands (16) were present in diacetyl 27 but not in diacetyl 26 it was obvious that 26 and 27 were epimeric at C-12 and that the stereoisomers resulted from the saturation of a double bond C-11, C-12. Thus the structure and configuration of lucidioline were established.
E. 12-EPILYCODOLINE (ALKALOID L23, PSEUDOSELAGINE, ISOLYCODOLINE) Recent independent studies (2, 4) have shown that the alkaloids previously designated alkaloid L23 and pseudoselagine (C,,H,,NO,) are identical and are represented by structure 28. This alkaloid is thus
3 28
epimeric with lycodoline (5)a t C-12. It has been suggested that the compound be called isolycodoline ( 4 ) but 12-epilycodoline is more descriptive. The alkaloid has carbonyl absorption at 1690 cm-l and a concentration-independent band in the I R at 3510 em- suggesting the presence of an internally bonded hydroxyl group. The NMR spectrum established the presence of a CHCH, group, while the absence of absorption which could be attributed to a hydrogen geminal to the hydroxyl function implied that the OH was tertiary. This supposition was strengthened by the resistance of the alkaloid to acetylation. The mass spectrum of 28 was very similar to that of lycodoline,
360
D. B. MACLEAN
suggesting that the two were stereoisomers. The presence of strong Bohlmann bands in the I R spectrum of 28 but not in that of 5 indicated that the two were epimeric at C-12. Verification of the structure and configuration came from dehydration of 28 t o anhydrolycocodoline (9) which had previously been prepared from 5 and had been in turn converted into lycopodine (23).
V. Alopecurine and Related Alkaloids
A. ALOPECURINE, DEBENZOYLALOPECURINE, ACETYLDEBENZOYLALOPECURINE
Lycopodium alopecuroides elaborates alkaloids belonging to the lycopodine and fawcettidine ring systems and a new group of pentacyclie alkaloids (9, 10). The pentacyclic system arises from the lycopodine skeleton by bond formation between C-4 and C-lo. Recently it has been shown that alkaloids of this type are also present in L. inundatum ( 5 ) . The first alkaloid of this new group to be investigated was alopecurine (29). A preliminary examination (9) of the alkaloid showed the presence of a benzoyloxy group, a hydroxyl group, and a tertiary nitrogen. The presence of the benzoyloxy group was revealed by hydrolysis of 29 to benzoic acid and debenzoylalopecurine (30) while the presence of the hydroxyl group and the tertiary nitrogen came from spectroscopic and chemical evidence. Thus the I R spectrum of the alkaloid showed OH but not NH absorption, and acetylation of 29 yielded an O-acetyl but not an N-acetyl derivative. The NMR spectrum of 29 (10) has a broad signal at 6 5.35 ( W + = 15 Hz) assigned to the proton geminal to the benzoyloxy group. By spin decoupling it was found that this proton was coupled to four adjacent protons all of which were definitively located. The two pairs of vicinal protons were coupled only to one another and to the proton geminal to the benzoate group. It was concluded from chemical shift data that one pair was vicinal to nitrogen; therefore the other pair must be adjacent to a quaternary carbon. Through NMR and chemical studies the environment about the hydroxyl function was established. Alopecurine has a signal of area one at 6 4.02 ( J = 8 Hz) that shifts to 6 5.28 in O-acetylalopecurine (31) but is absent in dehydroalopecurine (32). Compound 32, prepared by oxidation of 29 with Jones reagent, has vmax 1715 (benzoyl), 1690, and 1410cm-l, indicating that the new carbonyl at 1690cm-1 is flanked by at least one methylene group. Debenzoyldehydroalopecurine
9.
361
THE LYCOPODIUM ALKALOIDS
(33)also has peaks at 1690 and 1410 cm-I and is readily oxidized to a diketone, vmax 1720, 1690 cm-l. Further information was derived from an NMR study of the dehydration product of alopecurine (34).Two vinyl protons were present, one a doublet at 6 5.50 ( J = 9 Hz) and the other a quartet at 6 5.35 (J = 9 and 2 Hz). Thus the double bond is disubstituted with one substituent quaternary and the other tertiary. On the basis of the coupling of the proton geminal to the hydroxyl group, placement of the CHOH adjacent to the quaternary center of 29 was favored. H3CfH
29 R, =z COC&; R, = H 30 R l = R, = H 31 R1 = COCeH5; R, = COCH,
35 R1 = COCH,; R, = H
lo@H
32 R = COC6H5 33 R = H
kg
C6H5CO0
--__
N
OH 5
9
E 0-C
yo '6H5
34
29
At this point in the study chemical degradation was abandoned and an X-ray analysis begun. Both debenzoylalopecurine hydrobromide and alopecurine methobromide were examined. From these studies the structure and configuration shown in the formulas were assigned. It is noteworthy that the deductions made from the chemical and spectroscopic study were correct and are incorporated in the final structure. In the solid state, ring C is in a twist boat conformatJion (stereostructure 29) and both rings B and D are considerably distorted from a chair conformation. The authors point out that the NMR evidence suggests a similar conformation in solution. I n the case of ring C a
362
D. B. MACLEAN
chair conformation would result in a strong interaction between C-9-H and the substituent at C-2 which is relieved in the twist boat. Distortion of ring B to the half-chair relieves a strong interaction between the C-5 hydroxyl and C-15-H. It is because of this distortion that C-5-H gives rise to a doublet in the NMR spectrum. This is explicable on the grounds that C-5-H and C-6-Ha have a dihedral angle approaching 0" while C-5-H and C-6-HP have a dihedral angle approaching 90". Thus the coupling observed is between C-5-H and C-6-Ha. Debenzoylalopecurine (30) and acetyldebenzoylalopecurine (35) in which an acetyl group has replaced the benzoyl group have also been isolated from this plant (9, 10).
B. LYCOPECURINE AND DEHYDROLYCOPECURINE Lycopecurine (36) was isolated in small amounts from Lycopodium alopecuroides (10) and in the course of structural investigation (24) was converted into dehydrolycopecurine (37). The latter has recently been
36
37
found among the alkaloids of L. inundatum ( 5 ) .The molecular formula (C,,H,,NO) of 36 was established by mass spectrometry. A distinguishing feature of the mass spectrum is a strong peak at M-15 which is not common to alkaloids of the Lycopodium family. The NMR spectrum showed the presence of a CHCH, group and the absence of olefinic protons. IR examination showed the presence of a hydroxyl band and a band at 1505 em-I which the authors point out has structural significance. A band in this region is also present in the spectra of alopecurine and debenzoylalopecurine and is apparently associated with methylene absorption in the doubly bridged hydrojulolidine system. Bands at this frequency are absent in the tetracyclic Lycopodium alkaloids and the observation of this band provided the first clue that lycopecurine belonged to the pentacyclic group of alkaloids. The hydroxyl function was shown to be secondary by its oxidation to a ketone (v,, 1695 cm-I). Further chemical studies were precluded by lack of material,
9. T H E LYCOPODIUM ALKALOIDS
363
and an X-ray analysis of lycopecurine hydrobromide was carried out. From this study the structure and configuration depicted in 36 were assigned. It is noteworthy that, in the absence of an oxygen substituent a t C-2 as in alopecurine and debenzoylalopecurine, ring C assumes a normal chair conformation in the solid state.
C. INUNDATINE AND ISOINUNDATINE Besides dehydrolycopecurine (37) two other pentacyclic alkaloids, inundatine (38; Cl6Hz3NOZ) and isoinundatine (39; C,,H,,NO,) are present among the alkaloids of Lycopodium i n u n d a t u m (5). The structures of both were established by relating them to alopecurine (29) of known structure (10). Spectroscopic examination revealed the presence of a secondary hydroxyl function and a carbonyl function in each of 38 and 39. Since there was no unsaturation in these molecules other than the carbonyl functions it was apparent that they were pentacyclic. Oxidation converted inundatine into the diketone 40 previously derived from 29, thereby establishing the structural framework and the sites of functionality. Deuterium exchange in alkaline D20 resulted in the uptake of
o@ l;
+ Rz = 0 ; R3 = R4 = H
2
37 R1 38 R, 39 R1
%+
29 R i = O H ; Rz = H; R3 = H; R, = OC,//O 40 R1 Rz 2 0; R3 R4 = 0 CBHS 33 R i Rz = 0; R3 = H; R4 = O H
N" --.__
+ R,
+ R,
+
R3
+
= 0; R3 = O H ; R4 = H =H
+ OH; R3 + R4 = 0
+
R4
two deuterium atoms into 38 and thus the carbonyl function must be at C-5. Since inundatine was different from dehydrodebenzoylalopecurine (33) it must be epimeric with 33 at C-2. Its structure and configuration are represented in 38. Isoinundatine was converted by Jones reagent into the diketone 40 and thus has the same skeleton and substitution pattern as 38 and 29. The presence of the ketone function at C-2 was established by the uptake of four deuteriums on basic exchange in D20. The configuration of the hydroxy function at C-5 was not established in this study. The authors point out that attempted acetylation of isoinundatine with pyridineacetic anhydride gave an enol acetate at C-2 as well as the O-acetate at C-5. The formation of the enol acetate is facilitated very likely by the
364
D. B. MACLEAN
relief of steric strain resulting from the incorporation of a double bond into ring C.
VI. Annopodine As its name implies, annopodine (41) is one of the many alkaloids of Lycopodium annotinum where it occurs in minute amount. Extensive degradative studies were precluded and resort to an X-ray analysis was necessary to resolve its structure (13). Several simple transformation products were prepared .and examined spectroscopically along with the alkaloid itself in order to gain insight into the nature of the functional groups and their immediate environment. Thus the alkaloid was easily converted into its 0-acetate (42) and into an anhydro derivative (43). From a spectroscopic examination of 41, 42, and 43 it was established that the alkaloid had a tertiary nitrogen but not an N-alkyl group, a secondary hydroxy group, a carbomethoxy group conjugated to a fully substituted double bond, a
41 42
R = H R = COCH,
43
44
CHCH, group, and that the new double bond of 43 was not conjugated with the chromophore already present in 41. Examination and comparison of the NMR spectra of the three compounds showed that the secondary hydroxyl group was flanked on one side by a methine. Partial structure 44 is in harmony with these observations and with the observation that the molecule readily loses C,H, on electron impact. It is also compatible with current ideas with respect to the biogenesis of C,,N alkaloids of this family. However, the site of attachment of the two-carbon bridge to the molecular framework was not established and there was not any firm evidence for the presence of a hydrojulolidine system in the alkaloid. An X-ray crystal structure determination, carried out on annopodine hydrobromide, resolved the structural and stereochemical problem
9. THE LYCOPODIUM
ALKALOIDS
365
and showed that annopodine has the structure and configuration found in 41. At the time of writing, the ring system found in annopodine is unique among the alkaloids of this family.
VII. Serratinine and Related Alkaloids A. SERRATININE, SERRATINE, SERRATANIDINE, AND 8-DEOXYSERRATININE Preliminary reports (25, 26) leading to the assignment of the structure and stereochemistry of serratinine were reviewed previously ( 1 ) . Since then this work has been communicated in full detail (27-30) and an X-ray study of a serratinine derivative has been carried out (31). The X-ray study showed that the structural and stereochemical deductions made from chemical and spectroscopic examination were correct except for the assignment of configuration at C-4. The C-3-C-4 bond should be in the p position as shown in revised structure 45 for serratinine. Serratine has been isolated from the same source as serratinine, with which it is isomeric, and has been assigned structure 46 on the following evidence (32, 33). Both 13-monoacetylserratinine and 13monoacetylserratine undergo dehydration to the same product (47) and therefore both must have the same ring system and the same configuration at carbon centers 4, 7, 12, and 13. From spectroscopic studies it is evident that 46 has one tertiary and one secondary hydroxyl group. The secondary hydroxyl is known to be at C-13 because of the conversion of 46 into 47. The tertiary hydroxyl is considered to be at C-15 since the methyl group of serratine appears as a singlet at 6 1.31. The position of the tertiary hydroxyl group was confirmed and its configuration established by conversion of 46 into the cyclic carbonate 48. Thus the hydroxyl groups of serratine must be cis to one another on ring D and located at C-13 and C-15. Serratanidine (49) (33, 34) has one oxygen more than 45 and 46 and is closely related to both. The nature of its ring system was established by relating it to serratinine in the following manner. Acetylation of 49 gave a diacetyl derivative (50) that still retained hydroxyl absorption in its IR spectrum but had two signals of area 1 attributed to protons geminal to acetoxy groups in its NMR spectrum. The methyl group of 50 appears as a singlet at 6 1.18 and, as in 46, the tertiary hydroxyl group is probably situated at C-15.
366
D. B. MACLEAN
45
48
41
46
51 52 53 54
R1 = H; R2 + R3 = 0 R, = Ac; R, + R3 = 0 R, = Ac; R, = R3 = H R1 = R, = R, = H
I n the course of hydrolysis of 50 it also dehydrated, yielding the compound 51 of established structure. This finding permitted the assignment of structure 49 to serratanidine and defined the configuration at all sites save C-8 and C-15. The structure was confirmed by the conversion of compound 47 into serratanidine by treatment of 47 with HCO,H-H,O, followed by hydrolysis. This experiment verified the sites of hydroxylation of 49 and established that the hydroxyl groups at C-8 and (3-15 were trans to one another but did not establish which of the two was cis to the hydroxyl group at C-13. This last feature was clarified by conversion of 49 to a cyclic carbonate. The NMR spectrum of the cyclic carbonate showed that its free hydroxyl group was secondary and, since only cis hydroxyls can interact in this bridged system, the hydroxy a t C-15 must be cis to that a t C-13. I n this way the structure and configuration of serratanidine were established. 8-Deoxyserratinine ( 7 ) has been derived from serratinine (35). Treatment of the acetate 52 with ethane dithiol gave the corresponding cyclic thioketal a t C-8. Desulfurization over nickel gave the acetate 53 which on hydrolysis yielded 8-deoxyserratinine (54).
B. SERRATINIDINE, FAWCETTIDINE, FAWCETTIMINE, AND ALOLYCOPINE The ring system of all four of the title alkaloids is similar and was established by correlation with the structure of serratinine. Early
9.
THE LYCOPODIUM ALKALOIDS
367
in the study of the alkaloids of Lycopodium serratum it was proposed (26) that the ring system of alkaloids of the serratinine group might be derived by a rearrangement of the ring system of lycopodine and an attempt was made to interrelate the two series chemically. As a result of this work the serratinine system was converted into the ring system found in serratinidine although the original objective was not realized. In a series of straightforward%reactions (35, 36) serratinine was converted into compound 55 which gave the two compounds 56 and 57 upon treatment with zinc and acetic acid. Zinc in acetic acid is known to cleave a-amino ketones and compound 58 is expected to be an intermediate in this reaction. Interaction of the newly formed secondary amino group of 58 with the carbonyl at C-13 leads to carbinolamine 57 and under the reaction conditions used 57 is dehydrated to the vinyl amine 56. It should be noted that both 56 and 57 were isolated from the reaction mixture and that 57 and 58 are ring-chain tautomers. The authors demonstrated conclusively that 57 was a carbinolamine by the preparation of tricyclic derivatives with a free carbonyl at C-13 and that 57 was convertible to 56 by dehydrating agents . The I R spectrum of 56 has a band at vmox1662 cm-l attributed to the double bond of the enamine and carbonyl absorption associated with the cyclopentanone and acetoxy groups. The NMR spectrum of 56 has a single vinyl proton appearing as a doublet at 6 5.41 ( J = 6 Hz), a proton geminal to the acetoxy group appearing as a quartet at 6 4.45 (J = 6 and lOHz), and a signal attributed to a CHCH, group appearing as a doublet at 6 0.98 ( J = 7 Hz). When the methine proton a t C-15 was irradiated the signal of the methyl group collapsed to a singlet, as did the signal assigned to the vinyl proton while the quartet assigned to the proton geminal to the acetoxy group became a doublet. These observations confirmed the structure assigned to ring D of 56 in the sequence C-13, C-14, (3-15, and C-8. Serratinidine (59) has one basic and one nonbasic nitrogen (35, 36). Spectroscopic examination showed the presence of the following structural features: a >-OH
group, a \CH-NHCOCH,
/
group, a
CHCH, group, and a trisubstituted double bond. An NMR examination of O-acetylserratinidine (60) showed that it had the same structural unit as that found in ring D of 56 and it seemed probable that 0acetylserratinidine differed from 56 in having an acetamide group at C-5 instead of a carbonyl, and this proved to be the case. Thus 56 was converted into an oxime, thence into an amine by reduction over RaNi, and finally into an acetamide by reaction with acetic anhydride.
368
D. B. MACLEAN
N 11111111111
0 55 62
58 64
R = OAc R = H
R1 = H ; Rz = OAc R1 = COCH,; Rz = H
56 61
R = OAc R = H (fawcettidine)
59 60
57
63
R = H (serretinidine) R = Ac
67 68
R = OAc R = H (fawcettimine)
65 66
R = OCOCH3 R=OH
R = H R = AC
From the crude reaction mixture a compound was separated by chromatography that was identical with natural O-acetylserratinidine. Thus structure 59 may be assigned to this alkaloid but the configuration a t C-4 and C-5 is not established and is still unknown. Fawcettidine (37, 38) has been shown to have a CHCH, group, a trisubstituted double bond, and a carbonyl (v,, 1740 cm-l) probably in a five-membered ring and it has been shown to be a weak base (pK, = 6.2). It was noted that the spectroscopic properties of 56 and fawcettidine had many features in common and that their basicities were comparable, indicating that fawcettidine might have structure 61 (35,39).The preparation of 61 from serratinine was therefore attempted.
9.
THE LYCOPODIUM ALKALOIDS
369
For this purpose serratinine was converted by conventional procedures into 62 which was treated with Zn and acetic acid in a manner similar to 55 and with a similar result. Two products were isolated from the reaction, one a, carbinolamine assigned structure 63, the other, an anhydro compound 61, that proved to be identical with natural fawcettidine by comparison of the natural and synthetic picrates. Fawcettimine, now known to be 63 (37, 38, 40)) has urnax 1732 and 3585 cm-l assigned to a carbonyl in a five-memberedring and hydroxyl absorption, respectively. Acetylation of fawcettimine gave a compound (64; C,,H,,NO,) which, in its I R spectrum, had carbonyl absorption at 1730 and 1690 cm-l attributed to ketonic groups in five- and sixmembered rings, respectively, and absorption at 1615 cm-l assigned to the carbonyl of an acetamide group. There was no absorption, however, that could be assigned to NH or OH functions (38). These observations suggested that in fawcettimine there is a transannular interaction between a secondary amine and a carbonyl group in a sixmembered ring and that acetylation of the open-chain form occurs in the formation of the acetamide. The properties of fawcettimine are very similar to those of the carbinolamines 57 and 63 and an attempt was therefore made to establish a correlation with the serratinine system (41).To this end compound 53 (Section VII, A) was prepared from serratinine and treated with zinc and acetic anhydride. The product, 65, resulting from cleavage of the a-aminoketone and acylation at nitrogen, was hydrolyzed to the alcohol 66. Reduction of N-acetylfawcettimine (64) with sodium borohydride gave a product identical with 66. Thus the structure of fawcettimine may be represented as 63. Although 63 was prepared by the Japanese workers in the course of the elucidation of the structure of fawcettidine (35)and should be identical with fawcettimine, they state that a direct comparison of the natural and synthetic material was not made. Alolycopine (67) is one of the new alkaloids isolated from L. alopecuroides (10,42). It was obvious from its properties that it did not belong to the new pentacyclic series of alkaloids discovered in this plant but instead was related to the already known fawcettidine (61) (39)) also a constituent of this species. The presence of a secondary hydroxyl function was apparent from the I R spectrum of 67 (vOH 3625 cm-l) and fi-om a signal in the NMR spectrum of O-acetylalolycopine (68) at 6 4.54 (J = 12 and 5 Hz). The fact that an NH band was absent in the I R spectrum of 67 and that only an O-acetyl derivative of alolycopine was formed upon acetylation implied that the nitrogen was tertiary. Like fawcettidine, which has a vinyl amine function, there is an intense band in the spectrum of 68
370
D. B. MACLEAN
a t 1665 em-l. An NMR examination of 68 revealed the same relationship of the vinyl amine function, the CHCH, group, and the oxygen function a t C-8 as that found in ring D of 56 and 60. The presence of a cyclopentanone with an exocyclic double bond was evident from the I R and the UV spectra of 67. The single vinyl proton of the exocyclic double bond appeared as a quartet at 6 6.82 (J = 6 and 1.5 Hz) and is probably adjacent to a methylene. A broad band at 1410 em-l in 67 and 68 indicates that there is a methylene adjacent to the ketone function of the cyclopentanone system. The structural features deduced from the spectroscopic studies may be incorporated into the ring system found in fawcettidine as shown in expression 67. This structure was confirmed through catalytic reduction of O-acetylalolycopine to 56 whose preparation from serratinine has already been described.
VIII. Luciduline Alkaloid L2 1, originally isolated from Lycopodium lucidukum, has been reinvestigated and assigned the trivial name, luciduline. Its composition (C1,H,,NO) has been verified and its structure has been elucidated by both a degradative and an X-ray study (8).The structure of luciduline shown in 69 is unique among the alkaloids of this family and intriguing from a biosynthetic viewpoint. The bands in the IR spectrum of luciduline a t 2780, 1690, and 1400 em-l are assigned to N-CH,, carbonyl, and methylene adjacent to carbonyl, respectively. I n luciduline-d,, formed by acid-catalyzed exchange, the band at 1400cm-l is absent as expected. Upon borohydride reduction 69 yielded dihydroluciduline (70)which, with pyridine acetic anhydride, gave 0-acetyldihydroluciduline (71). The study of the NMR spectra of these compounds showed the presence of N-CH,
DCH3
0
R
69 70 71
R, + R, = 0 (luciduline) R l= OH; Rz = H R, = OAc; R, = H
72
73
R = Br
74
R = H
9. THE
371
LYCOPODIUM ALKALOIDS
and CHCH, groups and gave useful structural information as discussed below. I n 71 there is a multiplet, assigned to the proton geminal t o the acetoxy group, at 6 4.97 (WQ = 24 Hz) whereas in O-acetyldihydroluciduline-d, (71-d,) formed from luciduline-d, this signal appears as a doublet a t 6 4.98 (J = 4.5 Hz); therefore the carbonyl is flanked by a methine as well as methylene and enolization toward the methine does not occur readily. Further information concerning the environment about the carbonyl was obtained from the spectrum of luciduline. A quartet of area 1 at 6 3.05 ( J = 16 and 11 Hz) present in the spectrum of 69 was absent in the spectrum of luciduline-d, and must be assigned to the axial proton vicinal to the carbonyl. The 16Hz coupling is assumed to be due to a geminal proton and the 11 Hz coupling to a vicinal axial coupling. The other proton of the methylene was located
I
I
at 6 2.3. Thus the partial structure -CH-CH,-CO-CHwas established. Another proton, also a quartet, present in the spectrum of luciduline at 6 2.93 (J = 13 and 4 Hz), shifted downfield when the spectrum was recorded in acetic acid-d, and appeared at 6 3.33 (J = 13 and 4Hz). Two other protons also shifted downfield appearing, respectively, as a broad singlet a t 6 3.57 and a doublet centered at 6 3.8 ( J = 13 Hz). These three protons were considered to be adjacent to nitrogen. The 13 Hz coupling of the quartet was considered to be a geminal coupling with the proton at 6 3.8 while the 4 Hz coupling was considered to be a vicinal coupling. Further studies with 71-d, showed that the methine proton vicinal to the acetoxy group was also vicinal to the methylene adjacent to nitrogen and the partial structure above could be expanded to include both nitrogen and carbonyl as follows:
Dehydrogenation of luciduline over selenium gave 2,6-dimethylnaphthalene in high yield. By assuming that the carbon framework of luciduline is preserved in this molecule and by invoking the Conroy hypothesis of biogenesis of these alkaloids (43) structure 69 for luciduline was evolved. The structure is compatible with the NMR and dehydrogenation data. Further chemical studies supported structure 69. Oxidation of luciduline with KMnO, gave a lactam, vmax 1640 and 1730 crn-l. The IR bands were in agreement with the presence of a lactam in a sixmembered ring and a 1,3 relationship of the two carbonyls. The methine proton at C-3 in the lactam (72) appeared as a quartet at 6 3.64 (J = 3
372
D. B. MACLEAN
and 6 Hz) in agreement with structure 69. Bromination of luciduline in CHC1, with two equivalents of Br, gave 73, vmax 1670, 1603 and A,, 263 mp. I n accord with the assigned structure there was no resonance for a vinyl proton in the NMR spectrum. Selenium dioxide oxidation of 69 gave the conjugated ketone 74, vmax 1668 and 1628 cm-l. The single vinyl proton in the NMR spectrum of this compound appeared at 6 6.02. Catalytic reduction of 74 to 70 proved that rearrangement had not occurred in this series of reactions. A mass spectral examination of luciduline and several of its derivatives was undertaken. The spectra were all interpretable on the basis of structure 69, thus lending credence to its validity. An X-ray study of the p-bromobenzoate of 70 fully confirmed the conclusions drawn from the chemical and spectroscopic studies and at the same time established the relative configuration at C-8 and the absolute configuration of the molecule, The X-ray study showed that the molecule is somewhat distorted from an ideal chair toward a half-chair conformation in rings A and C. In this way the interaction between the axial hydrogen at C-1 and the nitrogen is considered to be relieved.
IX. Cernuine and Related Alkaloids A. CERNUINE, LYCOCERNUINE, AND ANHYDROLYCOCERNUINE 1. Structural Studies
The structure and stereochemistry of cernuine (75) and lycocernuine (76) were reported previously (1).At that time the structural studies had been published only in preliminary form and the work leading to the assignment of stereochemistry had not yet appeared in the open literature. I n the interim three papers have been published (44-46) in which full details of the structural studies are given, the work leading to the assignment of configuration is described, and the synthesis of a stereoisomer of cernuine is reported. Only those structural studies not reported in the earlier review are discussed here. Anhydrolycocernuine (77), which had been prepared from lycocernuine, has been reported to be a constituent of two species, Lycopodium caroliniunum (14) and L. inundutum (6). Both anhydrolycocernuine (77) and dehydrolycocernuine (78) were key compounds in elucidating the structure and stereochemistry of these alkaloids. By the routes outlined in Scheme 1 the two were converted
9. THE
373
LYCOPODIUM ALKALOIDS
into a common intermediate (79)characterized as its methyl ester (80). The structure of the ester is supported by the mass spectrum which shows an intense ion at m/e 235, formed by loss of the ester side chain,
77
78
HI04-KMn04
Oa(OII -)
COPR 79 80
R = H R = CH,
SCHEME 1
to which structure 81 is assigned, and by the NMR spectrum of 80 in which the proton at C-9 has shifted downfield to 6 7.32 and appears as a triplet rather than as a quartet at 6 5.46 as it does in cernuine. This work defines beyond doubt t;he sites of functionality in 76,77,and 78.
81
75a 76a
R =H R = OH
83
2. The Configuration of Cernuine and Lycocernuine
The point of reference used in developing the relative configuration of the alkaloids was the hydroxyl group of lycocernuine. In the NMR spectrum of 0-acetyllycocernuine (82) the proton geminal to the
374
D. B. MACLEAN
acetoxy group appears as a multiplet at 6 4.88 ( W i = 5 Hz). Double irradiation experiments showed that this signal was decoupled to a triplet (J = 2.5 Hz) by irradiation a t 6 3.19 (C-13-H) and to a doublet (J = 2.1 Hz) by irradiation a t 6 1.88 (C-11 methylene). The absence of a la,rge vicinal coupling implies that C-12-H is equatorial and therefore that the hydroxyl group is axial at C-12. Neither cernuine nor lycocernuine have Bohlmann bands in their I R spectra favoring a cisquinolizidine arrangement of rings C and D. This arrangement is compatible with the NMR data. The proton at C-9 is clearly visible in the NMR spectra of cernuine and lycocernuine and their derivatives and invariably appears as a quartet with one large and one small vicinal coupling attesting to its axial character. The configuration at C-7 was deduced from the behavior of cernuine and lycocernuine toward mercuric acetate. I n both cases oxidation occurred a t C-7 and, in analogy with other systems, the hydrogen at this site is considered to be trans diaxial to the lone pair on N,. Evidence was presented that the double bond of the enamine derived from cernuine was at C-6-C-7 and not at C-7-C-8. The product of oxidation of lycocernuine has been formulated as the oxazolidine 83, providing further support for an axial hydroxyl in the transquinolizidine system of rings C and D. The oxidation products were reconverted into 75 and 76 by catalytic hydrogenation showing that the carbon skeleton was unaltered in the reaction with mercuric acetate. The hydrogen at C-5 is considered to be cis to that at C-7 because dihydrodeoxycernuine (84) has weak Bohlmann bands in its I R spectrum. Since these bands are absent in the spectrum of cernuine itself they are attributed to the new trans-azaquinolizidine made up of rings A and B. This argument is valid only if the assumption is made that the configuration is not altered in the course of the reduction of 75 to 84 by lithium aluminum hydride. These studies define the relative configuration of 75 and 76 at the ring junctions and a t the site of the hydroxyl function of 76. Based on the following argument the methyl group at C-15 was placed in an equatorial position on ring C. It was found that the borohydride rgduction of 78 yielded not only 76 but about 20yo of an epimer of 76. Had the CH, group been axial at c - 1 5 the proportion of the epimeric alcohol would have been expected to be much smaller since an axial methyl would seriously hinder approach of the hydride from that side of the molecule. Other more convincing evidence for the configuration at (3-15 is presented in Section IX, A, 4. Based upon ORD studies on 78 and on the stereochemical outcome of the reaction of 76 with a-phenylbutyric anhydride it was concluded
9.
THE LYCOPODIUM ALKALOIDS
375
that the configuration at C-13 is R and that cernuine and lycocernuine have the absolute configurations shown in the formulas and the conformations shown in 75a and 76a. 3. Allocernuine and Epiallocernuine
The reduction of 77 with H, over Pt in ethyl acetate (45) gave only a small amount of cernuine; the major product, an epimer at C-13, was named allocernuine. Both allocernuine (85) and 77 were converted into the same compound, dihydroallocernuine (86), when treated with H, over Pt in methanol solution. Structure 86 was assigned on the basis of an examination of the mass spectra of 86, its dihydrodeoxy derivative (87), and the N-methyldihydrodeoxy derivative (88). In the polar
86
85
87 88
+ R, R, = R, R, = R, R,
= 0;R, = H = R3 = H = H;R, = CH,
H
"/*H
89
85a
+
90 R1 Rz = 0 91 R, = Rz = H
+
90a R, Rz = 0 91a R, = R, = H
376
D. B. MACLEAN
solvent methanol, but not in the nonpolar solvent ethyl acetate, allocernuine is postulated to be in equilibrium with the zwitterion 89 which then undergoes reduction to 86. I n support of this postulate it was found that 85 is converted into 86 by treatment with sodium borohydride in methanol and is isomerized to epiallocernuine (90) in boiling methanol. Compound 90 is assumed to be epimeric with cernuine at both C-9 and C-13. Allocernuine does not show Bohlmann bands in its I R spectrum and is considered to exist mainly in conformation 85a, whereas epiallocernuine has Bohlmann bands and is considered to have conformation 90a in which all hydrogens at ring junctions are trans diaxial to the nitrogen lone pairs. Both allocernuine and epiallocernuine are converted by lithium aluminum hydride in ether to dihydrodeoxyepiallocernuine (91) which has strong absorption as expected (see stereoformula 91a) in the 2700-2800 cm-l region of the spectrum. An explanation has been offered for the conversion of the all0 series into the epiallo series during hydride reduction. It is probably because of the highly strained character of the allocernuine system that it isomerizes to the epiallo compound and undergoes facile reduction to the dihydroall0 compound. Neither cernuine itself nor epiallocernuine are converted to dihydro derivatives under conditions that convert 85 into 86. 4. Synthesis of Dihydrodeoxyepiallocernuine
Dihydrodeoxyepiallocernuine (91), the most stable of the stereoisomers of dihydrodeoxycernuine, has been synthesized (46) by an unambiguous route. The synthesis confirms the nature of the ring system of the alkaloids and strengthens the stereochemical assignments already discussed. The synthesis is outlined in Scheme 2. I n the first step of the synthesis, 2,4,6-collidine, whose ring will eventually become ring C of 91, was converted into the lithium derivative shown and condensed with ally1 bromide. The product (92) was subjected to hydroboration-oxidation, yielding alcohol 93 which was converted into its tetrahydropyranyl ether (94) before proceeding to the next step. I n the treatment of 94 with phenyllithium it was shown that hydrogen abstraction occurred a t the methyl group a t C-6 and not at C-4 of the pyridine. The lithium derivative of 94 was then treated with 3,4,5,6-tetrahydro-2-ethoxypyridine to give an unstable enamine which was hydrogenated directly. Hydrolysis removed the tetrahydropyranyl group giving 95 containing the sixteen carbons, the two nitrogens, and rings A and C of the cernuine system. To complete the synthesis it was necessary to reduce the pyridine to a piperidine and oxidize the alcohol to an aldehyde, whereupon rings B and C were
377
9. THE LYCOPODIUM ALKALOIDS
1 4 . H,O, H +
2.
EtO
96
97
I
I
95
c,o,-PY
CZOS-PY
98
I-.+
91
100
101
SCHEME 2
expected to form spontaneously. Reduction of the racemate 95 over Rh-C a t 2000 psi and 100” gave a mixture of two racemic hexahydro compounds assigned structures 96 and 97, only one enantiomer of each racemate being shown. The same products were obtained by reduction with sodium in isoamyl alcohol. The assignment of stereochemistry to 96 and 97 is based on analogy with other aromatic systems which are known to give mainly products of cis addition upon catalytic hydrogenation. It is also known that, in the presence of hydrogenation catalysts, isomerization of substituents cc to nitrogen occurs leading to the more stable isomer, and that dissolving metal reductions normally
378
D. B. MACLEAN
give the most stable products. Thus, in both 96 and 97, it was anticipated that the three groups in the trisubstituted ring would all assume the stable equatorial conformation. The separation of 96 and 97 was accomplished by chromatography of their N,N-diformyl derivatives prepared by selective hydrolysis of the O,N,N-triformyl compounds. After separation, hydrolysis of the formyl groups gave the pure amines. The diamino alcohol of higher R, value (96) when oxidized by CrO, in pyridine, yielded a single racemic product identical with 91 in its physical properties in solution. Presumably the initially formed aldehyde cyclized to the immonium salt (98) which in turn was attacked by N, to form the tetracyclic system. Attack of N, from the bottom side of the carbon-nitrogen double bond to give the epimer at C-9 was not expected because of the strain involved and it did not occur. Similar treatment of 97 gave an inseparable mixture of two stereoisomeric compounds, 100 and 101, formed by attack of N, on either side of the carbon-nitrogen double bond of the intermediate (99). I n agreement with the stereochemical assignment 91 shows intense Bohlmann bands since both nitrogens have the stereochemistry required for their appearance. Such is not the case with the mixture of 100 and 101 where only one nitrogen is so disposed and the Bohlmann bands are much weaker. In the course of this work the preparation of tricyclic compound 87 was accomplished by treatment of the mixture of 96 and 97 with concentrated hydrobromic acid. Chromatography of the mixture gave a racemate whose properties in solution were identical with those of 87. This conversion confirms the structural assignments made on the spectroscopic evidence and discussed in the previous section.
B. CAROLINIANINE Carolinianine (C16H24N202) is a constituent of Lycopodium curoliniunum where it occurs in conjunction with lycocernuine and anhydroly-
cocernuine. Not unexpectedly it has been shown to belong to the cernuine group (14). The I R spectrum has uEyx 1625 and 3480 cm-l attributed to amide and hydroxyl functions. The secondary nature of the hydroxyl group in carolinianine (102)was established by conversion into an O-acetate (103) which showed a quartet of area 1 in its NMR spect,rum at 6 4.89 (shifted from 6 3.50 in 102) ascribed to the proton
9.
379
THE LYCOPODIUM ALKALOIDS
geminal to the acetoxy group. The NMR spectrum also shows the presence of a single vinyl proton at 6 5.23 and a vinyl methyl group at 6 1.67. Catalytic reduction of 102 gave a dihydro derivative (104) isomeric with lycocernuine. The mass spectrum of 104 was virtually identical with that of lycocernuine, indicating that the two compounds have the same ring system. Except for the fact that many of the peaks appeared two mass units lower the mass spectra of 102 and 103 were very similar to those of lycocernuine and 0-acetyllycocernuine. There was also a correspondence in the NMR spectra in the two sets of compounds. It was on this basis that it was concluded that carolinianine was dehydrolycocernuine with the double bond between C-8 and C-15 or between C-14 and (2-15.
OH
OR 102 103
R =H R = Ac
104
To define the structure completely it was necessary to fix the position of the double bond and to establish the configuration at C-5, C-7, C-9, C-12, and C-13. Comparison of the NMR spectra of 102 and 103 with the spectra of lycocernuine along with decoupling experiments with 103 provided the solution to these problems. Examination of the protons of 103 at C-9 and C-12 showed that they were remarkably similar in chemical shift and coupling constants to the corresponding protons of 0-acetyllycocernuine and must have the same configuration. Moreover the hydroxyl group at C-12 is not internally hydrogen bonded and thus the configuration at C-13 must also be similar to that in lycocernuine. The chemical shifts and multiplet character of the signals assigned to H-5 and H-7 in 102 and 103 are similar to those observed in lycocernuine and 0-acetyllycocernuine, respectively, a situation that would not be expected if there was a difference in configuration at either site between the two systems. By double irradiation studies it was possible to locate the double bond between C-14 and C-15. Thus it was shown that the proton at C-13 was couplied to the proton at C-12 geminal to the acetoxy group as well as to the vinylic proton. Carolinianine is therefore A14,15 dehydrolycocernuine and dihydrocarolinianine is epimeric at C- 15 with lycocernuine.
380
D. B. MACLEAN
X. Selagine Studies leading to the assignment to selagine of the structure shown in 105 were reported in the previous review ( I ) . I n that study the configuration of the methyl at C-11 was not rigorously established.
105
Selagine
Evidence based upon the relative rates of methylation of selagine and 11,12-dihydroselagine has recently been published that suggests that the structure shown in 105 is indeed correct (47).
XI. Synthesis of the Alkaloids A. INTRODUCTION The synthesis of annotinine was described in 1967, approximately one decade after its structure was elucidated. It was the first alkaloid of this family to be synthesized, just as it was the first to have its structure established. Shortly after the synthesis of annotinine wits announced, two different syntheses of lycopodine were reported simultaneously. The synthesis of lycopodine also constituted a synthesis of alkaloids of the lycodine group since conversion of lycopodine into lycodine had already been achieved ( I ) . The cernuine ring system has been constructed but not cernuine itself (Section IX, A, 4). This work was discussed along with the structural and stereochemical studies because it was directly related to them. At the time of writing the synthesis of alkaloids belonging to the other ring systems found in Chart 1 (Section I) has not been reported but constitute interesting synthetic challenges for future study. Several syntheses of 12-epilycopodine have been published and although this compound has not been found in nature 12-epilycodoline has. Moreover, there is one member of the lycodine group of alkaloids, namely sauroxine ( I ) , that has the 12-epi configuration. The methods
9. THE
LYCOPODIUM ALKALOIDS
381
used to synthesize 12-epilycopodinewill therefore be discussed because they are novel and they may be useful in other applications in this family of alkaloids. Also included here is an account of several abortive approaches to the lycopodine system and an account of work that promises to lead to alkaloids of both the lycopodine and serratinine series.
B. ANNOTININE The synthesis of annotinine was carried out at the University of New Brunswick by Professor K. Wiesner's group. It was reported initially in a series of short communications (48-51) and finally in full detail (52). A key step in the total synthesis, the construction of the four-membered ring through a photochemical addition of allene to a vinylogous amide, was studied first in a model system. It was found that compound 106 added allene under irradiation yielding a mixture of the tricyclic compounds 107 and 108. The former was converted into its ethylene ketal, then hydrogenated, and finally hydrolysed to compound 109. The ketal function effectively shields one side of the methylene leading to the product with the desired configuration upon reduction. The elaboration of the synthesis from this intermediate was not pursued because a more promising starting material 110 was found. Compound 110, readily prepared from 111 and acrylic acid at 135", underwent the same sequence of reactions used in the model series, yielding exclusively 112 in which it is inferred that the hydrogen at C-4 is trans to the bridging group. The ketone was converted into the alcohol 113 and thence to the mesylate 114 which in turn was transformed to the alkene 115 with potassium tertiary butoxide in DMSO. Only under these conditions was 115 obtained in high yield uncontaminated with rearranged products. Functionality a t C-5 was introduced by oxidation with selenium dioxide in glacial acetic acid. Acetate 116 so obtained was hydrolysed to the alcohol 117 and oxidized to the racemic ketone 118. One of the enantiomers of 118 had already been prepared from annotinine ( 1 ) and comparison of the spectroscopic properties of 118 with the naturally derived sample established the identity of the two systems. The carbon necessary to complete the annotinine skeleton was introduced by treatment of 118 with HCN in dimethyl formamide, yielding a mixture of the epimeric nitriles 119. Hydrolysis of the nitriles in methanolic sulfuric acid gave the racemic ester 120 identical
382
D. B. MACLEAN
109
110
112
o@ \
113 114
111
R =H R = S0,Me
115 116 117
R =H R = OAc R = OH
H
0
118
119 120 121
+
+
R1 Rz = H CN R, = C0,Me; Rz = H R1 = COZH; Rz = H
122
9. THE
383
LYCOPODIUM ALKALOIDS
in spectroscopic properties with a sample derived directly from annotinine ( 1 ) .The racemic acid 121 obtained by hydrolysis of 120 was resolved through its brucine salts. Regeneration of the acid from the less soluble diastereomer and conversion of the acid into its methyl ester gave a compound belonging to the same enantiomeric series as annotinine. The structure and configuration shown in the formulas had already been assigned ( 1 ) to this compound and from this stage onward the synthesis was completed with optically active material. The next objective of the synthesis was the lactone 122, a compound that is also readily available from annotinine ( I ) . Borohydride reduction of the enol acetate 123 derived from 121 yielded a mixture of the hydroxy esters 124 and 125. This mixture was hydrolysed to the corresponding acids, 126 and 127, and the acids treated with p-toluenesulfonic acid in boiling benzene. The product was a mixture of the desired lactone 122 and the hydroxy acid 127 in approximately equal amounts. Another less attractive method of preparation of 124 was described in the course of the structural study of annotinine ( I ) .
123
124 125 126 127
129
R, = OH; R, = H;R, = CH3 R, = H;R, = O H ;R, = CH3 Rl = O H ; R, = R, = H Rz = O H ; R1 = R3 = H
128
130
The introduction of the epoxide into ring A constituted the final step in the synthesis since a procedure for the conversion of oxoannotinine (128)into annotinine was already known (53).Bromination of 122
384
D. B. MACLEAN
with N-bromosuccinimide in CC1, under irradiation with visible light gave 129 and this upon treatment with hot aqueous hydrobromic acid yielded the broniohydrin 130 that was readily converted into 128 by refluxing with sodium carbonate in acetone. Both 129 and 130 may be derived from oxoannotinine by established procedures and their structures were verified in this way. The final step was achieved by treatment of 128 with H, over Pt in methanol containing hydrochloric acid, yielding annotinine in better than 50% yield. The allene addition reaction which made this approach possible has also been applied in the construction of the lycopodine skeleton (Section XI, D). C. APPROACHES TO
THE
LYCOPODINE SKELETON
The construction of the four rings of lycopodine in the proper steric relationship but lacking the C-methyl group and functionality in ring B has been described by Wiesner’s group (54). Intermediate 131, prepared by Grignard addition of ally1 magnesium bromide to the immonium salt 132 followed by subsequent hydrolysis and isomerization of the product, was cyclized to 133 in a Prins type reaction and then converted into 134. An analogous cyclization was used in an attempted preparation of an intermediate suitable for elaboration to lycopodine ( 5 4 ) . Compound 135, prepared by treatment of 136 with allylmagnesium bromide and subsequent hydrolysis, cyclized readily. Unfortunately the initially formed compound 137 underwent internal hydride transfer to 138 with consequent loss of the funtionality of ring B which was requisite for the construction of the fourth ring of lycopodine. I n the cyclized products discussed above the position of the double bond was not established and this is indicated by the dashed lines of the formulas. Compound 135 was not characterized but it must be an intermediate in the sequence 136 to 138. The bicyclo[3.3.l]nonane system found in rings B and D of lycopodine has been used by two groups in efforts to arrive a t the lycopodine system. In the work of Colvin et al. (55) the readily available bicyclo[3.3.1] nonane derivative 139 was converted in straightforward steps to the amine hydrobromide 140. For the construction of the potential ring A of lycopodine the amine hydrobromide was converted into the pyruvamide 141 which cyclized to 142 in high yield in the presence of sodium hydride in THF. Conversion of 142 into the imino ether 143 followed by reduction with lithium aluminum hydride gave 144 in which the lactam function was removed and the ketone reduced to an alcohol. The two double bonds of 144 were saturated and the oxygen function
p wOcH 9. THE
385
LYCOPODIUM ALKALOIDS
A
131
132
X = OH X =H
133 134
I
ti
p 139 140 141
R = C0,Et R = NiHBrR = NHCOCOCH,
142
143
144 145
&
N-COCH3
146
R =H R = Ao
H I
147
148
0
149
386
D. B. MACLEAN
removed by hydrogenolysis in the treatment of the diacetyl derivative 145 with hydrogen over Pd-C in ethanolic perchloric acid. The product is represented in 146 but it was not established whether the configuration corresponded to that of lycopodine as shown or to that of 12epilycopodine. A similar approach was followed by Horii et al. (56) who carried out an analogous series of reactions leading eventually to the preparation of 147. I n a later paper (57), in which a different approach to the construction of ring A was used, the same group describe the preparation of the tricyclic ketone 148 and its rearrangement to 149. The former system comprises three of the four rings of lycopodine in proper steric array while the latter has three of the four rings found in fawcettidine and its relatives (Section VII, B). Surprisingly, the elaboration of the synthesis to specific alkaloids has not been reported. The method of Horii et al. for the synthesis of 148 and 149 follows. The bicyclo[3.3.l]nonane 150 was converted in 66y0 yield into the oxirane 151 by treatment with a fivefold excess of dimethylsulfonium
151 R = NHCOZCHzPh
150 R = NHCOZCHzPh
HO
154 R l + Rz = 0 ; R3 = H 155 R l = R, = R3 = H 156 R l = Rz = H ; R3 = COzEt
fp
R2 152 R, = NHCOzCHzPh; Rz = COsEt 153 R1 = NHZ; RZ = H
R, = H; Rz = OH; R3 = COzEt 159 R1 Rz = 0 ; R3 = COzEt
157
+
158
9.
THE LYCOPODIUM ALKALOIDS
387
methylide in DMSO-THF. The two carbons necessary for the completion of ring A were introduced by treatment of 151 with ethyl ethoxy magnesium malonate. The product (152) was hydrolysed in concentrated hydrochloric acid to 153 which was converted into 154 by boiling in ethanol containing catalytic amounts of Triton B. Reduction with lithium aluminum hydride converted the lactam into the secondary amine 155 which was then transformed to its carbamate (156). Hydroboration-oxidation was used to hydrate the double bond of 156, resulting in the formation of 157 in 74y0 yield. Only minor amounts of the isomer with the hydroxyl at C-6 were formed. I n straightforward steps 157 was converted into 148 and into the enone (158). Rearrangement of the tricyclic system found in 148 t o that of 149 was easily accomplished. When the ketone 159 was treated with concentrated hydrochloric acid or 48Y0 HBr in glacial acetic acid the carbamate suffered hydrolysis and dehydration occurred yielding a compound to which structure 149 was assigned on the basis of its spectroscopic properties and its composition. The I R absorption at 1735 cm-l assigned to the ketone function is appropriate to this structure but the band at 1630 cm-l assigned to the enamine double bond is considerably lower than that found in fawcettidine and its analogs (Section VII, B). The chemical shift of the vinyl proton also differs considerably from that reported in the model series (Section VII, B).
Three syntheses of this compound have been achieved by the Wiesner group. I n two of them an allene addition to a vinylogous amide was a key step while in the third and most direct synthesis a Michael addition to the vinylogous amide system was used in one of the ring-forming reactions. I n the first approach to be reported (58) compound 159, derived from dihydroorcinol and acrylonitrile, was benzylated and the product (160) treated with allene as already described (Section XI, B). The adduct 161 formed in 30y0 yield was transformed to the ketal 162 which was treated with perbenzoic acid, yielding the epoxide 163. Treatment of the epoxide with lithium borohydride yielded the alcohol 164. Hydrolysis of the ketal group of 164 in 2y0aqueous hydrochloric acid in THF was accompanied by opening of the four-membered ring, giving the diketone represented as 165 in which rings A and D are
388
D . B. MACLEAN
shown in a cis fusion although this configuration has not been established. However, when treated with base the diketone yielded the aldol 166 and it must have been in the cis-fused form that aldolization occurred. I n a series of reactions the alcohol was converted into the halide 167 and the halogen was replaced by hydrogen in a reduction reaction giving 168. I n the reduction step the ketone was prot,ected by ketalization and the reduction was accompanied by debenzylation.
R3Jf
a +
0 159 160 172 175
RI
Lc)kf
R,
CH3
H
N-R,
N-CH2CsH5
R
= H R = CH,C6H5 R = (CH,),C=C=CH, R = (CH2),C-CH,
// 176
0 0 U R = -(CH2),-CO-CH3
1 : t i i O H
0
163
R, = CH2C6H5; Rz R3 = 0 162 R, = CH2CaH5; R2 R, = -O(CH2)20161
+
&
+
&d
N-CH,C6H5
N-R,
N-CH,C6H5 0 164
169 170
R =H R = CO-CH=CHz
165
171
166 167 168
Rl = CH,C6H,; R, = O H Rl = CH2C6H5; R, = C1 Rl = R2 = H
4
389
9. THE LYCOPODIUM ALKALOIDS
The ethylene ketal of 168 was reduced with lithium aluminum hydride in dioxane and then hydrolysed to the amino ketone 169. Treatment of 169 with acrylyl chloride and triethylamine gave the acrylamide 170 containing all the carbons of the lycopodine system. Cyclization to the tetracyclic system shown in 171 occurred when 170 was refluxed in toluene containing p-toluenesulfonic acid. Reduction of the lactam with lithium aluminum hydride in T H F followed by Jones oxidation of the product gave racemic 12-epilycopodine (4) identical in spectroscopic properties with the enantiomer derived by reduction of anhydrolycodoline. I n a refinement of the previous synthesis (59) compound 159 was alkylated with 6-bromo-1,Z-hexadiene in the presence of sodium hydride in DMF giving 172 containing all the carbon atoms necessary for completion of the carbon skeleton. Irradiation in the manner previously described gave 173 in 70y0 yield and this compound was converted into the lactam 174 in a series of reactions similar to those used in the previous synthesis to convert 161 into 168. Lactam 174 was then converted into racemic 12-epilycopodine by established routes. I n still a third synthesis of this compound (59) a further refinement was achieved. The compound 175 prepared by alkylation of 159 with the ethylene ketal of 6-bromo-2-hexanone was treated with 20yo HC1
173
174
178
177
390
D. B. MACLEAN
to remove the ketal function. When the resulting ketone 176 was placed in methanolic sodium methoxide and the solution allowed to stand for 36 hr there was obtained in 307, yield the compound 177. This compound had been prepared as one of the intermediates in the conversion of 173 into 12-epilycopodine and apparently forms in a stereoselective intramolecular Michael addition to the enone system of 176 followed by an intramolecular aldolization of the postulated intermediate 178.
E. LYCOPODINE Lycopodine has been synthesized by the groups of Ayer (60) and of Stork (61).I n the Ayer synthesis the closure of ring D between C-7 and C-8 was visualized as the final step in the construction of the tetracyclic system. When the last review was prepared (1)progress in this synthesis had already been made. The preparation of 179 had been realized in which rings A, B, and C were in the proper steric array (62). A compound with a suitable leaving group on the side chain was now required. For this purpose a mixture of compounds 180 and 181 was prepared in a manner analogous with that used for the preparation of 179. Thus the Grignard of l-chloro-2-methyl-3-methoxy propane was used instead of that of isobutyl chloride in the reaction with 182. The diastereomers, 180 and 181, were separated in the form of their alcohols, 183a and 183b, derived from the ethers by treatment with BC1,. Both series were taken through to the tetracyclic system but only the one with the configuration corresponding to that a t C-15 of lycopodine will be considered. Compound 183a was acetylated to 184 and oxidized with potassium permanganate to the lactam 185. Hydrolysis of the ester to the alcohol and treatment of the latter with methane sulfonyl chloride in pyridine resulted in the formation of the mesylate 186. Treatment of the mesylate with potassium tertiary butoxide-tertiary butanol a t reflux gave the racemic tetracyclic lactam 187 which was available from lycopodine in its optically active form. The spectroscopic properties in solution of the racemic and optically active forms were identical. The first objective of the synthesis was realized and it was necessary now only to devise a met'hod to transpose the carbonyl group from C-6 to C-5. The synthesis was completed using optically active 187 derived from lycopodine. For the preparation of 187, lycopodine was converted by known procedures into the diol 188 (63) and this in turn into the acetate 189. Dehydration of the latter gave the unsaturated compound 190 that
/p4fi 9.
391
THE LYCOPODIUM ALKALOIDS
H2C
R2 R3 179 R, = Rz = R3 = H 180 R, = OCH,; R2 = R3 = H 183a R, = OH; R2 = R, = H 184 R1 = OAc; R, = R3 = H R3 = 0 Rl = OAC;R, 185
181 R = OCH3 183b R = OH
182
+
I
187
192 R, 193 Ri
+ R2 = 0 + R2 = H + OH
188 R = H 189 R = Ac
194
190 R, = H ; R, = OAc 191 R, R, = O 195 R, = R, = H
+
196
392
D. B. MACLEAN
was hydrolysed and then oxidized with MnO, to the enone 191. Reduction with Li-NH, gave the ketone 192 that underwent oxidation with permanganate in acetone to the lactam 187. This compound served as a natural relay for further synthesis. The conversion of 187 into lycopodine was readily accomplished. Reduction of 187 with lithium aluminum hydride gave the mixture of epimeric alcohols 193 that was oxidized with Jones reagent t o the ketone 192. Selenium dioxide gave the known diosphenol 194 which was converted into a separable mixture of lycopodine, anhydrodihydrolycopodine (195),and dihydrodeoxylycopodine (196) by heating with hydrazine in diethylene glycol a t 155". I n the second synthesis of lycopodine, that of Stork (61),the closure of ring B between C-4 and C-13 was the key step. The preparation of 197 was therefore undertaken with a view of cyclizing it to 198, modifying the potential ring A and the aromatic ring to yield 199 and converting this by established routes into lycopodine. All of these objectives were realized but not without difficulty. Compound 197 was synthesized in the following manner. The cyclohexenone 200, prepared by conventional procedures, was methylated a t C-3 with methyl magnesium iodide in the presence of cupric chloride in a conjugate addition. On workup, compound 201 was obtained in which the methyl and methoxybenzyl groups are in the trans configuration as required. Annelation of 201 was achieved by treatment of its pyrrolidine enamine with acrylamide followed by simultaneous hydrolysis of the enamine and ring closure to 197. The mixture of 197 and an isomer resulting from this reaction were separated and identified. I n a later paper (64) Stork reported an alternative and ingenious method of derivation of 197 in which the formation of the unwanted isomer is avoided. I n the new procedure a Michael addition of 3methoxybenzyl magnesium bromide to 5-methyl-2-cyclohexenonein the presence of cupric chloride was carried out. The resulting magnesium enolate (202) was alkylated directly with ally1 bromide giving 203. Conversion of the latter into 204 was brought about by conventional methods and it in turn was converted into 197 by heating with methanolic ammonia. I n the next and key stage of the synthesis the cyclization of 197 was effected in acid media giving 198 in 557, yield accompanied by a minor amount of an isomer shown 60 be the product of ortho substitution on the aromatic ring. Of the two possible products of protonation of the enamine function a t the potential C-12 of lycopodine only one, that leading to 198, exists in a conformation suitable for cyclization. None of the isomer with the 12-epi configuration was formed.
9.
oqq0 393
THE LYCOPODIUM ALKALOIDS
QH3
0@ L q C H H 3
R202C Rl
H
H
\
OCH,
197
198
200
201
199
Rl = R, = H
208
R1 = C-OCHZCC1,; R, = CH,
No
202
H 203
204
205
C02CH,
I
I
,CHz
,CH,
C1,C
C1,C 206
207
209
The transformation of the aromatic ring of 198 to the system found in 199 was the final phase of the synthesis. The lactam function of 198 was reduced with lithium aluminum hydride and the aromatic ring converted into its dihydro derivative (205)by Birch reduction. Compound 205 was isomerized to the conjugated diene, the amino group
394
D. B. MACLEAN
was protected, and the resultant compound subjected to ozonolysis yielding 206. The enol formate 207 was derived from 206 by oxidation (SeO, + H,O, in t-butyl alcohol) and upon transesterification (CH,OH + NaOCH,) was converted into 208. The lactam 209 of known structure was obtained by heating the keto ester with Zn dust in methanol. The conversion of 209 first into dihydrolycopodine and then into lycopodine is unexceptional.
XII. Biogenesis and Biosynthesis of the Alkaloids A. BIOGENESIS The hypothesis that the Lycopodium alkaloids were of polyketide origin was advanced by Conroy a t a time when only a few alkaloids of this family were known (43). By suitable combination of two 3,5,7triketooctanoic acid chains in conjunction with a nitrogen source it is possible to account for the structures of the alkaloids of Chart 1. With the exception of luciduline the manner in which the two chains are considered to combine is implicit in the numbering system adopted for these alkaloids; carbons 1 to 8 comprise one chain and carbons 9 to 16 the other. A discussion of this proposal as it applied to the alkaloids known a t the time appeared in the previous review ( 1 ) .The new ring systems are also readily accommodated by the polyacetate hypothesis. Thus fawcettidine is related to serratinine, alopecurine to lycopodine, and annopodine appears to be a variant of the annotinine system. Of the new ring systems only luciduline with four fewer carbon atoms deserves special comment but it too can be readily accommodated. Thus luciduline may be considered to be derived (8) from one intact eight-carbon chain, corresponding to carbons 9 to 16, and four carbons, 5 to 8, of the other chain as illustrated. Another biogenetic proposal conceived in these laboratories and outlined in Scheme 3 (65) envisaged the CI6N alkaloids like lycopodine
Luciduline
210
Cernuine
9. THE
395
LYCOPODIUM ALKALOIDS
to be derived from a binitrogenous precursor. A consideration of the structure of flabelline led to this hypothesis. Flabelline (210)has the lycopodine skeleton with an acetamido group a t C-5 ( I ) . It was considered that the nitrogen a t C-5 might be a vestige of a binitrogenous precursor and that the C1,N alkaloids like lycopodine and the C,,N, alkaloids like lycodine had a common origin. Serratinidine is another more recent example of an alkaloid with the CI6N framework carrying
('0"'
\A
v
Pelletierine
Lycodine
Lycopodine
SCHEME 3
Annotinine
396
D. B. MACLEAN
a nitrogen a t C-5. It is also significant that most of the C,,N alkaloids have an oxygen function a t C-5, the site of the attachment of nitrogen in the C,&, alkaloids of the lycodine group. The C,,N, alkaloids of the lycodine series may be visually dissected into two C,N units comprising, respectively, carbons 1 to 8 and N, and carbons 9 t o 16 and N,. The C,N unit that was considered to lead to the alkaloids is pelletierine. I n t~ suitably oxidized state, pelletierine was postulated to condense as shown in Scheme 3 to a binitrogenous species (65) that could be elaborated into alkaloids of either the lycopodine or lycodine system. The two pelletierine units are indicated by dotted lines in the formulas. Both schemes account equally well for the structures of the alkaloids particularly if one accepts that annotinine and the other C,,N alkaloids arc derived from the lycopodine system as outlined before ( 1 , and references therein). The cernuine alkaloids fit perfectly into the newer scheme, being simple dimers of pelletierine as shown by the dotted lines in the formulas. Luciduline may be considered t o arise by combination of one pelletierine and one acetoacetate unit (8) or alternatively from one intact and one degraded pelletierine unit. Selagine may be simply a degraded lycodine system in which C-9 has been extruded as suggested in the earlier discussion of the polyacetate hypothesis (1).Alternatively, selagine might be a product of the combination of a C,N unit (pelletierine) and a C,N unit (desmethyl hygrine). I n the next two sections studies are reported on the biosynthesis of lycopodine and cernuine which demonstrate that the polyacetate hypothesis does not account for the biosynthesis of these alkaloids and that the pathway to the alkaloids incorporates some but not all features of the pelletierine hypothesis outlined above.
B. BIOSYNTHESIS OF LYCOPODINE Two proposals for the biogenesis of the Lycopodium alkaloids were outlined in the previous section. To test these alternative hypotheses a study of the biosynthesis of lycopodine was undertaken. Lycopodine was chosen for experimental study not only because it is the most widely distributed member of this family of alkaloids but also because degradation procedures for the isolation of individual carbon centers or fragments were available from the extensive structural work (1). It was shown that the polyketide hypothesis was untenable through a study of the incorporation of acetate-lJ4C and - V 4 Cinto lycopodine (66). Acetate is predicted to be the only precursor in the polyketide
9.
397
THE LYCOPODIUM ALKALOIDS
SCHEME 4
hypothesis and along with lysine is predicted to be a precursor in the pelletierine hypothesis. It has been demonstrated (67-70) that acetate and lysine are involved in the biosynthesis of N-methylpelletierine, the former supplying the three carbons of the side chain, the latter the five carbons and the nitrogen of the piperidine ring as outlined in Scheme 4. The predicted pattern of incorporation of acetate into lycopodine by each route is illustrated in Scheme 5 , and the manner in which lycopodine was degraded in order to isolate radioactive centers or fragments in the acetate and subsequent experiments is outlined in Scheme 6. Radioactive lycopodine, isolated from L. tristachyum Pursh* to which radioactive acetate had been administered, was degraded by
g5
12.5
12.5
0
12.5
Polyketide
Acetate-1-I4C
12.5 12.5
Pelletierine Q o2
12.5 12.5
12.5
Polyketide
A ~ e t a t e - 2C 2~ SCHEME5
Pelletierine
*All experiments on the biosynthesis of lycopodine were carried out with this plant material. The labels were administered either by the wick method to intact plants or direct to cuttings.
398
D. B. MACLEAN
Kuhn-Roth oxidation to acetic acid. From the experiment with acetatel-I4C the acetic acid contained 4707, of the activity of the lycopodine, and from the experiment with acetate-2-14C the acetic acid contained 21ojb of the activity of lycopodine. These data are in harmony with the pelletierine but not with the polyketide hypothesis. When it was found (see below) that two molecules of lysine were specifically incorporated into lycopodine (65, 66) the polyketide hypothesis could be dismissed.
1
9
HCOzH
I \ 16 CH,CO,H 15
HO,;
0 -
SCHEME 6
Administration of both 1ysine-2-l4C and lysine-6-14C led to the formation of labeled lycopodine. Degradation showed that approximately 25y0 of the label was located a t C-5 (isolated as benzoic acid) and 2507, a t C-9 (isolated as formic acid). The remainder was assumed to be a t C-1 (25%) and C-13 (25y0)and although neither C-1 nor C-13 was isolated individually it was possible to obtain C-9 in conjunction with C-13 as 7-methyltetrahydroquinoline. This fragment contained approximately 50y0 of the activity of lycopodine. These results are compatible with the incorporation of two five-carbon chains derived from lysine into the lycopodine skeleton but they indicate that, unlike the incorporation of lysine into N-methylpelletierine shown in Scheme 4, the incorporation proceeds via a symmetrical intermediate. Next it was found that cadaverine-1-l4C was incorporated into lycopodine and gave the same distribution of activity as lysine. Thus it was likely that cadaverine was the symmetrical intermediate on the pathway from lysine to pelletierine. These findings are incorporated into Scheme 7 in which 1ysine-6-l4Cis used as an example but the same distribution of activity would also apply to lysine-2-14C. This scheme for the incorporation of lysine was supported by experiments with a doubly labeled lysine, 4,s3H,-6- 4C-lysine.
9.
399
THE LYCOPODIUM ALKALOIDS
100
0
H
I
I
\ SCHEME
7
I n another study the incorporation of Al-piperideine and of pelletierine into lycopodine was investigated (71, 7 2 ) . Both 2- and 6-14C-A1piperideine yielded radioactive lycopodine as predicted from Scheme 7. Degradation showed that 50% of the label from the 2-14C-A1-piperideine experiment was located at C-5 (isolated as benzoic acid) and the rest is inferred to be at C-13 and that 5007, of the label from the 6J4C-A1piperideine experiment was located at C-9 (isolated as formic acid) and the rest is inferred to be at C-1. These results show that the activity is not randomized in the course of incorporation of this precursor and that two molecules are incorporated equally into the lycopodine system, one into each half of the molecule as shown in Scheme 8.
6
SCHEME8
400
D. B. MACLEAN
The experiments reviewed up to this point demonstrate that the labeled compounds are incorporated with equal efficiency into both “halves” of the lycopodine system. This is consistent with the premise that two monomeric precursors combine to a dimeric product that is an intermediate in the biosynthetic pathway. However, experiments with multiply labeled pelletierine demonstrated that an intact unit was incorporated only into that portion of the lycopodine molecule corresponding to carbons 9-16. Contrary to the predictions of Schemes 3 and 7, carbons 1-8 were not derived from pelletierine. A more thorough study of the role of pelletierine in the biosynthesis of lycopodine was therefore necessary, Recent experiments (73)have shown that pelletierine is present in L. tristachyum and that both labeled cadaverine and Al-piperideine are incorporated specifically into it a t the same time that lycopodiiie is
I
SCHEME9
9.
THE LYCOPODIUM ALKALOIDS
401
being synthesized in the plant. It has also been demonstrated that the distribution of label within lycopodine derived from experiments with 1 ,5-l4C-cadaverineand 8-14C-Al-piperideine is altered when the labeled compounds are administered in conjunction with large amounts of inactive pelletierine. The inactive pelletierine repressed the incorporation of the labeled precursors into that portion of the molecule comprising C-9 to C-16. I n the piperideine experiment approximately 90% of the activity was located at C-5 compared to approximately 5007, when inactive pelletierine was absent. The comparable figures in the cadaverine experiment were 44y0 and 25y0. These results provide evidence that pelletierine is an intermediate in the biosynthesis of lycopodine. In order to account for the apparent anomaly that pelletierine is incorporated into only one half of the molecule while the other precursors are incorporated with equal efficiency into both halves of lycopodine the proposals outlined in Scheme 9 have been put forward (73). This hypothesis is tenable provided that the steady-stat,e concentration of pelletierine is small compared to that of its immediate precursor and that the reaction leading to pelletierine is irreversible. This scheme also proposes that 8-piperidineacetic acid is implicated in the biosynthesis. At the present time experiments are in progress in this laboratory to test this hypothesis.
C . BIOSYNTHESIS OF CERNUINE
The same precursors that were incorporated into lycopodine were also incorporated into cernuine (74, 7 5 ) . Thus specific incorporation of lysine, cadaverine, Al-piperideine, and pelletierine has been demonstrated through administration of labeled compounds to intact plants of L. cernuum According to the pelletierine hypothesis two molecules of pelletierine should combine as shown in Scheme 10 to yield cernuine. Provided that the incorporation follows the pattern established for lycopodine the labelled precursors under study would be expected to
SCHEME 10
402
D. B. MACLEAN
I 2-14C-Lysine 6-14C-Lysine 1,5- 4C-Cadaverine
T 6,2' -14C2-4-3H-Pelletierine
6-14C-A'-Piperideine
SCHEME 11
be incorporated as shown in Scheme 11. Cernuine is not so amenable to degradation as lycopodine but it was possible to obtain the fragments shown in Scheme 12 in which the numbering of the fragments corresponds to the carbon atoms of cernuine. Carbon-1 of cernuine was obtained either directly as /I-alanine or y-aminobutyric acid or by difference. Carbons 15 and 16 were obtained together as acetic acid by Kuhn-Roth oxidation.
-
16
15
CH,C02H
2 12
211
I
LiAIIIl
IcrOa 1
2
3
NH&H2CH,C02H
+
1
2
3
4
NH&H,CH,CH2C02H SCHEME 12
It was found that one-quarter of the activity of radioactive cernuine derived from the experiments with 2-14C-lysine, 6-14C-lysine, and 1,5-14C-cadaverinewas located at C-1 and that one-half of the activity was at C-1 in the experiment with 6-14C-A1-piperideinein accord with predictions. Administration of a multiply labeled pelletierine and degradation of the radioactive cernuine showed that incorporation occurred only in that portion of the molecule corresponding to carbons 9-16 (heavy lines in Scheme 11). The acetic acid, obtained by Kuhn-
9.
THE LYCOPODIUM ALKALOIDS
403
Roth oxidation of the radioactive cernuine, contained the same proportion of the total I4C activity as that present in the side chain of the precursor. Had two pelletierine units been incorporated, a distribution of activity corresponding to one-half that present in the side chain of the precursor would have been expected. These results show a complete analogy with those obtained for lycopodine and Scheme 10 must therefore be modified. The proposals put forward for lycopodine in Scheme 9 are equally applicable in modified form to the cernuine system. REFERENCES 1. D. B. MacLean, i n “The Alkaloids” (R. H. F. Manske, ed.), Vol. 10, p. 305. Academic Press, New York, 1967. 2. W. A. Ayer, B. Altenkirk, R. H. Burnell, and M. Moinas, Can. J . Chem. 47, 449 (1969). 3. W. J. Rodewald and G. Grynkiewicz, Bull. A d . Pol. Sci., Ser. Sci. Chim. 15, 579 (1967). 4. W. J. Rodewald and G. Grynkiewicz, Rocz. Chem. 42, 465 (1968). 5. J. C. Braekman, C. Hootele, and W. A. Ayer, Bull. SOC.Chim. Belg. 80, 83 (1971). 6. Y. Inubushi, T. Harayama, T. Hibino, and M. Akatsu, Yakugaku Zasshi 91, 980 (1971). 7. Y. Inubushi, H. Ishii, B. Yasui, T. Harayama, M. Hosokawa, R. Nishino, and Y. Nakahara, Yakugaku Zasshi 87, 1394 (1967). 8. W. A. Ayer, N. Masaki, and D. S. Nkunika, Can. J . Chem. 46, 3631 (1968). 9. W. A. Ayer, B. Altenkirk, S. Valverde-Lopez, B. Douglas, R. F. Raffauf, and J. A. Weisbach, Can. J . Chem. 46, 15 (1968). 10. W. A. Ayer, B. Altenkirk, N. Masaki, and S. Valverde-Lopez, Can. J . Chem. 47, 2449 (1969). 11. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 22, 1317 (1969). 12. N. Miller, F. Mees, and J. C . Braekman, Phytochemistry 10, 1931 (1971). 13. W. A. Ayer, G. G. Iverach, J. K. Jenkins, and N. Masaki, Tet. Lett. 4597 (1968). 14. N. Miller, C. Hootele, C. Braekman-Danheux, and J. C . Braekman, Bull. SOC. Chim. Belg. 80, 629 (1971). 15. T.-L. Ho, Tet. Lett. 1307 (1969). 16. F. Bohlmann, Ber. 91, 2157 (1958). 17. N. Chin-You, D. B. MacLean, A. Prakash, and C . Calvo, Can. J . Chem. 49, 3240 (1971). 18. W. A. Harrison, M. Curcumelli-Rodostamo, D. R. Carson, L. R. C. Barolay, and D. B. MacLean, Can. J . Chem. 39, 2086 (1961). 19. Y. Inubushi, T. Harayama, M. Akatsu, and H. Ishii, Chem. Commun. 1138 (1968). 20. W. A. Ayer and B. Altenkirk, Can. J . Chem. 47, 499 (1969). 21. D. B. MacLean, Can. J . Chem. 41, 2654 (1963). 22. W. A. Ayer and D. A. Law, Can. J . Chem. 40, 2088 (1962). 23. W. A. Ayer and G. G . Iverach, Can. J . Chem. 42, 2514 (1964). 24. W. A. Ayer and N. Masaki, Can. J . Chem. 49, 524 (1971). 25. Y. Inubushi, H. Ishii, B. Yasui, M. Hashimoto, and T. Harayama, Tet. Lett. 1537 (1966). 26. Y. Inubushi, H. Ishii, B. Yasui, and T. Harayama, Tet. Lett. 1551 (1966).
404
D. B. MACLEAN
27. Y. Inubushi, H. Ishii, B. Yasui, M. Hashimoto, and T. Harayama, Chem. Pharm. Bull. 16, 82 (1968). 28. Y. Inubushi, H. Ishii, B. Yasui, M. Hashimoto, and T. Harayama, Chem. Pharm. Bull. 16, 9 2 (1968). 29. Y . Inubushi, H. Ishii, B. Yasui, and T. Harayama, Chem. Pharm. Bull. 16, 101 (1968). 30. Y. Inubushi, T. Ibuka, T. Harayama, and H. Ishii, Tetrahedron 24, 3541 (1968). 31. K. Nishio, T. Fujiwara, K. Tomita, H. Ishii, Y. Inubushi, and T. Harayama, Tet. Lett. 861 (1969). 32. Y . Inubushi, H. Ishii, and T. Harayama, Chem. Pharm. Bull. 15, 250 (1967). 33. Y. Inubushi, T. Harayama, M. Akatsu, H. Ishii, and Y. Nakahara, Chem. Pharm. Bull. 16, 2463 (1968). 34. Y. Inubushi, T. Harayama, M. Akatsu, H. Ishii, and Y. Nakahara, Chem. Pharm. Bull. 16, 561 (1968). 35. H. Ishii, B. Yasui, R. Nishino, T. Harayama, and Y. Inubushi, Chem. Pharm. Bull. 18, 1880 (1970). 36. B. Yasui, H. Ishii, T. Harayama, R. Nishino, and Y. Inubushi, Tet. Lett. 3967 (1966). 37. R. H. Burnell, J . Chem. SOC.London 3091 (1959). 38. R. H. Burnell, C. G . Chin, B. S. Mootoo, and D. R. Taylor, Can. J . Chem. 41, 3091 (1963). 39. H. Ishii, B. Yasui, T. Harayama, and Y. Inubushi, Tet. Lett. 6215 (1966). 40. R. H. Burnell and B. S. Mootoo, Can. J . Chem. 39, 1090 (1961). 41. Y. Inubushi, H. Ishii, T. Harayama, R. H. Burnell, W. A. Ayer, and B. Altenkirk, Tet. Lett. 1069 (1967). 42. W. A. Ayer and B. Altenkirk, Cam. J . Chem. 47, 2457 (1969). 43. H. Conroy, Tet. Lett. 34 (1960). 44. W. A. Ayer, J. K. Jenkins, S. Valverde-Lopez, and R. H. Burnell, Can. J . Chent. 45, 433 (1967). 45. W. A. Ayer, J. K. Jenkins, K. Piers, and S. Valverde-Lopez, Cum. J . Chem. 45, 445 (1967). 46. W. A. Ayer and K. Piers, Can. J . Chem. 45, 451 (1967). 47. M. Shamma, C. D. Jones, and J. A. Weiss, Tetrahedron 25, 4347 (1969). 48. E. H. W. Bohme, Z. Valenta, and K. Wiesner, Tet. Lett. 2441 (1965). 49. K. Wiesner, I. JirokovskQ, M. Fishman, and C. A. J. Williams, Tet. Lett. 1523 (1967). 50. K. Wiesner and I. JirokovskQ, Tet. Lett. 2077 (1967). 51. K. Wiesner and L. Poon, Tet. Lett. 4937 (1967). 52. K. Wiesner, L. Poon, I. Jirokovskf, and M. Fishman, Can. J . Chern. 47, 433 (1969). 53. E. E. Betts and D. B. MacLean, Can. J . Chem. 35, 211 (1957). 54. H. Dugas, R. A. Ellison, 2. Valenta, K. Wiesner, and C. M. Wong, Tet. Lett. 1279 (1965). 55. E. Colvin, J. Martin, W. Parker, and R. A. Raphael, Chem. Commun. 596 (1966). 56. Z. Horii, S.-W. Kim, T. Imanishi, and I. Ninomiya, Chem. Pharm. Bull. 16, 2107 (1968). 57. Z. Horii, S.-W. Kim, T. Imanishi, and T. Momose, Chem. Pharm. Bull. 18, 2235 (1970). 58. H. Dugas, M. E. Hazenberg, Z. Valenta, and K. Wiesner, Tet. Lett. 4931 (1967). 59. K. Wiesner, V. Musil, and K. J. Wiesner, Tet. Lett. 5643 (1968). 60. W. A. Ayer, W. R. Bowman, T. C. Joseph, and P. Smith, J . Amer. Chem. SOC.90, 1648 (1968).
9.
THE LYCOPODIUM ALKALOIDS
405
61. G. Stork, R. A. Kretchmer, and R. H. Schlessinger, J. Amer. Chem. SOC.90, 1647 (1968). 62. W. A. Ayer, W. R. Bowman, G. A. Cooke, and A. C. Soper, Tet. Lett. 2021 (1966). 63. W. A. Ayer and D. A. Law, Can. J. Chem. 40, 2088 (1962). 64. G. Stork, Pure AppZ. Chem. 17, 383 (1968). 65. R. N. Gupta, M. Castillo, D. B. MacLean, I. D. Spenser, and J. T. Wrobel, J. Amer. Chem. SOC.90, 1360 (1968). 66. M. Castillo, R. N. Gupta, D. B. MacLean, and I. D. Spenser, Can. J . Chem. 48, 1893 (1970). 67. R. N. Gupta and I. D. Spenser, Chem. Commun. 85 (1968). 6 8 . R. N. Gupta and I. D. Spenser, Phytochemistry 8, 1937 (1969). 69. M. F. Keogh and D. G. O’Donovan, J. Chem. SOC.London 1792 (1970). 70. H. W. Liebisch, N. Marekov, and H. R. Schiitte, 2.Naturjorsch. B 23, 1116 (1968). 71. M. Castillo, R. N. Gupta, Y . K. Ho, D. B. MacLean, and I. D. Spenser, J. Amer. Chent. SOC.92, 1074 (1970). 72. M. Castillo, R. N. Gupta, Y . K. Ho, D. B. MacLean, and I. D. Spenser, Can. J . Chem. 48, 2911 (1970). 73. J . C. Braekman, R. N. Gupta, D. B. MacLean, and I. D. Spenser, Can. J . Chem. 50, 2591 (1972). 74. R. N. Gupta, Y . K. Ho, D. B. MacLean, and I. D. Spenser, Chem. Commun. 409 (1970). 75. Y . K. Ho, R. N. Gupta, D. B. MacLean, and I. D. Spenser, Can. J. Chem. 49, 3352 (1971).
This Page Intentionally Left Blank
-CHAPTER
10-
THE CANCENTRINE ALKALOIDS RUSSELLRODRIGO Department of Chemistry Waterloo Lutheran University Waterloo Ontario, Canada
I. Introduction and Occurrence ........................................ 11. The Structure ofcancentrine ........................................ A. Preliminary Data ............................................... B. Hofmann Degradation ....................... ................ C. NMR Spectra ............................... ................ D. Mass Spectra .................................................... E. Acetolysis Products ........................................... 111. Dehydrocancentrine-B ........... ................................ IV. Dehydrocancentrine-A ........................... ............ V. Stereochemistry .................................................... VI. Biogenesis ......................................................... VII. Physical Properties ................................................. References ........................................................
407 408 408 408 410 411 412 418 419 419 420 42 1 423
I. Introduction and Occurrence Forty years ago Manske reported ( I ) the isolation of a bright yellow alkaloid from Dicentra canadensis Walp. Subsequently it was designated F,, and shown to contain three methoxyl groups and two nitrogen atoms of which one was nonbasic. A tentative molecular formula C37H400~oN, was proposed (2). It is the major alkaloid of D. canadensis where it occurs in sufficient quantity to color the tubers yellow but it has not been isolated from any other source. I n 1970 the alkaloid was named cancentrine, assigned the novel structure 1, and since then publications describing some chemical transformations and mass spectral properties of cancentrine have appeared. I n addition, two more alkaloids of the cancentrine type have been isolated from the same source. Brief reference has been made t o the structure of cancentrine in Volume XI11 of this series. This chapter is aimed a t providing a review of the work done on the subject to date.
408
RUSSELL RODRIGO
11. The Structure of Cancentrine A. PRELIMINARY DATA The molecular formula of cancentrine was established as C,,H,,N,O, by high-resolution mass spectrometry and confirmed by accurate mass measurement of the molecular ions of the O-methyl ether 2 and the O-acetate 3.The alkaloid contains one phenolic hydroxyl, one conjugated carbonyl group (IR),three methoxyl and one N-methyl group, but no C-methyl or methylenedioxy groups (NMR). This accounted for five of the seven oxygen atoms and suggested the presence of two ether linkages in the molecule. The nitrogen atom of the N-methyl group was responsible for the basicity of the alkaloid and this implied that the second nitrogen atom was conjugated with the carbonyl group in some way, thus accounting for its nonbasicity (3). The UV spectrum was complex and novel, bearing no similarity to the spectra of any known dimeric benzylisoquinoline alkaloid. Bands at 291 nm and 435 nm were shifted to 308 nm and 446 nm, respectively, in basic solution, thus confirming the presence of the phenolic hydroxyl group and implying that it was part of the chromophore responsible for the long wavelength absorption and yellow color of the alkaloid. B. HOFMANN DEGRADATION Cancentrine methiodide was degraded to the methine 4 by aqueous methanolic potassium hydroxide and the latter converted into the O-methyl ether 5 by diazomethane and then by hydrogenation to the dihydromethine-O-methyl ether 7.Compound 7 was also obtained by carrying out the hydrogenation first to the dihydromethine 6 followed by diazomethane methylation to 7.The methiodide of 4 was stable to alcoholic potassium hydroxide but was degraded to the bis-methine 8 in high yield by potassium t-butoxide. The structure of 7 was determined by X-ray crystallographic analysis of its hydrobromide and the structure of cancentrine derived from it by detailed study of the NMR spectra of 1, 3,4, and 7 (Section 11,C). The X-ray data showed that the bond lengths N-C26-C24C,--0 are consistent with these atoms being a conjugated system-an observation in accord with the carbonyl absorption at 1660 & 5 cm-l in the I R spectra of compounds 1-8 and the nonbasicity of this nitrogen atom. The novel UV spectra of all these compounds and their yellow color was attributed to the cis-s-trans-/3-aminoenone chromophore which is part of the oxygenated dibenzoxepine.
10.
R = H R=Me R=Ac
1 2 3
6 7
409
THE CANCENTRINE ALKALOIDS
4 5
R = H R=Me
8
R = H R=Me
Me0
$., 14
HOIIIIII HH / 9
Me
410
RUSSELL RODRIGO
The NMR spectra of compounds 4-8 were consistent with the structures assigned. This evidence together with the great similarities in UV and IR spectra discussed above clearly established that the degradations had not caused any major skeletal changes. The facile aromatization characteristic of the morphine alkaloids appears to be blocked in this case by the five-membered ring and spiro carbon atom C-6. This explains the stability of cancentrine methine methiodide to potassium hydroxide and the need for the much stronger base to effect the second elimination to the bismethine 8 (3, 4).
C. NMR SPECTRA 1. The Terminus of the Ethanamine Bridge
The nitrogen atom of the ethanamine bridge may be attached to carbon atom 5, 9, 10, or 14. Carbon atom 8 is excluded by the intolerable strain that such an attachment would cause. Carbon atom 5 is easily ruled out because all of the compounds 1-8 have a sharp singlet at 6 5.0 0.2 characteristic of the C-5-H ( 5 ) . Attachment of the bridge at carbon atom 14 is rendered unlikely by the observation that the spectrum of cancentrine methine 4 shows the presence of two olefinic protons constituting the A and B parts of the ABX system C-g-H, C-10-H, C-1PH. TABLE I CHEMICAL SHIFTS AND COWLINGCONSTANTSFOR H,, Hl0, Compound
Codeine 9 (5) Cancentrine 1 (3)
HlO,
H104
3.34 3.43
2.48 2.43
3.06 3.18
HlO4
Coupling constants J (Hz)
Chemical shifts 6 (ppm)
Hs
AND
H r H 1 0 . H,--H104 6.0 6.0
1.o 1.0
H1oa-H1o(q 18.6 18.6
The attachment to C-9 rather than to C-10 is biogeneticallymuch more likely and this was confirmed by comparison of the C-9-C-10 region of the NMR spectra of codeine (9) and of cancentrine (1). The virtual identity of the chemical shifts and coupling constants (Table I) firmly establishes C-9 as the site of attachment of the ethanamine bridge since a pattern different from that of codeine would have resulted had the nitrogen atom been joined a t C-10 or C-14.
10.
THE CANCENTRINE ALKALOIDS
411
2. The Position of the Phenolic Hydroxyl Group
The mass spectra (Section 11,D) indicated that the phenolic function was located in the “cularine” half of the molecule, whereas a comparison of the NMR spectra of cancentrine (1)and its 0-acetate (3)indicated that there is a proton puru to a phenolic hydroxyl group ( 6 ) and hence the latter must be placed at C-20. This assignment was confirmed by observed nuclear Overhauser effects (NOE) of 25, 25, and 24y0, respectively, in three aromatic signals when the methoxyl resonances of cancentrine were saturated in turn. Such a result is possible only if each of the three methoxyl groups is vicinal to an aromatic proton. Since the location of the substituents on the aromatic rings was known from the X-ray structure of 7 this result unambiguously places the hydroxyl group a t C-20 (3). 3. Other NMR Assignments From a combination of decoupling and NOE studies it was possible to assign all the aromatic signals in the spectrum of cancentrine 0-acetate (3).The signal centred at 6 3.18, assigned to H-10/3 was used as the point of reference in the “morphine” half of the molecule. Irradiation of this signal sharpened the aromatic doublet at 6 6.65 by release of the long-range ortho-benzylic coupling. Thus the latter is defined as the H-1 resonance which when irradiated collapses the H-2 doublet at 6 6.83. An NOE of 25y0 is observed at H-2 when the methoxyl signal at 6 3.91 is saturated. Thus the C-3 methoxyl resonance is defined at 6 3.91. I n a similar way the signals for the “cularine” half of the molecule were also assigned using the resonance position of H - 2 3 t h e low field proton (6 7.88), paru to the acetoxy group, as the reference point ( 4 ) . The following assignments were made for 3. H-1 = 6.65, H-2 = 6.83 6, Jl,2= 9.0 Hz; H-17 = 6.85, H-18 = 6.98 6, J,,,,, = 8.5 Hz; H-22 = 6.68, H-23 = 7.88 6, J22,23= 8.0 Hz; 3-OMe = 3.91, 21-OMe = 3.76, 19-OMe = 3.85 6.
D. Mass SPECTRA The mass spectra of cancentrine and its derivatives have been of great structural value because of the tendency of these molecules to fragment across the five-membered ring into a “cularine” part and a “morphine ” part producing ions corresponding to each fragment. Thus, in the spectrum of cancentrine (Scheme l), ions at m/e 363 and
412
RUSSELL RODRIGO
m/e 243 correspond to fissions “ a + b ” in the five-membered ring, while ions at m/e 350 and m/e 256 arise from fissions “ a + c ” with hydrogen transfer. Ions from the “cularine” part of the molecule do not fragment further to any appreciable extent but ions of the morphine segment undergo further fragmentations. Indeed the ion [CI2HgO2]+ at m/e 185 is the base peak in many spectra. The spectra of the 0-methyl ether 2 and the 0-acetate 3 are similar and show shifts in the m/e 350 and m/e 363 ions expected from methylation and acetylation, respectively. This evidence placed the hydroxyl group in the “cularine” moiety of the molecule as only these ions were affected. The 0-acetate has a pronounced tendency to eliminate ketene so that, its spectrum has all the peaks associated with cancentrine itself as well as ions 42 mass units greater in those ions involving the “cularine ” half. The mass spectrum of the methine-0-methyl ether 5 and the dihydromethine-0-methyl ether 7 were also studied. The fragmentations are similar to cancentrine but for some undetermined reason ions from the “morphine” moiety corresponding to the “ a + c ” fission are lacking. Thus the ‘‘morphine” part produces only one ion in each case, corresponding to the “ a + b ” fission mode, which are now located a t m/e 257 and m/e 259, respectively, and are of low intensity. These ions fragment further and the m/e 185 ion is again the base peak in the spectrum of the methine-0-methyl ether. However, in the dihydro compound lack of the C-9,C-10 double bond drastically reduces the intensities of all ions derived from the “morphine” part and the ion [CI2HgO2]+at m/e 185 now has an intensity of only 1407,.In both 5 and 7 significant (13y0 and 58y0, respectively) ions resulting from the loss of dimethylamine are observed ( 4 ) .
E. ACETOLYSIS PRODUCTS Treatment of cancentrine methiodide with sodium acetate-acetic anhydride under reflux for 48 hr produced about equal amounts of two compounds, 10 and 11, of molecular formula C37H2gN08and C42H38N20g, respectively ( 7 ) . Compound 10 was shown to be a diacetate (In, NMR, and mass spectrometry) also containing three methoxyl groups (NMR). It could be hydrolyzed and methylated to the pentamethoxy compound 12 (C35H29N06) which had the expected IR and NMR properties. The NMR spectrum of 10 also revealed the presence of a -CH2-CH2moiety and ten aromatic protons in four ortho-related pairs and two
Me0 Me0 -C3HsN
Me
+--I fissions “a
N\
+ b”
1, 2, 3
m/e 243 (Cl5H,,NO2)
i
MF
c.l
1 R = H , m/e 363 (Cz,H17N05) 2 R = Me, m/e 377 (CzzHlsNOd 3 R = Ac, m/e 405 (CZ3H,,NO6)
0
-CH&O
3
m/e 363 (Cz,H,,N05)
Me0 Me0
w
-CH*0
1 R = H , m/e 606 (C,,H,,NzO,) 2 R = Me, m/e 620 (C,,H,,NzO,) 3 R = Ac, m/e 648 (C38H36N20a)
i
\
+O%N\
CHz Me
+
fissions “ a C” with H transfer
-CHICO
3
--f
+ m/e 226 (C15H16NO)
U
1, 2, and 3
8
m/e 256 [Cl6HIaNOzI
v1
m/e 606 ( C s 6 H d z O 7 )
1 R = H , m/e 350 (CzoH16N05) 2 R = Me, m/e 364 (CZ1H,,NO5) 3 R = Ac, m/e 392 (CzzHiaNOa)
1
-CH&O
Me0
SCHEME 1. The mass spectra of cancentrine and its derivatives.
3
m/e 350 (CzoH16N05)
414
RUSSELL RODRIGO
singlets. One of the singlets at extremely low field (6 9.9) is crucial to the structural argument and was assigned to the C-5 proton which lies in the deshielding zone of three benzene rings, A, C, and F. This assignment was prompted by the analogy with the C-14-H of dibenz-(a,j)anthracene(l3), which resonates at 6 9.97 (8),and supported by the observation of significant NOE's in the signal when the acetate methyl groups of 10 and the O-methyl groups of 12 were saturated. The difference in molecular formula between 10 and 11 amounts to C,H,,NO which suggested the presence of an acetylated N-methylethanamine side chain in the latter product. The mass spectrum of 11 indicated the presence of two O-acetyl groups and also contained the fragment ions diagnostic of the presence of an Ar--CHZ--CHz-N(Me)Acunit, thus confirming the presence of such a side chain. The I R spectrum, in accord with this conclusion, showed absorption corresponding to the presence of phenyl acetate and amide carbonyl groups. The room-temperature NMR spectrum of 11 was considerably complicated by the existence of amide tautomerism. Coalescence of the peaks due to the various conformers was achieved by determination of the spectrum at ca. 95". Similar behavior of a related phenanthrene had previously been observed (9). The spectrum of 11had seven threeproton singlets, six of which were assigned to three O-methyl, two 0acetyl, and one N-acetyl group, respectively. The other singlet at unusually high field (6 1.3) was attributed to the N-methyl group. In addition the NMR spectrum indicated the presence of eight aliphatic and nine aromatic protons. The aromatic region of 11was very similar to that of 10 with the significant exception that it lacked the low-field proton present in the spectrum of the latter compound. The side chain was therefore placed at this position and in a model of compound 11 thus constructed the N-methyl group was found to lie in the shielding zone of ring F, thus accounting for its unusually high chemical shift. The formation of 10 and 11from cancentrine methiodide was rationalized as in Scheme 2. The key to the subsequent aromatization is the ring expansion which is the reverse of step 5 in the postulated biogenesis (Section VI). There are two apriori possibilities which lead to either 10 or 14. The former was preferred on the basis of the transition state for the ring expansion. H-8a is much closer to being trans and coplanar with the migrating C-5-C-6 bond than H-5a is to the C-6-64 bond. In any event, the structure of 10 received powerful support from the detection of a strong NOE (32y0)between the low-field proton a t C-5 and the lowest-field doublet in the spectrum of 10 centered at 6 7.94 and assigned to the C-6 proton because it is para to the acetoxy group. Structure 14 was clearly excluded by this observation. An N demethylation must necessarily have taken place at some stage to
?
10. THE CANCENTRINE ALKALOIDS
3 (as
VI
a
dj+
H
$-a
I 0
9
415
owz 3
416
RUSSELL RODRIGO
produce both the acetamide group of 11 and the N-methylethanolamine t h a t was isolated from the reaction. The retention of the ethanamine side chain during acetolysis had no precedent hitherto with the sole exception of the acetolysis of two closely related compounds, sinomeninone (15) and l-bromosinomeninone (16),when both products 17 and 18, and 19 and 20 were formed in each case, respectively (10). Concerted opening of the oxide ring and trans elimination of the side chain (11)is impossible in these instances,
HO
AcO
AcO
AcO 15 16
0 R = H R = Br
17 19
R = H R = Br
18 20
R = H R = Br
and this may explain retention of the latter in one of the products of acetolysis. The presence of the second nitrogen atom in cancentrine probably induces opening of the oxide ring independently of the loss
(nm)
FIG. 1. The UV spectra of 10 (-), 11 (---), 22 (---.-), and 23 ( - - - - - - ) . [Reproduced by permission of the National Research Council of Canda from the Can. J. Chem., 50, pp. 3900-3910 (1972).]
10. THE CANCENTRINE ALKALOIDS
417
22
21
23
of the side chain by stabilizing the incipient carbonium ion, thus leading to both products 10 and 11 as indicated in Scheme 2. Compound 11 is an isomer of the product 21 that would result from a thebenine type of rearrangement ( I I ) ,and the mechanism (in Scheme 2 ) leading to its formation has therefore been called the “isothebenine” rearrangement. The evidence above, adduced for the structure of 11, does not completely rule out the alternative structure 21. Compounds 22 and 23 which correspond to the ring systems of 10 (11)and 21, respectively, were therefore synthesized by standard methods in order that UV and NMR comparisons with 10 and 11 could be made. The UV spectra of 10,11, and 22 were very similar. There were only slight shifts in the absorption maxima which were consistent with the variation in the degree of substitution of the chromophore in the three compounds. The UV spectrum of 23 was substantially different (Fig. 1). The NMR spectrum of 22 had singlets integrating for one proton each a t 6 9.39 and 6 10.86. The latter signal was removed by D,O and
418
RUSSELL RODRIGO
was therefore assigned to the indole proton. The signal at 6 9.39 which was unaffected by D 2 0 was attributed to the C-5 proton by analogy
\
with 10. The spectrum of 23 contained the indole NH singlet at 6 11.22
/
but had no other signals below 6 8.8. Structure 21 was therefore excluded by these comparisons (7).
111. Dehydrocancentrine-B Dehydrocancentrine-B, a cherry-red alkaloid isolated from the same source, had the same functional groups as cancentrine (NMR, IR). However, its I R spectrum indicated the presence of an additional double bond in agreement with the molecular formula (C,,H,,N,O,) obtained by high-resolution mass spectrometry (HRMS). The mass spectrum was very similar to that of cancentrine with the exception that ions from the “cularine” half of the molecule appeared two mass units lower. Thus there were ions at m/e 361 (C,,H,,NO,) and m/e 348 (C,,H,,NO,) arising from fissions “ a + b ” and “a + c,” respectively (Scheme 1).This indicated that the extra double bond was in the “cularine” part of the molecule and must be located at the only available position, namely, C-31-C-32 (12). The NMR spectrum supported the location of the double bond in this position by the presence of a fourth AB system one half of which was visible at 6 6.25 (JAB = 7.0 Hz). The location of the substituents and the relative stereochemistry of the alkaloid were shown to be identical with those
Me0
Me0
24
25
10.
THE CANCENTRINE ALKALOIDS
419
for cancentrine by catalytic hydrogenation of it to the latter compound. Thus dehydrocancentrine-B was represented as 24.
IV. Dehydrocancentrine-A Dehydrocancentrine-A, a yellow alkaloid also obtained from Dicentra canadensis, had the same functional groups as cancentrine (NMR,IR).It was isomeric with dehydrocancentrine-B (HRMS) and again its IR spectrum indicated the presence of an extra double bond. The NMR spectrum, very similar to that of cancentrine, had an extra vinylic singlet at 5.26. Since this proton is not coupled to any other, the double bond has to be located at C-9=C-l0 or C-8=C-14. The latter was preferred, as a double bond at C-9=C-l0 would be at a bridgehead. The mass spectral fragmentation pattern of the alkaloid is markedly different from that of cancentrine because of the inhibition of cleavages “ b ” and “ c ” by the presence of the 8,14 double bond. The only important fragment ion is formed by the loss of the nitrogen bridge from the molecular ion to give rise to the stable aromatic ion a t m/e 546 (Scheme 3). Again, the location of the substituents and the relative stereochemistry of the alkaloid were shown to be identical with those of cancentrine by a similar hydrogenation experiment. I n this case a small amount of another compound, probably the C-14 epimer of cancentrine, was also formed. Thus the structure of dehydrocancentrine-A was represented as 25.
V. Stereochemistry The absolute stereochemistry of cancentrinedihydromethine-0methyl ether (7) has been determined by X-ray analysis of its hydrobromide (13). The absolute stereochemistry of cancentrine (1) is easily derived from this as the C-9-C- 13 ethanamine bridge must necessarily be cis-fused. The slight possibility that epimerization at C-14 could have occurred in the conversion 1 + 7 may be discounted on the basis of past experience (14)with morphine systems. Moreover the hydrogenation of dehydrocancentrine-A to a product consisting mainly of cancentrine indicates that the C-8, C-14 double bond is hydrogenated from the “lower” side of the molecule since approach to the “upper” side
420
RUSSELL RODRIGO
Me0
I
25 m/e 604 (C3,H3,N,07)
-C3HsN
Me0
mle 546 (C33H24NZ07)
SCHEME 3. The mass spectrum of dehydrocancentrine-A.
is greatly hindered by both the benzene ring of the “morphine” part and the C-7 carbonyl group. It follows that the C-14-H is in a a-configuration in cancentrine. The absolute configuration of cancentrine is therefore expressed by 1 which is the opposite of morphine and the same as kreysigine (15).
VI. Biogenesis The structure of cancentrine represents a novel type of dimeric benzylisoquinoline in that the manner of linkage of the constituent
10. THE CANCENTRINE ALKALOIDS
42 1
units through the spiro system is unprecedented. Cularine alkaloids (16) occur only in the closely related Corydalis and Dicentra genera, and two morphinanedienone alkaloids sinoacutine (26) and pallidine (27) have been isolated from Corydalis pallida (17). On this basis a simple five-step biogenetic proposal for the formation of the spiro linkage of cancentrine from N-norcularine and sinoacutine precursors has been
SCHEME 4. Biogenetic proposal for oancentrine.
adduced ( 4 ) (Scheme 4). It is noteworthy that sinoacutine and cancentrine belong to the same stereochemical series-antipodal with morphine at C-9, (3-13.
VII. Physical Properties Some physical properties of the three cancentrine alkaloids are recorded in Table 11.
TABLE I1 PHYSICAL PROPERTIES OF THE CANCENTRINEALKALOIDS Alkaloid
+P E3 E3
Cancentrine ( 4 ) C36H34N207
238
3450, 1660
Dehydrocancentrine A (12) C36H32NZO7
194
3440, 1660, 1620
Dehydrocancentrine-B (12) C36H32N207
206
3450, 1660, 1630
a
UV (EtOH)
Mass Spectruma
213, 230 (sh), 268, 291 (sh) 330 (sh), and 435 nm log emax 4.80, 4.63, 4.32, 4.22, 3.62, and 3.82, resp. A,, 216, 269 (sh),and 445 nm log emax4.77, 4.36, 4.29, and 3.87, resp. A,, 216 (sh), 242, 270 (sh), 310 (sh), 370, 446, 492, and 525 (sh) nm log emax4.86, 4.78, 4.23, 4.16, 3.90, 4.00, 3.95, and 3.85, resp.
606 (75), 363 (25), 350 (17) 256 (12), 243 (40), 226 (25), and 185 (100)
Mp ("C) IR, CHCl:, (ern-')
Ion intensities are given in parentheses.
A,,
604 (35), 546 (100)
604 (IOO), 361 (ll),348 (6), 256 (2), 243 (12), and 185 (21)
10. THE CANCENTRINE ALKALOIDS
423
REFERENCES 1. R. H. F. Manske, Can. J . Res., Sect. B 7, 258 (1932). 2. R. H. F. Manske, Can. J . Res., Sect. B 16, 81 (1938). 3. G. R. Clark, R. H. F. Manske, G . J. Palenik, R. Rodrigo, D. B. MacLean, L. Baczynskyj, D. E. F. Gracey, and J. K. Saunders, J. Amer. Chem. 9oc. 92, 4998 (1970). 4. R. Rodrigo, R. H. F. Manske, D. B. MacLean, L. Baczynskyj, and J. K. Saunders, Can. J . Chem. 50, 853 (1972). 5. T. J. Batterham, K. H. Bell, and U. Weiess, Aust. J. Chem. 18, 1799 (1965). 6. R. J. Highet and P. F. Highet, J. Org. Chem. 30, 902 (1965). 7. R. Rodrigo, R. H. F. Manske, V. Smula, and D. B. MacLean, Can. J . Chem. 50, 3900 (1972). 8. P. Durand, J. Parello, and N. P. Buu-Hoi, Bull. SOC.Chim. Fr. 2438 (1963). 9. W. Dopke, H. Flentje, and P. W. Jeffs, Tetrahedron 24, 4459 (1968). 10. K. Goto, H. Shishido, and K. Takubo, Ann. 497, 289 (1932). 11. G . Stork, i n “The Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.), Vol. 2, p. 189. Academic Press, New York, 1952. 12. D. B. MacLean, L. Baczynskyj, R. Rodrigo, and R. H. F. Manske, Can. J . Chem. 50, 862 (1972). 13. G. R. Clark and G . J. Palenik J . Chem. SOC. Perkin Trans. 2, 1219 (1972). 14. J. Kalvoda, P. Buchschacher, and 0. Jeger, Helw. Chim. Acta 38, 1847 (1955). 15. J. Fridrichsons, M. F. Mackay, and A. M. Mathieson, Tetrahedron 26, 1879 (1970). 16. F. Santavy, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 12, p. 368. Academic Press, New York, 17. T. Kametani, M. Ihara, and T. Honda, J . Chern. SOC.,C 1060 (1970).
This Page Intentionally Left Blank
-CHAPTER
11-
THE SECURINEGA ALKALOIDS V . SNIECKUS Department of Chemistry University of Waterloo Waterloo. Ontario. Canada
.
I Introduction and Occurrence ........................................ I1. Securinine-Type Alkaloids ...........................................
425 427 A Securinine ...................................................... 427 B Dihydrosecurinine .............................................. 447 C . Mass Spectra of Securinine, Dihydrosecurinine, and Tetrahydrosecurinine 447 D . Allosecurinine ( = Phyllochrysine) ................................. 452 E . NMR Spectra of Securinine, Allosecurinine, and Some of Their Hydro458 genated Derivatives ............................................. F. Virosecurinine .................................................. 464 G . Stereochemical Interrelationships of Securinine, Allosecurinine, and Virosecurinine .................................................. 470 H Viroallosecurinine ............................................... 477 I Securitinine .................................................... 477 J . Phyllanthine 481 K SecurinolA,B, and C ........................................... 484 L Alkaloids of Undetermined Structure .............................. 488 489 I11 Norsecurinine-Type Alkaloids ........................................ 489 A . Norsecurinine ................................................... 495 B Antipodal Norsecurinine ......................................... 495 C . Dihydronorsecurinine ........................................... IV . Synthesis .......................................................... 495 A . Total Synthesis of Securinine and Virosecurinine .................... 496 B Partial Synthesis of Dihydrosecurinine ............................. 499 V . Biological Activity .................................................. 499 VI Analytical Methods ................................................. 500 VII . Biosynthesis ....................................................... 500 References ...................................................... 502
. .
.
.
.
. .
....................................................
. .
.
.
I Introduction and Occurrence Plants within the Euphorbiaceae family elaborate a diverse number of alkaloids most of which defy distinct biogenetic classification ( 1 . 2 ). Two groups which can be distinguished are the benzylisoquinoline
426
V. SNIECKUS
and tropane structural types. Although a very large number of Euphorbiaceae alkaloids have not been structurally elucidated ( I ) ,it is possible to discern from an overview of recent studies the emergence of three new groups based on chemical structure similarity: a relatively small number of alkaloids possessing a common imidazole nucleus (3); a new and immensely complex diterpenoid alkaloid group isolated from the Duphniphyllum genus (4); and the Securinega alkaloids. The Xecurinega group comprises a total of sixteen alkaloids isolated mainly from two or three species of the Securinega and the Phyllanthus genera. Apart from many investigations establishing their high alkaloid content, recent studies have shown that some Securinega species contain coumarins ( 5 ) ) flavonoids ( 6 ) , triterpenoids (7)) and other products
(8).
4
5
7
1
15
Securinine type
7
2
15
Norsecurinine type
Securinine, the most abundant alkaloid of this group, was first isolated by Russian workers in 1956 but its structure was fully established only in 1962.I n the subsequent years a variety of alkaloids of the same skeletal type (1) but differing in stereochemistry and minor functionality were isolated and characterized. More recently, three alkaloids possessing a lower homolog structure (2)" of the securinine type were discovered. Table I lists the known alkaloids according to these two subgroups. Several alkaloids (phyllanthidine, suffruticodine, and suffruticonine) have not been structurally elucidated but their molecular formulas and spectral properties indicate most probably a securininetype skeleton (Section 11, L). Although reference to individual securinine alkaloids have been made in previous volumes of this treatise (Vol. VII, XIII) and the literature dealing with work since 1969 has been summarized (9),no comprehensive review on this subject has appeared. It is the purpose of this contribution t o fill this gap in the alkaloid literature. Coverage is complete through March 6, 1972 Chemical Abstracts.
* Three numbering systems have been used for the alkaloid skeleton by different groups of workers. In this review, the system according t o Chemical Abstracts [cf. Chem. Abstr. 73 (Index Guide), 1290G, and 1620G (1970)l has been adopted.
11.
THE SECURINEGA ALKALOIDS
427
11. Securinine-Type Alkaloids A. SECURININE 1. Skeletal Structure
Securinine, the major alkaloid in the leaves of Securinega suffruticosa (Pall.) Rehd. * was first described by Murav’eva and Bankovskii (10, 11). These Russian workers determined the empirical formula (C,,H,,NO,) and some other physical properties of securinine and prepared a series of derivatives. They also established the absence of N-methyl, O-methyl, hydroxyl, methylenedioxy, and ketone groups by functional group analysis and the presence of a lactone moiety and extended conjugation by I R and UV spectroscopy (12). The skeletal structure was first established independently and almost simultaneously by two Japanese teams on securinine isolated from domestic S. suffruticosa plants (13, 14). Subsequently, securinine was also isolated from S . suffruticosa grown in India ( 1 5 ) , from Phyllanthus discoides Muell. Arg. obtained from the Belgian Congo (16) and from Nigeria (17) and its structure was apparently independently determined in China (18). More recently, securinine has been extracted from S. suffruticosa grown in Poland (19) as well as from two other Xecurinega species (20).Finally, a total of fifty Secwinega species of Russian origin have been screened and shown to contain various amounts of securinine (21).Most species have been found to be unusually rich in securinine, averaging about 0.15y0 of the weight of dry plant material (10,11,21).As a result of its promising pharmacological properties (Section V), patents on the isolation of the alkaloid (22),its dihydro and tetrahydro derivatives (23), and various quaternary salts (24) have been obtained. Following the initial input from the Russian workers (10, 11) the structural elucidation of securinine became the property of Japanese organic chemists (14, 25, 26). Securinine showed a UV maximum at 256 (log E 4.26) mp and I R bands at 1840 and 1760 cm-l indicating the presence of an a,P,y,&unsaturated lactone unit (3)(25,26).Furthermore, the split carbonyl absorption in the I R spectrum implied the presence of a hydrogen a to the lactone carbonyl and this was supported by the observation of an appropriately low-field singlet at 7 4.46 (1H) in the NMR spectrum of securinine. In addition, the NMR spectrum revealed two quartets at 7 3.33 (1H) and 3.58 (1H) and a broad triplet at T 6.14 (IH) which could be interpreted as an ABX
* The confusing taxonomic history of this plant has been noted by Manske (Vol. VII, p. 518).
TABLE I
PLANT SOURCES AND PHYSICAL AND SPECTRAL DATA References to
Alkaloid
Plant Sourcea (plant part)b, Refs.
Securinine Type Allosecurinine a(r) 16, 39; e(1, r) (phyllochrysine) 14, 37, 38 Dihydrosecurinine e(1) 34; h 35 Phyllanthine a(r) 41a, 56 Phyllanthidine a(r) 41a, 56 Phyllochrysine (see Allosecurinine) Securinine a(1, r, s) 17; c, d 20; e(1, s ) 1013, 15, 19 Securinol A e(1) 57, 58 Securinol B e(1) 57, 58 Securinol C e(1) 57, f 58 Securitinine e(r) 5 4 , 55 Suffruticodined e 59 Suffruticonined e 59
Formula
C13H15N02
Melting point ("C)
PK,'
IR
UV
NMR
Mass spec.
136-138 - 1082(e)
6.91
14, 16, 37
16, 35
16, 37
16, 37
58-60 -8l(e) 96-98 - 8 9 8 ( ~ ) 169-170 - 4 5 0 ( ~ )
8.35 5.28
16,26 41a 56
35 41a 56
36 41a 56
36 4la
142-143 - 1042(e)
7.17
16, 26, 37
16, 26
16,26
16.36
57 57 58 55 59 59
57 57 58 55
57 58 58 55
57 57 58 55
[alDC
135-136 +58(c) 120(e) 158-160 114-115 -82(e) 129-130 - 952(e) 120-122 O(e) 237-238 O(e)
+
-
Absolute configuration
2s,7s,9s
2R,7S,9S
TABLE I (continued) References to
Alkaloid Viroallosecurinine Virosecurinine Norsecurinine Type Dihydronorsecurininee Norsecurinine Norsecurinine (optical antipode)
Plant Sourcea (plant part)*, Refs.
Formula
Melting point (“C)
[ahC
+ 1085(e) + 1035(e)
h(1) 52, 53 h(1) 42, 43
CI3Hl5NO2 136-138 Cl3HI5NO2 141-142
g(1) 52; h(r) 52, 62 g 60; h(r) 61, 62 b 64
C12H1,N02 135-136 - 13(d) 36-37 -272(e) Cl2Hl,NO2 +213(c) C12H13N02 Oil ~~
~
pK,’
IR
UV
NMR
Mass spec.
-
43
43
43
-
-
62 60, 62
62 60, 62
64
64
60 64
60 64
6.85 -
-
Absolute configuration 2R,7R,9R 2S,7R,9R 2R,7S,9S 2R,7S,9S 2S,7R,9R
~~
Phyllanthus discoides Muell. Arg.; b, P . niruri L.;c, Securinega durissima J.F. Gmel. Syst. 1008; d, S.fluggeoides Muell. Arg.; e, S. suffruticosa (Pall.) Rehd.; f, S. suffruticosa Rehd. var. amamiemis Furusawa; g, S. virosa Baill.; h, S. virosa Pax. et Hoffm. * 1 = leaves; r = roots; s = stems. Rotation measured in c = chloroform; d = dioxane, e = ethanol. Alkaloid of unknown structure. Originally named virosine ( 5 2 ) .This name was subsequently abandoned (61) in favor of dihydronorsecurinine in order to avoid its confusion with an indole alkaloid of the same name (see M. Hesse, “Indolalkaloide in Tabellen,” p. 115. Springer-Verlag, Berlin and New York, 1964). a
a,
430
V. SNIECKUS
0 I/
'HE4 3
4
5
6
pattern, the AB portion of which was due to HA and H, respectively in partial structure 3. This assignment was later confirmed by double irradiation studies (Section 11, E). I n the early work (14, 25, 26) catalytic hydrogenation gave dihydro [UV (max) 215 (log E 4.25) mp, I R (max) 1815 and 1770 cm-l; NMR: absence of peaks a t T 3.33 and 3.581 and tetrahydro [UV (max) 210 (log E 3.25) mp, I R (max) 1790 cm- l , NMR: no vinyl protons] derivatives corroborating the presence of the partial structure 3 in securinine. Some interesting degradation studies led to the assignment of the complete skeletal structure of securinine (14, 26). I n one study (26), hydrolysis of the alkaloid with potassium hydroxide followed by catalytic hydrogenation over Raney nickel gave a compound (C,,H,,NO,, mp 185'; [a];' + 3" in EtOH) designated lactam-carbinol A. When this compound was subjected to dehydrogenation with palladium it produced the pyridine derivative 4, thus defining twelve of the thirteen carbons of securinine in the form of partial structure 5. Zinc dust distillation of securinine gave, among other products) p-toluidine and on this basis partial structure 5 could be expanded to 6 with the proviso that no rearrangement had occurred during the dehydrogenation. Finally) rational stepwise degradation led to the formulation 7 for the skeletal structure of securinine (Scheme 1). von Braun reaction on securinine gave a single product (8) in 60% yield resulting from the predicted more facile cleavage towards the allylic (C-7) position. Catalytic hydrogenation of 8 yielded a mixture of 9 and 10. Hydrolysis of 10 gave the secondary amine derivative 11 which could also be obtained more conveniently and in higher overall yield by treatment of securinine with aluminum amalgam followed by distillation (7 -+ 12 + 11). The transformation 7 + 12 appears to be a n interesting example of a 1,4-hydrogenation reaction. Compounds 8, 10, and 11 were readily
1 1. THE SECURINNEGA
ALKALOIDS
431
0
J
BrCN, 7 CHCl,, 40°
c1 " &;I& NC Br
8
10% Pd-C,
I
Hz,
15&lf30°/0.6 mm
6% HCl
H
NC
NC 9
11
10
110% Pd-C, Hz
Ac 14 PtOz, Ha or
1. KOH, H.O--THF 2. Raney Ni
lO?L Pd-C 280-290"
15a Lactam-carbinol A 15b Lactam-carbinol B SCHEME 1. Structural elucidation of securinine by Saito et al. (25, 26). 4
432
V. SNIECKUS
characterized by UV and I R spectroscopy since they still possessed the conjugated y-lactone unit present in the natural product; compounds 9 and 12 could be compared spectrally with the previously available dihydrosecurinine. Catalytic hydrogenation of 11 or 12 gave the same dihydro amine 13 which upon acetylation and further reduction produced the N-acetyl tetrahydro derivative 14. This compound upon treatment with base, followed by hydrogenation over Raney nickel, gave a lactam-carbinol (15a) which was shown to be identical with lactamcarbinol A (mp 185') obtained directly from securinine previously. Alternately, reduction of 13 in the presence of platinum oxide gave an isomeric lactam-carbinol (mp 223-224"; [a];5 + 32.6" in EtOH) designated lactam-carbinol B (15b). Lactam-carbinol B was also obtained in this manner by Satoda and associates (14). Both lactam-carbinols A and B gave 4 upon catalytic dehydrogenation. Finally, racemic lactamcarbinol B was synthesized (Scheme 4) thus unequivocally establishing the skeletal structure 7 for securinine. Satoda and co-workers executed several different degradation reactions on securinine which, aside from leading to the proposal of the same structure (7)for securinine, also yielded interesting new chemistry (Scheme 2) (14).The presence of the structural unit 3 was established as before. When securinine was successively reduced with sodium borohydride and lithium aluminum hydride it gave the oily diol 16 (hydrochloride, mp 165") which upon ozonolysis yielded glycoaldehyde and the a-ketol 17 characterized as its hydrochloride (mp 213'). A series of qualitative tests established the tertiary nature of the hydroxyl group in compound 17 and therefore in securinine 7. Furthermore, exposure of securinine to zinc and sulfuric acid at room temperature resulted in an extensive rearrangement to give the lactam 20. This reaction was reasonably considered to proceed by conjugate reduction (18) via. the intermediate 19 and was also carried out with the same result by Parello and co-workers (16). The structure of 20 was established by its further degradation to hydroxylactam 22 and finally to the lactam 23. The formation of 22 is the result of a benzylic acid rearrangement of the intermediate 21 followed by further oxidation. On the other hand, treatment of securinine methiodide with zinc in acetic acid gave the aminolactone 24 while exposure of securinine niethiodide to the zinc-sulfuric acid conditions gave the aminoester 25. On the basis of these degradation products, whose structures were fully supported by physical and spectral evidence and by careful consideration of all likely structural possibilities, Satoda and co-workers cleverly deduced that securinine must be represented by skeletal structure
7 (14).
11. THE
433
SECURINEGA ALKALOIDS
& & CH,OH
F 03,HOAc
iHOCH,CHO
17
16 1. NaBH4 2. LiAlH4
18 2. Zn, HOAc
\
24
C0,Et
0
25
20
i
KMn04
V Q p [ C 3 + $ 1 0
0
23
22
0
21
SCHEME 2. Structural elucidation of securinine by Satoda et al. (14).
2 . Relative Configuration
Of the three chiral centers in securinine, the relative configuration a t C-7 and C-9 is defined as cis by the nature of the ring A/C fusion.
434
V. SNIECKUS
Therefore knowledge of the configurational relationship of C-2 to C-7 or C-9 would establish the relative configuration of the alkaloid. Analysis of the configurations of quinolizidine A (26a)and B (26b) obtained by metal hydride reduction of lactam-carbinol A (15a)and B
15a Lactam-carbinol A 15b Lactam-carbinol B
26a Quinolizidine A 26b Quinolizidine B
R
H OH 15a R = 0 26a R = H,
@ H
0 H OH
15b R = 0 26b R = H,
H 27
SCHEME 3. Assignment of relative configuration of securinine 27 by Saito et al. ( 2 6 ) .
11.
THE SEGURINEGA ALKALOIDS
435
(15b), respectively, led to a tentative assignment of the relative configuration of securinine as represented by structure 27 (Scheme 3) (26).[In the original communication (25) Saito and co-workers hypothesized without supporting evidence a C-2-a-H stereochemistry in structure 271. Both lactam-carbinols A (15a) and B (15b) show I R absorption at 3370 (OH), 1630 (lactam),and 1150 (tertiary OH) cm-l but this information alone obviously cannot be taken (25) as evidence for the compounds being epimeric a t C-7a. On the other hand, consideration of the eight theoretically possible configurations of the quinolizidine structure 26 in conjunction with the I R data led to the configurational and conformational formulations 26a and 26b for quinolizidines A and B, respectively. Quinolizidine A (mp 163-165') showed bands a t 2760 and 2682 cm-l indicative of a trans-quinolizidine structure and no intramolecularly hydrogen-bonded hydroxyl absorption, while quinolizidine B (mp 60-61') exhibited absorption a t 3505 cm-l and no transquinolizidine bands supporting the assignments above. On this basis, lactam-carbinol A and B could be assigned structures 15a and 15b, respectively. An attempt to prepare the other theoretically possible quinolizidine isomers by a mercuric acetate dehydrogenation-metal hydride reduction sequence failed (26).However, the synthesis of racemic quinolizidine B (26b) and lactam-carbinol B (15b) was achieved, thus unequivocally proving the structural assignments (Scheme 4) (26, 27). Essentially no NMR spectroscopy was used in the structural and stereochemical assignments which follow. Treatment of 2-pyridyllithium with the cyclohexanone derivative 28 gave the hydroxy ester 29 whose stereochemistry was assigned on the basis of the steric approach (kinetic) control principle leading to the predicted formation of the axial alcohol. Catalytic hydrogenation of 29 gave an oily lactone characterized as the N-acetate 30 (mp 143-145') (see also Section 11,D, 2) and a mixture of racemic lactam-carbinol B (15b) and a new lactam-carbinol (31) designated lactam-carbinol C. The former (15b) was found to be identical with the degradation product of securinine (Schemes 1 and 3) by I R spectral comparison; the latter (31)was not isolated in pure form at this time (but see Section 11,D, 2). Lithium aluminum hydride reduction of the lactam-carbinol mixture gave, after chromatographic separation, racemic quinolizidine B (26b), identical by I R spectral comparison with the product of reduction of lactam-carbinol B (Scheme 3) derived from securinine, and the trans-anti-trans-quinolizidine C (32) (mp 92-94') whose stereochemistry was assigned on the following basis. Compound 32 was found to be different from either quinolizidine A or B but showed in its I R spectrum trans-quinolizidine bands a t
436
V. SNIECKUS
Et0$
EtaO, -50"
O y p 1. 10% NaOH 2. HCl
Et0,C
28
34
11'"
29 2. HCl
PtOa, Ha. HOAc
+
35
31
H OH
26b
32 H
& H OH
33
u
SCHEME4. Synthesis of lactam-carbinol A (15a) and quinolizidine B (26b)by Horii et al. (26, 27).
HC1
11. THE SECURINEGA ALKALOIDS
437
2757 and 2681 cm-l and strong absorption at 3509 cm-l due to intramolecular hydrogen bonding. Both the remaining theoretically possible isomers 32 and 33 are in agreement with these spectral data. However, accepting the stereochemical assignment of 29 as written leads rationally to the formation of only the two particular lactam-carbinols 15b and 31 by reductive cyclization from which only the quinolizidines 26b and 32 could be produced. Treatment of the hydroxy ester 29 with concentrated hydrochloric acid readily gave the lactone 34 whose cis stereochemistry was certainly not assured by the rather vigorous reaction conditions used (27). However, it was also obtained by saponification of 29 to the hydroxy acid 35 followed by mild acidic treatment of the latter compound. The cis stereochemical assignment in 35 (and in 34) received solid support from a rational synthesis of the corresponding trans hydroxy acid (Scheme 6). Initially compound 34 was produced by catalytic hydrogenation of the cc,B-unsaturated lactone 40 which was synthesized by the route described in Scheme 5. The cis stereochemical assignment in 34 was inferred by analogy with hydrogenations of similar systems which invariably led to compounds exhibiting cis ring junctions.
mo HO
07
0 3aLi+ EtzO, -30"
36
\
N
37
34
Ho
OH
_____, 1. 10; H C I 2. L i C E C O E t , EtzO, -15'
40
38
39
SCHEME 5 . Synthesis of lactone 34 by Horii et al. (27).
Thus treatment of the cyclohexanone ketal 36 with 2-pyridyllithium gave the hydroxy ketal 37 which by hydrolysis and a two-carbon chain extension sequence yielded the diol 38. Acid treatment of 38 produced a mixture of the hydroxy lactone 39 and the unsaturated
438
V. SNIECKUS
lactone 40. The latter upon hydrogenation gave lactone 34 which was found to be identical with the compound obtained by cyclization of the hydroxy ester 29 (Scheme 4). The rational synthesis of the trans hydroxy acid 44 and lactamcarbinol A (15a) erased any remaining doubts in the stereochemical assignments of the degradation products of securinine (Scheme 6) 0
41
(!> C0,Et
,o 1
c
U
42
43
I
10% HCI
0
45
44
15a
SCHEME6. Synthesis of trans hydroxy acid 44 and lactam-carbinol A (15a) by Horii et al. (27).
(27). Epoxidation of the pyridylcyclohexene 41 gave compound 42 which, without isolation, was treated with diethyl malonate in the presence of base to give the lactone 43. Mild acid hydrolysis of 43 gave the hydroxy acid 44 which was found to be different from the hydroxy acid 35 (Scheme 4). Epoxide opening of 42 is predicted t o take place a t the less substituted position with inversion of configuration and thus produce 43 after lactonization. Mild hydrolysis of 43 assures that the trans-hydroxycarboxylic acid 44 is formed. Attempted lactonization of 44 to 45 even under more vigorous conditions than those which
11. THE SEGURINEGA ALKALOIDS
439
were effective for the transformation of 29 to 34 (Scheme 4) resulted in recovery of starting material. This fact lays aside the fears of possible cis-trans interconversions of 35 and 44 via a benzylic carbonium ion intermediate and coupled with the reduction result (40 +-34, Scheme 5) fully confirms the stereochemical assignments of compounds 35 and 44 (Schemes 4 and 6). Finally, hydrogenation of the hydrochloride of 44 gave raoemic lactam-carbinol A (15a) which now, as expected, was shown to be identical by I R spectral comparison with the degradation product from securinine (Schemes 1 and 3). I n summary the establishment of configurations for 35 and 44 and their interrelations with quinolizidine B (26b) (Scheme 4) and lactamcarbinol A (15a) (Scheme 6) offers a fully consistent picture for the structural and stereochemical outcome of the degradation reactions carried out on securinine (27) (Scheme 7). The cis C-Ila-OH, C-llb-H relationship in both the lactam-carbinols A (15a)and B (15b) deems it obligatory that the C-2-H and C-9 lactone oxygen function in securinine (27) are in a trans relationship. (Conformation of ring A in 27 and in 46 is assumed as written at this time; see Section 11,A,4). For it is this arrangement only coupled with the reasonable and precedented assumptions concerning the two different degradations effected on compound 13 (paths a and b, Scheme 7; see also Scheme 1) which correctly predicts the formation of lactam-carbinols A (15a) and B (15b). On the other hand, the same assumptions and inspection of models shows that the alternate and sterically more encumbered cis C-2-H, C-9 lactone oxygen function arrangement (46) would predict the formation of other stereoisomeric lactam carbinols and not the two lactam-carbinols 15a and 15b. I n later work (28), Horii and collaborators described the Hofmann degradation of tetrahydrosecurinine (47) which established its cislactone stereochemistry and corroborated the arguments used in the stereochemical assignment of lactam-carbinol B (15b) [and thus also quinolizidine B (26b)lobtained in the degradation of securinine (Schemes 1 and 3). The Hofmann degradation of 47 is outlined in Scheme 8. The normal Hofmann pretreatment gave the hydroxy ester 48 which, upon pyrolysis, yielded a mixture of the olefin 49 and the alcohol 50. Both of these compounds were separately converted into a single lactone (51) which was also obtained by a two-step sequence from the pyridyllactone (34) prepared previously (Scheme 4). Compound 51 was accompanied by an epimeric lactone assigned structure 52 resulting from nonstereospecific hydrogenation of the pyridine ring of 34. Since the stereochemistry of 34 had been previously proved (27) and the configuration at C-2 in securinine had been convincingly demonstrated
rp rp 0
15a
c
15b
SCHEME7. Rationalization of the formation of lactam-carbinol A (15a) and B (15b)by reductive degradation of securinine ( 2 6 ) .
11.
441
THE SECURINEGA ALKALOIDS
1: CHJ, CH,OH 2 Ag.0
or Amberlite IRA-400-OH
,I
a H3C
H
H
’\
H
47
48
I
240-250O
49
50
1. H3P04 2. PtO., H.
1. PtO., Ha. HOAc 2. 10% Pd-C,
Ha,
CHzO
CH3
CH3
52
51
34
SCHEME8. Hofmann degradation of tetrahydrosecurinine (47) by Horii et al. ( 2 8 ) .
(Scheme 7) (86),the result above also established the complete relative stereochemistry of tetrahydrosecurinine (47). To this point the conformation with cis A/B ring stereochemistry has been drawn for securinine (structure 27, Scheme 7 ) although this relationship had certainly not been shown experimentally. Information on this interesting feature of the securinine molecule was obtained in the study of its absolute configuration (Section 11, A, 4).
442
V. SNIECKUS
3. The Piperidyl-Cyclohexene Acetic Acid y-Lactone to Isoquinuclidine Rearrangement
When the unconjugated amino lactone 12a, previously obtained as a degradation product of securinine (Scheme 1 ) ) was heated under reduced pressure the isoquinuclidine 53 was obtained in low yield (Scheme 9) (29). This rearrangement appears not to have had any significance in the structural elucidation of securinine but it has intrinsic chemical interest and thus will be discussed separately here. The I R spectrum of 53 shows bands at 2821, 2721, and 2681 cm-l, representative of a trans-quinolizidine structure and at 1794, 1735, and 1644
180-190°/1-2 mm, 1.5 hr Repeated distillation
H - -
H 12a
mo & QH
?H
1. 2. 10% NaOCl HCI
3. CP3C02H, hv
Ac
H 54
55
OH
b 56
rc:'"; N,,'
H 17a SCHEME9. Rearrangement of a degradation product (12) of securinine to the isoquinuclidine 53 (29).
11.
THE SECURINEGA ALKALOIDS
443
cm characteristic of an a,P-unsaturated y-lactone system but no NH absorption. The UV spectrum [UV max 215 (log E 4.21) mp] and the NMR spectrum (74.4,t, lH, J = 2 Hz) further supported the presence of the unsaturated lactone functionality. The structural assignment 53 was fully confirmed by degradation as follows. Metal hydride reduction of 53 followed by ozonolysis gave the a-ketol 54 which showed carbonyl absorption (1733 cm-I) in the I R spectrum typical of a bicyclo[2,2,2]octanone system. Finally, racemic 54 was prepared, although in low yield, from 55, a compound available from synthetic work on securinine alkaloids (Section IV) by the application of the Hofmann-Loeffler-Freytag reaction. Interestingly, the compound 17a corresponding to an alternate hydrogen abstraction (path b from 56) was not detected, presumably owing to a higherenergy transition state required for this reaction compared with the one leading to compound 54 (path a from 56). 4. Absolute Configuration and Conformation
ORD and molecular rotation studies on various degradation products of securinine led to the assignment of its absolute configuration. Previously Satoda and his collaborators obtained (14) two degradation products (lactam 20 and amino ester 25, Scheme 2) which provided evidence for the gross structure of securinine. I n the hands of Horii and co-workers these compounds (20a and 25a, Scheme 10) served admirably in the studies of absolute configuration (30). Lithium aluminum hydride reduction of 20a gave the benzoquinolizidine 57 which was converted into the styrene derivative 59 by a Hofmann degradation. An alternative route (25a +- 58 +- 59) using milder conditions gave the identical compound with the same optical rotation, thus offering a set of structural interrelationships and confirming that the asymmetric center was not affected in the former degradation sequence. Since the relative configuration of securinine had been established and since the asymmetric center in 57 corresponds to C-2 of securinine (27), clearly the absolute configuration of securinine now rested on the determination of the absolute configuration of 57. The ORD curves of 57 and its salts were compared with those of several protoberberine alkaloids and their salts (60) which were known to possess the S-configuration. Since 57 showed a positive Cotton effect whereas compounds of the type 60 all showed a negative Cotton effect it was concluded that the chiral center in 57 possesses the R-configuration. The same conclusion was derived from a more tenuous comparative molecular rotation (M,) study. These results suggest that securinine has
V. SNIECKUS
444
<:.3Cf. Scheme 2
H
H
H 27
1
20a
I
1. CH31
Cf. Scheme 2
25a
57 2. IRA-400-OH 3. 120-130°
58
59
0
12a
63
62
SCHEME 10. Degradations leading to assignment of absolute configuration of securinine (27) by Horii et al. ( 3 0 ) .
11.
THE SECURINEGA ALKALOIDS
445
a n R-configuration a t C-2 and leads tentatively to the absolute configuration for securinine as shown in 27. Satoda also obtained an a-ketol (17, Scheme 2) by degradation of securinine, and this derivative (17a, Scheme 10) was used by Horii and associates to provide an alternative proof of the absolute configuration (30). Since equatorial hydroxyl groups are known not to change the sign of the Cotton effect, direct comparison of the ORD curves of 17a = 61 and ( - )-homocamphor (62) is allowed. I n this manner or by direct application of the octant rule it was shown that compound 17a must have the R-configuration a t the chiral center adjacent to the carbonyl. This corresponds to the S-configuration a t C-9 of securinine and again suggests the absolute configuration as written (27). Unequivocal proof of the absolute configuration a t C-2 of securinine was obtained by a three-step degradation of the previously obtained compounds 12a (12 in Scheme 1) to give (+)-N-benzoylpipecolic acid (63) which was known to possess an R-configuration. With this observation the absolute configuration of securinine (27) was rigorously established. The same conclusion was reached by Nakano and his group mainly from a study of the absolute configuration of virosecurinine which bears an antipodal relationship to securinine; on the other hand, using as a criterion the relative rates of methiodide formation of securinine and allosecurinine (phyllochrysine), Parello and co-workers arrived a t a different conclusion (see Section 11,G). Further investigations by Horii and co-workers were directed toward the assignment of the preferred conformation for securinine (Scheme 11) (30-32). Neglecting boat forms for ring A, three conformational formulations, 64, 65, and 66, must be initially considered (30). Securinine exhibits two UV absorption bands a t 256 (log E 4.27) and 330 (log E 3.30) mp which correspond to those of two negative CD maxima a t 250 mp ([el - 80, 480) and 328 ([el - 52,300) or to the mid- 11,840°, [4Izg8 points of two negative ORD Cotton effects, [4]367 [4]262 O", and [4Iz4,, + 13,500" (32). The high molecular + 17,280°, ellipticities of the CD maxima or the high amplitudes of the ORD Cotton effects were taken as evidence of the inherently dissymetric transoid diene chromophore in securinine. That the short-wavelength CD maximum or ORD Cotton effect is due to this chromophore and that the long-wavelength maximum arises from homoconjugation of the nitrogen with the conjugated diene system was supported by comparison of CD and ORD curves of securinine with the degradation products 67 and 68. Both 67 and 68 show only one negative CD maximum of high-molecular ellipticity and ORD Cotton effects of high amplitude
446
V. SNIECKUS
64
65
66
Ac 67
68
69
SCHEME 11. Conformations of securinine (64 or 6 5 ) and its hydrobromide (69) (30-33).
+ 55,000" for 68) but - 19,000", - 17,800" for 67; lack the CD maximum or Cotton effect due to the long-wavelength absorption. The negative sign of the short-wavelength CD maxima or ORD Cotton effects of securinine, 67, and 68 conform to the helicity rule for the transoid diene chromophore. That the lactone function within these molecules does not affect the sign was assured when it was observed that the dihydro and tetrahydro derivatives of securinine as well as compounds 67 and 68 show only weak ORD curves. Consistent with the view that the 330 mp maximum in securinine is due to transannular interaction of the nitrogen function with the conjugated diene are the facts that it is unaffected in intensity or position by changing solvents (ethanol, dioxane, chloroform, and n-hexane) (30, 31) and that it is absent in the spectra of securinine hydrochloride and 67 (30). Furthermore, securinine hydrochloride also shows a single ORD Cotton effect - 4000°, [+I273 - 13,500", + 23000") (32). On the basis of these results it may be concluded that securinine is best represented by conformation 64 or 65 but not by 66 in which interaction between the nitrogen lone pair and the conjugated system is not possible. The absolute configuration of securinine was confirmed by X-ray analysis on its hydrobromide dihydrate (33).Interestingly, in the crystal state, it was found that ring A exists in a boat conformation with the
11. THE imcuRmmA
ALKALOIDS
447
nitrogen atom approximately tetrahedrally arranged and its lone pair in a cis relationship with the C-2 hydrogen (69). Whether the boat conformation and lone pair orientation also obtains in the free base is an open question. The X-ray study also indicated the nonplanar nature of the C-12, C-13 and C-14, (3-15 double bonds (dihedral angle between rings C and D 21 loo), a result in agreement with ORD and CD studies (31, 32).
B. DIHYDROSECURININE This alkaloid was isolated in 0.007370 yield from the mother liquor of the extract from S . suffruticosa (26, 34, 35). Since it was found to be identical with a sample of dihydrosecurinine obtained by catalytic
& b,$q N
3
H
70
71
hydrogenation of securinine (Section 11, A, 1) its absolute configuration is represented by structure 70 (26, 34). Nakano and co-workers showed that the UV spectrum of dihydrosecurinine exhibited, besides the high extinction maximum a t 215 mp, a weaker band a t 300 (log E 2.12) mp which disappeared upon addition of acid (35). On the basis of this observation and arguments bearing on CD and ORD measurements already discussed (Section 11,A, l ) , conformation 71 was assigned to dihydrosecurinine.
C. MASS SPECTRA OF SECURININE, DIHYDROSECURININE, AND TETRAHYDROSECURININE Mass spectral data played a relatively minor role in the structural elucidation of securinine (Section 11, A, 1 ) . Somewhat later Audier and Parello carried out a detailed analysis of the mass spectral fragmentation of securinine, dihydrosecurinine, and tetrahydrosecurinine using deuterium-labeled compounds (36). This investigation has intrinsic
448
V. SNIECKUS
interest and proves to be valuable in interpreting mass spectra of other Xecurinegu alkaloids [e.g., securitinine (Section 11, I), phyllanthine (Section 11, J), and securinol A, B, and C (Section 11, K)].
72
74
73
m/e 217 ( M + )
+
1.
O H I
76
m/e 84
mr 37.5
75
77
78
m/e 134
-I m* 83.5-84.0
[CeHe]+ m/e 78
m* 57.5
79
m/e 56
[C,H,O]+ m/e 106
SCHEME 12. Mass spectral fragmentation pathways for securinine (36).
The proposed major fragmentation pathways of securinine as obtained by high-resolution mass spectrometry are summarized in Scheme 12 (36). Two modes of fragmentation (a and b) of the parent molecular ion 72 may be envisaged as leading to the stabilized ions 73 and 75, respectively. The former (path a) may lead by an intramolecular hydrogen transfer to produce the base peak at m/e 84 assigned to fragment 76 and the radical 74. Further fragmentation of 76 to ethylene and ion 79 at m/e 56 was supported by detection of the appropriate metastable ion (m*). Ion 75 resulting from cleavage of securinine in the alternative direction (path b) leads to d2-piperideine (77)and the ion at m/e 134 (78).The identity of the latter ion was also supported by the presence of a metastable peak. Further fragmentation to ions at m/e 106 (C,H,O) and m/e 78 (C,H,) was observed but neither structure nor mode of fragmentation was proposed.
11.
THE SECURINEGA ALKALOIDS
449
In comparison with securinine the mass spectra of its hydrogenated derivatives showed different and much more complicated patterns. The ion at m/e 84 which comprises the base peak in securinine appears only as a weak peak in both dihydrosecurinine and tetrahydrosecurinine. Secondly, the ions which would correspond to m/e 134 and 106 in securinine are totally absent in the spectra of both hydrogenated derivatives. The mass spectra of these compounds were interpreted with the aid of deuterated derivatives. Dihydrosecurinine (80, R = H) exhibited major peaks at m/e 124, 110, and 84 which were interpreted by the fragmentation pathways outlined in Scheme 13. The presence of the m/e 84 peak (ion 76) indictates the operation of the fragmentation pathway analogous to that in securinine via ion 81. The base peak at m/e 110 may be assigned structure 83 (R = H) and interpreted also as arising from ion 81 (R = H) or, alternatively, from ion 82 (R = H). The observation of the base peak at m/e 111 assigned to ion 83 (R = D) in the spectrum of the dideuterio derivative 80 (R = D) is consistent with this interpretation. A peak at m/e (rel. intensity) 124(60) in dihydrosecurinine was assigned to ion 85 (R = H) also on the basis of the observed fragmentation of the dideuterio derivative 80 (R = D). The latter showed peaks at m/e (rel. intensity) 125(25) and 126(50) assigned to the two sets of imminium ions 86 (R = D) and 85 (R = D), respectively, arising from the common ion 84. The mass spectrum of tetrahydrosecurinine presented important fragment ions at m/e 220, 192, 148, 138, 121 (base peak), 110, and 84 mass units and these were interpreted by the pathways outlined in Scheme 14. Ions at m/e 84 and 110 were readily attributed to fragments 76 and 83 (R = H) by reference to the analogous fragmentation modes of securinine (Scheme 12) and dihydrosecurinine (Scheme 13), respectively. The structure of the latter ion (83, R = H, C,HI2N+ by high resolution) was confirmed by observing the appearance of a peak at m/e 111 for the dideuterio (87, R = D, R' = H) and tetradeuterio (87, R = R' = D) derivatives. The most important mode of fragmentation for tetrahydrosecurinine occurs by path g yielding peaks at m/e 121, 138, and 148. The base peak m/e 121 may be assigned structure 94; it remains constant in both dideuterio and tetradeuterio derivatives as satisfied by either of the fragmentation pathways 89 -+ 90 -+ 93 + 94 or 89+92-+94 which could not be distinguished. The fact that tetrahydroallosecurinine (Section 11, D), epimeric a t C-2 with tetrahydrosecurinine, shows a relatively weak intensity peak at m/e 121 appears to favor the mechanism 89-+90-+93+94 since the operation of this pathway involves a migration of a hydrogen from C-2 to
450
V. SNIECKUS
m/e 84
m/e 219 ( M + ) , R = H m/e 221 ( M + ) , R = D
76
81
80
I
Arrows
0
R
m/e 110, R = H m/e 111, R = D 83
82
I
f, Cis-R
-
C8
0
m/e 124, R = H m/e 126, R = D
R
85
m/e 124, R = H m/e 125, R = D 86
SCHEME13. Mass spectral fragmentation pathways for dihydrosecurinine (80, R = H) ( 3 6 ) .
I
H
0: 0
r--Cf. Scheme 12
.
’.
kk m/e 221 m/e 223 m/e 223 m/e 225
( M + ) ,R (M’), R (M+),R (M+), R
= R’ = H = D, R’ = H = H, R’ = D = R’ = D
m/e 84 76
i Cf. Scheme 13
m/e 110, R = H m/e 1 1 1 , R = D
87
83
R‘
u
0
H
91 mle 138 92
93
\
Arrows
-COz, -(Ft’HC=C(R)-
I
95 m/e 192 94 m/e 121 SCHEME 14. Mass spectral fragmentation pathways for tetrahydrosecurinine (87, R = R = H) ( 3 6 ) .
45 1
452
V. SNIECKUS
C-15 and would be sterically prohibitive for a C-2-a-H arrangement as is present in tetrahydroallosecurinine. The peak at m/e 148 is assigned to ion 88 on the basis of the observations that it remains unchanged in the dideuterio derivative 87 (R = D, R’ = H) but that it is displaced to m/e 150 in the dideuterio 87 (R = H, R’ = D) and tetradeuterio 87 (R = R’ = D) compounds. Ion 91 is assigned to the peak at m/e 138 by high resolution). As expected, this peak remains un(C,H,,NO changed in the mass spectrum of the dideuterio derivative 87 (R = D, R‘ = H). However, the derivatives deuteriated in the lactone ring (87, R = H, R’ = D, and 87, R = R’ = D) show peaks at m/e (rel. intensity) 138(53-55) and 139(45-47) in agreement with the proposed mechanism involving a hydrogen transfer from C-12 (92 -+ 91). The fact that the m/e 138 ion is still observed may be explained either by the competitive operation of hydrogen as well as deuterium transfer from C-12 or the alternative fragmentation mode without deuterium transfer (89+91). Finally, the relatively minor peak at m/e (rel. intensity) 192(3)in the mass spectrum of tetrahydrosecurinine was explained by the fragmentation mode, 89 (R = R’ = H) 3 95 and supported again by the examination of the spectra of the dideuterio and tetradeuterio derivatives. The stereochemistry of all deuterated derivatives is discussed in Section 11, E. +
D. ALLOSECURININE ( = PHYLLOCHRYSINE) 1. Skeletal Structure
Allosecurinine was first isolated by Satoda and co-workers as a minor alkaloid from X. suffruticosa grown in Japan (14). Somewhat later it was also obtained from the roots (37) and leaves (38) of the same species grown in India and from Phyllanthus discoides cultivated in Nigeria (39) and native to the Belgian Congo (16).The Indian workers point out that allosecurinine may be present as a salt in the leaves of S. suffruticosa since it could not be extracted without pretreatment with ammonia (38). Allosecurinine isolated (39) from P. discoides showed a slightly lower melting point and higher optical rotation than the sample obtained from the other sources (37, 38); nevertheless, on the basis of spectral data and melting points of picrates from the two different laboratories (36,38),it was concluded that the two samples are identical although a direct comparison appears not to have been made (39). Allosecurinine showed the same molecular formula as securinine. Compared to securinine, it showed a slightly higher rotation and ex-
11. THE SECURINEGA
ALKALOIDS
453
hibited only minor differences in the UV and I R spectra (14, 16, 37). Sodium borohydride reduction (14) of allosecurinine gave dihydroallosecurinine which was different from dihydrosecurinine but which showed UV, IR, and NMR spectral features very similar to those of the latter compound. I n contrast to securinine, which readily yielded a tetrahydro derivative upon catalytic reduction over platinum oxide in ethanol solution (Section 11,A, I ) , allosecurinine gave dihydroallosecurinine and a hexahydroallo product (C,,H,,N02; mp 263") whose structure was not assigned by Satoda (14).On the other hand treatment of allosecurinine with zinc and sulfuric acid in ethanol solution, conditions found previously to be very useful in the degradation of securin-35" in CHC1,) which showed an ine, gave a lactam (mp 69"; I R spectrum identical with that of lactam 20 (Scheme 2) obtained from securinine but which had a different melting point and optical rotation. Oxidation of the lactam with potassium permanganate gave the hydroxylactam shown to be identical by I R spectral comparison with compound 22 obtained from securinine. From these experiments it could be concluded that allosecurinine was a stereoisomer of securinine (27) possibly only differing in the configuration at C-2. Similar degradative work on allosecurinine confirming the basic skeletal features was reported almost simultaneously by Parello (16) and later by Chatterjee (37) and their respective collaborators.
2. Relative Configuration
The early work (14, 16, 37) attempting to assign the relative configuration of allosecurinine is somewhat confusing. For example, the pertinent data on hexahydroallosecurinine, a degradation product of allosecurinine obtained in the three laboratories, are given in Table 11. Whereas Satoda and his group did not propose a structure for hexahydroallosecurinine (14) Chatterjee and co-workers stated that this degradation product was "identical with the lactam-carbinol obtained from securinine" (37). Obviously, this identity can only be taken as far as the gross structure 15 (Scheme 1) is concerned since the compound was obtained optically inactive by the Indian workers and thus no stereochemical information may be extracted from this result. On the other hand, examination of the physical constants of hexahydroallosecurinine obtained by Satoda (14) and by Parello (16) and their respective co-workers (Table 11)indicates that they were dealing with the same degradation product. This information and the fact that neither lactam-carbinol A (15a) nor B (15b) reported by Horii and
TABLE I1
HEXAHYDROALLOSECURININE BY CATALYTICHYDROGENATION OF ALLOSECURININE Catalyst and solvent
MP ("C)
[((ID, (temp.
("C), in CHCl,)
IR,,,,
(cm-')
Refs.
ip
$!
PtOz,EtOH 157' Pd-C, MeOH PtOz, E t O H
263 255-255.5 235
+44.7 (27)
+ 36.2 +o
(30)
3311, 1613 (KBr) 3623, 3435 (CC1,); 1620 (KBr) 3320, 1620 (Nujol)
14 16 36
11.
THE SECURINEGA ALKALOIDS
455
co-workers (Scheme 3) (26) was identical with hexahydroallosecurinine leads one to suspect that the latter may be an epimer of lactam-carbinol B (15b)differing in stereochemistry at C-llb and that allosecurinine is represented by structure 96 (Scheme 15) and thus is a C-2 epimer of securinine (27). This relative configuration of allosecurinine was fully established mainly by Nakano and co-workers by various interrelationships with securinine and virosecurinine (Section 11,G). Independently, Horii and co-workers arrived at the same result by extensive degradative studies (40) similar to those used for securinine (Scheme 1) which will now be discussed (Scheme 15). Reduction of allosecurinine (96) with aluminum amalgam gave the aminolactone 97 and an unsaturated lactam 97a whose structure was not fully assigned. The structure of 97, however, was strongly suggested by comparison of its spectral data with those of the corresponding reduction product obtained from securinine (compound 12 in Scheme 1). Catalytic hydrogenation of the acetate 98, readily prepared from 97, gave the dihydro and the tetrahydro acetates 99 and 100,respectively. The former was also obtained in two steps from the aminolactone 97 via compound 101 while the latter was synthesized in racemic form as shown from either the hydroxy ester 29 or lactone 34 which were available from previous work (Schemes 4 and 5). The last sequence of reactions also produced the epimeric racemic tetrahydroacetate (30) already described in the degradative experiments on securinine (Scheme 4). Alternatively, catalytic reduction of 97 or of 101 produced the aminolactone 102 whose salt, when passed through an alumina column or allowed to remain in ethereal solution for a few hours, was transformed into lactam-carbinol C (31). This compound could also be obtained from compounds 97a or 101 as shown in Scheme 15 and it was synthesized in racemic form together with racemic lactam-carbinol B (15b)from the hydroxy ester 29 as already described (Scheme 4). Finally, metal hydride reduction of lactam-carbinol C (31)gave quinolizidine C (32) which showed an I R spectrum identical with that of racemic quinolizidine C previously synthesized (Scheme 4). The characterization of the degradation products 31, 32, and 100, facilitated by the previous synthetic and degradative work on securinine, fully describes the relative configuration of the three centers of chirality (C-2, C-7, and C-9) in allosecurinine (96). In addition, it may be seen that one of these, lactam-carbinol C (31)(mp 258-260"; [a]$1+ 45.3" in EtOH; I R (KBr) 3289 and 1634 cm-I), corresponds fully in physical constants to the hexahydroallosecurinine obtained by Satoda (14) and Parello (16) and their co-workers (Table 11). Interestingly, Horii
&& +
H OH 97a
Ac
101
NaOH 2. PtOa,
Pa-c,
0 chromatog.
H,
LiAlH4
H OH 31
32
N
H
Ac
PtOa, Ha, HOAc
100
99
1. Pd-C, Ha 2. AcaO 3. Ala03,
chromatog.
30
34
29
SCHEME 15. Assignment of relative configuration of allosecurinine (96) by Horii et al. (40).
456
OH 15b
457
11. THE S E C U R I N E f f A ALKALOIDS
and associates also were able to obtain tetrahydroallosecurinine (stereochemistry at C - 13 unassigned) by catalytic hydrogenation of allosecurinine over platinum oxide in glacial acetic acid ( 4 0 ) whereas previous workers (16, 37) noted that they were not able to prepare this reduction product. Aside from securinine, allosecurinine is the only other Securinega alkaloid whose structure and relative stereochemistry has been confirmed by X-ray analysis. Although Nakano’s stereochemical investigations (Section 11,G) pointed to a trans A/B ring junction (103) for allosecurinine, the X-ray determination on allosecurinine methiodide showed a cis A/B arrangement (104) ( 4 1 ) . This is almost certainly a
103
104
result of the S,2 reaction of the alkaloid with methyl iodide proceeding by way of a more unencumbered transition state resembling conformation 104. As with securinine (Section 11,A, 4)further interpretation of the relevance of the X-ray result on the conformation of allosecurinine is not possible. It may be noted here than an X-ray determination of a Securinega free base has not yet been achieved. Thus allosecurinine (96) is a C-2 epimer of securinine (27). Further stereochemical interrelationships of allosecurinine with other Securinega alkaloids which establish its absolute configuration as represented by formulation 96 are described in Section 11,G. 3. The Piperidyl-Cyclohexene Acetic Acid y-Lactone to
Isoquinuclidine Rearrangement Horii and co-workers discovered that the aminolactone 97 (Scheme 15) upon standing at room temperature or upon distillation produced the isoquinuclidine derivative 105 in good yield (Scheme 16) (40). This interesting isomerization has its counterpart in the degradative chemistry of securinine (Section 11,A, 3) but requires milder conditions. The structure of 105 rests mainly on this securinine analogy and on spectral evidence. The presence of an a,P-unsaturated y-lactone was indicated by IR and NMR spectroscopy. The absence of I R absorption due to NH and the inability to obt,ain an N-acetyl derivative showed the tertiary nature of the nitrogen. Furthermore, the presence in the
458
V. SNIECKUS
.HA-4
170-180°/0.5 mm,
H 97
105
\
H
106
/
107
SCHEME 16. Rearrangement of a degradation product (97) of allosecurinine t o the isoquinuclidine (105) ( 4 0 ) .
IR spectrum of trans-quinolizidine bands at 2770, 2703, and 2632 cm-l was consistent with the bridgehead location of the nitrogen. Catalytic reduction of 105 gave a dihydro derivative (106) whose perchlorate showed the expected IR absorption at 1779cm-l for a y-lactone function. The milder reaction conditions necessary to effect the rearrangement of 97 compared with its securinine counterpart (12a, Scheme 9) may be a reflection of the lower transition state energy in 107 for the intramolecular Michael attack of the nitrogen lone pair at C-15 as a result of the absence of C-2-H-lactone ring repulsive interaction.
E. NMR SPECTRA OF SECURININE, ALLOSECURININE, AND SOME OF
THEIRHYDROGENATED DERIVATIVES
In their structural elucidation work on securinine and allosecurinine, Parello et al. carried out detailed NMR analysis by which they were able t o assign precisely most of the protons in the alkaloids (16). Subsequently, Parello elaborated on certain aspects of these assignments (41a) and also investigated the NMR spectra of dihydro and tetrahydro derivatives of these alkaloids with the aid of deuterated
11.
THE SECURINEGA ALKALOIDS
459
derivatives available from a mass spectral study (Section 11,C) (36). Aside from offering structural verification, these results aided in interpreting the NMR spectra of various other securinine- and norsecurininetype alkaloids and thus clarified their structure and stereochemistry. The NMR spectra of securinine and allosecurinine in CDC1, are recorded in Table I11 (16, 4 1 ~ )I.n the case of securinine, the ABX pattern for H-14, H-15, and H-7 at T 3.25-3.70 (2H) and T 6.16 (IH), respectively, was elucidated by double resonance studies (16).Irradiation of H-7 led to a typical AB quartet at T 3.57 (H-14, H-15). The signs of the coupling constants J 1 4 , 1 5 ) J7,15,and J 7 , 1 4 were found to be positive ( 4 1 ~ )The . positive coupling constant, J 7 . 1 4 , is that expected for the C-7 proton being in the same plane as the C-14, C-15 double bond within a rigid framework on the basis of a large number of studies with allylic systems. Interestingly, the value of J 7 . 1 4 is smaller ( < 0.5 Hz) in trifluoroacetic acid and essentially zero for securinine methiodide, effects which may be ascribed to certain changes in the conformation of ring A resulting from nitrogen lone pair solvation or reaction with methyl iodide. Irradiation of H-7 also brings about the collapse of the quartet a t T 7.50 to an AB doublet. This signal can be assigned to H-8a coupled to H-8P ( J s U , 8 4 = 9.5 Hz). The latter appears as a doublet at T 8.23 and, as expected, collapses to a sharp singlet upon irradiation of H-8a. Simultaneous irradiation of H-14 and H-15 resulted in simplification of the broad triplet at T 6.16 assigned to H-7 into a doublet. Examination of models and application of the Karplus curve leads to the conclusion that H-7 must be coupled to H-8a (J7,8a= 4.5 Hz) and not to H-8P (dihedral angle for H-C-7, C-8-H-/3 80-90’). This coupling was proved conclusively in allosecurinine. A later study of securinine at 100 MHz in trifluoroacetic acid led to the assignment of a weak “Wtype” coupling between H-15 and H-8a ( 4 1 ~ )I .n this solvent, irradiation of H-7 simplified the pattern for H-14, H-15, H-8a, and H-8P and gave rise to two unsymmetrical and broadened AB patterns centered at T 6.82 for H-8a and at T 3.10 for H-15, respectively. The slight broadening of the AB peaks was taken as an indication of the “Wtype’’ coupling (J15,8U< 1 Hz) which had general precedents in bicyclo(3,2,l)oct-2-eneand norbornene systems. The double triplet at T 7.01 and the quartet at T 7.6 were assigned to the methylene protons at C-6 of securinine on the following basis. Irradiation at 7 7.01 (H-6‘) transformed the quartet at T 7.6 to a doublet, indicating the presence of a coupling between H-6 and one of the C-5 protons (J6,5= 6.5 Hz) while the inverse decoupling process (irradiation at T 7.6) produced a quartet (X of an ABX) for H-6‘ at N
TABLE I11
NMR SPECTRA OF SECURININE AND ALLOSECURININE H
Securinine
%
Allosecurinine
-
7
value
Securinine 3.25-3.70 4.46 6.16 7.01 7.50 7.6 7.95 8.23 8.2-9.0
--
Number of protons
Multiplicitya
0 S
brt dt q q (masked) CI d m
Coupling constant (Hz)*
Assignment
H-14, H-15 (AB of ABX) H-12 H - 7 ( X of ABX) H-6 H-8a H-6‘ H-2 H-8P (2-3, C-4, C-5-H
TABLE 111 (continued) 7
value
Allosecurinine 3.0-3.46 4.26 6.10 6.33 7.12 7.36 8.10 8.16-9.0 a
Number of protons
Coupling constant ( H z ) ~
Multiplicitya
2
0
J I ~ , I ~
1
S
-
1 1 2 1
brt 4 m q d m
J7,15
1
6
+9-3
f5.5,
J z , ~ 11, J
J7,14
+
1 - 1 9
J7.m
4.5
4.8
z , ~ ,
Jea.8u
9.2, J e n , 7 4.5
Assignment
H-14, H-15 (AB of ABX) H-12 H-7 ( X of ABX) H-2 H-6, H-6' H-8a
J e n , ~9.2
H-$8
-
(3-3, C-4, C-5-H
s = singlet, d = doublet, q = quartet, o = octet, m = multiplet, dt = double triplet, br = broad. A prime (') does not carry stereochemical implication for a particular proton.
462
V. SNIECKUS
T 7.01. Additionally, irradiation in the region of the C-5 protons gave = 11 Hz) a t T 7.6, indicating suppression of rise to a doublet (J6,5 coupling between one of the C-5 protons and H-6'. Unfortunately, double irradiation studies did not fully decouple H - 2 (broad quartet a t T 7.95) owing to the proximity of the signals for H - 3 and H-2. Similar but more detailed interpretation of double resonance studies of allosecurinine in CDC1, led to the assignments shown in Table I11 (16). I n this case it was possible to demonstrate that irradiation of H-8P did not affect the signal a t T 6.10 assigned to H-7, thus assuring that J7,80 0 as expected for the H-C-7, C-8-H-/3 dihedral angle of 80-90". Furthermore, simultaneous irradiation in the region of the C-3 protons gave rise to a singlet a t T 6.33 compatible with the assignment of this peak to H-2. Similarly, simultaneous irradiation of the C-5 methylene protons simplified the signal a t T 7.12 to a singlet, showing the equivalency of the C-6 protons in direct contrast to the situation which obtains for securinine (vide supra). Many of these assignments could be confirmed by double irradiation studies in trifluoroacetic acid. I n particular, a multiplet at T m 5.66 assigned to H - 2 in this solvent was shown to be coupled (J2,,= 9 H z ) to one (equatorial?) of the C-3 protons. Further interpretation of these data, in particular the higher field absorption of the olefinic ABX pattern for securinine than for allosecurinine and the assumed axial location for H - 2 based on the coupling in both cases, led Parello et al. to constant J2,3axial and J2,Sesuatorial propose incorrect assignments for the relative configurations of the two alkaloids (Section 11,G) (16). The correct relative configurations were assigned by Nakano and co-workers who argued in large part on the basis of diamagnet,ic anisotropy effects of the extended conjugated 7.95) system on the chemical shift difference of H - 2 in securinine ( T and allosecurinine ( T 6.33). Discussion in Section 11,G makes it clear that the configurations proposed by Parello also qualitatively satisfy this chemical shift difference. However, Parello subsequently argued that this large chemical shift diffsrence ( A ppm = 1.6) is difficult to justify solely on the basis of an effect resulting from interaction of H - 2 with the conjugated system ( 4 l a ) . If this were the case, protons H-8a and H-sP, which occupy, respectively, positions almost identical with those of H - 2 in allosecurinine and in securinine with respect to the conjugated system, should also show a similar chemical shift difference. This was not found t o be the case [ A ppm ( H - 8 a , H-8P) = 0.72 and 0.74 for securinine and allosecurinine, respectively]. It appears that the only remaining plausible explanation for the chemical shift
-
-
-
11.
THE SECURINEGA ALKALOIDS
463
difference of H-2 may be related to the conformational preference of the nitrogen lone pair in the two alkaloids as shown by the structures of Table 111. Several deuterated derivatives of securinine and allosecurinine provided very useful information in the elucidation of mass spectral fragmentation pathways (Section 11,C). Examination of NMR spectra of these derivatives clarified or corrected some other proton assignments previously advanced ( 3 6 ) . Catalytic deuteration of securinine over palladium gave 14,15-dideuteriosecurinine(87, R = D, R,’ = H, Scheme 14); 14,15-dideuterioallosecurinine was similarly obtained. The NMR spectra of these two dideuterated derivatives showed simplification in the absorption due to H-12, H-7, and H-8a (refer to securinine structure in Table 111). H-12 now appeared as a clear doublet a t T 4.46 in 14,15-dideuteriosecurinineand at T 4.34 in 14,15-dideuterioallosecurinine. The coupling constant in both cases, J = 2.5 Hz, is that expected for the allylic H-12 to H-14 coupling and, if a ring C chair conformation is assumed, speaks for an axial H-14 arrangement. This then implies that deuteration has taken place from the a-face, leading to the stereochemistry shown in structure 87 (R = D, R‘ = H) (Scheme 14) for both 14,15-dideuterated derivatives. Furthermore, H-8a appears as a double quartet in both compounds. If the smallest coupling (J = 1.5 Hz) in this signal is attributed to a long-range “ W-type ” coupling between H-8a and H-15 (wide supra) the conclusion may be reached that H-15 is equatorially oriented in the dideuterated derivatives. Therefore the (3-15 deuterium must be axially located consistent with the proposal that deuteration taken place from the a-face of the alkaloids. Catalytic deuteration of 14,15-dihydrosecurinine over platinum in (87, benzene solution gave 12,13-dideuterio-14,15-dihydrosecurinine R = H, R’ = D; Scheme 14) while complete deuteration of securinine (87, R = R’ = D; Scheme provided 12,13,14,15-tetradeuteriosecurinine 14). Examination of the NMR spectra of both compounds showed that incorporation of deuterium had proceeded to a greater extent than predicted, and that this extra deuterium content was incorporated a t C- 12 was evidenced from diminuition of the broad signal associated with the C-12 hydrogens. On the other hand, when the deuteration reaction was carried out in methanol solution, the respective products obtained showed a smaller deuterium content a t C-12 than that expected from the theoretical uptake of deuterium gas. This obviously also was due to exchange of the acidic C-12 methylene hydrogens in the prot,ic solvent.
464
V. SNIECKUS
The signal at T 6.83 assigned to H-7 and observed in the NMR spectra of both tetrahydrosecurinine and 12,13-dideuterio-14,15dihydrosecurinine as a poorly resolved triplet was transformed int,o a quartet (J7,15E= 4 Hz) in ,14,15-dideuteriosecurinineand a broad doublet in tetradeuteriosecurinine. These results led to the conclusion that generally J,,15E 0 Hz in a tetrahydrosecurinine-typestructure (dihedral angle H-C-7, C-15-Hp 90') but not in a dihydrosecurininetype structure. The difference in the coupling of H-7 to H-15/3 in the dihydro and tetrahydro securinine derivatives was attributed to a conformational difference of ring C for the two systems (see also Section 11,K). A similar splitting pattern was observed for H-7 in the corresponding 14,lEi-dideuterated derivative of allosecurinine. Finally, the observed multiplicity of the signal at T 6.83 in the 14,15-dideuterated derivatives of securinine leaves no doubt about its assignment to H-7 and not to H-2 as previously advanced by Nakano and co-workers. A significant amount of weight was placed on this result by Nakano in the assignment of stereochemistry of allosecurinine (Section 11,G). N
-
F. VIROSECURMINE 1. Skeletal Structure
The structure determination of virosecurinine isolated from 8. virosa Pax. et Hoffm. was announced by Nakano and his collaborators (42) virtually at the same time as that of securinine from the laboratories of Horii and Saito (25). Using degradative reactions similar to those described for securinine and allosecurinine, Nakano and co-workers first derived the skeletal structure represented by 108 without stereochemical implications for virosecurinine (Scheme 17)" (42, 43). Virosecurinine possessed the same molecular formula as securinine and showed no N- or O-methyl groups. Its I R and UV spectra indicated the presence of an extended a,/?-unsaturated y-lactone moiety. On hydrogenation over palladium in benzene solution, virosecurinine gave dihydrovirosecurinine (109) and an oily aminolactone (110) characterized as its crystalline picrate (mp 215', dec) and N-acetyl derivative (mp 166-1665"). Appropriate I R and UV spectra were observed for the two products 109 and 110. Lithium aluminum hydride reduction
* The relative stereochemistry of virosecurinine and its degradation products were not determined by the reactions of Scheme 17; this is indicated to facilitate further discussion and for differentiation with structurally identical degradation products of other Securinega alkaloids.
11. THE SECURINEBA
465
ALKALOIDS 0
PhH
H 10s
Pd-C,
109
Ha.
110
Br 115
H
bH
111
I
H
Zn, HzO-
1. 03,HOAc 2. Zn
114
113
3. PhNHNHz
eNNHP "NHPh
112
116
117
SCHEME 17. Key degradations leading to the determination of the skeletal structure of virosecurinine (10s) (42, 4 3 ) . Indicated stereoohemistry not determined in these studies (see text).
of 109 gave a liquid diol 111 which upon ozonolysis followed by reductive workup gave glycoaldehyde identified as the phenyl osazone 112. On the other hand, catalytic hydrogenation of the alkaloid over palladium in ethanol gave tetrahydrovirosecurinine (113) and a lactamcarbinol, 114 (mp 220-221"; -32.9'; IR max 3275 (OH), 1610 (lactam) em-'). The latter was also obtained by a two-step sequence from 109 and its gross structure only was assigned at this stage purely on the basis of its elemental analysis and I R spectrum. von Braun degradation of virosecurinine yielded the bromocyanide 115 whose structure was fully supported by IR, UV, and NMR spectral
466
V. SNIECKUS
data. I n particular in the NMR spectrum the C-7 proton showed the expected downfield shift (T 6.18 in 108; T 5.08 in 115) resulting from bromo substitution. Treatment of the bromocyanide with aqueous sulfuric acid resulted in recyclization to 108; however, addition of zinc to a sulfuric acid solution of 115 gave the lactam 116 (mp 75-76'; [aID - 35.7') whose gross structure was fully established by potassium permanganate oxidation to phthalic acid and by metal hydride reduction to the benzoquinolizidine 117 (hydrochloride, mp 260-261'; [.ID - 84.4") identical by I R spectral comparison with a n authentic sample. Compound 116 was also obtained directly from virosecurinine as shown in Scheme 17. On the basis of these characterizations and reasonable mechanistic postulates virosecurinine was assigned the skeletal structure 108 without implication of stereochemistry (43).
108
118
I
LiAlH,
-
CH20H OH \
1. PhCOCI, CsHsN
2. KMnO,
120
119
A 121
SCHEME 18. Degradation of virosecurinine establishing its absolute stereochemistry as 108 or 121 ( 4 5 ) .
11.
THE SECURINEGA ALKALOIDS
467
2. Absolute Configuration a t C - 2 .
Further degradative work established the absolute configuration a t C-2 for virosecurinine and led to the two formulations (108, 121) for the absolute configuration of the alkaloids (Scheme 18) (44, 45). Treatment of virosecurinine with amalgamated aluminum yielded the unconjugated aminolactone 118, a compound analogous to one already encountered in securinine and allosecurinine degradative chemistry (Schemes 1 and 15). Its structure was assigned on the basis of spectral evidence, in particular, the NMR spectrum which exhibited absorption a t T 4.12 (1H) and 4.3-4.4 (2H) attributable to H-12 and H-7 and H-15, respectively, and a t T 4.9 (1H) which was assigned to H-2 on the basis of decoupling experiments with protons in the piperidine ring. Additionally, a signal a t T 6.8 (2H) was shown to be coupled to H-7, H-15, and H-12 and thus could be assigned to the doubly allylic methylene a t C-14. Reduction of 118 gave the unsaturated amino diol 119 which, when subjected to benzoylation followed by potassium permanganate oxidation, produced N-benzoyl-L-( - ) -pipecolic acid (120) whose absolute configuration was known. On the basis of these results the absolute stereochemistry of the alkaloid could be formulated as 108 or 121. That structure 108 correctly represents the absolute stereochemistry of virosecurinine was determined by a study of stereochemical interrelationships among virosecurinine, allosecurinine, securinine, and their structurally common degradation products. These investigations will be discussed in Section 11,G. 3. Monoperphthalic Acid-Promoted Oxidative Rearrangement
I n the course of degradative work Nakano and his group discovered an interesting rearrangement of virosecurinine which was fully elucidated only after the structure and absolute stereochemistry (Sections 11, F, 1 and 11,G) of the alkaloid had been rigorously established (Scheme 19) (46). Treatment of virosecurinine 108 with monoperphthalic acid gave two nonbasic isomeric products, 123 and 124, in a 1:5.5 ratio. The oxidative reaction may be envisaged to proceed via the N-oxide intermediate 122 which suffers rearrangement analogous to known transformations of N-allyl- and N-benzylamine oxides to 0-ally1 and 0-benzylhydroxylamines ( 4 7 ) . The structures of 123 and 124 were assigned on the basis of the following spectral and chemical data. The IR (1775, 1650 cm-l) and UV [259 (log E 4.20) mp] spectra of the 1,2oxazolactone 123 showed that the extended conjugated lactone moiety was still present. Further, a strong band a t 1020 cm-l in the
468
V. SNIECKUS
ion
122
133
132
SCHEME19. Monoperphthalic acid rearrangement of virosecurinine (108) ( 4 6 ) .
IR spectrum could be assigned to a n N-0 vibration. That the oxygen is directly attached to the allylic C-7 position was ascertained from the NMR spectrum which exhibited a clear ABX pattern ( T 3.05, d, HA,JAB= 1 0 H z ; 3.76, q, H,, JAB= lOHz, J,, 6 H z ; 5.21, m, H,). The large downfield shift of H, in 123 compared with that of virosecurinine 108 was reminiscent of a similar shift observed in the von N
11.
469
THE SECURINECA ALKALOIDS
Braun degradation product of the alkaloid (structure 115, Scheme 17) and was consistent with oxygen-inserted structure 123. The isomeric 1,2-oxazolactone 124, also obtained by either hydrogen peroxide or ozone oxidation of 108, showed I R absorption a t 1755, 1635, and 1040 cm-l indicative of the presence of an a$-unsaturated lactone and an N-0-C function, respectively, but its UV spectrum [213.5 (log E 4.25) mp] pointed to lack of extended conjugation. Analysis of its 100-MHz NMR spectrum and double irradiation experiments offered strong evidence for the structure 124. A singlet a t T 4.29 was assigned to proton H, and a doublet a t T 4.84, J,, = 6 Hz, to proton H,. Proton H, was observed as a complex multiplet centered a t T 4.15, J,, = 6, J,, = 9, J,, 2.5, and J,, 1.5 Hz, and proton H, was 2.5 Hz. To seen as an octet a t T 3.78, J,, = 9, J,, = 4, and J,, complete the interpretation, proton H, was found to resonate as a 1.5 Hz, and proton multiplet a t T 6.88, J,, = 18, J,, = 4, and J,, HAappeared at T 7.77, JAB= 18 and JAW + J AZ 6 Hz. Pyrolysis of 124 readily gave the isomeric 1,2-oxazolactone 123 but the reverse reaction could not be effected under these conditions, showing that 123 was the thermodynamically more stable isomer. Catalytic hydrogenation of 123 gave compounds 125, 126, and 127. Compounds 125 (picrate, mp 225-226", dec) and 126 (picrate, mp 221222", dec) were transformed by chromatography into lactam-carbinol 114 and lactam-diol 128, respectively. It was claimed (46)that the Nacetate of 125 (mp 155-156.5"; [a],,- 127") was identical with a degradation product of virosecurinine, although reference to this compound cannot be found in the available literature (43, 45). Its gross structure is assured, however, by spectral comparison with a synthetic product obtained in the structural elucidation work on securinine and allosecurinine (compound 30 in Schemes 4 and 15). On the other hand, lactam-carbinol 114 had been obtained previously from virosecurinine (Scheme 17) and its physical constants show that it is the optical antipode of lactam-carbinol B (structure 15b, Scheme 4) obtained from securinine. Compound 128 showed IR spectral features similar to those of 114 and was further characterized as its 0-monoacetate, mp 233237". The other product of the catalytic hydrogenation was shown to possess structure 127 by its further hydrogenation in the presence of excess of unreduced platinum oxide to the hydroxy amine 126. The trans configuration of the C/D ring juncture in compound 127 was deduced from a comparison of its ORD and CD curves with those of compounds 125 (N-acetate) and tetrahydrosecurinine. Although the absolute trans C/D ring configuration had been clearly established for tetrahydrosecurinine (Scheme 8), again it is not clear that this is the N
N
N
-
N
470
V. SNIECKUS
case for the N-acetate of compound 125. Nevertheless, negative Cotton effects are observed for all three compounds, thus assuring the trans C/D ring assignment. Since compound 126 was directly obtained from 127 it may also be assigned trans C/D ring stereochemistry. Hydrogenation of the isomeric 1,2-oxazolactone 124 also produced three products-the new compounds 129 and 130 and the lactamcarbinol 114 previously obtained from 125. The rearranged tetrahydro1,2-oxazolactone 129 and the tetrahydro-1,2-oxazolactone130 both showed I R absorption near 1035 cm-l indicative of an N-0 function; however, the NMR spectrum of compound 130 showed a predicted multiplet a t T 5.76 due to C-14-H whereas this absorption was absent in compound 129. Furthermore, a singlet a t T 7.28 in the spectrum of 129 was readily assigned to the magnetically equivalent and uncoupled C-12 methylene hydrogens whereas compound 130 showed a complex pattern for these hydrogens due to coupling with proximate ring C protons. Hydrogenation of 129 gave the hydroxyamine 131 which could be transformed via 132 to the known N-acetyl lactone 133 (mp 166-166.5') (Section 11,A, 1). Alternatively, compound 129 was transformed to the lactam-diol 134 which also yielded compound 133 under vigorous acetylation conditions. The configuration of the ring C/D junction in both 129 and 130 was assigned on the basis of their ORD and CD curves in conjunction with compounds 125 and 127 which were previously correlated with compounds of known absolute configuration. I n contrast to compounds 125 (iV-acetate), 127, and 129 which all showed negative Cotton effects and thus possess trans C/D ring stereochemistry, the 1,2-0xazolactone 130 showed a positive Cotton effect suggesting its cis C/D ring junction. The tetrahydro-1,2-oxazolactone 130 was found to be stable to the hydrogenation conditions employed for reduction of compound 129. However, in the presence of a large excess of unreduced platinum oxide it yielded the lactam-diol 128a which was characterized exclusively on the basis of the spectral properties of its crystalline O-monoacetate (46).
G. STEREOCHEMICAL INTERRELATIONSHIPS OF SECURININE, AND VIROSECURININE ALLOSECURININE, Arguments used in interrelating these three key alkaloids will be presented in this section. The isolation of L-( - )-pipecolic acid by degradation of virosecurinine established that the alkaloid must be represented by either structure 108 or 121 (Scheme 18). Furthermore, it was shown that virosecurinine upon treatment with zinc and sulfuric
11. THE
SECURINEGA ALKALOIDS
47 1
acid provided a lactam, 116 (mp 75-76'; [.ID - 35.7') (Section 11,F, 1). The same lactam, 116 (mp 69'; [.ID - 32.7') was obtained by the same degradative reaction on allosecurinine (14)indicating that virosecurinine and allosecurinine have the identical absolute configuration a t C-2. Securinine, on the other hand, when subjected to the zinc-sulfuric
116
20a
SCHEME 20. Degradations leading to stereochemical interrelationships of securinine, allosecurinine, and virosecurinine.
acid reaction conditions, gave the antipodal lactam, 20a (mp 74-75'; [.ID + 13.9') (Section 11,A, 4). This information is reconstituted in Scheme 20. Direct comparison of the optical rotation values (43) and ORD curves (48, 49) of virosecurinine and securinine showed an antipodal relationship of these two alkaloids. Whereas securinine showed a negative Cotton effect (Section 11, A, 4),that of virosecurinine presented a positive Cotton effect + 2,360', [+IsT5 + 20,200', -39,000") and the two curves were perfect mirror images (35, 49). From these results it follows that (cf. Scheme 21): (a) virosecurinine and allosecurinine must bear a diasteriomeric relationship; if virosecurinine corresponds to structure 108, then allosecurinine must be 121 or vice versa; and (b) securinine must possess stereochemical formulation 27 or 135 depending on whether virosecurinine is represented by 108 or 121 respectively. It also follows that securinine is a diasteriomer of allosecurinine. Analysis of the NMR spectra of virosecurinine and several of its degradation products led to the assignment, albeit as will be seen fortuitously, of its absolute configuration and therefore the absolute configurations of securinine and allosecurinine (Scheme 2 1) (50, 51). For each of the possible formulations 108 and 12€ for virosecurinine two conformational isomers may be constructed (if ring A boat conformations are neglected) depending on whether it is assumed that the
472
V. SNIECKUS
0
43 ---
H
108 108a
amo'
108b
'H
H
104
103
121
H 135
H 27
SCHEME21. Determination of absolute configuration of securinine (27), allosecurinine (121),and virosecurinine (108)by Nakano et 02. (50, 51).
nitrogen lone pair is cis (108a and 104) or trans (108b and 103) with respect to the C-2 hydrogen. Nakano reasoned (50)from examination of models that in 108a and 108b the C-2 proton should be substantially shielded by the ring-C double bond whereas in 103 and 104 a slight deshielding effect due to the same factor should be expected on C-2-H. The shielding effect in 108b would be expected to be slightly less than in 108a but still observable. On the basis of this analysis it would be predicted that, if structures 108a or 108b represent virosecurinine, the dihydrovirosecurinine (109 in Scheme 17) obtained therefrom should show a downfield shift for C-2-H while, if structures 103 or 104 are correct, the corresponding dihydro compound would show a slight up-
11. THE SECURINEGA ALKALOIDS
473
field shift for the C-2 proton. Nakano assigned NMR absorption a t r 7.1 to C-2-H in virosecurinine and a t r 6.7 to the corresponding proton in dihydrovirosecurinine (50). The virosecurinine assignment appeared reasonable in view of the fact that Saito and Horii had attributed a triplet a t r 6.98 to the C-2 proton in securinine which, being antipodal with virosecurinine, would be expected to show an identical NMR spectrum (25).On the basis of this and similar information obtained from other degradation products Nakano assigned absolute configuration 108 (conformation 108a or 108b) to virosecurinine (50).From what was deduced above it was reasoned that allosecurinine must be represented by absolute configuration 121 (conformation 103 or 104) and in support of this formulation the presence of an absorption a t r 6.33 assigned to C-2-H was offered. To complete the analysis the known enantiomeric relationship between virosecurinine and securinine led Nakano and co-workers to assign the absolute configuration 27 to the latter alkaloid (51). Subsequently, detailed NMR investigations by Parello and coworkers (Section 11,E) showed that the crucial virosecurinine ( r 7.1) and dihydrovirosecurinine ( r 6.7) absorptions due to C-2-H in both compounds had been misassigned. Since securinine and virosecurinine bear an antipodal relationship, the NMR spectra of the alkaloids and of their dihydro derivatives should be identical and therefore can be used interchangeably for each set of compounds. Decoupling experiments showed that C-2-H for securinine (and thus virosecurinine) falls at r 7.98 and analysis of the NMR spectrum of dihydrosecurinine (and therefore dihydrovirosecurinine) deuterated in ring C showed unambiguously that a signal at 6.83 was due to C-7-H and not to C-2-H. I n fact the absorption due to the C-2 proton in this compound could not be pinpointed. These results detract rather forcefully any confidence originally placed in Nakano’s NMR analysis on which rests the absolute stereochemistry of securinine (27),allosecurinine (121),and virosecurinine (108) (Scheme 21) (51). It may be noted, however, that Parello confirmed the r 6.33 assignment for C-2-H in allosecurinine and thus in comparison with the new assignment (T 7.98) for the corresponding proton in securinine (and therefore virosecurinine) the chemical shift difference ( A ppm = 1.65) is overwhelmingly in the right direction if based on the predicted diamagnetic anisotropy of the carbon-carbon double bond in ring C, i.e., C-2-H in virosecurinine conformations 108a and 108b is expected to be strongly shielded in comparison with allosecurinine conformations 103 and 104 (51).However, even this assignment is not unambiguous (Section 11,E) and therefore it may be concluded that Nakano’s formulations of absolute configuration for
474
V. SNIECKUS
securinine (27), allosecurinine (121), and virosecurinine (108), although correct as evidenced from independent studies (Sections 11,A, 4; D, 2; F , 2), were fortuitous. Parello and co-workers reached a different conclusion from the one expounded by Nakano and his group by comparison of relative rates of methiodide formation for allosecurinine and securinine (16). This generally accepted method is based on the expected correlation between rate of reaction with methyl iodide and steric encumbrance of the nitrogen function. The French workers found that methiodide formation was 26 times slower for securinine than for allosecurinine and on this basis assigned relative configurations 121 or 135 for securinine (and therefore virosecurinine) and 108 or 27 for allosecurinine using the conformational models 103 and 108b respectively (Scheme 21). However, Nakano and co-workers pointed out that each formulation may be represented by two ring-A chair conformations, and consideration of these does not allow a firm conclusion to be reached regarding the relative configurations on the basis of rates of methiodide formation (51). Thus, neglecting boat forms as before, if the set 103 and 108b represent the conformations for 135 and 108, respectively, conformation 103 should be more hindered and therefore less reactive, leading to the conclusion that securinine should be represented by 103. On the other hand, if the other set, 104 and 108a, represent the conformations for securinine (135) and allosecurinine (108), respectively, 108a is more hindered, suggesting that securinine should be formulated as structure 108a. Obviously, interpretation of results based on these considerations leads to ambiguous conclusions. Furthermore, if a correlation between basicity and steric hindrance to methiodide formation may be made, the pK, measurements reported (14) for securinine (pK, = 7.17) and allosecurinine (pK, = 6.91) are inconsistent with the results of Parello and associates (16).Thus Nakano suggested that the results from rates of methiodide formation cannot be interpreted without complete kinetic data and amine inversion rates on the four theoretically possible conformational species, 108a, 108b, 103, and 104. Interestingly, the large difference in chemical shift for C-2-H between securinine (7 7.98) and allosecurinine ( T 6.33) is not explicable on the basis of the two conformations, 103 and 108b, advanced for the two alkaloids and this point was recognized by the French workers (16).Further, Nakano noted that these conformations are incompatible with the UV spectra of the two alkaloids (35). These results, now t o be discussed, not only supported the assignments 108 and 121 originally elaborated by Nakano for the absolute configuration of virosecurinine and allosecurinine, respectively, but also clarified the remaining uncertainty in the conformation of ring A.
11. THE SECURINEGA
ALKALOIDS
475
Allosecurinine, virosecurinine, and securinine are bright yellow and show two UV absorption bands, one around 256mp and the other above 300mp (Table IV). The 256mp band is that predicted from Woodward rules for an a,p-unsaturated lactone with one double bond within a ring extending conjugation and may be confidently assigned t o a T-T* transition. The other band ( > 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<$Yr
168b
I
C02Me
169
169a R = H 170 R = Me
0
171
172
173
12.
UNCLASSIFIED ALKALOIDS
55 1
169. Phyllobates aurotaenia
A review of the chemistry of batrachotoxin (171) and of its remarkable neuromuscular and other effects has appeared (208). The X-ray analyses have determined the structures of batrachotoxinin A (171, R = H), of batrachotoxin (171, R = 172), and of homobatrachotoxin (171, R = 173). 170. Piper trichostachyon C.DC. (Piperaceae) (XIII, 417)
A new pyrrolidine amide, trichonine (C,,H,,ON; mp 65-67") has been isolated from this plant. Its structure (174) was arrived at primarily by mass and NMR spectroscopy. Catalytic hydrogenation generated the expected tetrahydro derivative (mp 38-50") and hydrolysis afforded eicosanoic acid and pyrrolidine. Finally, a synthetic specimen was prepared by reacting eicosanoyl chloride with pyrrolidine (209). 17 1. Pisum sativum L. (Leguminosae)
Three derivatives of 2-methoxypyrazine (175) were isolated from the volatile constituents of green peas: those in which R is isopropyl, S-butyl, and isobutyl. They are considered to be the compounds which give peas their characteristic flavor (and odor) and are estimated to be present to the extent of one part in 10l1 to 10l2 parts. They have also been detected in oil from Ferula species (Umbelliferae) and the lastmentioned was detected in bellpeppers (Solanaceae). Their biogenetic origin is reasoned to be analogous to their laboratory syntheses from simple derivatives of known amino acids and glyoxal (210). 172. Poranthera corymbosa Brogn. (Euphorbiaceae)
Porantherine (Cl5HZ3N; mp 36-40'; [.ID + 29"; hydrobromide, mp - 13") was the main base in this plant. Its absolute structure (210a) was determined by X-ray diffraction methods and is consistent with other spectral data (176). There is mooted a biosynthetic resemblance between this alkaloid and a base (C,H,,ON; mp 30'; [.ID + 6') (177) reported earlier from Euphorbia atoto Forst. f. (211). 340"; [.ID
173. Priestleya elliptica DC. (Leguminosae)
Anabasine was the main basic constituent (212).
552
R. H. F. MANSKE
C
N. CO(CH=CH),. (CH2)14Me
174
175
176
174. Protostemonine (IX, 550; XIII, 421)
Some earlier errors regarding this alkaloid have been corrected. It forms a hydrate hydrochloride (C23H3,0,N.HC1. H,O) which on reaction with aqueous potassium carbonate gave stemonine and a neutral oil which was identified as 4-hydroxy-3-methoxy-2-methyl crotonolactone (178). In view of the known structure of stemonine (179) the structure of protostemonine is given as either 180 or 181. The chief tools in this work were spectral methods ( 2 1 2 ~ ) . n
179 R = 0
180 R =
MePo"" 0
181 R =
0
175. Pseuduvaria Spp. (Mitrephora Spp.) (Anonaceae)
Liriodenine, anonaine, 1,2-dirnethoxynoraporphine,glaucine, and 1,2,9,10-tetramethoxynoraporphine were isolated from several of these species. Liriodenine was also isolated from Polyalthia nitidissima Benth. and from Xchefferomitra subaequalis (Scheff.) Diels (Anonaceae) (213).
12.
553
UNCLASSIFIED ALKALOIDS
176. Ptelea trifoliata L. (Rutaceae) (IX, 230; XIII, 417)
I n addition to several oxygenated compounds this plant yielded choline, hydroxylunine, hydroxylunidine, as well as a new alkaloid, ptelefoline (C,,H,,O,N), whose structure is given as 182 (214). In a later publication a furoquinoline alkaloid (C,,H190,N; mp 70'), not distantly related to ptelefoline, of structure 183 was reported (215). All structures are based on spectral data. OMe
Me I
I
182
183
177. Ptelea trifoliata L.
The quaternary pteleatinium chloride (C,,H,,O,N+Cl- ; mp 267270") isolated from this plant was shown to be bioactive in vitro against
Mycobacterium smegmatis and Candida albicans. When heated with pyridine it generates compound 185 (R = H ) which on treatment with diazomethane yields ( + )-balfouridine (185,R = Me) of known structure. Consequently the structure of the new base is 184 which exhaustive spectral data confirm (216). 178. Pterogyne nitens Tul. (Leguminosae)
Pterogynidine (picrate, mp 105') was isolated from this plant in addition to the pteroginine (187) which had previously been reported and which is identical with ti base isolated from Alchornea javanensis (p. 509) (216a, 217). 179. Ruta graveolens
1. (Rutaceae) (IX, 224; XII, 462)
Ribalinidine (mp 255-258") in addition to a number of quaternary quinoline alkaloids (217a). 180. Sceletium joubertii (L.) Bolus (Aizoaceae; Ficoidaceae) (IX, XII, 490)
I n addition to the known hordenine three new alkaloids were isolated from this plant. Separation was effected by repeated chromatography and the structural details are based on spectral observation. In all of
554
wJ$oH
R. H. P. MANSKE
W OH 7 F O ORH Me 184
185
186 OMe I
187
188
189
them the mesembrane skeleton is lacking but it is obvious that they are 186), closely related to mesembrane. Joubertiamine (C,,H,,O,N; dihydrojoubertiamine (C,,H,,O,N; 187), and dehydrojoubertiamine (C,,H,,O,N; 188) have the structures shown. The three bases upon catalytic hydrogenation yield the same dihydrojoubertiaminol (mp 226") and (218). 181. Sceletium mamaquense (L.) Bolus Alkaloid A4 (C20N,,0,N,; mp 154"; [.ID +131") from this plant was shown to be identical with that already described (219). Its structure (189) was determined by spectral methods, and finally by an X-ray study (220). 182. Sceletium strictum (L.) Bolus N-Demethylmesembrenol and N-demethylmesembranol were isolated from the aerial parts (221).
12.
555
UNCLASSIFIED ALKALOIDS
183. Sceletium stsictum (L.) Bolus Four new alkaloids were isolated from this plant and their structures were determined by a combination of spectral and chemical methods. The previously known mesembrenone, mesembrine, and mesembranol were isolated in minor amounts. Mesembrenol (C,,H,,O,N; mp 145"; [a]g5 +91") (190, R = Me, R1 = H); 0-acetyl mesembrenol (C,,H,,O,N; oil) (190; R = Me, mp 219'; [a]:5 R1 = Ac); 4'-O-demethylmesembrenol (C,,H,,O,N; +533") (190, R = R' = H); and 4'-O-demethylmesembranol (C16H2303N;mp 201"; [a]g5 - 199") (191) (222). 184. Sceletium tortuosum N.E.Br.
A contemporary study of this species also yielded Alkaloid A 4 which (192) upon catalytic hydrogenolysis yielded tortuosamine (C,oH,602N2; oil; -29"), also isolated from this plant. Its structure follows from that of its progenitor and from spectral and chemical examination. It readily yields an N-methyl and an N-acetyl derivative (both oily) (223). OH
190
191
OMe
192
185. Xcopoliu tanguticu Maxim. (Solanaceae) (X, 17) Hyoscyamine, scopolamine, cuscohygrine, tropine, and two unidentified bases in a total of l.56Y0 in the roots (224, 2 2 4 ~ ) . 186. Xcutiu buxiifoliu Reiss. (Rhamnaceae) (XII, 499) I n addition to the scutianine which was originally described and which is now termed scutianine-A there was isolated scutianine-B which lacks the pyrrolidine moiety of the former. Its mass spectrum indicated C,,H,,O,N, (mp 248-250"; [a]gO- 296") and the fragments pointed to structure 193. Acid hydrolysis of the dihydro derivative yielded
556
R. H. F. MANSKE
N,N-dimethylphenylalanine, phenylalanine, 3-hydroxyleucine7 and p-tyramine, all detected chromatographically (225). 187. Skytanthines (XI, 501) The p- and a-forms of this base are not present in Skyunthus acutus Meyen but are artifacts generated during the process of isolation (226). 188. Shepherdia urgenteu Nutt. and S. canudensis (L.) Nutt. (Eleagnaceae) Acetylation of a mixture of the bases from the former gave acetylpyrrolidine, N-acetyl-p-anisidine, and a crystalline compound which proved to be 0,N-diacetyltetrahydroharmol (193a, R = CO .Me) (mp 202"). The alkaloid itself was isolated from the crude base mixture and shown to be harmol (193a, R = H) (mp 254"). Shepherdia cunudensis also yielded tetrahydroharmol as well as serotonine and a new base, shepherdine, isomeric with tetrahydroharmol, whose structure (193b), was determined by physical methods and confirmed by a synthesis. Its 0,N-diacetyl derivative melts at 192" (227).
R O O Z Q E t Me 193a
I
193
Me 193b
189. Siburu virginica (L.) Rollins (Cruciferae) The fluorescence of an extract of the seeds of this plant proved to be due to the cation of the choline ester of isoferulic acid (228). 190. Skimmiu foremanni Hort. (8.juponica Thunb.) (Rutaceae) (111, 69; VII, 235; IX, 227) Dictamnine and a number of nonalkaloid compounds were identified
(229).
12.
UNCLASSIFIED ALKALOIDS
557
191. Solanum lchasianum C. B. Clarke (Solanaceae) The dried ripe berries yielded 2.67', of solasodine (230). 192. Solenopsis saevissima
This is the "fire ant" occurring in the southern parts of the United States. Its venom has pronounced hemolytic, insecticidal, and antibiotic activity. The main constituents are five pyridine derivatives of the structures shown (194-198). Milligram quantities of the venom were chromatographed and the structures determined largely by spectral methods. The structures were confirmed by syntheses (231).
194 n = 10 195 n = 12 196 n = 14
197 n = 3 198 n = 5
193. Sophora grifithii Stocks (Keyserlingia grifithii Boiss.) (Leguminosae) (VII, 258; I X , 208) I n addition to cytisine, N-methylcytisine, and pachycarpine a new alkaloid, A (C,,H,,O,N,; mp 260'; [elD-305"), was isolated. It contains two lactam groups and a 2(1H)-pyridone ring. Its NMR spectrum is similar to that of cytisine. Hydrogenation gave an octahydro derivative (mp 208"; [elD- 143") (232). 194. Spathiostemon javensis Blume (Homonoia riparia Lour.) (Euphorbiaceae) The major constituent of the alkaloids from the leaves of this plant was N,-methyltetrahydroharman, the first example of a carboline found in Euphorbiaceae (232a). 195. Speciosine (VI, 250; XI, 418) -22) found along This alkaloid (C,,H,lO,N; mp 211-214'; with demecolcine and colchicine in Colchicum speciosum Stev. (233) is present only in small amounts and these vary seasonally. Insufficient for chemical degradation was available so that the given structure (199) is based entirely upon spectral data. However, it was possible to confirm it by converting demecolcine (200) into speciosine. For this purpose the latter was alkylated with 2-bromomethylphenyl acetate
558
R. H. F. MANSKE
and the acetoxy derivative thus generated was hydrolysed to speciosine (234).
OMe
OMe
199
200
196. Spherophysine (X, 581)
The structure of this base has been revised to Me,C: CHCH,N(C( :NH)NH,)(CH,),NH, on the basis of spectral evidence. Its dehydro derivative was prepared by the reaction between cyanamide and the hydrochloride of Me,CH. CH,CH, .NH(CH,),NH. COMe (235). 197. Spireine (X, 581; XII, 187; XIII, 421)
This alkaloid from Spireae japonica L. is C,,H,,O,N and on the basis of spectral data was given structure 201 in which RR' = CH,, R = Me, R3 = OH, or in which R = Me, R' = OH, R2R3 = CH, (236). 198. Stemona japonica Mig. ('2) 421)
(Roxburghiaceae) (XII, 502; XIII,
The new alkaloid, stemofoline (CZ2Hz9O5N; mp 87-89"; [.ID + 273"), was given structure 202 on the basis of an X-ray analysis of its hydrobromide hydrate (mp 224") (237).
R1 \ R %
201
202
H 0
203 204
!
0
H R = H, R' = O M e R = OMe, R' = H
12.
559
UNCLASSIFIED ALKALOIDS
199. Strychnos nux-vomica L. (Loganiaceae) (XI, 194; XII, 422) 16-Hydroxy-a-colubrine (203) (mp 225; [a]gO- 54") and 16-hydroxy/?-colubrine (204) (mp 140"; [a]gO-56") were isolated from the seeds and from mother liquors from the commercial preparation of strychnine. Their structures were assigned by spectral methods and confirmed by oxidation of the a- /?-colubrines (238). 200. Strychnos camptoneura Gilg & Busse
The main alkaloids were serpentine and alsonine among a total of ten revealed in thin-layer chromatography (239). 201. Strychnos Species (XII, 503) Sixty-nine African species of Strychnos were examined. The isolated bases were discussed in respect to botanical classification and pharmacodynamic activity (240). 202. Symphytum aspersum Lepech. (Boraginaceae) The alkaloid asperumine (C,,H,,O,N; picrate, mp 135-137"; picrolonate, mp 169-171") on alkaline hydrolysis generates heliotridine and 2 moles of angelic acid and consequently it has structure 205. There were also present heliosupine N-oxide, echinatine, and a trace of an unidentified base (241). 203. Symphytum spp. (Boraginaceae) The main alkaloid in the three species examined proved to be lasiocarpine (242). 204. Tarenna bipindensis (K. Schum.) Bremek. (Chomelia bipindensis K. Schum.) (Rubiaceae) (XII, 476; XIII, 407) The alkaloid tarenine isolated from this plant (243) is identical with dihydrochloride, mp 264-269") dihydroelaeocarpidine (C,,H,,N,; (205a) which had previously been synthesized (244, 245). HdMe
r c o z
Me
Me
mCHZ* Me
Ozc*H
205
205a
560
R. H. F. MANSKE
205. Taspine (VII, 328) When diacetyl magnoflorine methine (mp 244-245') was ozonized in methanol followed by further oxadation with silver oxide and lactonization it generated taspine (206) (246). 206. ThaZictrum fendleri Engelm. (Ranunculaceae) (IX, 1 7 ; X, 418; XIII, 316)
Three new alkaloids have been isolated: tetrahydrothalifendine (207) (mp 209-21 1'; [.ID - 175"); N-methylthalidaline (208) (oil); N-methylcorydaldine (209) (oil). The previously reported veronamine (210, Rh = rhamnose) (amorphous; [a],, -145') (247) was further characterized by hydrolysis to rhamnose and the expected aglycone (mp 177") (248). 207. ThaZictrumJEavumL. ('1) (XIII, 313)
The roots of this plant yielded thalicarpine and thalflavine which was given structure 211 (249). 208. Thalictrum minus L. (X, 432; XII, 504) Thalmethine (250). 209. Thalictrum simplex L. (IX, 155; XIII, 332) Thalicmine, thalicminine, allocryptopine, and magnoflorine were isolated from this plant for the first time. The last plus hernandesine
12.
UNCLASSIFIED ALKALOIDS
561
seem t o be the principal alkaloids. Two new bases, thalicsimidine (C,,H,,O,N; mp 131'; [.ID + 66.9") and thalictricine (C,,H,,O,N; mp 261"; [.ID -I 0) were reported as well as two further bases (mp 245" and mp 182') (251). 210. Thermopsis ulterni$oru Regel & Schmalh. (Leguminosae) (VII, 256; XII, 505) At early flowering the aerial portion of this plant yielded 3.35y0 total alkaloid from which cytisine, N-methylcytisine, pachycarpine, thermopsine, and the new alteramine (212)were isolated (252). 211. Thermopsis lanceolutu R.Br. (VII, 256, 259; XII, 505) I n addition to pachycarpine, thermopsine, N-methylcytisine, rhombifoline, and cytisine, there was isolated the new alkaloid thermopsamine (mp 154-155'; [.ID + 26.4") (213)which on dehydration with phosphorus pentoxide gives dehydrosparteine. Oxidation with the Oppenauer reagent gives a n 0x0 compound, and treatment with hydrogen iodide and phosphorus in acetic acid generates pachycarpine; hence the given structure as 13-hydroxysparteine (253). The same known alkaloids had been reported in another publication (254) as well as argentine [bis(6,9-dimethylenequinolizidine)carbacarbamide]. Also, the seeds were reported to yield 0.9% cytisine (255).
NMe 0
@
CHz. CH=CH,
0
211
212
213
212. Thermopsis montana Nutt. (XII, 505) Cytisine, hydroxylupanine, N-methylcytisine, anagyrine, and thermopsine (256). Another contemporaneous examination disclosed the above as well as spartcine (257).
562
R. H. F. MANSKE
213. Tiliacora racemosa Colebr. (Menispermaceae) (IX, 161; XIII, 342)
A new alkaloid, tiliacoridine (C39H4008N2; mp 153-156") has three methoxyls, eight aromatic protons, but no N-methyl (258). 2 14. Timonius kaniensis Valeton (Rubiaceae)
The alkaloid in the bark of this tree was shown to be dehydrocupreine (glass; [a],,- 143"; hydrochloride, mp about 220"; picrate, mp 250-252') (259). 215. Trewia nudi$ora L. (Euphorbiaceae) (XI, 495)
The base from this plant was shown to be ricinidine (mp 46") (214) (260). 216. Tylophora asthrnatica Wight et Am. (Asclepiadaceae) (IX, 518; XIII, 425)
A new phenolic alkaloid, tylophorinidine (C,,H,,O,N; mp 213-214"; +108"; diacetyl-, mp 192") was shown to have structure 215 on the basis of a spectral study. Methylation with diazomethane yielded a methyl ether identical with neither tylophorine nor tylocrebrine (262). 217. Urechites karwinsky Muell. (Apocynaceae)
The roots of this plant have yielded loroquine (C,Hg02N; mp 77"; acetyl-, mp 67-68') whose structure (216) was largely determined by spectral methods (262). It was converted into the corresponding diol by reduction with sodium borohydride and the product was identical with a specimen which had been previously synthesized (263). OH O
C 0N
I
Me
o
MeO@NJ
HO
~
c
,-' \ OMiIe
214
215
216
H
2
'
o
H
12.
UNCLASSIFIED ALKALOIDS
563
218. Uvariopsis solheidii (De Wild.) Robyns & Ghesquihe (Tetrastemma solheidii De Wild.) (Anonaceae) The methine base, uvariopsine, isolated from this plant was shown t o have structure 217 (264). 219. Vanda cristata Lindl. (Orchidaceae) Laburnine acetate (picrate, mp 138'; methiodide, mp 104') (218) was isolated from this orchid and identified by comparison with a synthetic specimen (265). 220. Vandop8is longicaulis Schlechter (Orchidaceae)
l-Methylpiperidine N-oxide as the hydrobromide and l-methylpiperidinium as the iodide were obtained in 0.201, yield (266). 221. Vepris ampody H. Perrier (Rutaceae)
This plant was shown to contain N,N-dimethyltryptamine, kokusaginine, 2,4-dirnethoxy-lO-methylacridan-9-one, evoxanthine, and phenylacetamide. In addition three new alkaloids, structures 219 (C,,H,,ON; mp 103'), 220 (C,,H,,O,N; mp 250"), and 221 (C,,,H,,O,N; mp 126') were isolated (267).
217
d
H 218
Z
A
C 219 220 221
R
=
(CH2)2*CH:CH*CH2*CH:CHEt
R = (CH,),*CH,OH R = (CH,),CH2O2CMe
222. Verbascum nobile Vel. (Scrophulariztceae)
Verbasine (C,,H4,04N4; mp 74-75"), verbascine (C,,H,,O,N,; mp 125-126'), and a third (mp 100') not further characterized. A
564
R. H. F. MANSKE
fourth compound (mp 133-135') was regarded as probably identical with pediculine (268). REFERENCES 1. G. Faugeras, Plant. Med. Phytother. 4, 9 (1970); CA 73, 73839x (1970). 2. S. Johne, D. Groeger, and M. Hesse, Helv. Chim. Acta 54, 826 (1971). 3. A. Chatterjee and R. Majumder, Indian J . Chem. 9, 763 (1971); C A 75, 141029b (1971). 4. R. S. Kapil, A. Shoeb, S. P. Popli, A. R. Burnett, G. D. Knowles, and A. R. Battersby, J. Chem. Soc., D 904 (1971). 5. F. Khuong-Huu-Laine,J. P. Leforestier, G. Maillard, and R. Goutarel, C. R. Acad. Sci., Ser. C 270, 2070 (1970); CA 73, 66787a (1970). 6. N. K. Hart, S. R. Johns, J. A. Lamberton, and R. I. Willing, Aust. J . Chem. 23, 1679 (1970). 7. T. R. Govindachari and P. C. Parthasarathy, I n d i a n J . Chem. 8, 567 (1970); C A 73, 6 6 7 6 9 ~(1970). 8. T. R. Govindachari and P. C. Parthasarathy, Tetrahedron 27, 1013 (1971). 9. T. R. Glovindachari, P. C. Parthasarathy, and H. K. Desai, I n d i a n J . Chem. 9, 931 (1971); C A 76, 25447h (1972). 10. T. Onaka, Tet. Lett. 4387 (1971). 11. D. G. O'Donovan and H. Horan, J . Chem. Soc., C 331 (1971). 12. K. Sasaki and Y . Hirata, Tetrahedron 26, 2119 (1970). 13. T.-H. Yang and C.-M. Chen, J . Chin. Chem. SOC.( T a i p e i ) 17, 243 (1970); CA 74, 121337b (1971). 14. K. J. Harkiss and D. Swift, Tet. Lett. 4773 (1970). 15. K. J. Harkiss, Planta Med. 20, 108 (1971); CA 76, 23052b (1972). 16. K. J. Harkiss, Phytochemistry 10, 2849 (1971); CA 76, 11970m (1972). 17. R. Tschesche, L. Behrendt, and H.-W. Fehlhaber, Ber. 102, 50 (1969). 18. R. Tschesche, E. Frohberg, and H.-W. Fehlhaber, Ber. 103, 2501 (1970). 19. L. M. Garcia, K. Jewers, A. H. Manchanda, P. Martinod, J. Nabney, and F. V. Robinson, Plzytochemistry 9, 613 (1970); C A 73, 53009y (1970). 20. F. R. Stermitz, S. M. Workman, and W. M. Klein, Phytochemwtry 10, 675 (1971); CA 75, 31279a (1971). 21. M. D. Miller, J . Ass. Ofic,Anal. Chem. 53, 123 (1970); CA 72, 75644h (1970). 22. J. M. Neal, P. T. Sato, C. L. Johnson, and J. L. McLaughlin, J. Pharm. Sci. 60, 477 (1971); CA 74, 121319X (1970). 23. J. M. Neal and J. L. McLaughlin, Lloydia 33, 395 (1970); C A 74, 505332 (1971). 24. I. R. C. Bick, J. B. Bremner, N. W. Preston, and I. C . Calder, J . Chem. SOC.,D 1155 (1971). 25. S. Ghosal, R. K. Chaudhuri, and S. K. Dutta, Phytochemistry 10, 2852 (1971); C A 76, 23008s (1972). 26. T. R. Govindachari, N. Viswanathan, B. R. Pai, V. N. Ramachandran, and P. S. Subramaniam, Tetrahedron 26, 2905 (1970). 27. S. Ghosal and N. K. Majurnder, Phytochemistry 10, 2840 (1971); CA 76, 1 1 9 9 9 ~ (1972). 28. W. D. S. Motherwell, N. W. Isaacs, and 0. Kennard, J . Cliem. Soc., D 133 (1971). 29. C. Tani and N. Takao, Yakugaku Zasshi 82, 755 (1962). 30. H. Ishii, K. Hosoya. and N. Takao, Tet. Lett. 2429 (1971).
12. UNCLASSIFIED ALKALOIDS
565
31. H. Grabarezyk and H. Gertig, Ann. Pharm. (Poznan) 8 , 75 (1970); C A 74, 95419h (1971). 32. C. C. J. Culvenor, S. R. Johns, J. A. Lamberton, and L. W. Smith, Aust. J . Chem. 23, 1279 (1970); C A 23, 35596h (1970). 33. T. M. Smalberger, R. Vleggaar, and H. L. DeWaal, Natuurwetensk. 10, 213 (1970); CA 74, 95432g (1970). 34. A. Z. Gulubov and A. P. Venkov, Nauch. T r . Vissh. Pedagog. Inst., Ploudiv, Mat., Fiz., Khim., B i d . 8 , 137 (1970); C A 7 5 , 16118d (1971). 35. W. Doepke and G. Fritsch, Pharmazie 25, 128 (1970); CA 73, 42378s (1970). 36. J. A. Kepler, M. C. Wani, J. M. McNaull, M. E. Wall, and S. J. Levine, J . Org. Chem. 34, 3853 (1969). 37. G. Stork and A. G. Schultz, J . Amer. Chem. SOC.93, 4074 (1971); CA 7 5 , 118435 (1971). 38. T. Kametani, M. Ihara, and T. Honda, J . Chem. SOC., C p. 2342 (1970). 39. S. Jurisson, Tartu Riikliku Ulikooli Toim.270, 71 (1971); C A 26, 23018v (1972). 40. I. V. Terent’eva, G. V. Lazur’evskii, and T. I. Shirshova, K h i m . Prir. Soedin. 5 , 397 (1969); C A 72, 6 7 1 6 6 ~(1970). 41. I. V. Terent’eva, T. I. Shirshova, A. F. Sholl, and V. I. Kovalenko, Ref. Zh., Khim. Abstr. 7 Zh. 639 (1970); C A 74, 50497r (1971). 42. H. L. Kim, B. J. Camp, and R. D. Grigsby, J . Agr. Food Chem. 19, 198 (1971); C A 74, 50512s (1971). 43. G. A. Santos, J . Chem.Soc., C 842 (1971). 44. G. A. Santos and M. S. Doty, Lloydia 34, 88 (1971); C A 75, 8521837 (1971). 45. A. I?. Halim, R. P. Collins, and M. S. Berigari, Planta Med. 20, 44 (1971); CA 75, 85202p (1971). 46. W. Oppolzer and K. Keller, J . Amer. Chem. Soc. 93, 3836 (1971). 47. A. Z. Gulubov, T. Sunguryan, V. B. Chervenkova, a n d I . Z. Bozhkova, Nauch. T r . Vissh. Pedagog. Inst., Plovdiv, Mat., Fiz., Khim., Biol. 8, 135 (1970); CA 75, 16066k (1971). 48. J. R. Cannon and C. D. Shilkin, Aust. J . Chem. 24, 2181 (1971); C A 7 5 , 126629d (1971). 49. E. Gellert and R. E. Summons, Aust. J . Chem. 23, 2095 (1970);C A 74, 989g (1971). 50. E. Gellert and R. E. Summons, Tet. Lett. 5055 (1969). 51. B. Turch, D. Daloze, M. Dupont, C. Hootele, M. Kaisin, J. M. Pasteels, and D. Zimmerman, Chimia 25, 307 (1971); C A 75, 14897th (1971). 52. R. W. Doskotch, A. B. Ray, and J. L. Beal, Chem. Commun. 300 (1971). 53. S. F. Matkalikova, V. M. Malikov, and S. Y. Yunusov, Khim. Prir. Soedin. 5 , 30 (1969); C A 71, 132452 (1969). 54. S. F. Matkalikova, V. M. Malikov, and S. Y. Yunusov, Khim. Prir.Soedin. 5 , 606 (1969); C A 73, 15050x (1970). 55. S. F. Matkalikova, V. M. Malikov, M. R. Yagudaev, and S. Y. Yunusov, Khim. Prir. Soedin. 7, 210 (1971); CA 7 5 , 36409c (1971). 56. S. F. Matkalikova, V. M. Malikov, and S. Y. Yunusov, Khim. Prir. Soedin. 5 , 607 (1969); C A 73, 25712d (1970). 57. Kh. Turdikulov, M. K. Yusupov, and A. S. Sadykov, Khim. Prir. Soedin. 7, 541 (1971); C A 76, 1791q (1972). 58. T. Baytop and G. Ozcobek, Istanbul Univ. Eczacilik Fak. Mecm. 6, 21 (1970); C A 74, 1029f (1971). 59. R . Tschesche, R. Geipel, and H.-W. Fahlhaber, Phytochemistry 9, 1683 (1970); C A 73, 117202r (1970).
566
R. H. F. MANSKE
60. H. Guinaudeau, A. Cave, and R. R. Paris, Phytochemistry 10, 1963 (1971); C A 75, 126641b (1971). 61. S. F. Cooper, J. A. Mockle, and J. Beliveau, PZanta Med. 19, 23 (1971); CA 74, 20373e (1971). 62. S.-T. Lu, S.-J. Wang, and T.-L. Su, Yakugalcu Zasshi 91, 778 (1971); CA 75, 95393r (1971). 63. Kh. Sh. BaisLeva and B. K. Rostotskii, Lek. Rust. 376 (1969); CA 75, 14848711 (1971). 64. Kh. Sh. Baisheva and B. K. Rostotskii, Tr.Vses. Nauch.-Issled. Inst. Lek. Aromat. Rust. 15, 376 (1969); CA 75, 20711j (1971). 65. M. U. Ibragimova, M. S. Yunusov, and S. Y. Yunusov, Khim. Prir. Soedin. 7. 211 (1971); CA 75, 36400t (1971). 66. T. Kametani, M. Ihara, and T. Honda, Phytochemistry 10, 1881 (1971); CA 75, 126589r (1971). 67. K. S. Baisheva, D. A. Fesenko, B. K. Rostotskii, and M. E. Perel’son, K h i m . Prir. Soedin. 6, 456 (1970); CA 74, 10343f (1971). 68. K. S . Baisceva, D. A. Fesenko, M. E. Perel’son, and B. K. Rostotskii, Khim. Prir.Soedin. 6, 574 (1970); CA 74, 50522v (1971). 69. L. I. Stekol’nikov, Priroda (Moscow) 107 (1970); C A 74, 1075t (1971). 70. M. U. Ibragimova, M. S. Yunusov, and S. Y. Yunusov, K h i m . Prir. Soedin. 6, 438 (1970); CA 73, 1277381 (1970). 71. C.-N. Lin, Hua Hsueh 22 (1971); C A 75, 85178k (1971). 72. R. S . Sawhney and C. K. Atal, J . Indian Chem. Soc. 47, 741 (1970); CA 74,84001q (1971). 73. D. S. Bhakuni, S. Satish, and M. Dhar, Phytochemistry 9, 2573 (1970); CA 74, 95428k (1971). 74. S. R. Johns, J. A. Lamberton, A. A. Sioumis, and R. I. Willing, Aust. J . Chem. 23, 353 (1970); C A 72, 1 0 7 7 8 4 ~(1970). 75. J. Kunitomo, K. Morimoto, K. Yamamoto, Y. Yoshikawa, K. Azuma, and K. Fujitani, Chem. Pharm. Bull. 19, 2197 (1971); C A 76, 14759k (1972). 76. A. H. Jackson and G. W. Stewart, J. Chem. SOC.,D 149 (1971). 77. W. Wiegrebe, H. Budzikiewicz, and L. Faber, Arch. Pharm. ( Weinheim)303, 1009 (1970). 78. N. K. Hart, S. R. Johns, J. A. Lamberton, J. W. Loder, and R. H. Nearn, J . Chem. Soc., D 441 (1970). 79. X. A. Dominguez, D. Butruille, and J. Wapinsky, Phytochemistry 10, 2554 (1971); C A 75, 137549d (1971). 80. R. B. Hoerhammer, A. E. Schwarting, and J. M. Edwards, 2. Naturforsch. B 26, 970 (1971); CA 76, 14766k (1972). 81. I. Granelli and K. Leander, Acta Chem. Scand. 24, 1109 (1970); C A 73, 355672 (1970). 82. I. Granelli, K. Leander, and B. Luning, Acta Chem. Scand. 24, 1209 (1970); C A 73, 1 1 7 1 2 1 ~(1970). 83. K. Hedman, K. Leander, and B. Luning, Acta Chem. Scand. 25, 1142 (1971); C A 75, 954222 (1971). 83a. M. Elander and K. Leander, Acta Chem. Scand. 25, 717 (1971); CA 75, 363983. (1971). 84. H. Rosenberg and A. G. Paul, Phytochemistry 9, 655 (1970); CA 73, 56289a (1970). 85. D. G. O’DonovanandH.Horan,J.Chem.Soc.,G2083(1971);CA 7 5 , 5 9 8 8 9 ~ (1971). 86. M. F. Grundon and K. J. James, Yet. Lett. 4727 (1971).
12.
UNCLASSIFIED ALKALOIDS
567
87. J. Kolodzieski and L. Stecka, Gdansk. Tow. N a u k . , Rozpr. W y d z . 3, 125 (1971); C A 75, 126626a (1971). 88. W. Doepke and G. Fritsch, Pharmazie 24, 782 (1969); C A 73, 11366g (1970). 89. G. W. A. Slywka and R . H. Locock, Tet. Lett. 4635 (1969). 90. K. Hedman, K. Leander, and B. Luning, Acta Chem. Scand. 23,3261 (1969); C A 72, 129376t (1970). 91. E. P. White, N . 2. J . Sci. 13, 359 (1970); C A 73, 127747m (1970). 92. S. Ghosal, S. K. Majumder, and A. Chakraborti, Aust. J . Chem. 24, 2733 (1971); C A 76, 23007r (1972). 93. W. J. Griffin, J. H. Phippard, C. C. J. Culvenor, J. W. Loder, and R. Nearn, Phytochemistry 10, 2793 (1971); C A 76, 1767m (1972). 94. A. Cronlund and F. Sandberg, Acta Pharm. Suecica 8, 351 (1971); C A 76, 119953. (1972). 95. 0. E. Schultz and K. L. Hoenicke, Pharm. Ztg. 116, 713 (1971); C A 75, 13746813 (1971). 96. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 23, 421 (1970); CA 72, 1077862 (1970). 97. J. Slavik and L. Slavikova, Collect. Czech. Chem. Commun. 36, 2067 (1971); CA 75, 77102r (1971). 98. D. W. Bishay, Z. Kowalewski, and J. D. Phillipson, J . Pharm. Pharmacol. 23, suppl., 233s (1971); C A 76, 25449k (1972). 99. H. Wada, Y. Shizuri, K. Yamada, and Y. Hirata, Tet. Lett. 2655 (1971). 100. Y. Shizuri, H. Wada, K . Sugiura, K. Yamada, and Y. Hirata, Tet. Lett. 2659 (1971). 101. K. Sigiura, Y. Shizuri, H. Wada, K. Yamada, and Y . Hirata, Tet. Lett. 2733 (1971). 102. H. Wada, Y. Shizuri, K. Sugiura, K. Yamada, and Y. Hirata, Tet. Lett. 3131 (1971). 103. K. Zechmeister, F. Brandl, W. Hoppe, E. Hecker, H. F. Opferkuch, and W. Adolf, Tet. Lett. 4075 (1970). 104. D. Uemura and Y. Hirata, Tet. Lett. 3673 (1971). 105. J. M. Calderwood, N. Finkelstein, and F. Fish, Phytochemistry 9, 675 (1970); C A 73, 5 3 0 1 2 ~(1970). 106. F. Fish and P. G. Waterman, J . Pharm. Pharmacol. 23, 67 (1971); CA 74, 72790h (1971). 107. F. G. Torto, P. Sefcovic, B. A. Dadson, and I. A. Mensah, G h a n a J . Sci.9, 3 (1969); C A 72, 87149p (1970). 108. F. G. Torto and I. A. Mensah, Phytochemistry 9, 911 (1970); C A 73, 32332h (1970). 109. Z. F. Amed, A. M. Rizk, F. M. Hammouda, and M. M. Abdel-Gawad, J . Pharm. Sci. U.A.R. 10, 115 (1969); C A 74, 103378 (1971). 110. T. R. Chamberlain and M. F. Grundon, J . Chem. Soc., C 910 (1971). 111. J. W. Huffman and T. M. Hsu, Tet. Lett. 141 (1972). 112. I. A. Isailov, M. S. Yunusov, and S. Y. Yunusov, I n s t . Khim. Rast. Veshch., Tashkent 189, 1262 (1969); C A 73, 25715g (1970). 113. D. M. Tsakadze, A. Abdusamatov, R. Razakov, and S. Y. Yunusov, K h i m . P r i r . Soedin. 6, 773 (1970); CA 74, 100246f (1971). 114. G. Faugeras and M. Paris, Plant. M e d . Phytother. 3, 175 (1969); C A 72, 75688a (1970). 115. G. Faugeras and R. R. Paris, C. R. Acad. Sci., Ser. D 270, 203 (1970); C A 72, 1 0 7 8 0 0 ~(1970). 116. F. Rulko and K. Nadler, Diss. Pharm. Pharmacol. 22, 329 (1970); C A 74, 83989F (1971).
568
R. H. F. MANSKE
117. N. S. Narasimhan, M. V. Paradkov, and A. Gokhale, Tet. Lett. 1665 (1970). 118. K. G. Kiryakov and P. Panov, Farmatsiya (Moscow)20, 45 (1970); C A 74, 83991a (1971). 119. L. D. Yakhontova, Tr. Vses. Nauch.-Issled. Inst. Lek. Aromat. R a t . 15, 348 (1969); C A 75, 20721n (1971). 120. L. D. Yakhontova, Lek. Rust. 15, 348 (1969); C A 75, 16171r (1971). 121. I. Ribas, J. Sueiras, and L. Castedo, Tet. Lett. 3093 (1971). 122. L. E. Fellows and E. A. Bell, Phytochemistry 9, 2389 (1970). 123. T. Onaka, Tet. Lett. 4393 (1971). 124. C. A. Mammarella and J. Comin, An. Asoc. Quim. Argent. 59, 239 (1971); C A 76, 43980f (1972). 125. C. Carling and F. Sandberg, Acta Pharm. Suecica 7, 285 (1970); C A 73, 63154f (1970). 126. S. M. Sharafutdinova and S. Y. Yunusov, Khim. Prir. Soedin. 5,394 (1969); C A 72, 67 152f (1970). 127. Z. S. Faizutdinova, I. A. Bessanova, Y. V. Rashkes, and S. Y. Yunusov, Khim. Prir. Soedin. 6, 239 (1970); C A 73, 1 3 1 1 7 9 ~(1970). 128. Z. S. Faizutdinova, I. A. Bessanova, and S. Y. Yunusov, K h i m . Prir. Soedin. 5 , 455 (1969); C A 72, 7926733 (1970). 129. M. Ionescu and I. Mester, Phytochemistry 9, 1137 (1970); CA 73, 42388v (1970). (1971). 130. F. N. Lahey and K. F. Mak, Aust. J . Chem. 24, 671 (1971); CA 74, 1 1 2 2 6 0 ~ 131. K. Ito and H. Furakawa, Tet. Lett. 3023 (1970). 132. M. N. S. Nayar, C. V. Sutar, and M. K. Bhan, Phytochemistry 10,2843 (1971); CA 7 6 , 11968s (1972). 133. A. E. Wick, P. A. Bartlett, and D. Dolphin, Helv. Chim. Acta 54, 573 (1971). 134. L. Bergmann, W. Grasse, and H. G. Ruppel, Planta 94, 47 (1970); C A 74, 2040th (1971). 135. S. Brandange, I. Granelli, and B. Liining, Acta Chem. Scand. 24, 354 (1970); C A 72, 1 1 1 6 6 2 ~(1970). 136. I. V. Man’ko and P. N. Vasil’kov, T r . Leningrad. Khim.-Farm. Inst. 26, 166 (1968); C A 73, 73849a (1970). 137. S. K. Talapatra, B. C. Maiti, B. Talapatra, and B. C. Das, Tet. Lett. 4789 (1969). 138. T. R. Chamberlain, J. F. Collins, and M. F. Grundon, Chem. Commun. 1269 (1969). 139. S. K. Talapatra, B. C. Maiti, and B. Talapatra, Tet. Lett. 2683 (1970). 140. D. Kamalitdinov, S. Iskandarov, and S. Y. Yunusov, K h i m . Prir. Soedin. 5 , 409 (1969); C A 72, 75653k (1970). 141. N. M. Molov and I. C. Ivanov, Tetrahedroa 26, 3805 (1970); P. P. Panov, N. M. Mollov, and L. N. Panova, Dokl. Bolg. Akad. Nauk 24,675 (1971); C A 75, 1484652 (1971). 142. E. G. Tkeshelashvili, S. Iskandarov, K. S. Mudzhiri, and S. Y. Yunusov, Khim. Prir. Soedin. 7,539 (1971); C A 75, 1 3 7 5 3 6 ~(1971). 143. A. Klasek, P. Sedmera, and F. Santavf, Collect. Czech. Chem. Commun. 36, 2205 (1971); CA 75, 126592m (1971). 144. E. Steinegger andE. Schlunegger, Pharm. Acta Helv. 45,369 (1970); CA 7 3 , 6 2 3 0 3 ~ (1970). 145. B. Lindstrom and B. Liining, Acta Chem. Scand. 25, 895 (1971); CA 75, 852402 (1971). 146. K. Nisikawa, M. Miyamura, and Y. Hirata, Tetrahedron 25, 2723 (1969). 147. T. Kametani, Y. Satoh, K. Fukumoto, and B. R. Pai, I n d i a n J. Chem. 9, 770 (1971); CA 75, 1374802 (1971).
12.
UNCLASSIFIED ALKALOIDS
569
148. E. B. L. Borio, Trib. Farm. 36, 25 (1968); C A 75, 1351a (1971). 149. J. A. D. Jeffreys, J . Chem. SOC.,C 1091 (1970). 150. C. Poupat, B. Rodriguez, H. Husson, P. Potier, and M. M. Janot, C. R. Acad. Sci., Ser. C 269, 33-35 (1969); C A 71, 91732v (1969). 151. I. Ribas-Marques and M. Rugueiro-Garcia, An. Quim. 67,93 (1971); C A 75, 31280u (1971). 152. C. A. Mammarella and J. Comin, An. Asoc. Quim.Argent. 59, 239 (1971); C A 76, 43980f (1972). 153. E. Fujita, K. Bassho, Y. Saeki, M. Ochiai, and K. Fuji, Lloydia 34, 306 (1971); C A 75, 148531t (1971). 154. E. Fujita, K. Fuji, and K. Tanaka, J. Chem. SOC.,C 205 (1971). 155. E. Fujita and K. Fuji, J. Chem. SOC.,C 1651 (1971). 156. E. Fujita and Y . Saeki, J. Chem. SOC.,D 368 (1971). 157. N. K. Hart, S. R. Johns, and J. A. Lamberton, Awt. J . Chem. 24, 223 (1971); CA 74, 50496q (1971). 158. R. R. Arndt, S. H. Eggers, and A. Jordaan, Tetrahedron 25, 2767 (1969). 159. T.-H. Yang and S.-C. Liu, T a i - W a n K'o Hsueh 24, 94 (1970); C A 75, 31299g (1971). 160. L. P. Maidovich, D. A. Fesenko, and B. K. Rostotskii, Khim. Prir. Soedin. 6, 775 (1970); C A 74, 954188 (1971). 161. B. K. Zharkeev: M. V. Telezhenetskaya, and S. Y. Yunusov, Khim. Prir.Soedin. 7, 538 (1971); CA 75, 126561a (1971). 162. B. Lindstrom, B. Liining, and K. Siirala-Hansen, Acta Chem. Scand. 25, 1900 (1971); CA 75, 1 3 7 4 6 5 ~(1971). 163. S. M. Kupchan, R. M. Smith, and R. F. Bryan, J. Amer. Chem. SOC.92, 6667 (1970). 164. T.-H. Yang, S.-T. Lu, S.-J. Wang, T.-W. Wang, J.-H. Lin, and 1.3. Cheng, Yakugaku Zasshi 91, 782 (1971); C A 75, 95382m (1971). 165. H. Mehri, M. Plat, and P. Potier, Ann. Pharm. Fr. 29, 291 (1971); C A 75, 115892h (1971). 166. I. R. C. Bick and N. W. Preston, Aust. J. Chem. 24, 2187 (1971); C A 75, 1 2 6 6 1 7 ~ (1971). 167. Y. Okamoto, S. Tanaka, K. Kitayama, M. Isomoto, M. Masaishi, H. Yanagawa, and J. Kunitomo, Yakugaku Zasshi 91, 684 (1971); C A 75. 72505q (1971). 168. B. Chommadov, M. K. Yusupov, and A. S. Sadykov, Khim. Prir. Soedin. 5, 457 (1969); C A 72, 75671q (1970). 169. A. A. Trotzyan, M. K. Yusupov, and S. Sadykov, Khim. Prir. Soedin. 7,541 (1971); C A 76, 1819e (1972). 170. P. W. Jeffs, W. C. Archie, R. L. Hawks, and D. S. Farrier, J . Amer. Chem. SOC.93, 3752 (1971). 171. S. Yamada and G. Otani, Pet. Lest. 1133 (1971). 172. E. A. Bell, J. R. Nulu, and C. Cone, Phytochemistry 10,2191 (1971);C A 75,13755413 (1971). 173. S. P. Kureel, R . S. Kapil, and S. Popli, Chem. Ind. (London) 958 (1970); C A 73, 77449t (1970). 174. B. S. Joshi, V. N. Kamat, and D. H. Gawad, Tetrahedron 26, 1475 (1970). 175. N. S. Narasimhan, M. V. Paradkov, and A. Gokhale, Pet. Lett. 1665 (1970). 176. E. E. Schweizer, E. Shaffer, C. Hughes, and C. Berninger, J. Org. Chem. 31, 2907 (1966). 177. W. M. Bandaranayake, L. Crombie, and D. A. Whiting, Chem. Commun. 58 (1969).
570
R. H. F. MANSKE
178. G. Ferrari, 0. Fervidi, and M. Ferrari, Phytochemistry 10, 465 (1971); C A 75, 1347d (1971). 179. T.-H. Yang and C.-M. Ching, J . Chin. Chem. SOC.( T a i p e i ) 17, 235 (1970); C A 74, 1002548 (1971). 180. J. Kunitomo, Y. Nagai, Y. Okamoto, and H. Furukawa, Yakugaku Zasshi 90, 1165 (1970); C A 74, l l l O a (1971). 181. W. Doepke and W. Fritsch, Pharrnazie 25, 69 (1970); C A 73, 42377r (1970). 182. C. F. Wong and R. T. Lalonde, Phytochemistry 9, 1851 (1970); C A 73, 10993711 (1970). 183. R. T. Lalonde, C. F. Wong, and W. P. Cullen, Tet. Lett. 4477 (1970). 184. R. H. F. Manske and Q . A. Ahmed, Can. J . Chem. 48, 1280 (1970). 185. T. Kametani, S. Hibino, and S.Takano, J . Chem. Soc., D 925 (1971). 186. C. Kan-Pan, B. Das, P. Potier, and M. Schmid, Phgtochemistry 9, 1351 (1970). 187. H. J. Veith, M. Hesse, and H. Schmid, Helv. Chim.Acta 53, 1355 (1970). 188. Ha-Huy-Ke, M. Luckner, and J. Reisch, Phytochemistry 9, 2199 (1970); C A 74, 2037013 (1971). 189. S. J. Price and A. R. Pinder, J . Org. Chem. 35, 2568 (1970). 190. S. R. Johns, J. A. Lamberton, J. W. Loder, and A. A. Sioumis, Aust. J . Chem. 23, 1919 (1970); C A 73, 117131s (1970). 191. E. Brochmann-Hanssen, C.-C. Fu, and G. Zanati, J . Pharm. Sci. 60, 873 (1971); C A 75, 59887w (1971). 192. E. Brochmann-Haussen, A. Y. Leung, K. Hirai, and G. Zanati, Planta Med. 18, 366 (1970); C A 73, 10633311 (1970). 193. I. V. Man’ko and L. G . Marchenko, Khim. Prir. Soedin. 7, 537 (1971); C A 75, 126598t (1971). 194. J. L. Pousset, A. Bouquet, A. Cave, and R. R. Paris, C. R. Acad. Sci., Ser. C 272, 665 (1971); C A 74, 112281b (1971). 195. A. Abdusamatov, S. Khakimdzhanov, and S. Y. Yunusov, Khim. Prir. Soedin. 5, 457 (1969); C A 72, 67156k (1970). 196. K. N. Khashimov, M. V. Telezhenetskaya, and S. Y. Yunusov, Khim. Prir. Soedin 5, 599 (1969); C A 73, 322962 (1970). 197. K. N. Khashimov, M. V. Telezhenetskaya, and S.Y. Yunusov, Khim.Prir. Soedin 5, 456 (1969); C A 72, 7 5 6 7 0 ~(1970). 198. K. N. Khashimov, M. V. Telezhenetskaya, Y. V. Rashkes, and 8. Y. Yunusov, Khim. Prir. Soedin. 6, 453 (1970); C A 74, 10342c (1971). 199. S. Yamatodani, Y. Asahi, A. Matsukura, S. Ohmomo, and M. Abe, Agr. Biol. Chem. 34, 485 (1970); C A 72, 1 2 1 7 5 6 ~ (1970). 200. A. Hollerbach and G. Spiteller, Monatsh. Chem. 101, 141 (1970); C A 72, 100940m (1970). 201. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J . Chem. 24, 2399 (1971); C A 75, 1 4 1 0 2 4 ~ (1971). 202. N. Bourguignon-Zylberand J. Polonsky, Chim.Ther. 5, 396 (1970); C A 75, 31236; (1971).
203. G. M. Sharma and P. It. Burkholder, J . Chem. Soc., D 151 (1971); C A 74, 125893~ (1971). 204. S. Brandange, B. Liining, C. Moberg, and E. Sjostrand, Acta Chem. Scand. 25, 349 (1971); C A 74, 125886~(1971). 205. F. L. Frahn and D. F. O’Keefe, Aust. J . Chem. 24, 2189 (1971); C A 75, 126591k (1971). 206. N. Langlois, B. C. Das, P. Potier, and L. Lacombe, Bull. SOC.Chim. Pr. [51 3535 (1970); C A 74, 83986c (1971).
12.
UNCLASSIFIED ALKALOIDS
57 1
207. N. M. Hoang, N. Langlois, B. C. Das, and P. Potier, C . R. Acad. Sci., Ser. C 270, 2154 (1970); C A 73, 77450m (1970). 208. F. X. Albuquerque. J. W. Doly, and B. Witkop, Science 172, 995 (1971). 209. J. Singh, K. L. Dhar, and C. K. Atal, Tet. Lett. 2119 (1971). 210. K. E. Murray, J. Shipton, and F. B. Whitfield: Chem. I n d . (London) 897 (1970). 210a. W. A. Denne, S. R. Johns, J. A. Lamberton, and A. McL. Mathieson, Tet. Lett. 3107 (1971). 211. N. K. Hart, S. R. Johns, and J. A. Lamberton, Aust. J. Chem. 20, 561 (1967). 212. E. Schlunegger and E. Steinegger, Pharm. Acta Helv. 45, 147 (1970); CA 72, 97300v (1970). 212a. H. Irie, H. Hirada, K. Ohno, T. Mizutani, and S. Uyeo, J. Chem. Soc., D 268 (1970). 213. S. R. Johns, J. A. Lamberton, C. S. Li, and A. A. Sioumis, Aust. J. Chem. 23, 423 (1970); C A 72, 118432g (1970). 214. I. NovAk, K. Szendrei, V. Papay, E. Minker, and M. Koltai, Herba Hung. 9, 23 (1970); C A 75, 77090k (1971). 215. J. Reisch, K. Szendrei, V. Papay, I. NovAk, and E. Minker, Tet. Lett. 3365 (1970). 216. L. A. Mitscher, M. S. Bathala, and J. L. Bea1,J. Chem.Soc., D 1040 (1971). 216a. R. A. Corral, 0. 0. Orazi, and M. F. de Petruccelli, Ezperientia 25, 1020 (1969). 217. R. A. Corral, 0. 0. Orazi, and M. F. de Petruccelli, Chem. Commun. 556 (1970). 217a. J. Reisch, K. Szendrei, E. Minker, and I. NovAk, Pharmazie 24, 699 (1969); C A 72, 87162n (1970). 218. R. R. Arndt and P. E. J. Kruger, Tet. Lett. 3237 (1970). 219. A. Popelak, E. Haack, G. Lettenbauer, and H. Springer, Naturwiss. 47, 156 (1960); C A 54, 19742 (1960). 220. P. W. Jeffs, P. A. Luhan, A. T. McPhail, and N. H. Martin, J . Chem. Soc., D 1466 (1971). 221. P. E. J. Kruger and R. R. Arndt, J. S.Afr. Chem. In&. 24, 235 (1971); C A 75, 151942h (1971). 222. P. W. Jeffs, G. Ahmann, H. F. Campbell, D. S. Farrier, G. Ganguili, and R. L. Hawks, J. Org. Chem. 35, 3512 (1970). 223. F. 0. Snyckers, F. Strelow, and A. Wiechers, J. Chem. Soc., D 1417 (1971). 224. B. A. Samoryadov and S. A. Minina, Khim. Prir. Soedin. 7, 209 (1971); C A 75, 31332n (1971). 224a. I. Barene and S. A. Minina, Khim. Prir. Soedin. 7, 379 (1971); CA 75, 115920r (1971). 225. R. Tschesche, E. Ammermann, and H. W. Fehlhaber, Tet. Lett. 4405 (1971). 226. H. H. Appel and P. Streeter, Rev. Latinoamer. Quim. 1, 63 (1970); C A 74, 72815v (1971); Scientia (Valparaiso) 36, 105 (1970). 227. W. A. Ayer and L. M. Browne, Can. J . Chem. 48, 1980 (1970). 228. R. Gmelin and A. Kjaer, Phytochemistry 9, 667 (1970); C A 73, 22144j (1970). 229. B. Weinstein and A. R. Craig, Phytochemistry 10, 2556 (1971); CA 75, 148546b (1971). 230. V. M. Bakshi and Y. K. Harnied, I n d i a n J. Pharm. 33, 54 (1971); C A 75, 148490d (1971). 231. J. G. MacConnell, M. S. Blum, and H. M. Fales, Tetrahedron 27, 1129 (1971). 232. I. Primukhamedov, K. A. Aslanov, and A. S. Sadykov, Nauch. Tr., Tashkent. Gos. Univ. 341, 128 (1968); C A 72, 79280j (1970). 232a. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Aust. J. Chem. 23, 213 (1970). 233. V. V. Kiselev, Zh. Obshch. Khirn. 26, 3218 (1956). 234. R. Ramage, Tetrahedron 27, 1499 (1971). 235. A. Heesing and R. Eckard, Ber. 103, 534 (1970).
572
R. H. F. MANSKE
236. V. D. Gorbunov, A. I. Ban’kovskii, M. E. Perel’son, and 0. S. Chizhov, Khim. Prir. Soedin. 5 , 454 (1969); C A 72, 67159p (1970). 237. H. Irie, N. Masaki, K. Ohno, K. Osaki, T. Taga, and S. Uyeo, Chem. Commun. 1066 (1970). 238. A. Villar de Fresno, E. M. Delle Monache, C . Galeffi, M. A. Ciasca Rendina, and G. B. Marini Bettolo, Atti Accad. Naz. Lincei, Cl. Sci. Pis.,Mat. Natur., Rend. 48, 250 (1970); C A 73, 1 0 9 9 4 8 ~(1970). 239. R. Verpoorte and F. Sandberg, Acta Pharm. Suecica 8, 119 (1971); C A 75, 72494k (1971). 240. N. G. Bisset and J. D. Phillipson, Lloydia 34, 1 (1971); C A 7 5 , 72512q (1971). 241. I. V. Man’ko and B. K. Kotovskii, J . Gen. Chem. USSR 40, 2506 (1970); C A 75, 1243s (1971). 242. I. V. Man’ko, M. P. Korotkova, and N. M. Shevtsova, Rust. Resur. 5, 508 (1969); C A 72, 8717511 (1970). 243. J. R. Boissier, G. Combes, A. H. Effler, K. Klinga, and E. Schlittler, Eqerientia 27, 677 (1971); CA 75, 72510n (1971). 244. J. Harley-Mason and C. G . Taylor, Chem. Commun. 281 (1969). 245. G. W. Gribble, J . Org. Chem. 35, 1944 (1970). 246. M. Shamma and J. L. Moniot, J . Chem. SOC.,D 1065 (1971). 247. M. Shamma and B. S. Dndock, Tet. Lett. 3825 (1965). 248. M. Shamma and M. A. Podczasy, Tetrahedron 27, 727 (1971). 249. K. S. Umarov, Z. F. Ismailov, and S. Y. Yunusov, Khim. Prir. Soedin. 6, 444 (1970); C A 74, 1042e (1971). 250. V. G. Khodzhaev and K. Allayarov, Khim. Prir. Soedin. 6, 496 (1970); C A 74, l060j (1971). 251. K. S. Umarov, M. V. Telezhenetskaya, Z. F. Ismailov, and S. Y. Yunusov, Khim. Prir.Soedin. 6, 224 (1970); C A 73, 63193t (1970). 252. R. A. Shaimardanov, S. Iskandarov, and S. Y. Yunusov, Khim. Prir. Soedin. 7 , 169 (1971); CA 75, 31253n (1971). 253. V. I. Vinogradova, S. Iskandarov, and S. Y. Yunusov, Khim. Prir. Soedin. 7 , 463 (1971); C A 76, 3222111 (1972). 254. K. Orazgel’diev, K. A. Aslanov, A. S. Sadykov, and D. A. Abdullaeva, Tr. Sarnarkand Univ. 167, 154 (1969); C A 7 5 , 16085r (1971). 255. T. T. Shakirov and K. A. Sabirov, Khim. Prir. Soedin. 6, 723 (1970); C A 74, 84006v (1970). 256. W. J. Keller and F. R. Cole, Lloydia 32, 498 (1969); C A 72, 129409f (1970). 257. E. Balcar-Skrzydlewska and B. Borkowski, Herba Pol. 15, 227 (1969); CA 73, 42359m (1970). 258. A. K. Barua, P. Chakrabarti, and A. S. Gupta, J . Indian Chem. SOC.47,920 (1970); C A 74, 954464 (1971). 259. S. R. Johns and J. A. Lamberton, Aust. J . Chem. 23, 211 (1970). 260. S. N. Ganguly, Phytochemistry 9, 1667 (1970); CA 73, 77440h (1970). 261. N. B. Mulchandani, S. S. Iyer, and L. P. Badheka, Chem. Ind. (London)p. 505 (1971); C A 7 5 , 36418e (1971). 262. J. Borges del Castillo, J. L. Bretbn, A. G. GonzBles, and J. Trujillo, Tet. Lett. 1219 ( 1970). 263. C. C. J. Culvenor, J. A. Edgar, L. W. Smith, and H. J. Tweedale, Tet. Lett. 3599 (1969). 264. A. Bouquet, A. Cave, and R. R . Paris, C . R. Acad. Sci.,Ser. C 271, 1100 (1970);C A 74, 2304311 (1971).
12. UNCLASSIFIED ALKALOIDS
573
265. B. Lindstrom and B. Liining, Acta Chem. Scand. 23, 3352 (1969); C A 72, 90687t (1970). 266. S. Brandange and B. Luning, Acta Chem. Scand. 24, 353 (1970); C A 72, 118430e (1970). 267. C. Kan-Fan, B. C . Das, P. Boiteau, and P. Potier, Phytockemistry 9, 1283 (1970); C A 73, 95426n (1970). 268. P. Ninova, A. Abdusamatov, and S. Y . Yunusov, Khim. Prir. Soedin. 7, 540 (1971); C A 76, 1812x (1972).
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AUTHOR INDEX Numbers in parentheses are reference numbers and indicate t h a t a n author’s work is referred t o although his name is not cited in the text. Numbers in italics show the page on which the complete reference is listed.
A Abdel-Gawad, M. M., 530(109), 567 Abdullaeva, D. A., 561(254), 572 Abdurakhimova, N., 93(35), 94(47), 109 (47), 117(61), 119(47), 120, 121, 144(59), 156 Abdusamatov, A., 532(113), 548(195), 564(268), 567, 570, 573 Abe, M., 549(199), 570 Abu El-Haj, M. J., 9, 79 Abushanab, E., 68(107, 108), 71(107, 108), 82 Adhya, R. N., 426(8), 502 Adolf, W., 530(103), 567 Adam, G., 20(65, 66), 21(66), 24(70, 71, 72), 27(72, 74), 28(75, 76), 68(110, l l l ) , 80, 81, 82 Agui, H., 323 Ahmad, Y., 158(10, l l ) , 159(10, I l ) , 178 Ahmann, G., 555(222), 571 Ahmed, Q. A., 546(184), 570 Akatsu, M., 350(6), 352(6), 353(6), 357(19), 365(33, 34), 372(6), 403, 404 Akramov, S. T., 227(11), 228(11), 263 Alabran, D. M., 16(51), 80 Alam, M. Z., 93(29), 120, 127(25, 26, 27, 28, 29, 30), 255 Albuquerque, F. X., 551(208), 571 Aleshkina, Ya. A,, 499(75), 500(75, 76), 505 Alibekova, Sh., 502(100), 506 Aliev, A. M., 158(8a), 159(8a), 178 Allayarov, K., 560(250), 572 Alonso, M., 3(9), 68(9), 7 9 Altenkirk, B., 350(2, 9, lo), 351(2, 9, lo), 352(2), 353(2), 354(2), 355(2), 358(20), 359(2), 360(9, lo), 362(9, lo), 363(10), 369(10, 41, 42), 403, 404
Alves, A. C., 168(32), 179 Amed, Z. F., 530(109), 567 Ammermann, E., 556(225), 571 An Cu, N., 123(13a), 124(13a), 130(13a) 133(13a), 154 Anjaneyulu, B., 426(7), 502 Aoki, M., 500(84), 501(84), 505 Appel, H. H., 556(226), 571 Archie, W. C . , 543(170), 569 Arndt, R. R., 93(31), 120, 158(18), 159 (IS), 178, 540(158), 554(218, 221), 569, 571 Arya, V. P., 427(15), 428(15), 503 Asada, S., 228(20), 263 Asahi, Y., 549(199), 570 Aslanov, K. A., 552(232), 571 Aslanov, K. H., 561(254), 572 Atal, C. K., 522(72), 551(209), 566, 571 Audier, H.-E., 428(36), 447(36), 448(36), 450(36), 451(36), 452(36), 454(36), 459(36), 463(36), 481(36), 503 Augustine, R. B., 192(18), 205(18), 217, 223 Ayer, W. A., 350(2, 5, 8, 9, lo), 351(2, 5, 9, 10, 13), 352 (2), 353(2, 5), 354(2), 358(20), 359(2, 22), 360(5, 9, 10, 23), 362(5, 9, 10, 24), 363(5, lo), 364(13), 369(10,41,42), 370(8),372(44, 45,46), 375(45), 376(46), 390, 394(8), 396(8), 403, 404, 405, 556(227), 571 Azuma, K., 523(75), 566
B Babaev, N. A., 158(8a), 159/8a), 178 Baczynskyj, L., 408(3), 410(3, 4), 411 (3, 4), 412(4), 418(12), 421(4), 422 (4, 12), 423
576
AUTHOR INDEX
Badger, G. M., 268(6), 270(6), 278(6), 281(6), 321 Badheka, L. P., 562(261), 572 Baig, M. I., 158(10), 159(10), 178 Baisheva, Kh. Sh., 520(63,64), 521(67,68), 566 Bakshi, V. M., 557(230), 571 Balcar-Skrzydlewska, E., 561(257), 572 Bandaranayake, W. M., 544(177), 569 Banerjee, P. K., 168(41), 179 Banerjee, S. K., 277(12), 228(12), 263 Ban’kovskii, A. I., 427(12), 428(10, 11, 12), 502, 503, 558(236), 572 Barclay, L. R. C., 355(18), 403 Barene, I., 555(224a), 571 Bartlett, P. A., 536(133), 568 Barton, D. H. R., 68(112, 113), 82, 289 (36, 37), 294, 321, 322 Barua, A. K., 562(258), 572 Bassho, K., 539(153), 569 Bathala, M. S . , 553(216), 571 Batterham, T. J., 410(5), 423 Battersby, A. R., 157, 178, 211(34, 35, 36, 38, 39, 40), 213(34, 36, 40, 42), 216 (36, 40), 217(42), 223, 267(8), 268 (18, 13), 269(2a), 270(20), 271(20), 277(2a, 4), 278(5, 8), 279(12, 13), 281 (20), 288(12, 13, 28, 29, 30), 289(32), 290(2a),292,293(20), 296(13), 310,314 (13), 319(70), 320,321,323,508(4),564 Bauer, s., 10(39), 80 BauerovA, O., 32(86a), 33(86a), 36(86a), 68(86a), 81 Baytop, T., 520(58), 565 B e d , J. L., 32(103), 33(103), 66(103), 81, 227(10), 228(10), 263, 519(52), 553 (216), 565, 571 Beckett, A. H., 92(19, 20), 93(26, 27), 94 (26, 27, 49, 52), 98(27), 103(27), 104, 105(27, 52), 106(27), 107(27, 49), 108 (26, 27, 49), 109(19), 119(19, 65), 120, 121, 123(10, 13, 18, 19), 124(10, 13), 125(10, 18, 19), 125(18, 19), 127(13, 33, 34, 35, 36), 130(13), 131(13, 36, 40), 132(13), 133(13, 34, 41), 134(36, 45), 135(45), 138(19, 51), 145(19, 51), 154, 155, 156 Bedwell, D. R., 93(36), 121 Beecham, A. F., 109(56), 113(56), 114(56), 121, 136(48, 49), 137(48, 49), 138 (48, 49), 140(48), 142(48), 155
Behrendt, L., 512(17), 564 Beisler, J. A., 146(63), 148(63), 156, 170 (45), 179 Beliveau, J., 566 Bell, E. A., 533(122), 544(172), 568, 569 Bell, K. H., 410(5), 423 BBnBchie, M., 73(118), 78(125), 82 Bereznegovskaya, L. N., 502(101), 506 Bergmann, L., 536(134), 568 Berigari, M. S., 517(45), 565 Berninger, C., 544(176), 569 Bessanova, I. A., 534(127), 535(128), 568 Betts, E. E., 383(53), 404 Bevan, C. W. L., 427(17), 428(17, 39), 452(39), 503, 504 Bhakuni, D. S., 321, 522(73), 566 Bhan, M. K., 535(132), 568 Bhattacharyya, J., 93(43), 109(43), 118 (43), 121, 136(48b), 138(48b), 155 Bick, I. R. C., 226(2), 228(2, 26, 27), 230 (27), 231(30), 233(30, 31), 236(2, 40), 237(40), 238(30), 253(31), 255(26, 30, 40), 257(30, 31), 258(26, 30, 31, 40), 261(30, 31), 262, 263, 278(5), 321, 327(2), 346, 513(24), 543(166), 564, 569 Bindra, J. S., 87(12), 104(12), 120 Binns, W., 10(36), 20(36), 80 Biringi, N. V., 92(17), 95(17), 111(17), 120 Bishay, D. W., 529(98), 567 Bisset, N. G., 39(88), 81, 559(240), 572 Blaschke, G., 321 Blum, M. S . , 557(231), 571 Boaz, H., 171(47), 179 Bobbitt, M., 211(32), 223 Bobokhodzhaev, I. Ya., 500, 505 Bodmer, F., 174(49), 179 Bohler, P., 289(32), 321 Bohlmann, F., 354, 359, 403 Bohme, E. H. W., 381(48), 404 Bohrmann, H., 182(5), 222 Boissier, J. R., 559(243), 272, 344(17), 346 Boiteau, P., 136(48a), 138(48a), 155, 168(37), 179, 563(267), 573 Bojthe, G., 427(20), 503 Bonati, A., 168(29), 179 Bondarenko, N. V., 19(60, 61), 32(60), 80 Borchardt, R. T., 251(53), 252(53), 257 (53), 264 Borges del Castillo, J., 562(262), 572 Borio, E. B. L., 538(148), 569
577
AUTHOR INDEX Borkowski, B., 427(19), 428(19), 503, 561(257), 572 Borys, I. V., 500(85), 501(85), 505 Bouquet, A., 547(194), 563(264), 570, 572 Bourguignon-Zylber, N., 549(202), 570 Bourrinet, P., 500(82), 505 Bowie, J. H., 233(31), 253(31), 257(31), 261(31), 263 Bowman, W. R., 390(60, 62), 404, 405 Bozhkova, I. Z., 518(47), 564 Bradbury, R. B., 267(8), 268(6, 8), 270 (6, 20), 271(20), 278(6, 8), 281(6, 20), 293(20), 321 Braekman, J. C., 158(15), 159(15), 178, 350(5, 12), 351(5, 12), 352(12, 14), 353(5), 360(5), 362(5), 363(5), 372(14), 378(14), 400(73), 401(73), 403, 405 Braekman-Danheux, C., 352(14), 372(14), 378(14), 403 Brandange, S., 536(135), 549(204), 568,570 Brandl, F., 530(103), 567 BrBzdov.4, V., 30(77), 78(128), 81, 82 Bremner, J. B., 327(2), 346, 513(24), 564 Brener, Z., 220(51), 222(51), 223 Bretbn, J. L., 562(262), 572 Bringi, N. V., 217, 223 Britten, A. Z., 158(7), 160(7), 163(7), 178 Brochmann-Hanssen, E., 547(191, 192), 570 Brockson, T. J., 321 Brossi, A., 220(51), 222(51), 223, 279(14, 15), 282(21), 293, 311(66), 321, 323 Brown, K. S., Jr., 1, 66(106a), 76, 79, 82 Brown, R. T., 211(34), 213(34), 223 Brown, S. H., 158(18), 159(18), 178 Browne, L. M., 556(227), 571 Bruneton, J., 158(20a), 159(20a), 167 (20a), 168(20a), 178 Bryan, R. F., 542(163),569 Buohanan,M.A.,227(6),235(6),255(6),262 Buchschacher, P., 419(14), 423 Budzikiewioz, H., 17(54), 80, 93(42), 121, 144(57), 156, 524(77), 566 Burckhardt, U., 7(23), 13(47), 79, 80 Burkhardt, F., 279(14), 321 Burkholder, P. R., 549(203), 570 Burnell, R. H., 350(2), 351(2), 352(2), 353(2), 354(2), 355(2), 359(2), 368(37, 38), 369(37, 38, 40, 41), 372(44), 403, 404
Burnett, A.R., 211(38,39), 223,508(4), 564 Burtner, R. R., 319(23), 323 Butruille, D., 525(79), 566 Bur-Hoi, N. P., 414(8), 423 Buzas, A., 182(2, 3), 222 By, A. W., 1, lO(33, 42), 11(42), 68(108), 71(108), 79, 80, 82
C Cable, J., lO(41, 42), ll(41, 42), 16(41, 50), 80 Calame, J. P., 3(12), 79 Calder, I. C., 513(24), 564 Calderwood, J. M., 530(105), 567 Calvo, C., 355(17), 403 Cameron, A. F., 319(70), 323 Camp, B. J., 517(42), 565 Campbell, H. F., 555(222), 571 Cannon, J. R., 518(48), 565 Carling, C., 534(125), 568 Carrazzoni, E. P., 158(18), 159(18), 178 Carrick, J., 126(24), 155 Carson, D. R., 355(18), 403 Casagrande, C., 233(35), 235(35), 263 Castedo, L., 247(51), 248(51), 249(51), 250(51), 256(51), 259(51), 264, 533 (121), 568 Castillo, M., 394(65), 396(65, 66), 398(65, 66), 399(71, 72), 405 Cava, M. P., 227(10, 17), 228(10), 230 (27a), 236(40a), 238(40a, 41, 41a), 239(41, 41a), 240(41, 42a), 241(43), 242(41), 243(27a), 244(27a, 48), 245 (27a); 252(27a), 253(27a), 256(41, 43, 48, 54), 257(27a, 41), 258(41, 43, 48), 262(54), 263, 264 CavB, A., 32(79), 33(79), 40(79), 42(79), 53(79), 81, 158(20a), 159(20a), 167(20a), 168(20a), 178, 547(194), 563(264), 570, 572 Cave, H., 520(60), 565 Cernf, v., 1, 2(2), 79 Chakrabarti, J. K., 86(9), 120 Chakrabarti, P., 562(258), 572 Chakraborti, A., 527(92), 567 Chakravarti, D., 168(31), 179 Chakravarti, N. N., 426(8), 502 Chakravarti, R. N., 168(31), 179, 227(12), 228(12), 263
578
AUTHOR INDEX
Chamberlain, T. R., 531(110), 536(138), 567, 568 Chan, K. C., 84(7), 93(30), 109(7, 30), 114 (58), 118(30), 120, 123(20, 22), 124 (22), 125(20), 126(22, 24), 144(20), 145(20), 155, 168(29c), 179 Chang, C.-J., 84(10), 86(10, 13), 87(12, 13), 88(10), 90(10), 91(10), 104(12), 120 Chanley, J. D., 190(15), 222 Chapman, G. M., 321 Charubala, R., 310(64), 322 Chatterjee, A., 168(36, 41, 42), 170(36), 176(42), 178, 179, 226(3), 227(3), 228(3), 262, 427(15), 428(15, 37, 38), 452(37, 38), 453, 457(37), 489(37), 502(37), 503, 508(3), 564 Chaudhuri, R. K., 513(25), 564 Chen, C.-M., 511(13), 564 Chen, S.-F., 427(18), 503 Ch'en Ch'an-pai, 207(24, 25), 223 Cheng, I.-S., 542(164), 569 Chervenkova, V. B., 518(4), 565 Cheung, H. T., 126(24), 155 Chin, C. G., 368(38), 369(38), 404 Ching, C.-M., 544(179), 570 Chin-You, N., 355(17), 403 Chizhov, 0. S., 558(236), 572 Chommadov, B., 543(168), 569 Chow, Y. L., 499(74), 505 Chu, J. H., 32(78), 81 Ciasca Rendina, M. A., 558(238), 572 Clark, G. R., 408(3), 410(3), 411(3), 419 (13), 423 Clauder, O., 427(20), 503 Clements, J. H., 288(28, 29), 321 Clezy, P. S., 228(27), 230(27), 263 Clouse, A. O., 86(13), 87(13), 120 Clyde, P. F., 222(53), 223 Cochran, D. W., 84(10), 86(10, 13), 87 (12, 13), 88(10), 90(10), 91(10), 104 (12), 120 Coffen, D. L., 205, 223 Cohen, J., 235(39), 250(52), 251(52), 254 (39), 255(39), 257(52), 263, 264 Cole, F. R., 561(256), 572 Collins, J. F., 536(138), 568 Collins, R. P., 517(45), 565 Colvin, E., 384, 404 Combes, G., 344(17), 346, 559(243), 592 Comin, J., 534(124), 539(152), 568, 569 Cone, C., 544(172), 569
Conroy, H., 86(9), 120, 371, 394(43), 404 Cook, J. M., 168(33, 38, 39), 169(33, 39), 173(33, 39), 176(39), 179 Cook, R. E., 241(43), 256(43), 258(43), 263 Cooke, G. A., 390(62), 405 Cooper, S. F., 566 Cope, A. C., 467(47), 504 Corral, R. A., 553(216a, 217), 571 Coverdale, C. E., 13(47), 80 Cox, J. M., 13(48), 80 Cox, J. S. G., 69(115), 82 Crabb6, P., 471(49), 504 Craig, A. R., 556(229), 571 Croatto, A., 499(74), 505 Crombie, L., 544, 569 Cronlund, A., 528(94), 567 Crow, W. D., 168(35), 169(35), 171(35), 172(35), 176(35), 179, 228(27), 230 (27), 263 Cullen, W. P., 545(183), 570 Culvenor, C. C. J., 514(32), 528(93), 562 (263), 565, 567, 572 Curcumelli-Rodostamo, M., 355(18), 403 Curran, W. V., 319(74), 323
D Dadson, B. A., 530(107), 567 Daloze, D., 578(51), 565 Dalton, D. R., 227(17), 263 Danks, L. J., 68(113), 82 da Rocha, A. I., 241(43), 256(43), 258(43), 263 Das, B., 427(15), 428(15, 37, 38), 452(37, 38), 453(37), 457(37), 489(37), 502 (37), 503, 546(186), 570 Das, B. C., 158(9), 159(9), 168(36, 37, 42), 170(36), 176(42), 178, 179, 272(25), 273(25), 282(25), 321, 536(137), 550 (206, 207), 563(267), 568, 570, 571, 573 Dastoor, N. J., 170(44), 179 Dauben, W. G., 13(46), 80 Dave, K. G., 146(62), 147(62), 156 de Jongh, H. A. P., 7(23), 13(47), 79, 80 Delle Monache, E. M., 558(238), 572 Denne, W. A., 551(210a), 571 de Petruccelli, M. F., 553(216a, 217), 571 Despreaux, C. W., 190(14), 222
579
AUTHOR INDEX DeWaal, H. L., 515(33), 565 Desai, H. K., 510(9), 564 Dey, P. K., 500(80), 505 Dhar, K. L., 551(209), 571 Dhar, M., 522(73), 566 Dickey, E. E., 227(6), 235(6), 255(6), 262 Djerassi, C., 93(42), 121, 144(57), 156, 158(18), 159(18), 178 Doddrell, D., 17(52), 80 DO6 deMaindreville,M., 158(6),160(6), 178 DOpke, W., 32(80, 85, 90, 91, 92, 94, 95, 96, 101, 102), 33(91, 93, 94, 102), 35 (85), 40(85), 44(90), 46(91, 92), 49 (93), 51(92, 94, 95, 96), 53(95, 96), 57(90), 64(91, 96), 65(94), 66(102), 67(101), 68(90), 81, 82, 414(9), 423, 515(35), 527(88), 544(181), 565, 567, 5 70 Doering, W. E., 190(15), 222 Dolphin, D., 536(133), 568 Doly, J. W., 551(208), 571 Dominguez, X. A., 525(79), 566 Doskotch, R. W., 519(52), 565 Doty, M. S . , 517(44), 565 Douglas, B., 238(41), 239(41), 240(41), 242(41), 256(41), 257(41), 258(41), 263, 350(9), 351(9), 360(9), 362(9), 403 Douglas, G. K., 226(2), 228(2, 26), 230, 231(30), 233(30, 31), 236(2, 40), 237 (40), 238(30), 253(31), 255(26, 30), 256(40), 257(30, 31), 258(26, 40), 261 (30, 31), 262, 263 Dryden, H. L., Jr., 319(73), 323 Duarte, A. P., 158(18), 159(18), 178 Dudock, B. S . , 560(247), 572 Dugan, J. J., 158(16), 159(16), 178 Dugas, H., 384(54), 387(58), 404 Dunstone, E. A., 325(1), 326(1), 346 DuPont, H. L., 222(53), 223 Dupont, M., 518(51), 565 Durand, P., 414(8), 423 Durant, R. C . , 500(79), 505 Durham, L. J., 7(23), 17(54), 79, 80, 467 (46), 468(46), 469(46), 470(46), 471 (50, 51), 472(50, 51), 473(50, 51), 474 (51),504 Dutschevska, H., 93(39), 121 Dutta, N. L., 181(1), 222 Dutta, S. K., 513(25), 564 Dwuma-Badu, D., 93(27), 94(27, 49), 98 (27), 103(27), 104(49), 105(27), 106
(27), 107(27, 49), 108(49), 120, 121, 123(13), 124(13), 127(13, 33, 34, 35, 36), 130(13), 131(13, 36), 132(13), 133 (13, 34), 134(36), 154, 155 Dzhakeli, E. Z., 93(44), 121
E Eastham, J. F., 13(46), 80 Eckard, R., 558(235), 571 Edgar, J. A., 562(263), 572 Edie, D. L., 230(27a), 243(27a), 244(27a), 245(27a), 252(27a), 253(27a), 257 (27a), 263 Edwards, J. M., 525(80), 566 Edwards, 0. E., 426(4), 502 Edwards, P. N., 160(25),178 Effler, A. H., 344(17), 346, 559(243), 572 Eggers, S. H., 540(158), 569 Egnell, C., 182(3), 222 Elander, M., 526(83a), 566 Elderfield, R. C . , 168(33, 40), 169(33, 40), 170(46), 171(47), 173(33, 40), 179 El-Gangihi, S., 268(7), 278(7), 321 El-Hamidi, A., 267(2), 268(2, 7), 270(2), 277(2), 278(7), 279(2), 320, 321 Ellison, R. A., 384(54), 404 Evans, D. A., 158(19), 159(19), 178 Evans, R.M., 13(45), 80 Evstigneeva, R. P., 207(24, 25), 223
F Faber, L., 524(77), 566 Fahlhaber, H.-W., 520(59), 565 Faizutdinova, Z. S . , 534(127), 535(128), 568 Fales, H. M., 227(12), 228(12), 263, 557 (231), 571 Farrier, D. S., 543(170), 555(222), 569, 571 Faugeras, G., 507(1), 532(114, 115), 564, 567 Fehlhaber, H. W., 32(102), 33(102), 66 (102), 81, 556(225), 571 Fehlhaber, H.-W., 512(17, 18), 564 Fellows, L. E., 533(122), 568 Ferreira, J. hl., 158(18), 159(18), 178 Ferreira, M. A., 168(32), 179
580
AUTHOR INDEX
Ferrari, G., 544(178), 570 Ferrari, M., 544(178), 570 Fervidi, O., 544(178), 570 Fesenko, D. A., 521(67, 68), 541(160), 566, 569 Filarowska, A., 427(21), 500(21), 503 Finch, N., 94(48), 99(48), 109(48), 113(48), 121, 133(42), 155 Finkelstein, N., 530(105), 567 Fischer, B. A., 170(46), 179 Fish, F., 530(105, l06), 567 Fishman, M., 381(49, 52), 404 Fitzgerald, J. S., 271(23), 272(23), 273(23), 274(23), 275(23), 276(23), 282(23), 321, 325(1), 326(1), 346 Flentje, H., 414(9), 423 Flesia, E., 499(74), 505 Flom, M. S., 10(33), 7 9 Flores, S. E., 158(18), 159(18), 178 Foley, K. F., 110, 121 Foussard-Blanpin, O., 500(82), 505 Frahn, F. L., 550(205), 570 Frencet, I., 427(19, 21), 428(19), 500(21, 98), 502(98), 503, 506 Fridrichsons, J., 278(10, l l ) , 321, 420(15), 423 Friedrich, W., 35(83, 84), 81 Friess, S. L., 500(79), 505 Fritsch, G., 515(35), 527(88), 565, 567 Fritsch, W., 544(181), 570 Frohberg, E., 512(18), 564 Fu, C.-C., 547(191), 570 Fuji, K., 539(153, 154, 155), 569 Fujihara, M., 296(50), 303(55), 322 Fujita, E., 539(153, 154, 155, 156), 569 Fujitani, K., 523(75), 566 Fujiwara, T., 365(31), 404 Fukumoto, K., 267(56, 61), 277(2b), 279 279(18), 290(2b), 292(38, 39, 40), 293 (2b, 18, 40, 41), 294(47, 48), 296(50), 299(52,53),300(54), 303(55), 304(55a), 305(56, 57, 58), 310(61, 63, 64, 65), 315(40), 319(72), 320(75), 321, 322, 323, 538(147), 568 Furukawa, H., 226(4), 227(14), 228(22), 230(14), 235(14), 240(4), 243(46), 247 (51), 248(51), 249(51), 250(14, 41), 253(14), 255(14), 256(46 51), 257(14), 259(51), 262, 263, 264, 535(131), 544 (180), 568, 570 Furstoss, R., 499(73), 505
G Galeffi, C., 558(238), 572 Ganguili, G., 555(222), 571 Ganguly, A. N., 426(8), 502 Ganguly, S. N., 562(260), 572 Garcia, L. M., 512(19), 564 Garratt, S., 88(16), 89(16), 120 Gaskell, A. J., 113(57a),121, 138(50), 156, 158(4), 178 Gates, M., 194(21), 196(21), 223 Gawad, D. H., 594(174), 569 Geipel, R., 520(59), 565 Geissman, T. A., 230(29), 231(29), 255(29), 263 Gellert, E., 518(49, 50), 565 Gemenden, C. W., 174(49),179 Gerashczenko, G. J., 19(61), 86 Gertig, H., 514(31), 565 Gharbo, S. A., 227(10), 228(10), 263 Ghosal, S., 168(41), 179, 428(37), 452(37), 453(37), 457(37), 489(37), 502(37), 503, 513(25), 514(27), 527(92), 564, 56 7 Gilbert, B., 84(4), 110, 115(4), 120, 158 (18), 159(18), 178 Gilman, A., 222(54), 223 Gilman, R. E., 171(48), 179 Gladstone, W. A. F., 10(41,42), 11(41,42), 16(41), 80 Glick, M. D., 241(43), 256(43), 258(43), 263 Gmelin, R., 556(228), 571 Gnewuch, C. T., 146(62), 147(62), 156 Gokhale, A., 532(117), 544(175), 568 Gonzales, A. G., 562(262), 572 Gooden, E. L., 227(5), 228(5), 231(5), 254 (5), 255(5), 262 Goodman, L. S., 222(54), 223 Gorbunov, V. D., 558(236), 572 Gordon, E. M., 233(33), 234(33), 255(33), 258(33), 263 Gorman, A. A., 170(44), 179 Goto, K., 416(10), 423 Goutarel, R., 1, 3(8, 10, l l ) , 32(79, 97), 33(8, 10, 11, 79), 39(88), 40(79), 41 (10, 89), 42(10, 11, 79), 47(10), 49(89), 53(11, 79, 97), 54(10), 56(10), 58(11), 68(97), 74(11, 97), 76(11), 7 9 , 87, 123 (13a), 124(13a), 130(13a), 133(13a), 154, 182(7), 209(7), 222, 427(16), 428 (16), 432(16), 452(16), 453(16), 454
AUTHOR INDEX (16), 455(16), 457(16), 458(16), 459 (16), 462(16), 474(16), 475(16), 476 (16), 503,509(5), 564 Govindachari, T. R., 233(34), 235(34), 251 (34), 255(34), 257(34), 263, 320(75), 323, 426(5), 502, 510(7, 8, 9), 513(26), 564 Grabarezyk, H., 514(31), 565 Gracey, D. E. F., 408(3), 410(3), 411(3), 423 Graham, D. W., 13(48), 80 Granelli, I., 525(81, 82), 536(135), 566, 568 Grasse, W., 536(134), 568 Grethe, G., 164(27), 165(27), 178, 183(10), 187(12), 188(10), 192(16), 199(10, 16), 207(26), 222, 223 Gribble, G. W., 344(16), 346, 559(245), 572 Griffin, W. J., 528(93), 567 Grigsby, R. D., 517(42), 565 Gritsenko, S. V . , 500(97), 502(97), 506 Groeger, D., 508(2), 564 Grossman, E., 78(128), 82 Grundon, M. F., 526(86), 531(110), 536 (138), 566, 567, 568 Grynkiewicz, G., 350(4), 351(3, 4), 352(4), 353(3, 4), 359(4), 403 Guinaudeau, H., 520(60), 566 Gulubov, A. Z., 515(34), 518(47), 565 Gupta, A. S., 562(258), 572 Gupta, D., 93(21, 22, 23, 24), 118(62), 120, 121, 123(1, 2), 125(1), 126(1), 127(32), 254, 255, 158(12, 13), 159(12, 13, 22, 23), 178 Gupta, D. G., 123(4, 5), 124(4, 5), 125(4, 5), 128(4), 154 Gupta, R. N., 394(65), 396(65, 66), 397 (67, 68), 398(65, 66), 399(71, 72), 400 (73), 401(73, 74, 75), 405 Gurevich, E. L., 93(34), 120 Gurevich, H., 93(34), 120 Gutzwiller, J., 164(27, 28), 165(27), 167 (28), 170(28), 178, 183(10, l l ) , 185 (ll),187(11, 12), 188(10, 12), 190(14), 193(19), 194(20), 197(20), 199(10), 204(22), 220(51), 222, 223
H Haack, E., 554(219), 571 Haddock, R. E., 93(27), 94(27, 49), 98(27),
581
103(27), 104(49), 105(27), 106(27), 107(27,49), 108(49),120,121, 123(13), 124(13), 127(13, 34), 130(13), 131(13), 132(13), 133(13, 34), 154, 155 Haga, S., 299(51), 322 Haginawa, J., 123(21), 125(21), 155, 247 (51), 248(51), 249(51), 250(51), 256 (51), 254(51), 264 Ha-Huy-Ke, 546(188), 570 Halim, A. F., 517(45), 565 Hall, E. S., 211(35, 36), 213(36), 216(36), 223 Hamied, Y. K., 557(230), 571 Hamlet, J. C . , 13(45), 80 Hammouda, F. M., 530(109), 567 Hanaoka, M., 427(26), 428(26, 55), 430 (26), 431(26), 434(26), 435(26, 27), 436(27), 437(27), 438(27), 439(27, 28), 440(26), 441(26, 28), 442(29), 443(27), 447(26), 453(26), 455(26), 478(54, 55), 479(55), 480(55), 481(54), 496(27, 66, 67, 68, 69, 70), 497(67), 498(69), 499 (69, 70), 503, 504, 505 Hancox, N. C., 168(35), 169(35), 171(35), 172(35), 176(35), 179 Hannaway, C., 319(70), 323 Hano, H., 427(24), 503 Hano, K., 500(81), 505 Hansen, J. H., 88(16), 89(17), 120 Hanssen, H. W., 10(41), 11(41), 16(41), 80 Harayama, T., 350(6, 7), 351(7), 352(6, 7), 353(6), 357(7, 19), 365(25, 26, 27, 28, 29, 30, 31, 32, 33, 34), 366(7, 35), 367 (26, 35, 36), 368(35, 39), 369(35, 39, 41), 372(6), 403, 404 Harkiss, K. J., 511(14, 15, 16), 564 Harley-Mason, J., 344(18), 346, 559(244), 572 Harmon, R. E., 28(19), 322 Harris, W. M., 230(29), 231(29), 255(29), 263 Harrison, W. A., 355(18), 403 H a r t , N . K., 109(56), 113(56),114(56), 121, 136(48, 49), 137(48, 49), 138(48, 49), 140(48), 142(48), 155, 227(7), 228(7), 262, 278(9), 321, 326(12, 13), 338(12, 13), 341, 342(12, 13), 346, 509(6), 524 (78), 539(157), 551(211), 564, 566, 569, 571 Hfirtel, R., 32(102), 33(102), 66(102), 81
582
AUTHOR INDEX
Hartley, T. G., 325(1), 326(1), 346 Hashimoto, M., 365(25, 27, 28), 403, 404 Hawkes, R. L., 543(170), 555(222), 569, 571 Hayasaka, T., 294(47), 322 Hazenberg, M. E., 387(58), 404 Hecker, E., 530(103), 567 Hedman, K., 525(83), 527(90), 566, 567 Heesing, A., 558(235), 571 Henderson, T., 187(13), 188(13), 222 Hendrickson, J. B., 133(41), 155 Herbert, R. B., 268(13), 270(20), 271(20), 277(4), 279(12, 13), 281(20), 288(12, 13, 28, 30), 293(20), 296(13), 310(13), 314(13), 321 Herlem, D., 32(97), 53(97), 68(97), 71 (117), 73(118), 74(97, 119), 78(125), 81, 82 Herlem-Gauher, D., 3(8, 10, ll), 33(8, 10, l l ) , 41(10, 89), 42(10, I l ) , 47(10), 49 (89), 53(11), 54(10), 56(10), 58(11), 74 ( l l ) , 76(11), 79, 81 Hesse, M., 84(1), 109(1), 119, 123(14), 124 (14), 125(14), 126(14), 148(14), 154, 158(16), 159(16), 168(296), 174(49), 178, 179, 508(2), 546(187), 564, 570 Heusler, K., 35(83), 81 Hibino, S., 546(185), 570 Hibino, T., 350(6), 352(6), 353(6), 372(6), 403 Highet, P. F., 411(6), 423 Highet, R. J., 411(6), 423 Hiiragi, M., 323 Hillmann, M. J., 311(66, 67), 312(67), 323 Hinshaw, W. B., 104(50), 121, 134(44), 155, 158(5), 159(5), 160(5), 178 Hirada, H., 552(212a), 571 Hirai, K., 547(192), 570 Hirata, Y., 511(12), 529(99, 100, 101, 102), 530(104), 538(146), 564, 567, 568 Hirayama, K., 78(126, 127), 82 Hirschmann, R., 18(56), 80 Hiskey, C. F., 18(56), 80 Ho, T.-L., 353(15), 403 Ho, Y. K., 399(71, 72), 401(74, 75), 405 Hoang, N. M., 550(207), 571 Hoenicke, K. L., 528(95), 567 Hoerhammer, R. B., 525(80), 566 Hohne, E., 24(70, 72), 27(72), 8 1 Hollerbach, A., 549(200), 570 Holmes, H. L., 265(1), 320
Honda, T., 421(17), 423, 516(38), 521(66), 565, 566 Hootele, C., 350(5), 351(5), 352(14), 353(5), 360(5), 362(5), 363(5), 372(14), 378 (14), 403, 518(51), 565 Hoppe, W., 530(103), 567 Horan, H., 511(7), 526(85), 564 Horii, Z., 386(57), 404, 427(13, 23, 24, 25, 26), 428(13, 26, 33, 54, 55, 57, 58), 429 (52, 53, 61, 62), 430(25, 26), 431(25, 26), 434(26), 435(25, 26, 27), 436(27), 437, 438, 439(27, 28), 440(26), 441 (26, 28), 442(29), 443(27, 30), 444, 445(30, 31, 32), 446(30, 31, 32, 33), 447(26, 31, 32, 33), 453, 455(26), 456, 457, 458(40), 464, 471(48), 473(25), 476(30, 32), 477(32, 52, 53), 478(54, 55), 479(55), 480(55), 481, 484(57, 58), 485(57), 486(57, 58), 488(57, 58), 489 (61, 62), 490, 491(62, 63), 492(62), 493(62), 494(62), 495(61, 62), 496 (27, 65, 66, 67, 68, 69, 70, 71, 72), 497 (67), 498(53, 69), 499(65, 69, 70), 503, 504, 505 Hornick, R. B., 222(53), 223 Hosokawa, M., 350(7), 351(7), 352(7), 357(7), 366(7), 403 Hosoya, K., 514(30), 564 Houghton, P. J., 123(6, l l ) , 124(11), 126 (ll),128(6), 154, 168(29a), 179 Hrbek, J., Jr., 267(2c), 268(2c), 277(2c), 320 Hsiao, C.-A., 228(24), 263 Hsieh, C.-H., 427(18), 503 Hsu, T. M., 531(111), 567 Huang, W.-Y., 227(15), 253(15), 263 Huffman, J. W., 16(51), 80, 531(111), 567 Hughes, C., 544(176), 569 Hunt, J. S., 13(45), 80 Husson, H., 539(150), 569
I Ibraginova, M. U., 522(70), 566 Ibragomova, M. U., 520(65), 566 Ibuka, T., 365(30), 404 Ide, A., 427(26), 428(26), 430(26), 431(26), 434(26), 435(26), 440(26), 441(26), 447(26), 453(26), 455(26), 471(48), 503, 504
583
AUTHOR INDEX Ihara, M., 421(17), 423, 516(38), 521(66), 565, 566 Iijuma, I., 329, 330(7), 337(7), 346 Ikeda, M., 428(54, 55, 57, 58), 429(52, 61, 62), 439(28), 441(28), 443(30), 444 (30), 445(30, 31, 32), 446(30, 31, 32), 447(31, 32), 476(30, 32), 477(32, 52), 478(54, 55), 479(45), 480(55), 481(54), 484(57, 58), 485(57), 486(57, 58), 487 (57, 58), 488(57, 58), 489(61, 62), 490 (62), 491(62, 63), 492(62), 493(62), 494(62), 495(61, 62), 503, 504 Iketubosin, G. O., 429(60), 489(60), 490 (60), 491(60), 504 Imado, S., 446(33), 503 Imanishi, T., 386(56, 57), 404 Inouye, H., 211(37), 213(37), 223 Inubushi, Y., 350(6, 7), 351(7), 352(6, 7), 357(7, 19), 365(25, 26, 27, 28, 29, 30, 31, 32, 33, 34), 366(7, 35), 367(26, 35, 36), 368(35, 39), 369(35, 39, 41), 372 (6), 403, 404 Ionescu, M., 535(129), 568 Irie, H., 552(212a), 558(237), 571, 572 Isaacs, N. W., 514(28), 564 Iselin, B. M., 7(18, 22), 79 Ishii, H., 247(51), 348(51), 249(51), 250 (51), 256(51), 259(51), 264, 350(7), 351(7), 352(7), 357(7, 19), 365(25, 26, 27, 28, 29, 30, 31, 32, 33, 34), 366(7, 35, 36), 367(26, 35, 36), 368(35, 39), 369(35, 39, 41), 403, 404, 514(30), 564 Ishikawa, M., 219(49), 223 Ishimaru, H., 323 Iskandarov, S . , 537(140, 142), 561(252, 253), 568, 572 Ismailov, I. A., 532(112), 567 Ismailov, Z. F., 242(44, 45), 256(44), 263, 264, 560(249), 561(251), 572 Isomoto, M., 543(167), 569 Ito, K., 243(46), 247(51), 248(51), 249(51), 250(51), 256(46, 51), 259(51), 264, 535(131), 568 Ito, M., 247(51), 248(51), 249(51), 250(51), 256(51), 259(51), 264, 442(29), 496 (70), 499(70), 503, 506 It& S., 17(55), 80 Ivanov, I. C., 537(141), 568 Iverach, G. G . , 351(13), 360(23), 364(13), 403 Ives, D. A. J., 68(112), 82
Iwamoto, T., 427(24), 428(57), 429(52, 53), 477(52, 53), 484(57), 485(57), 486(57), 487(57), 488(57), 495(53), 503, 504 Iyer, S. S., 562(261), 572
J Jackson, A. H., 523(76), 566 Jacobson, M., 227(5), 228(5), 231(5), 235 (36), 245(36), 254(5, 36), 255(5, 36), 256(36), 258(36), 262, 263 Jadhav, S. J., 426(5), 502 James, K. J., 526(86), 566 James, R., 289(36), 294(49), 321, 322 Janot, M. M., 93(42), 121, 123(13a), 124 (13a), 130(13a),133(13a),144(57),254, 156, 182(7), 209(7), 222, 539(150), 569 Jeffreys, J. A. D., 538(149), 569 Jeffs, P. W., 32(80, 94), 33(93, 94), 49(93), 51(94), 65(94), 81, 414(9), 423, 543 (170), 554(220), 555(222), 569, 571 Jeger, O., 68(109), 82, 419(14), 423 Jenkins, J. K., 351(13), 364(13), 372(44, 45), 375(45), 403, 404 Jennings, J. P., 278(5), 321 Jenson, B. L., 281(19), 321 Jewers, K., 512(19), 564 Jin, K. D., 3(7a), 33(7a), 36(7a), 79 Jirokovskjr, I., 381(49, 50, 52), 404 Johne, S., 508(2), 564 Johns, S. R., 109(56), 113(56), 114(56), 121, 123(15), 125(15), 136(48, 49), 137 (48, 49), 138(48, 49), 140(48), 142(48), 155, 168(35), 169(35), 171(35), 172 (35), 176(35), 179, 227(7, 8), 228(7, 8), 262, 271(22, 23, 24), 272(22, 23, 24), 273(22, 23, 24), 274(22, 23, 24), 275 (22, 23, 24), 276(22, 23, 24), 278(9), 282(22, 23, 24, 27), 289(24), 316(24), 317(24), 321, 325(1), 326(1, 3, 4, 5, 9, 10, 11, 12, 13, 14, 15), 327(3, 4, 5), 330(4, 9), 331(4), 332(5, 9, 10, ll), 335(4, 5), 337(4, 5, 9), 338(12, 13), 341(13), 342(12, 13), 343(14, 15), 344 (15), 346, 350(11), 403, 509(6), 514 (32), 523(74), 524(78), 528(96), 539 (157), 547(190), 549(201), 551(210a, 211), 552(213), 557(232a), 562(259), 564, 565, 566, 567, 569, 570, 571, 572 Johns, W. F., 12(44), 80 Johnson, C. L., 512(22), 564
584
AUTHOR INDEX
Johnson, W. S., 7(23), 13(47, 48), 79, 80 Jones, C. D., 380(47), 404 Jones, P. G., 13(45), 80 Jordaan, A., 540(158), 569 Joseph, T. C., 390(60), 404 Joshi, B. S., 174(49),179, 426(5), 502, 544 (174), 569 Joule, J. A., 158(7, 19), 159(19), 160(7), 163(7), 178 Jurisson, S., 516(39), 565
K Kaisin, M., 518(51), 565 Kalvoda, J . , 419(14), 423 Kamalitdinov, D., 537(140), 568 Kamat, V. N., 426(5), 502, 544(174), 569 Kametani, T., 267(56, 61), 277(2b), 279 (18), 290(2b), 292(38, 39, 40), 293 (Zb, 18, 40, 41, 42, 43, 44), 294(45, 46, 47, 48), 296(50), 299(51, 52, 53), 300 (54), 303(55), 304(55a), 305(56, 57, 58, 59), 310(61, 62, 63, 64), 311(65), 314(69), 315(40), 319(72), 320(75), 321, 322, 323, 421(17), 423, 516(38), 521(66), 538(147), 456(185), 565, 566, 568, 570 Kaneko, C., 219(49), 223 Kaneko, K., 19(63), 23(63), 78(127), 78 (63), 80, 82 Kan-Fan, C., 168(37), 179, 136(48a), 138 (48a), 155, 546(186), 563(267), 570, 573 Kapil, R. S., 158(20), 159(20), 168(20), 178, 211(34), 213(34), 223, 508(4), 544 (173), 564, 569 Karaguishieva, D., 502(100), 506 Karle, J. M., 158(11a), 159(11a), 278 Kasymov, S. Z., 94(45, 46), 109(46), 119 (46, 64), 121, 144(58, 59), 156 Kasymov, Sh. Z., 94(47), 109(47), 119(47), 121 Katsui, N., 19(62), 80, 228(19), 229(19), 255(19), 258(19), 263 Kaul, J. L., 93, 109(41), 121 Kawakoshi, Y., 19(63), 23(63), 78(63), 80 Kawazu, M., 296(50), 303(55), 322 Kazlauskas, R., 69(116), 82 Keeler, R. F., lO(35, 36, 37, 38), 17(37), 20(36), 31, 79, 80
Keller, K., 517(46), 565 Keller, W. J., 561(256), 572 Kelly, R. B., 68(112), 82 Kennard, O., 514(28), 564 Kennedy, R. M., 33(88a), 39(88a),43(88a), 44(88a), 46(88a), 47(88a), 49(88a), 56 (SSa), 81 Keogh, RI. F., 397(69), 405 Kepler, J. A., 515(36), 565 Khakimdzhanov, S., 548( 195), 570 Khashimov, K. N., 548(196, 197, 198), 570 Khasimoff, A. M., 21(68), 23(69), 32(69), 80 Khodzhaev, V. G., 560(250), 572 Khodzhayeff, B. U., 33(105), 81 Khuong-Huu, F., 3(10), 32(79, 97), 33(10, 79, 87), 38(87), 40(79), 41(10, 87), 42 (10, 79), 46(87), 47(10), 53(79, 97), 54(10), 56(10), 68(97), 71(117), 73 (118), 74(97, 119), 78, 7 9 , 81, 8 2 Khuong-Huu, Q., 3(10), 33(10), 41(10), 42 ( l o ) , 47(10), 54(10), 56(10), 7 9 Khuong-Hau-Laine, F., 3(8, l l ) , 33(8, l l ) , 39(88), 41(89), 42(11), 49(89), 53(11), 58(11), 74(11), 76(11), 79, 81, 509(5), 564 Kibaltchich, P. N., 33(99), 54(99), 56(99), 67(99), 68(99), 81 Kigasawa, K., 294(47), 322, 323 Kim, H. L., 517(42), 565 Kim, S.-W., 386(56, 57), 404 King, F. E., 69(115), 82 King, M. L., 251(53), 252(53), 257(53), 264 King, T. J., 69(115), 8 2 Kirby, G. W., 289(36), 321 Kiryakov, K. G., 235(37), 263, 532(118), 568 Kiselev, V. V., 557(233), 571 Kitayama, K., 543(167), 569 Kjaer, A., 556(228), 571 Klasek, A., 537(143), 568 Klein, W. M., 512(20), 564 Kleinert, W., 182(4), 222 Klinga, K., 344(17), 346, 559(243), 572 Klyne, J. P., 278(5). 321 Klyne, W., 170(44), 179 Knight, J. A., 211(34), 213(34), 223 Knowles, G. D., 508(4), 564 Kobari, T., 293(43, 44), 322 Kobayashi, K., 7(20), 9(30), 7 9
585
AUTHOR INDEX Kodera, K., 427(23, 25, 26), 428(26, 54,55, 57), 429(61, 62), 430(25, 26), 431(25, 26), 435(25, 26), 439(28), 440(26), 441 (26, 28), 443(30), 444(30), 445(30, 31, 32), 446(30, 31, 32), 447(26, 31, 32), 453(26), 455(26, 40), 456(40), 457(40), 458(40), 464(25), 471(48), 473(25), 476(30, 32), 477(32), 478(54, 55), 479 (55), 490(55), 481(54), 484(57), 485 (57), 486(57), 487(57), 488(57), 489 (61, 62), 490(62), 491(62, 63), 492(62), 493(62), 494(62), 495(61), 496(69), 498(67), 499(69), 503, 504, 505 Koezuka, Y., 228(20),263 Kohlmunzer, S., 158(8), 159(8), 178 Kohno, T., 310(64), 322 Koizumi, M., 267(56, 61), 292(38, 39), 300 (54), 304(55a), 305(56, 57, 58, 59), 310 (61, 62), 322 Kolodzieski, J., 526(87), 567 Koltai, M., 553(214), 571 Kompis, I., 93(40), 109(40), 111(55), 112 (55), 117(40, 55), 118(40), 127, 135 (46), 143(46, 55), 144(55), 155, 156 KompiB, I., 143(55) Konojia, R. M., 308(60), 322 Korotkova, M. P., 559(242), 572 Korth, T., 113(57a), 121, 138(50), 156, 157(3), 158(4), 163(3), 170(3), 178 Kotorskii, B. K., 559(241), 572 Kovalenko, V. I., 517(41), 565 Kowala, C., 271(22), 272(22), 273(22), 274 (22),275(22), 276(22), 282(22, 26), 321 Kowanko, N., 210(28), 213(28), 223 Kowalewski, Z., 427(21), 500(21, 98), 502 (98), 503, 506, 529(98), 567 Kozuka, A., 292(38, 39), 322 Kozuka, M., 228(18, 25), 263 Kretchmer, R. A., 390(61), 392(61), 405 Krettli, A. U., 220(51), 222(51), 223 Krivut, B. A., 500(87, go), 501(87, go), 505 Kruger, P. E. J., 554(218, 221), 517 Kruglyak, S. A., 500(83), 505 Kumari, D., 68(113), 82 Kunitomo, J., 241(43), 256(43), 258(43), 263, 523(75), 543(167), 544(180), 566, 569, 570 Kupchan, S. M., 1, 7(21), 9, 10(33), 33 (SSa), 39(88a), 43(88a), 44(88a), 46 (SSa), 47(88a), 48(88a), 49(88a), 56 (88a), 66(106a), 68(107, 108), 71(107,
108), 76, 79, 81, 82, 233(33), 234(33), 251(53), 252(53), 255(33), 257(53), 258(33), 263, 264, 308, 322, 542(163), 569 Kurakina, I. O., 33(98, 99, 104), 53(98), 54(98, 99), 67(99), 68(98, 99, 104), 81 Kureel, S. P., 544(173), 569 Kutney, J. P., lO(41, 42), 11, 16(41), 80 Kuzovkov, A. D., 427(22), 428(59), 489 (59), 503, 504
L Lacombe, L., 550(206), 570 Lahey, F. N., 243(47), 239(42), 256(42,47), 257(42), 258(42), 263, 264, 535(130), 568 Lalonde, R. T., 545(182, 183), 570 Lamberton, J. A., 109(56), 113(56), 114 (56), 121, 123(15), 125(15), 136(48, 49), 137(48, 49), 138(48, 49), 140(48), 142(48), 155, 168(35), 169(35), 171 (35), 172(35), 176(35), 179, 227(7, 8), 228(7, 8), 262, 271(22, 23, 24), 272 (22, 23, 24), 273(22, 23, 24), 274(22, 23, 24), 275(22,23,24),276(22,23,24), 278(9), 282(22, 23, 24, 27), 289(24), 316(24), 317(24), 321, 325, 326(1, 3, 4, 5, 9, 10, 11, 12, 13, 14, 15), 327(3, 4, 5), 330(4, 9), 331(4), 332(5, 9, 10, ll), 335(4, 5), 337(4, 5, Q ) , 338(12, 13), 341(13), 342(12, 13), 343(14, 15), 344 (15), 346, 350(11), 403, 509(6), 514 (32), 523(74), 524(78), 528(96), 539 (157), 547(190), 549(201), 551(210a, 211), 552(213), 557(232a), 562(259), 564, 565, 566, 567, 569, 570, 571, 572 Langlois, N., 272(25), 273(25), 282(25), 321, 650(206, 207), 570, 571 Laos, I., 12(44), 80 Lapina, K. P., 500(88), 501(88, 92), 505, 550(92) Lasskaya, 0. E., 427(22), 500(90), 501(90), 503, 505 Lau-Cam, C., 182(5), 222 Law, D. A., 359(22), 390(63), 403, 405 Lazur’evskii, G . V . , 517(40), 565 Leander, K., 525(81, 82, 83, 83a), 527(90), 566, 567 Lee, C.-H., 235(38), 236(38), 263
586
AUTHOR INDEX
Lee, C. M., 92(19, 20), 93(26, 27), 94(26, 27), 98(27), 103(27), 105(27), 106(27), 107(27), lOS(26), 109(19), 119(19, 65), 120, 121, 123(13, 17, 18, 19), 124(13), 125(17, 18, 19), 126(17, 18, 19), 127 (13, 36), 130(13), 131(13, 36, 40), 132 (13), 133(13, 41), 134(36), 138(19, 51), 145(19, 51), 154, 155, 156 Lee, H. L., 164(27), 165(27),178, 183(10), 187(12), 188(10), 192(16), 199(10, 16), 207(26), 222, 223 Lee, K. H., 467(46), 468(46), 469(46), 470 (46), 504 Leete, E., ZlO(ZS), 211(30, 31, 33), 213(28, 30, 33), 216(31, 41), 217(43), 223, 288(31), 321 Leforestier, J. P., 509(5), 564 Legrand, M., 107(53), 115(53), 121, 130 (39), 255 Leicht, C. L., 88(16), 89(16), 120 Lella, J. A., 319(73), 323 Lemay, R., 93(42), 121, 144(57), 156 Le Men, J., 93(42), 121, 144(57), 156, 158 (5, 6, 9), 159(5, 9), 160(5, 6), 168(37), 178, 179 Le Quesne, P. W., 158(11, lla), 159(11, l l a ) , 168(33, 38, 39), 169(33, 39), 173 (33, 39), 176(39), 178, 179 Lettenbauer, G., 554(219), 571 Leung, A. Y., 547(192), 570 Levina, R. Z., 502(100), 506 Levine, S. J., 515(36), 565 LBvy, J., 158(5, 6, 9), 159(5, 9), 160(5, 6), 178 Li, C. S., 227(8), 228(8), 262, 552(213), 571 Li, H.-L., 425(1), 426(1), 502 Liang, H.-T., 427(18), 503 Libsch, S., 240(42a), 263 Liebisch, H. W., 397(70), 405 Lin, C.-N., 522(71), 566 Lin, F.-S., 226(1), 228(1), 226 Lin, J.-H., 542(164), 569 Lin, L.-C., 227(15), 253(15), 263 Lindstrom, B., 538(145), 541(162), 563 (265), 568, 569, 573 Ling, N. C., 158(18), 159(19), 178 Lipscomb, W. N., 5(15), 79 Liu, S.-C., 541(159), 569 Locock, R. H., 527(89), 567 Loder, J. W., 227(7), 228(7), 262, 524(78), 528(93), 547(190), 566, 567, 570
Long, A. G., 13(45), 80 Lovell, E. M., 84, 120 Lu, S.-T., 226(1), 228(1, 24), 235(38), 236 (38), 262, 263, 520(62), 542(164), 566, 569 Lu, T.-L., 520(62), 566 Luckner, M., 546(188), 570 Luhan, P. A., 554(220), 571 Luning, B., 525(82, 83), 527(90), 536(135), 538(145), 547(162), 549(204), 563(265, 266), 566, 567, 568, 569, 570, 573
M MacConnell, J. G., 557(231), 571 McDonald, E., 269(2a), 277(2a), SSS(Z8, 29), 290(2a), 292(2a), 320, 321 McEntee, T. E., 205(23), 223 McGhie, J. F., 68(113), 82 Mackay, M. F., 278(10, ll), 321, 420(15), 423 McLaughlin, J. L., 512(22, 23), 564 MacLean, D. B., 348(1), 349, 353(1), 355 (1, 17, 18), 358(2), 365(1), 372(1), 380(1), 381(1), 383(1, 53), 390(1), 394 (1, 65), 395(1), 396(1, 65, 66), 398 (65, 66), 399(71, 72), 400(73), 401 (73, 74, 75), 403, 404, 405, 408(3), 410(3, 4), 411(3, 4), 412(4, 7), 418(7, 12), 421(4), 422(4, 12), 423 McNaull, J. M., 515(36), 565 McPhail, A. T., 554(220), 571 Magdeleine, M. J., 33(87), 38(87), 39(88), 41(87), 46(87), 81 Maidovich, L. P., 541(160), 569 Mailland, G., 509(5), 564 Maiti, B. C., 536(137, 139), 568 Majumder, N. K., 514(27), 564 Majumder, P. L., 168(36), 170(36), 179, 226(3), 227(3), 228(3), 262 Majumder, R., 508(3), 564 Majumder, S. K., 527(92), 567 Mak, K. F., 239(42), 243(47), 256(42, 47), 257(42), 258(42), 263, 264, 535(130), 568 Makita, M., 429(52), 477(52), 504 Malikov, V. M., 158(14), 149(14), 178, 519 (53, 54, 55, 56), 565 Malykhina, S. A., 500(94), 501(94), 505 Mammarella, C. A., 534(124), 539(152), 568, 569
AUTHOR INDEX Manalo, G. D., 168(34, 43), 173(34), 179 Manchanda, A. H., 512(19), 564 Man’ko, I. V., 536(136), 559(241, 242), 568, 572 Man’ko, J. V., 547(193), 570 Manske, R. H. F., 84(5), 94(5), 107(5),120, 265(1), 320,407, 408(3), 410(3, 4), 411 (3), 412(4, 7), 418(7, 12), 421(4), 422 4, 12), 423, 546(184), 570 Marchenko, L. G., 547(193), 570 Marekov, N., 397(70), 405 Marini Bettolo, G. B., 558(238), 572 Marion, L., 88(14, 15), 90(14), 120 Martin, A , , 3(9), 68(9), 7 9 Martin, J., 384(55), 404 Martin, J. A., 211(34), 213(34), 223 Martin, N. H., 554(220), 571 Martin, S., 192(17), 194(17), 197(17), 199 (17), 222 Martined, P., 512(19), 564 Masaishi, M., 543(167), 569 Masaki, N., 350(8, lo), 351(10, 13), 360 ( l o ) , 362(10, 24), 363(10), 364(13), 369(10), 370(8), 294(8), 396(8), 403, 558(237), 572 Masamune, T., 6(16), 7(17), 8(24, 25, 28, 29), 9(30), lO(25, 32, 34, 40), 15, 19 (62), 7 9 , 80 Mathe, I., 427(20), 503 Mathieson, A. McL., 278(10, l l ) , 321, 420 (15), 423, 551(210a), 571 Mathieson, D. W., 429(60), 489(60), 490 (60), 491(60), 504 Matkalikova, S. F., 519(53, 54, 55, 56), 565 Matsukura, A., 549(199), 570 Matsumoto, C., 429(53), 477(53), 495(53), 504 Matsumura, C., 427(13), 428(13), 429(52), 477(52), 495, 503, 504 Matsumura, H., 209(27), 217, 223 Matsumura, T., 500(84), 501(84), 505 MaupBrin, M., 158(6), 160(6), 178 Mees, F., 350(12), 351(12), 352(12), 403 Mehri, H., 158(15a), 159(15a), 168(15a), 178, 542(165), 569 Melera, A., 427(16), 428(16), 432(16), 452 (16), 453(16), 454(16), 455(16), 457 (16), 458(16), 459(16), 462(16), 474 (16), 475(16), 476(16), 503 Mensah, I. A., 530(107, IOS), 567
587
Merlini, L., 146(61), 156, 168(29b), 179 Merotti, G., 233(35), 235(35), 263 Mester, I., 535(129), 568 Micodem, D. E., 219(48), 223 Mikhno, V. V., 500(86, 93, 95, 96), 501 (86, 93), 505, 506 Miller, M. D., 512(21), 564 Miller, N., 350(12), 351(12), 352(12, 14), 372(14), 378(14), 403 Miller, R. M., 222(53), 223 Milliet, A., 74(119), 82 Minami, I., 496(70), 499(70), 505 Minina, S. A., 555(224, 224a), 571 Minker, E., 553(214, 215, 217a), 571 Miranda, E. C., 158(18), 159(18), 178 Mitscher, L. A., 553(216), 571 Mitsuhashi, H., 11(43), 12(43), 13(43), 19 (63), 23(63), 78(63, 126, 127), 80, 8 2 Mitt, T., 192(16), 199(16), 222 Miyamura, M., 538(146), 568 Miyano, M., 104(50),121, 134(43, 44), 155 Mizushima, M., 294(46), 322 Mizutani, T., 552(212a), 571 &lo, L., 268(13), 279(13), 288(13), 296(13), 310(13), 314(13), 321 Moberg, C., 549(204), 570 Mockle, J. A,, 566 Moerloose, P. de, 210(29), 323 Mohamed, P. A., 426(5), 502 Moinas, M., 350(2), 351(2), 352(2), 353(2), 354(2), 355(2), 359(2), 403 Moitra, S. K., 426(8), 502 Mollov, N. M., 93(39), 121, 537(141), 568 Momose, T., 386(57), 4 0 4 , 4 2 8 ( 5 8 ) ,484(58), 486(58), 487(58), 488(58), 496(70), 499 (70), 504, 505 Mondelli, R., 123(14), 124(14), 125(14), 126(14), 148(14),154, 168(291), 179 Mondeshka, D. M., 33(98), 53(98), 54(98), 68(98), 81 Moniot, J. L., 560(246), 572 Moore, M., 7(18, 19, 22), 8(26), 79 Moorhouse, A., 227(7), 228(7), 262 Mootoo, B. S., 368(38), 369(38, 40), 404 Mori, Y., 8(24), 9(30), 19(62), 7 9 , 80 Morimoto, K., 523(75), 566 Morsingh, F., 84(7), 109(7), 111(55), 112 (55), 117(55), 120, 121, 135(46), 143 (46), 155 Mothemell, W. D. S., 514(28), 564 Mothes, K., 78(122), 82
588
AUTHOR INDEX
Mudzhiri, K. S., 93(44), 121, 144(60), 256, 537(142), 568 Mukherjee, M., 500(80), 505 Mukherjee, R., 427(15), 428(15, 37, 38), 452(37, 38), 453(37), 457(37), 489(37), 502(37), 503 Mukhitdinov, M., 426(5), 502 Mukjerjee, B., 168(41, 42), 176(42), 179 Mulchandani, N. B., 562(261), 572 Miiller, B., 32(80, 85, 90, 92, 94, 95, 96, 101), 33(90, 91, 93, 94), 35(85), 40(85), 44(90), 46(91, 92), 47(91), 49(93), 51 (92, 94, 95, 96), 53(95, 96), 57(90), 64 (91, 96), 65(94), 67(101), 68(90), 8 1 Munavalli, S., 428(56), 481(56), 488(56), 504 Munro, M. H. G., 267(8), 268(8), 269(2a), 270(20), 271(20), 277(2a), 278(8), 281 (20), 289(32), 290(2a), 292(2a), 293 (20), 320, 321 Murai, A., 7(20), 8(24, 27, 28, 29), 9(30), 10 (34), 15(49), 19(62), 79 Murav’eva, V. I., 427(12), 428(10, 11, 12, 59), 489(59), 500(91), 501(90), 502, 503, 504, 505 Murayama, M., 427(14), 428(14), 430(14), 432(14), 433(14), 443(14), 452(14), 453(14), 454(14), 455(14), 471(14), 474(14), 503 Murray, K. E., 551(210), 571 Musil, V., 389(59), 404
45, 46), 468(46), 469(43, 45, 46), 470 (46), 471(35, 43, 50, 51), 472, 473(50, 51), 474(35, 51), 475,476(35),483,503, 504 Nakasato, T., 228(20), 263 Narasimhan, N. S., 532(117), 544(175), 568, 569 Nasini, G., 123(14), 124(14), 125(14), 126 (14), 146(61), 148(14), 154, 156, 168 (29b), 179 Nayar, M. N. S., 535(132), 568 Neal, J. M., 512(23), 564 Nearn, R., 528(93), 567 Nearn, R. H., 524(78), 566 Neuss, N., 158(11), 159(11), 178, 182(6), 222 Niemczycka, M., 427(19), 428(19), 503 Ninomiya, I., 386(56), 404 Ninova, P., 564(268), 573 Nishino, R., 350(7), 351(7), 352(7), 357(7), 366(7, 35), 367(35, 36), 368(35), 369 (35), 403, 404 Nisikawa, K., 538(146), 568 Nkunika, D. S., 350(8), 370(8), 394(8), 396 (81, 403 Noguchi, I., 236(40a), 238(40a), 263 Norkina, S. S . , 93(34), 120 Novak, I., 553(217a), 571 Novgk, I., 553(214, 215), 571 Nulu, J. R., 544(172), 569 Numata, S., 8(29), 10(34), 7 9
N
0
Nabney, J., 512(19), 564 Nadler, K., 532(116), 567 Nagai, H., 496(69), 498(69), 499(69), 505 Nagarajon, K., 320(75), 323 Nakahara, Y., 350(7), 351(7), 352(7), 357 (7), 365(33, 34), 366(7), 403, 404 Nakai, H., 429(61, 62), 489(61, 62), 490 (62),491(62, 63), 492(62),493(62), 494 (62), 495(61), 496(67), 497(67), 504, 505, 544(180), 570 Nakano, T., 3(7a, 9), 33(7a, 81), 34(81, 82), 36(7a), 40(81), 58(81), 59(81), 60(81), 62(81), 63(81), 64(81), 68(9), 75(81), 76, 79, 81, 305(54), 320(75), 322, 323, 428(35), 429(43), 447(35), 458, 464 (43), 465(42, 43), 466(43, 45), 467(44,
Oboimakova, A. P., 500(94), 501(94), 505 O’Brien, J., 282(21), 293(21), 321 Ochiai, M., 539(153), 569 O’Donovan, D. G., 397(69), 405, 511(11), 526(85), 564, 566 Ogino, T., 17(55), 80, 311(65), 322 Ognyanov, I., 93(37, 38, 39, 40), 109(37, 40), 117(40),118(40),119(37, 63), 121, 138(54), 143(55), 144(55), 156 Ohmomo, S., 549(199), 570 Ohmori, S., 78(126), 82 Ohno, K., 552(212a), 558(237), 571, 572 Ohta, G., 33(88a), 39(88a), 43(88a), 44 (88a), 46(88a), 47(88a), 48(88a), 49 (88a), 56(88a), 81 Ohuchi, S., 19(62), 80
AUTHOR INDEX Okamoto, Y., 543(167), 544(180), 569, 570 O’Keefe, D. F., 550(205), 570 Oliver, A. T., 93(36), 121 Olivier, L., 158(9), 159(9), 178 Onaka, T., 329, 330(8), 346, 510(10), 534 (123), 564, 568 Onishchenko, Yu. V., 500(89), 501(89), 505 Ono, H., 6(16), 8(27, 29), 7 9 Opferkuch, H. F., 530(103), 567 Oppolzer, W., 517(46), 565 Orazgel’diev, K., 561(254), 572 Orazi, 0. O., 553(216a, 217), 571 Orekhoff, A. P., 93(34), 120 Orito, K., 8(27, 28, 29), lO(32, 40), 7 9 , 80 Orr, J. C., 88(16), 89(16), 120 Osowiecki, M., 182(2), 222 Otani, G., 543(171), 569 Oughton, J. F., 13(45), 80 Ozcobek, G., 520(58), 565 Ozhakeli, E. Z . , 144(60), 156
P Pai, B. R., 230(28), 231(28), 263, 320(75), 323, 513(26), 538(147), 564, 568 Pakrashi, S . C . , 93(43), 109(43), 118(43), 121, 136(48b), 138(48b), 155 Palenik, G. J., 408(3), 410(3), 411(3), 419(13), 423 Panov, P., 235(37),263,532(118),537(141), 568 Panova, L. N., 537(141), 568 Papay, V., 553(214, 215), 571 Paradkov, M. V., 532(117), 544(175), 568, 569 Parello, J., 414(8), 423, 427(16), 428(16, 36,41a, 56), 429(64), 432,447(36), 448 (36), 450(36), 451(36), 452(16, 36), 453, 454(16, 36), 455,457(16), 458(16), 459(16, 36,41a), 462(16, 41a), 463(36), 474, 475(16), 476(16), 481(36, 41a, 56), 482(41a), 483(41a), 484(41a), 488(41a, 56), 495(64), 503, 504 Paris, M., 532(114), 567 Paris, R. R., 32(79), 33(79),40(79), 42(79), 53(79), 81, 520(60), 532(115),547(194), 563(264), 566, 567, 570, 572 Parker, W., 384(55), 404 Parry, R. J., 211(40), 213(40, 42), 216(40), 217(42), 223
589
Parsons, P. G., 211(38, 39), 223 Parthasarathy, P. C., 426(5), 502, 510(7, 8, 9), 564 Pascard-Billy, C., 116(60),121,457(41),504 Pasteels, J. M., 518(51), 565 Patankar, S. J., 426(5), 502 Patchett, A. A., 68(112), 82 Patel, M. B., 93(32), 120, 427(17), 428 (17, 39), 452(39), 503, 504 Patra, A., 233(32), 234(32), 235(32), 255 (32), 263 Paul, A. G., 526(84), 566 Paulik, V., 33(86, 106), 35(86), 65(106), 66(106), 75(106), 81, 82 Pawluc, D., 500(98), 502(98), 506 Pecher, J., 158(15), 159(15), 178 Pellicciari, R., 84(10), 86(10), 88(10), 90(10), 91(10), 120 Pepinsky, R., 84(8), 120 Perel’son, M. E., 500(87), 501(87), 505, 521(67, 68), 558(236), 566, 572 Perry, R. A., 499(74), 505 Pesce, E., 168(29), 179 Phillipson, J. D., 92(19), 93(21, 22, 23, 24), 94(27), 98(22), 103(27), 105(27), 106 (27), 107(27), 109(19), 118(62), 119 (19, 65), 1 2 0 , 1 2 1 , 123(1,2,4, 5, 12, 13, 17, 18, 19, 23), 124(4, 5 , 12, 13), 125 (1, 4, 5, 17, 18, 19), 126(1, 17, 18, 19), 127(13, 31, 32), 128(4), 130(13), 131 (13), 132(13), 133(13), 134(45), 135 (45), 138(19, 51), 145(19, 51), 154,155, 156,158(12,13), 159(12,13,21,22,23), 178, 529(98), 559(240), 567, 572 Phippard, J. H., 528(93), 567 Piers, K., 372(46), 376(46), 404 Pijewska, L., 277(4), 321 Pinder, A. R., 546(189), 570 Pinder, R. M., 220(50, 52), 222(52), 223 Pinhey, J. T., 69(116), 8 2 Pinyazhko, R. M., 500(85), 501(85), 505 Pizzolato, G., 164(28), 167(28), 170(28),178 Plat,M.,93(42), 121,144(57),156,158(15a), 159(15a), 168(15a),178, 542(165), 569 Plunkett, A. O., 211(34), 213(34), 223 Podczasy, M. A., 560(248), 572 Poisson, J., 93(32, 33), 107(53), 109(57), 111(55), 112(55),113(57), 114(57), 115 (53, 59), 116(59), 117(55), 120, 121, 127(38), 130(39), 135(46, 47), 136(47), 138(47), 143(46, 47), 155
590
AUTHOR INDEX
Polonsky, J., 549(202), 570 Poon, L., 381(51, 52), 404 Popelak, A., 554(219), 571 Popli, S. L., 158(20), 159(20), 168(20), 178 Popli, S. P., 508(4), 544(173), 564, 569 PotliBilovB, H., 267(2), 268(2), 270(2), 277(2), 279(2), 320 Potier, P., 136(48a), 138(48a), 155, 158 (15a), 159(15a),168(15a, 37), 178,178, 272(25), 273(25), 282(25), 321, 539 (150), 542(165), 546(186), 550(206, 207), 563(267), 569, 570, 571, 573 Poupat, C., 539(150), 569 Pousset, J.-L., 93(32, 33), 107(53), 111(55), 112(55), 113(57), 114(57), 115(57, 59), 116(57, 59), 117(55, 57), 120, 121, 127(38), 130(39), 135(46, 47), 136 (47, 48a), 138(47,48a), 143(46,47),155,158 (17, 20a), 159(17, 20a), 167(20a), 168 (20a), 178, 547(194), 570 Powell, R. G., 319(71), 323 Pozdnyakova, V. T., 500(89), 501(89), 505 Prakash, A., 355(17), 403 Prakash, D., 426(5), 502 Prein, N., 93(34), 120 Preininger, V., 246(50), 264 Prelog, V., 182(7), 209 Preobrazhenskii, N. A., 207(24, 25), 223 Preston, N. W., 327(2), 346, 513(24), 543 (166), 564, 569 Preuss, D. L., 190(14), 222 Price, S. J., 546(189), 570 Primukhamedov, I., 557(232), 571 Prista, L. N., 168(32), 179 Proskurnina, N. F., 33(98, 99, 104), 53 (98), 54(98, 99), 56(99), 67(99), 68 (98, 99, 104), 81 Przybylska, M., 88(15), 120 Pulatova, Kh. G., 242(44), 256(44), 263 Pyuskyulev, B., 93(38, 40), 109(40), 117 (40), 118(40), 119(63), 121, 138(54), 143(54), 144(54), 156
Q Quassim, C., 181(1),222 Quevauviller, A., 500(82), 505 Quirin, F., 158(9), 159(9), 178 Qureshi, A. A., 157(2), 158(2), 159(2), 178
R Rachlin, A. J., 311(66), 323 Radunz, H. E., 138(50),156,157(3),158(4), 163(3), 170(3), 178 Raffauf, R. F., 1, 79, 350(9), 351(9), 360(9), 362(9), 403, 425(2), 502 Ramachandran, V. N., 513(26), 564 Ramage, R., 267(2a, 3), 270(20), 271(20), 277(2a, 3), 281(20), 288(28, 29), 289 (32), 290(2a), 292(2a), 293(20), 319 (70), 320, 321, 323, 558(234), 571 Randunz, H., 113(57a),121 Rane, D. F., 426(5), 502 Rao, K. V., 238(41), 239(41), 240(41), 242 (41), 256(41), 257(41), 258(41), 263 Raphael, R . A., 384(55), 404 Rashkes, Y. V., 534(127), 548(198), 568, 570 Rastogi, R . C . , 158(20), 159(20), 168(20), 178 Ray, A. B., 579(52), 565 Razafindrambao, R., 32(79), 33(79), 40 (79), 42(79), 53(79), 81 Razakov, R., 532(113), 567 Reber, L. J., 500(79), 505 Reeke, G. N., Jr., 5(15), 79 Rees, A. H., 427(17), 428(17, 39), 452(39), 505, 504 Reese, C., 164(27), 165(27), 178, 187(12), 204(22), 222 RBgnier, G . , 182(2), 222 Reichstein, T., 269(16), 279(16, 17), 281 (17), 322 Reiseh, J., 546(188), 553(215, 217a), 570, 571 Renner, U., 158(16), 159(16), 178 Rheiner, A., 279(15), 321 Ribas, I., 247(51), 248(51), 249(51), 250 (51), 256(51), 259(51), 264, 533(121), 568 Ribas-Marques, I., 539(151), 569 Ripperger, H., 27(73), 81 Rizk, A. M., 530(109), 567 Roberts, J. D., 17(52), 80 Robinson, F. V., 512(19), 564 Rodewald, W. J., 350(4), 351(3, 4), 352(4), 353(3), 359(4), 403 Rodrigo, R., 408(3), 410(3, 4), 411(3, 4), 412(4,7), 418(7, 12),421(4), 422(4, 12), 423
AUTHOR INDEX Rodriguez, B., 539(150), 569 Rogozkin, V. D., 500(78), 505 Roller, P., 158(18), 159(18), 178 Roque, A. S., 168(32),179 Rosenberg, H., 526(84), 566 Rostotskii, B. K., 427(22), 500(90), 501 (go), 503, 505, 520(63, 64), 521(67, 68), 541(160), 566, 569 Rouffiac, R . , 429(64), 495(64), 504 Rowson, J. M., 93(32), 120 Roychoudhurey, R., 500(80), 505 Ruggles, A. C . , 16(51), 80 Rugueiro-Garcia, M., 539(151), 569 Rulko, F., 532(116), 567 Ruppel, H. G . , 536(134), 568 Ruyssen, R., 210(29), 223 Ruzicka, L., 68(109), 82
S Sabirov, K. A., 561(255), 572 Sadykov, A. S . , 520(57), 543(168), 557 (232), 565, 569, 571 Saeki, Y., 3(7a), 33(7a, 81), 34(81), 36(7a), 40(81), 58(81), 59(81), 60(81), 62(81), 63(81), 64(81), 65(81), 75(81), 79, 81, 467(46), 468(46), 469(46), 470(46), 504, 539(153, 156), 569 Saito, S., 427(13, 23, 24, 25, 26), 428(13, 26, 34, 54, 55, 57), 429(52, 53, 61, 62), 430(25, 26), 431(25), 434, 435(25, 27), 436(26, 27), 437(27), 438(27), 439(27, 28), 440(26), 441(26, 28), 443(27, 30), 444(30), 445(30, 31, 32), 446(30, 31, 32), 447(26, 31, 32, 34), 453(26), 455 (26, 40), 456(40), 457(40), 458(40), 464 (25), 471(48), 473(25), 476(30, 32), 477 (32, 52, 53), 478(54, 55), 479(55), 480 (55),481(54),484(57),485(57), 486(57), 487(57), 488(57), 489(61, 62), 490(62), 492(62), 493(62), 494(62), 495(53, 61, 62), 496(27, 65, 66, 67, 68, 69, 71, 72), 497(67), 498(69), 499(65, 69), 503, 504, 505 Salch, M., 268(7), 278(7), 321 Samoryadov, B. A., 555(224), 571 Sandberg, F., 528(94), 534(125), 559(239), 567, 568, 572 Sandor, P., 427(20), 503 SantavJi, F., 246(50), 264, 267(2, 2c, 8), 268(2, 2c, 7, 8, 12), 269(16), 270(2),
591
277(2, 2c, 4), 278(7, S), 279(2, 12, 13, 16), 281(17), ZSS(l2, 13), 296(13), 310 (13), 314(13), 319(70), 320, 321, 323, 421(16), 423, 537(143), 568 Bantav9, J., 267(2), 268(2), 270(2), 277(2), 279(2), 320 Santos, G. A., 517(43, 44), 565 Sarpong, K., 93(25), 120, 123(7, 9, 12, 16), 124(7,9,12),125(7,9, l6), 138(82, 53), 145(52, 53), 154, 155, 156 Sasaki, K., 511(12), 564 Satish, S., 522(73), 566 Sato, K., 228(19), 229(19), 255(19), 258 (19), 263 Sato, N., 7(17), 19(62), 79, 80 Sato, P. T., 512(22), 564 Sato, Y., 1, 79, 496(67, 69), 497(67), 498 (69), 499(69), 505 Satoda, I., 427(14), 428(14), 430(14), 432, 433, 443(14), 452(14), 453, 454(14), 455, 471(14), 474(14), 503 Satoh, I?., 277(2b), 279(18), 290(2b), 292 (40), 293(2b, 18, 40, 41, 42), 294(45, 47), 299(52, 53), 315(40), 320, 321, 322 Satoh, Y., 267(61), 310(61), 319(72), 322, 538(147), 568 Saunders, J. K., 278(9), 321, 408(3), 410 (3, 4), 411(3, 4), 412(4), 421(4), 422 (4), 423 Sawa, Y. K., 209(27), 217, 223 Sawhney, R. S., 522(72), 566 Saxton, J. E., 84(2, 3, 6), 103(2), 104(2), 109(2), 113(2, 6), 114(6), 119, 120, 127(37), 155 Sbitneva, M. F., 500(78), 505 Schell, F. M., 87(12), 104(12),120 Schenker, E., 171(47),179 Schleigh, W. R., 33(88a), 39(88a), 43(88a), 44(88a), 46(88a), 47(88a), 48(88a), 49 (88a), 56(88a), 81 Schlessinger, R. H., 227(10), 228(10), 263, 390(61), 392(61), 405 Schlittler, E., 35, 81, 344(17), 346, 559 (243), 572 Schlunegger, E., 538(144), 551(212), 568, 571 Schmid, H., 158(16), 159(16), 170(44), 174 (49), 178, 179, 546(187), 570 Schmid, M., 546(186), 570 Schneider, G., 182(4), 222
592
AUTHOR INDEX
Schreiber, K., 1(3), 20(65, 66), 21(67), 24 (70, 71, 72), 27(72, 73, 74), 28(75, 76), 68(110, l l l ) , 78(123, 124), 79, 80, 81, 82 Schreiber, W. L., 194(21), 196(21), 223 Schultz, A. G., 515(37), 565 Schultz, 0. E., 528(95), 567 Schutte, H. R., 78(122), 82, 397(70), 405 Schwarting, A. E., 525(80), 566 Schwartz, H., 88(14), 90(14), 120 Schweizer, E. E., 544(176), 569 Scopes, P. M., 278(5), 321 Scott, A. I., 157(2), 158(2), 159(2), 178 Scott, J. W., 7(23), 13(47), 7 9 , 80 SedlBk, B., 33(86), 35(86), 81 Sedmera, P., 279(17), 281(17), 321, 537 (143), 568 Seebeck, E., 5(13, 14), 79 Sefcovic, P., 530(107), 567 Segebarth, K.-P., 211(32), 223 Seiber, R. P., 219(48), 223 Seino, C., 305(59), 320(75), 322 Seo, S., 123(21), 125(21), 155 Shaffer, E., 544(176), 569 Shaimardanov, R. A., 561(252), 572 Shakiroff, R., 21(68), 23(69), 32(69), 33 (105), 80, 81 Shakirov, T. T., 561(255), 572 Shamasundar, K. T., 6S(lOS), 71(108), 82 Shamma, M., 93(40), lOQ(40, 57), 110(54), 111(55), 112(55), 113(57), 114(57), 115 (57), 116(57), 117(40, 55, 57), 118 (40), 119(63), 121, 135, 136(47), 138 (47, 54), 143(46, 47, 54, 55), 144(54, 553 56), 255, 156, 311(66, 67), 312, 323, 380(47), 404, 560(246, 247, 248), 572 Shanmugasundaram, G., 230(28), 231(28), 263 Sharafutdinova, S . M., 534(126), 568 Sharma, G. M., 549(203), 570 Sheichenko, V. I., 264 Shellard, E. J., 92(19, 20), 93(25, 26, 29), 94(26, 52), 105(52), lOS(26), 109(19), 118(62), 119(19, 65), 120, 121, 123 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 17, 18, 19, 23), 124(4, 5, 7, 9, 10, 11, 12), 125(1,4, 5,7, 9, 10, 16, 17, 18, 19), 126(1, 11, 17, 18, 19), 127(25, 26, 27, 28, 29, 30, 31, 32), 128(3, 4, 6), 138 (19, 51, 52, 53), 145(19, 51, 52, 53),
154, 155, 156, 158(12, 13), 159(12, 13, 21, 22, 23, 24), 168(29a),178, 179 Shevtsova, N. M., 559(242), 572 Shibata, K., 11(43), 12(43), 13(43),80 Shibuya, S., 267(61), 310(61, 63), 320(75), 322, 323 Shigematsu, N., 427(26), 428(26, 34), 430 (26), 431(26), 434(26), 435(26), 439 (28), 440(26), 441(26, 28), 447(26, 34), 453(26), 455(26), 471(48), 496(65, 69, 71, 72), 498(69), 499(65, 69), 503, 504, 505 Shih, H.-T., 235(38), 236(38), 263 Shilkin, C. D., 518(48), 565 Shine, R. J., 93(40), 109(40, 57), 111(55), 112(55), 113(57), 114(57), 115(57), 116(57), 117(40, 55, 57), 118(40), 119 (63), 121, 135(46, 47), 136(47), 138 (47, 54), 143(47, 55), 144(55), 155, 156 Shinkarenko, A. L., 19(61), 80 Shipton, J., 551(210), 571 Shiro, M., 446(33), 503 Shirshova, T. I., 517(40, 41), 565 Shishido, H., 416(10), 423 Shishido, K., 305(57), 322 Shiuey, S. J . , 190(14), 222 Shizuri, Y., 529(99, 100, 101, 102), 567 Shoeb, A., 508(4), 564 Sholl, A. F., 517(41), 565 Shvydkii, B. I., 500(85), 501(85), 505 Siddiqui, S., 158(10), 159(10), 178 Siirala-Hansen, K., 541(162), 569 Simes, J. J . H., 69(116), 71(117), 82 Sims, J. J., 133(41), 255 Singh, J., 551(209), 571 Sioumis, A. A., 123(15), 125(15), 155, 227 (7, 8 ) , 228(7, S ) , 262, 271(22, 23, 24), 272(22, 23, 24), 273(22, 23, 24), 274 (22, 23, 24), 275(22, 23, 24), 276(22, 23, 24), 282(22, 23, 24, 27), 289(24), 316(24), 317(24), 321, 326(3, 4, 5, 9, 10, 11, 14, 15), 327(3, 4, 5), 330(4, Q ) , 331(4), 332(5, 9, 10, ll), 335(4, 5), 337 (4, 5, 9), 343(14, 15), 344(15), 346, 350(11), 403, 523(74), 528(96), 547 (190), 549(201), 552(213), 557(232a), 566, 567, 570, 571 Sjostrand, E., 549(204), 570 Slavik, J., 529(97), 567 Slavikova, L., 529(97), 567
593
AUTHOR INDEX
Slywka, G. W. A., 527(89), 567 Smalberger, T. M., 515(33), 565 Smith, G. F., 158(7, 19), 159(19), 160(7, 25, 26), 163(7), 178 Smith, L. W., 514(32), 562(263), 565, 572 Smith, P., 390(60), 404 Smith, R. M., 542(163), 569 Smith, T. K., 227(7), 228(7), 262 Smula, V., 412(7), 418(7), 423 Snatzke, G., 27(73), 81, 269(16), 279(16, 17), 281(17), 321 Snieckus, V. A., 426(3, 9), 502 Snoddy, C. S., Jr., 18(56), 80 Snyckers, F. O., 555(223), 571 Sonnet, P. E., 235(36), 245(36), 254(36), 255(36), 256(36), 258(36), 263 Soper, A. C., 390(62), 405 Borm, F., 1, 2(2), 79 Southgate, R., 211(35), 223 Spenser, I. D., 394(65), 396(65, 66), 397 (67, 68), 398(65, 66), 399(71, 72), 400 (73), 401(73, 74, 75), 405 Spiteller, G., 32(92), 46(92), 51(92), 81, 93 (40), 109(40), 117(40), 118(40), 121, 143(55), 144(55), 156, 549(200), 570 Spitteler-Friedmann, M., 32(92), 46(92), 51(92), 81 Spraque, P. W., 17(52), 80, 146(62), 147 (62), 156 Springer, H., 554(219), 571 Srinivasan, M., 230(27a), 241(43), 243 (27a), 244(27a), 245(27a), 252(27a), 253(27a), 256(43), 257(27a), 258(43), 263 Stanislas, E., 3(8, lo), 33(8, lo), 41(10), 42 (lo), 47(10), 54(10), 56(10), 79 Stauffacher, D., 5(14), 57(100), 79, 81 Stecka, L., 526(87), 567 Steinegger, E., 538(144), 551(212), 568,571 Stekol’nikov, L. I., 521(69), 566 Stenberg, V. I., 219(46), 223 Stepanyants, A. U., 33(98, 104), 53(98), 54(98), 68(98, 104), 81 Stephenson, L., 13(45), 80 Stermitz, F. R., 219(48), 223, 512(20), 564 Stern, P., 238(41a), 239(41a), 263 Stewart, G. W., 523(76), 566 Sticzay, T., 93(40), 109(40), 111(55), 112 (55), 117(40, 55), 118(40), 121, 135 (46), 143(46, 55), 144(55), 155, 156 Stoll, A., 5(13, 14), 79
Stork, G., 390, 392, 405, 416(11), 417(11), 423, 575(37), 565 Streeter, P., 556(226), 271 Strelow, F., 555(223), 571 Strothers, J. B., 87(11), 120 Suares, H., 182(27), 321, 326(5, l l ) , 327 (5), 332(5, l l ) , 335(5), 337(5), 346 Subramaniani, P. S., 320(75), 323, 513 (26), 564 Sueiras, J., 247(51), 248(51), 249(51), 250 (51), 256(51), 259(51), 264, 533(121), 568 Suffness, M. I., 7(21), 79, 233(33), 234(33), 255(33), 258(33), 263 Sugahara, H., 323 Sugahara, T., 310(63), 322 Sugavanam, B., 194(21), 196(21), 223 Sugi, H., 310(63), 322 Sugimoto, N., 427(13, 23, 24, 25, 26), 428 (13, 26, 54, 55), 429(52, 53, 61, 62), 430(25, 26), 431(25, 26), 434(26), 435 (25, 26), 436(26), 440(26), 441(26), 447(26), 453(26), 455(26), 564(25), 573(25), 477(52, 53), 478(54, 55), 479 (55),480(55), 481(54), 489(61,62), 491 (62, 63), 492(62), 493(62), 494(62), 495 (53, 61, 62), 496(66, 67, 68, 69, 71, 72), 497(67), 498(69), 499(69), 503, 504, 505 Suginone, H., 6, 7, 8(27, 29), 79 Sugiura, K., 529(100, 101, 102),567 Summons, R. E., 518(49, 50), 565 Sunguryan, T., 518(47), 565 Sur, R., 168(31),179 Surzur, J.-M., 499(74), 505 Sutar, C. V., 535(132), 568 Suzuki, M., 445(32), 446(32), 447(32), 476 (32), 477(32), 503 Suzuki, Y., 500(81), 505 Svoboda, G. H., 93(36), 121, 227(10), 228 (lo), 263 Swan, R. J., 170(44), 179 Swift, D., 511(14),564 Szendrei, K., 553(214, 215, 217a), 571
T Tackie, A. N., 93(26), 94(26, 52), 105(52), lOS(26), 120, 123(8), 124(8), 133(41), 154, 155
594
AUTHOR INDEX
Taga, T., 558(237), 572 Taguchi, M., 123(21), 125(21), 155 Takahashi, K., 300(54), 322 Takano, S., 293(43, 44), 299(51), 322, 546 (185), 570 Takao, N., 514(29, 30), 564 Takasugi, M., 7(20), 8(24, 25), 9(30), 10 (25, 40), 15(49), 19(62), 79, 80 Takeda, Y . ,211(37), 213(37), 223 Takeuchi, N., 228(19), 229(19), 255(19), 258(19), 263 Takubo, K., 416(10), 423 Talapatra, B., 168(30), 179, 233(32), 234 (32), 235(32), 255(32), 263, 536(137 139), 568 Talapatra, S. K., 168(30), 179, 233(32), 234(32), 235(32), 255(32), 263, 536 (137, 139), 568 Tamura,Y.,427(13, 23, 24,26), 428(13, 26, 54, 55, 57), 429(52, 53, 61, 62), 430 (25, 26), 431(25, 26), 434(26), 435(25, 26, 27), 436(26, 27), 437(27), 438(27), 439(27, 28), 440(26), 441(26, 28), 443 (27, 30), 444(30), 445(30, 31, 32), 446 (30, 31, 32), 447(26, 31, 32), 453(26), 455(26, 40), 456(40), 457(40), 458(40), 464(25), 471(48), 473(25), 476(30, 32), 477(32, 52, 53), 478(54, 55), 479(55), 480(55), 481(54), 484(57), 485(57), 486 (57), 487(57), 488(57), 489(61, 62), 490(62), 491(63), 492(62), 493(62), 494 (62), 495(53,61,62),496(27,65,66,67, 68, 69, 71, 72), 497(67), 498(69), 499 (65, 69), 503, 504, 505 Tanaka, K., 539(154), 569 Tanaka, S., 543(167), 56.9 Tanaka, T., 329, 330(7), 337(7), 346, 427 (13), 428(13, 54, 55), 429(52, 53, 61, 62), 477(52, 53), 478(54, 55), 479(55), 480(55), 481(54), 489(6l, 62), 491(62, 63), 492(62), 493(62), 494(62), 495 (53, 61, 62), 503, 504 Tani, C., 514(29), 564 Tantivatana, P., 92(19), 109(19), 119(19, 65), 120,122, 123(10, 19), 124(10), 125 (10, 19), 126(19), 138(19, 51), 145 (19, 51), 154, 155, 156 Tashiro, J., 182(5), 222 Taylor, C. G . , 344(18), 346, 559(244), 572 Taylor, D. A. H., 427(17), 428(17), 503 Taylor, D. R., 368(38), 369(38), 404
Taylor, E., 192(17), 194(17), 197(17), 199 (17), 222 Taylor, W. I., 94(48), 99(48), 109(48), 113 (48), 121, 133(42), 155, 174(49), 179, 182(7), 209(7), 222, 226(2), 227(9), 228(2), 235(9, 39), 236(2), 250(52), 251 (52), 254(39),255(39), 257(52), 258(9), 262, 263, 264 Teissier, P., 499(73), 505 Teitel, S., 282(21), 293(21), 311(66),321,323 Telezhenetskaya, M. V., 242(45), 264, 541 (161), 548(196, 197, 198), 561(251), 569, 570, 572 Terao,S.,3(7a),33(7a,81),34(81),36(7a),40 (81), 58(81), 59(81), 60(81), 62(81), 63(81), 64(81), 65(81), 75(81), 79, 81, 428(35), 429(43), 447(35), 458(42), 464(42, 43), 465(42), 466(43, 45), 467 (44, 45, 46), 468(46), 469(43, 45, 46), 470(46), 471(35, 43, 50, 51), 472(40, 51), 473(50, 51), 474(35, 51), 475(35), 476(35), 483 (42), 503, 504 Terent’eva, I. V., 517(40, 41), 565 Terui, T., 311(65), 314(69), 322, 323 Teslov, S. V., 426(6), 502 Thomas, R., 92(18), 120 Thommesen, W. C., 500(79), 505 Tirions-Lampe, M., 158(15), 159(15), 178 Tkeshelashvili, E. G . , 537(142), 568 Tobinaga, S., 228(19), 229(19), 255(19), 258(19), 263 Tolkachev, 0. N., 264 Tomczyk, H., 158(8), 159(8), 178 Tomita, M., 226(4), 227(14), 228(18, 22, 25), 230(14), 235(14, 38), 236(38), 240 (4), 250(14), 253(14), 255(14), 257(14), 262, 263 Tomko, J., 10(39), 17(53, 54, 55), 18(53, 57), 19(53), 20(64, 65, 66), 24(70, 71, 72), 27(72, 74), 28(75, 76), 30(77), 32 (103), 33(103), 66(103), 78(128), 80, 81, 82 Tordo, P., 499(74), 505 Torto, F. G . , 530(107, 108), 567 Torupka, E. J., lO(41, 42), ll(41, 42), 16 (411, 86 Trager, W. F., 93(27), 94(27), 94(27), 103 (27), 105(27), 106(27), 107(27), 120, 123(13), 124(13), 127(13, 36), 130(13), 131(13, 40), 132(13), 133(13), 134(45), 135(45), 154, 155
595
AUTHOR INDEX Travecedo, E. F., 219(46, 47), 223 Trofimova, N. A., 502(99, 101, 102), 506 TrojBnek, J., 109(41), 121 Trotzyan, A. A., 543(169), 569 Trujillo, J., 562(262), 572 Trumbull, E. R., 467(47), 504 Tsakadze, D. M., 532(113), 567 Tschesche, R., 512(17, 18), 520(59), 556 (225), 564, 565, 571 Tsuji, Y., 427(14), 428(14), 430(14), 432 (14), 433(14), 443(14), 452(14), 453 (14), 454(14), 455(14), 471(14), 474 (14), 503 Turch, B., 518(51), 565 Turdikulov, Kh., 520(57), 565 Turner, D. W., 289(36), 294(49), 321, 322 Turner, R. B., 182(9), 183(9), 185(9), 187 (9), 222 Turova, A. D., 499(75), 500(75, 76), 505 Tweedale, H. J., 562(263), 572
U Ueda, F., 247(51), 248(51), 249(51), 250 (51), 256(51), 259(51), 264 Ueda, S., 211(37), 213(37) Uemura, D., 530(104), 567 Umarov, K. S., 242(45), 264, 560(249), 561(251), 572 Urszulak, I., 427(21), 500(21), 503 Uskokovib, M. R., 164(27, 28), 165(27), 167(28), 170(28), 178, 183(10, l l ) , 185 ( l l ) , 187(12, 13), 188(10, 13), 190(14), 192(16), 193(19), 194(20), 197(20), 199(10, 16), 204(22), 207(26), 220(51), 222, 223 Uyeo, S.,552(212a), 558(237), 571, 512
V Valenta, Z., 381(48), 384(54), 387(58), 404 Valverde-Lopez, S., 350(9, lo), 351(9, lo), 360(9, lo), 362(9, lo), 363(10), 369 (lo), 372(44, 45), 375(45), 403, 404 van Tamelen, E. E., 104(50), 121, 134(43, 44), 155 Varga, J., 427(20), 503 Vasil’kov, P. N., 536(136), 568 VassovB, A., 17(53), 18(53, 57), 19(53), 20
(64), 24(70, 71), 27(74), 28(75, 76), 32 (103), 33(103), 66(103), 80, 81 Veith, H. J., 546(187), 570 Venkateswarlu, A., 230(27a), 243(27a), 244(27a, 48), 245(27a), 252(27a), 253 (27a), 256(48), 257(27a), 258(48), 263, 264 Venkov, A. P., 575(34), 565 Vermel, E. M., 500(83), 505 Vernengo, M. J., 278(5), 321 Verpoorte, R., 559(239), 572 Vijayr Nair, G . , 16(50), 80 Villar de Fresno, A., 558(238), 572 Vincent, R. L., 5(15), 79 Vinogradova, V. I., 561(253), 572 Viswanathan, N., 233(34), 235(34), 251 (34), 255(34), 257(34), 263, 426(5), 502, 513(26), 564 Vleggaar, R., 515(33), 565 Voigt, B., 68(110, l l l ) , 82 von Langenthal, W., 235(39), 254(39), 255(39), 263 Voser, W., 68(109), 82 Votickjr, Z., 17(54), 28(75, 76), 30(77), 32 (86a, 103), 33(86, 86a, 103, 106), 34 (82), 35(86), 36(86a), 65(106), 66(103, 106), 68(86a), 75(106), 76, 80, 81, 82
W Wada, H., 529(99, 100, 101, 102), 567 Waegell, B., 499(73), 505 Wakisaka, J., 238(41a), 239(41a), 263 Walker, T., 13(45), 80 Walkowiak, M., 113(57a), 121, 138(50), 156, 158(4), 178 Wall, M. E., 515(36), 565 Wanat, S. F., 192(18),205(18), 223 Wang, S.-J., 226(1), 228(1), 235(38), 236 (38), 262, 563, 520(62), 542(164), 566, 569 Wang, T.-W., 542(164), 569 Wani, M. C . , 515(36), 565 Wapinsky, J., 525(79), 566 Warnock, W. D. C., lO(41, 42), ll(41, 42), 16(41, 50), 80 Warthen, D., 227(5), 228(5), 231(5), 254 (5), 255(5), 262 Watanabe, M., 19(63), 23(63), 78(63), 80 Waterman, P. G., 530(106), 567
596
AUTHOR INDEX
Watson,,T. G., 69(116), 82 Webber, G. M., 319(73), 323 Weiess, U., 410(5), 423 Weinstein, B., 556(229), 571 Weisbach, J. A., 238(41), 239(41), 240 (41), 242(41), 256(41), 257(41), 258 (41), 263, 350(9), 351(9), 360(9), 362 (g), 403 Weiss, J. A., 119(63), 121, 138(54), 156, 380(47), 404 Welzel, P., 68(113), 82 Wemple, J. N., 211(30, 33), 213(30, 33), 223 Wendler, N. L., 18(56), SO Wenkert, E., 84(10),86(10, 13), 87(12, 13), 88(10, 16), 89(16), 90(10), 91(10), 92 (17), 95(17), 104(12), 111(17), 120, 146(62), 147(62), 156, 217, 223 Whitcomb, E. R., 500(79), 505 White, E. P., 527(91), 567 Whitfield, F. B., 551(210), 571 Whiting, D. A., 544(177), 569 Whitlock, H. W., Jr., 13(48), 80 Wick, A. E., 536(133), 568 Wickberg, B., 88(16), 89(16), 120 Widdowson, D. A., 289(36), 294(49), 321, 322 Wiechers, A., 555(223), 571 Wiegrebe, W., 524(77), 566 Wiesner, K., 381, 384, 387(58), 389(59), 404 Wiesner, K. J., 389(59), 404 Willaman, J. J., 425(1), 426(1), 502 Williams, C. A. J., 381(49), 404 Willing, R. I., 326(4, 5, l l ) , 327(4, 5), 330 (4), 331(4), 332(5, l l ) , 335(4, 5), 337 (4, 5), 346, 509(6), 523(74), 564, 566 Wilson, A. J. C., 84(8), 120 Wilson, B. M., 13(45), 80 Winterfeldt, E., 113(57a), 121, 138(50), 156, 157(3), 158(4), 163(3), 170(3), 178 Wintersteiner, O . , 7(18, 19, 22), 8(26), 7 9 Witkop, B., 182(8), 222, 551(208), 571 Wong, C. F., 545(182, 183), 570 Wong, C. M., 384(54), 404 Woodward, R. B., 68(112), 82, 182(9), 183 (9), 185(9), 187(9), 222 Workman, S. M., 512(20), 564 Wrbbel, J. T., 160(26), 178, 394(65), 396 (65), 398(65), 405
Wunderlich, J. A., 271(22), 272(22), 273 (22), 274(22), 275(22), 276(22), 282 (22, 26), 321, 326(3, 6), 327(3, 6), 346
Y Yagi, H., 277(2b), 279(18), 290(2b), 292 (40),293(2b, 18, 40, 41, 42), 299(52, 5 3 ) , 315(40), 320, 321, 322, 323 Yagudaev, M. R., 117(61), 121, 519(55), 565 Yakhontova, L. D., 264,533(119, 120), 568 Yamada, K., 529(99, 100, 101, 102), 567 Yamada, S., 219(49), 223, 543(171), 569 Yamamoto, K., 523(75), 566 Yamatodani, S., 549(199), 570 Yamauchi, M., 428(54,55, 58), 478(54,55), 479(55), 480(55), 48(54), 484(58), 486 (58), 487(58), 488(58), 496(70), 499 (70), 504, 505 Yamawaki, Y., 427(26), 428(26), 430(26), 431(26), 434(26), 435(26, 27), 436(26, 27), 438(27), 439(27, 28), 440(26), 441 (26, 28), 443(27, 30), 444(30), 445(30, 31), 446(30, 31), 447(26, 31), 453(26), 455(26, 40), 456(40), 457(40), 458 (40), 476(30), 496(27, 69), 498(69), 499(69), 503, 504, 505 Yamazaki, I., 6(16), 8(25), lO(25, 40), 79, 80 Yanagawa, H., 543(167), 569 Yang, H.-M., 227(14), 230(14), 235(14), 250(14), 253(14), 255(14), 257(14), 263 Yang, S.-S., 227(15), 253(15), 263 Yang, T. H., 428(35), 429(43), 447(35), 458(42), 464(42, 43), 465(42, 43), 466 (43, 45), 467(44, 45), 469(43, 45), 471 (35, 43, 50, 51), 472(50, 51), 473(50, 51), 474(35, 51), 475(35), 476(35), 483 (42), 503, 504 Yang, T.-H., 227(13, 14, 15), 228(13, 21, 23, 24), 230(14), 235(14), 250(14), 251 (53), 252(53), 253(14, 16), 255(14), 257(14, 53), 263, 264, 511(13), 541 (159), 542(164), 544(179), 564, 569, 570 Yardley, J. P., 104(50), 121, 134(43, 44), 155 Yasui, B., 350(7), 351(7), 352(7), 357(7), 365(25, 26, 27, 28, 29), 366(7, 35), 367
597
AUTHOR INDEX (26,35,36),368(35,39), 369(35,39), 403, 404 Yeh, P.-T., 227(15),253(15), 263 Yeoh, G. B., 84(7),109(7), 120 Yoshida, N., 78(127),82 Yoshii, E., 427(14),428(14),430(14),432 (14),433(14), 443(14), 452(14), 453 (14),454(14), 455(14), 471(14), 474 (14),503 Yoshii, N., 500(81), 505 Yoshikawa, H., 435(27),436(27),437(27), 438(27),439(27),443(27),455(40),456 (40),457(40),458(40),496(27,65,67, 69),497(67),498(69),499(65,69),503, 504, 505 Yoshikawa, Y., 523(75),566 Youngken, H. W., Jr., 182(5),222 Yuldashev, P. Kh., 93(35),94(45,46),109 (46),119(46, 64), 120, 121, 144(58), 156, 158(14),159(14),178 Yunusoff, S. Yu., 21(68),23(69), 32(69), 33(105), 80, 81 Yunusov, M. S., 227(11), 228(11), 263, 520(65),522(70),532(112),566, 567
Yunusov, S . Y., 94(45,46), 109(46), 117 (61),119(46,64),121, 144(58,59),156,
519(53,54,55,56),520(65), 522(70), 532(112, 113), 534(126, 127), 535 (128), 537(140, l42), 541(161), 548 (195, 196, 197, 198), 560(249), 561 (251,252, 253), 564(268), 565, 566, 567, 568, 569, 570, 572, 573 Yunusov, S. Yu., 93(35),94(47),109(47), 119(47), 120, 121, 158(14), 159(14), 178, 227(11),228(11),242(44,45),256 (44),263, 264, Yusupov, M. K., 520(57), 543(168, leg), 565, 569 Ywayama, Y., 500(84),501(84), 505
Z Zanati, G., 547(191, 192),270 Zechmeister, K., 530(103),567 ZemBnek, M., 78(128),82 Zharkeev, B. K., 541(161),569 Zimmerman, D., 518(51),565
SUBJECT INDEX A Abuta imene, 241, 262 N-Acetylcycloprotobuxine-D,43 Acetyldebenzoylalopecurine, 351, 360 Acetylcorynoline, 521 Acrifoline, 350 Adenocarpine, 507 Adenocarpus mannii, 507 Adhatodine, 508 Adhatoda vmica, 507 Adlumidine, 522 Aegelenine, 508 Aegle marmelos, 508 Ajmalicine, 126 Akuammicine, 158 Akuammidine, 159, 168 Akuammigine, 126, 159 Akuammiline, 158 Akuammine, 159 Alangium lamarckii, 508 Alangiside, 508 Albertidine, 537 Alchornea jloribunda, 509 Alchornea hirtella, 509 Alchornea javanensis, 509, 553 Alchorneine, 509 Alchornidine, 509 Alchornine, 509 Alkaloids A, 278, 282, 375, 557 A4, 554 B, 282 BX-6, 68 BX-10, 68 C, 282 CC-2, 319 CC-3b, 319 CC-10, 319 CC-20, 319 CC-21, 268 CC-24, 319 D, 282, 529 E, 67, 273, 282
F, 282 G, 274 H, 272 J, 275 K, 276 PO-3, 225, 246 Q, 31 Y, 32 387, 68 11, 111, IV, 319 Alkamine X, 31 Alloanodendrine, 511 Allocurnuine, 375 Allocryptopine, 512, 514, 520, 529, 532, 560 Alloelaeocarpiline, 326, 335 Allopecuridine, 351 Allosecurinine, 428, 452, 457 Alolycopine, 350, 366 Alopecurine, 349, 351, 360 Alsonine, 559 Alstonerine, 168 Alstonia congensis, 168 Alstonia constricta, 168 Alstonia macrophylla, 168 Alstonia muelleriana, 168, 177 Alstonia scandens, 168 Alstonia scholaris, 168 Alstonia venenata, 168 Alstonidine, 168, 171 Alstonilidine, 168, 170 Alstoniline, 170 Alstonine, 168 Alstonisidine, 168, 173, 178 Alteramine, 561 Ammodendrine, 538 Anabasine, 563, 539, 551 Anabazine D, 541 Anagyrine, 532, 561 Anamirta loureiri, 512 Ancistrocladine, 509 Ancistrocladus heyneanus, 509 Androcymbine, 277, 286 Androcymbium melanthioides, 268
SUBJECT IXDEX
9-Angelylretronecine, 514 Anhydrolycocernuine, 352 Anhydrolycodoline, 350 Anisessine, 510 h i s o t i n e , 508 Anisotes sessili$orus, 510 Annopodine, 349, 357, 364 Annotine, 349 Annotinine, 349, 353, 381 Annuloline, 511 Anodendrine, 511 Anodendron aflne, 511 Anolobine, 511, 544 Anona glabra, 228, 231 Anona purpurea, 235, 245 Anonaine, 511, 544, 552 Anona squamosa, 511 Antirrhynum majus, 511 Antirrhynum orontium, 511 Aralionine, 511 Araliorhamnus vaginatw, 511 Arborinine, 536 Argemonine, 537 Arcangelisia loureiri, 512 Argemone glauca, 512 Argentine, 561 Argyreia nervosa, 512 Ariocarpus kotschoubeyanus, 512 Ariocarpus retusus, 512 dris$o$eliapeduncularis, 327, 512 Armepavine, 529, 544 Arundo donax, 513 Asimilobine, 543 Asimina triloba, 228 Asperumine, 559 Aspidosperma rigidum, 93 Atalantia monophylla, 513 Atalaphylline, 513 Atheroline, 225, 236 Atherosperma moschatum, 228 Atherospermidine, 225, 230 Auriculine, 538 Aurotensine, 533
B Baikeine, 20 Baleabuxoxazine-C, 41 Balfouridine, 553
599
Bandeiraea simplicifolia, 533 Banisteriopsis argentea, 5 13 Batrachotoxin, 551 Batrachotoxinin, 551 Bellendena rnontana, 514 Bellendine, 514 Benzophenanthridine, 529 N-Benzoyl-0-acetylcycloxobuxoline-F, 48 N-Benzoylbuxidienine-F, 56 N-Benzoylcycloprotobuxoline-D, 44 N-Benzoylcycloxobuxidine-F, 47 N-Benzoylcyloxobuxine-F, 49 N-Benzoylcycloxobuxoline-F, 48 N -Benzoyldihydrocyclomicrophylline-F, 46 Berbsrine, 512, 520 Berberis aquifolium, 541 Bhesa archboldiana, 514 Bicuculline, 522 Bicyclomahanimbicine, 544 Bisnorargemonine, 529 Bocconia cordata, 514 Bocconia microcarpa, 514 Bocconoline, 514 Bolusanthus speciosus, 515 Brevicarine, 516 Byronia alba, 515 Bucharaine, 534 Bucharidine, 535 Bulbocodine, 269, 279 Bulbocodiurn vernum, 269, 279 Buxaltine-H, 57 Buxamine-A, 4, 32 Buxandonine-L, 64 Buxanine-M, 64 Buxarine-F, 51 Buxazidine-B, 35 Buxazine, 67 Buxene-0, 66 Buxenone-M, 65 Buxeridine-C, 40 Buxidieneine-I?, 52 Buxidine-F, 51 Buxitrienine-C, 40 Buxocyclamine-A, 34 Buxus alkaloids, Table, 32 Buxus balearica, 34 BUXWkoreana, 36 Buxus madagascarica, 32 Buxus microphylla, 34 B u m sempervirens, 34
600
SUBJECT INDEX
C Calycanthine, 514 Campanula medium, 515 Campedine, 515 Camptothecine, 515 Canadine, 541 Cancentrine, 407 Capaurimine, 516 Capsella bursa-pastoris, 516 Carapanaubine, 83,93,115,141 3-Carboxy-6,7-dihydroxy1,2,3,4-tetrahydroisoquinoline, 544 Carex brevicollis, 516 Carnegine, 534 Carolinianine, 352,378 Cassaide, 528 Cassamedine, 225,240 Cassameridine, 225,238 Cassamide, 528 Cassamidine, 528 Cassamine, 528 Cassia occidentalis, 517 Cassytha americana, 238 Cassytha jiliformis, 238 Caulerpa racemosa, 517 Caulerpin, 517 Celastrus orixa, 546 Cephalotaxus harringtonia, 319 Cernuine, 349,401 Cmtrum diurnum, 517 Cestrum nocturnum, 517 Cevanine, 1, 17 Cheilanthifoline, 543 Chelerythrine, 512,514,530 Chelidonine, 517 Chelidonium m a j w , 518 Cheline, 516 Chomelia bipindensis, 559 Chorilaena quercifolia, 518 Ciliaphylline, 83,93,94,105,124 Cinchona ledgeriana, 181,211 Cinchona succiruba, 209,211 Cinchonamine, 207,209,217 Cinchonidine, 220 Cinchonine, 220 Cinegalleine, 532 Cinegalline, 532 Cineverine, 532 Cinnamolaurine, 518
Cinnamomum species, 518 Clavatine, 351 Clavatoxine, 351 Clavolonine, 350,354 Clivorine, 537 Coccinella septempunctata, 518 Coccinellin, 518 Codeine, 410 Codonocarpine, 519 Codonocarpus australis, 519 Codonopsine, 519 Codonopsinine, 519 Codonopsis clematidea, 519 Codonopsis ovata, 519 Colchameine, 543 Colchamine, 543 Colchiceine, 543 Colchicine, 266,286,520,543,557 Colchicum autumnale, 277 Colchicum chalcedonicum, 521 Colchicum cornigerum, 268,319 Colchicum kesselringii, 520 Colchicum micranthum, 520 Colchicum szovitzii, 520 Colchicum speciosum, 557 Colchicum turcicum, 520 Colubrina asiatica, 520 Colubrina faralaotra, 521 Confusameline, 542 Coptis groenlandica, 520 Coramine, 522 Coreximine, 547 Corgoine, 520 Cornucervine, 549 Corpaine, 521 Corunnine, 225,247,533 Corycavine, 521 Corydaine, 521 Corydalis campulicarpa, 520 Corydalis jimbrillifera, 520 Corydalis gortschakovii, 520 Corydalis incisa, 521 Corydalis paczoskii, 521 Corydalis pallida, 521 Corydalis pseudoadunca, 522 Corydalis racemsa, 522 Corydalis stricta, 520 Corydine, 518,532 Corynantheidine, 125,130 Corynantheine, 134 Corynoline, 521
601
SUBJECT INDEX Corynoloxine, 521 Corynoxeine, 83, 94, 107, 124, 133 Corynoxine, 83, 94, 107, 124, 128 Corynoxine-B, 128 Corypalmine, 541 Coscinium fenestratum, 512 Coscinium wallichianum, 512 Cotinine, 517 Craspidospermum verticillatum, 168 Crotalaria medicaginea, 522 Croton sparsiiflorus, 522 Crotsparinine, 522 Crotspartine, 522 Cryptocarya pleurosperma, 522 Cryptopleuridine, 522 Cryptolpleurospermine, 522 Cularine, 523 Cuskohygrine, 555 Cycemanine, 521 Cyclobuxamine-H, 76 Cyclobuxidine-F, 53 Cyclobuxine-B, 35 Cyclobuxine-D, 76 Cyclobuxomicreine-K, 60 Cyclobuxophylline-K, 62 Cyclobuxophylline-M,65 Cyclobuxosuffrine-K,58, 76 Cyclobuxoviridine-L, 63 Cyclokorlanine-B, 36 Cyclomicrobuxeine-K,62 Cyclomicrosine-C,40 Cyclomicuranine-L, 64 Cyclopamine, 10 Cycloposine, 17 Cycloprotobuxine-A, 34 Cycloprotobuxine-F, 53 Cyclosuffrobuxine-K,65 Cyclosuffrobuxinine-M, 65 trans-Cyclosuffrobuxinine-M, 65 Cyclovirobuxeine-C,41 Cyclovirobuxine-C,41 Cycloxobuxazine-C,74 Cycloxobuxidine-F, 74 Cycloxobuxidine-H, 75 Cyclobuxoazine-A,75 Cycloxobuxoxazine-C,41 Cynanchum vincetoxicum, 524 Cynoglossum.imeretinurn, 547 Cypholophine, 524 Cypholophus frieskznus, 524 Cytisine, 515, 532, 557, 561
D Damascenine, 544 Damascinine, 544 Debenzoyalopecurine, 350, 360 Decatropic bicolor, 525 Decodine, 525 Dehydrocancentrine-A, 419 Dehydrocancentrine-B, 418 Dehydrocupreine, 562 Dehydrodecodine, 525 Dehydrojoubertiamine, 554 Dehydrolycopecurine, 350, 362 Dehydronuciferine, 253 Dehydrosparteine, 561 Demecolcine, 520, 557 3-Demethylcolchamine, 543 N-Demethylmesembrenol, 554 Dendramine, 526 Dendrine, 525 Dendrobine, 525 Dendrobium Jindleyanum, 525 Dendrobium friedriclcsianum, 525 Dendrobium hildebrandii, 525, 526 Dendroxine, 525 16-Deoxybuxidienine- C, 42 8-Deoxyserratinime, 351, 365 Deoxyvasicinone, 539 Des-N-methyl-a-obscurine, 352 Dibromophakellin, 549 Dicentra canademis, 407 Dicentrinone, 225, 244 Dictamnine, 518, 525, 534, 535, 556 Dihydrocorynantheine, 125, 135 Dihydroelaecarpidine, 559 Dihydrojoubertiamine, 554 Dihydrokreysiginone, 269, 279 Dihydrolycopodine, 350 Dihydronorsecurinine, 429 Dihydroquinamine, 185 Dihydrosecurinine, 428, 447, 499 Dihydrovirosecurinine, 473 2,4-Dimethoxy-lO-rnethylacridan-9-nine, 563 1,2-Dimethoxynoraporphine, 552 2,1O-Dimethoxyoxoaporphine, 225, 25 1 10,ll-Dimethoxypicraphylline,157, 167 4,7-Dimethoxy-1-vinyl-p-carboline, 549 p-Dimethylaminoethyl cinnamate, 528 2-Dimethylcolchicine, 520 2-Dimethyl-~-lumicolchicine, 520
602
SUBJECT INDEX
3-Dimethyl-~-lumicolchicine, 520 NN-Dimethylphenethylamine, 527 N,N-Dimethyltryptamine, 513, 514, 563 NN-Dimethyltryptophan, 527 Dioxypeganine, 548 6 fi-Dipiperidine, 507 Dolichothele sphaerica, 526 Dolichotheline, 526 Doritis taenialis, 536 Doryphora sassafras, 228 Dryadodaphne novoguineensis, 228 Dubinidine, 526
E Ecgonidine, 514 Echinatine, 547, 559 Echinops commutatus, 526 Echinops ritro, 526 Echinorine, 526 Echinospermum intermedium, 536 Echitamine, 168 Eorininine, 109 Elaecarpidine, 326, 343 Elaeocarpiline, 326, 333 Elaeocarpine, 326, 327 Elaeocarpus altisectus, 325 Elaeocarpus archboldianus, 325 Elaeocarpus dolichostylis, 325 Elaeocarpus densijlorus, 325 Elaeocarpus kaniemis, 325 Elaeocarpus polydactylus, 325 Elaeocarpus sphaericus, 325 Elaeocarpus trichophyllus, 326 Elaeokanidine A, 326, 342 Elaeokanidine C, 326, 343 Elaeokanine A, 326, 338 Elaeokanine B, 326, 339, 343 Elaeokanine C, 326, 339 Elaeokanine D, 326, 340 Elaeokanine E, 326, 341 Eleagnine, 513 Eleagnus argentea, 527 Eleagnus commutata, 527 Elegantine G3, 118 Ellipticine, 546 Enantia pdosa, 182 Enantia polycarpa, 182 Epiallocernuine, 375 Epialloelaeocarpiline, 326, 335
Epielaeocarpiline, 326, 334 Epi-isoelaeocarpiline, 326, 332 Epilupinine, 539 12-Epilycodoline, 351, 354, 359 12-Epilycopodine, 354, 387 Epimeloscine, 542 22,26-Epiminocholestane,1, 20 3-Epinuphamine, 545 Epiquinidine, 184 Epiquinine, 184 3-Epischelhammericine, 273 3-Epischelhammeridine, 274 3-Epischelhammerine, 272 Eria javensis, 527 Erica lustanica, 527 Erycinine, 94, 119 Erysodine, 527 Erysopine, 527 Erysotrine, 527 Erythraline, 527 Erythramine, 527 Erythratine, 527 Erythrina lithosperma, 527 fi-Erythroidine, 527 Erythrophlamide, 528 Erythrophlamine, 528 Erythrophleguine, 528 Erythrophleum chlorostachys, 528 Erythrophleum ivorense, 528 Erythroxylum ellipticum, 528 Eschscholtzia californica, 528 Eschscholtzia douglassi, 528 Eschscholtzia glauca, 529 Etioline, 20, 23 Eunonymus europaeus, 529 Euonymus sieboldianus, 529 Euphorbia atoto, 551 Euphorbia mil& 530 Evolitrine, 542 Evonine, 529 Evonymine, 529 Evoxanthine, 563
F Fagara capensis, 530 Fagara macrophylla, 530 Fagara xanthoxyloides, 530 Fagaradine, 530 Fagaramide, 530
603
SUBJECT INDEX
Pagonia erecta, 530 Fawcettidinc, 349, 350, 366 Fawcettimine, 366 Flabelliforminc, 350, 354 Plindersia iflaiana, 530, 536 Flindersiamine, 534 Flindersine, 531 Floramultine, 220, 281 Formosanine, 83, 113, 125, 139 N-Formylcyclovirobuxeine-B, 38 Pumaria parvijlora, 532
G Galanthus caucasicus, 532 Galanthusine, 532 Gambirdinc, 93, 118, 125 Gambirine, 125, 135 Gambirtannine, 123, 146 Gelsedine, 83, 88 Gelsemicinc, 83, 88 Gelseminc, 83, 84 Gelsevcrine, 83, 90 Genista angulata, 532 Genista cinerea, 532 Gentiabetin, 532 Gentiabutin, 532 Gentiana asclepiadea, 532 Gentianidine, 532 Gentianine, 532 Germine, 18 Girinimbinc, 532, 544 Glaucine, 533, 552 Glauciurn corniculaturn, 532 Glaucium jlavum, 235, 247, 262, 533 Glauvinc, 262 Gramine, 513, 539 Grandifolinc, 541 Griffonia simplicifolia, 533 Guatteria psilopus, 231 Guatterine, 231
H Halfordia scleroxyla, 508 Halfordinal, 508 Halfordinol, 534 Haloxylon articulatum, 534 Hammarbya paludosa, 538 Haplophyllum bucharicum, 534
Haplophyllum suaveolens, 535 Harman, 517, 530 Harmine, 517 Harmol, 517, 556 Heimia salicdfolia, 525 Helietta longifolia, 534 Heliotridinc, 559 Heliotrine, 532 Herbaline, 93, 119, 138 Herbavine, 93 Hernandesine, 560 Hernandia jamaicensis, 243 Hernandia ovigera, 243, 535 Hernandia papuana, 243, 535 Hernandonine, 225, 535 Hernangerine, 535 Hesperethusa crenulata, 535 Heteroyohimbane oxindolcs, 99, 109 Hirsutine, 125, 135 Histamine, 516 Homoaporphine, 289 Homobatrachotoxin, 55 1 Homoerythranes, 550 Homoerythrina alkaloids, 289 Homonoia riparia, 557 Homoproaporphine, 289 Homoprotoberberine, 311 Hordeninc, 512, 553 8-Hydrastine, 520, 522 16-Hydroxy-a-colubrine,559 2-Hydroxydendrobine, 525 6.Hydroxydendroxinc, 525 2-Hydroxyethylcinnamamide, 528 N-2-Hydroxycthyl-N-cinnamamidc, 528 N-2-Hydroxycthyl-N-mcthyl-trans-phydroxycinnamamide, 528 5-Hydroxyindole-3-acetic acid, 533 Hydroxylunidine, 553 Hydroxylunine, 553 Hydroxylupanine, 561 6-Hydroxynobilinc, 526 Hydroxytropane, 549 5-Hydroxytryptamine, 533 5-Hydroxytryptophan, 533 Hyoscyamine, 555 Hypaphorine, 527
I Ifflaiamine, 530 Imenine, 225
SUBJECT INDEX Inandenine, 546 J Inundatine, 350,363 Ipalbidine, 535 Japonine, 546 Ipalbine, 535 Jatrorrhizine, 512 Insertia hypoleuca, 182 Javaphylline, 109,125,137 Isoajmalicine, 126 Jervanine, 1, 5 Isoalchornine, 509 Jervine, 7 Isoboldine, 538,544 Joubertiamine, 554 N-Isobutyrylbaleabuxaline-F, 56 Juglans reqia, 536 1-1sobutyl- 1,2,3,4-tetrahydro-~-carboline,
527 N-3-Isobutyrylbuxidienine-F, 56 K N-Isobutyrylbaleabuxidine-F, 54 N-3-Isobutyrylcycloxo-buxidine-F, 54, 74 Keyserlingia griflthii, 557 N-3-Isobutylrylcycloxo-buxidine-H, 58 Kokusaginine, 534,542,546,563 Isocarapanaubine, 83,115,141 Kresigia multifiora, 268,279,281 Isocoptisine, 520 Kreysigine, 270,281,305,311,420 Kreysiginine, 268,278 Isocorydine, 522,533 Isocorynoline, 521 Kreysiginone, 269,279,315 Isocorynoxine, 94,107 Isodictamnine, 534 Isoelaeocarpicine, 326,330 L Isoelaeocarpiline, 326,331 Laburnine, 536,538,541,563 Isoelaeocarpine, 326,327 Isoformosanine, 83,113,125,137 Lanuginosine, 225,233 Lappula intermedia, 536 Isogambirdine, 93,118,125 Laudanidine, 535 Isoinundatine, 350,363 Isojavaphylline, 137 Lasiocarpine, 536,559 Isoliensinine, 544 Laudanosine, 527 Isolongistrobine, 540 Laurolitsine, 547 Isolycodoline, 351 Laurotetanine, 546 Isolycopodine, 351 Lemonia spectahilis, 536 Isolysergic amide, 512 Lemobiline, 536 Isoniacrorine, 540 Leontalbine, 536 Isomahanimbine, 544 Leontice albertii, 536 Isomajdine, 83,93,117,141 Leontice leontopetalum, 537 Isomitrajavine, 123,141,145 Leontice smirnowii, 537 Isomitraphylline, 83,93,113,125,137 Leontiformine, 537 Isoorensine, 507 Leontine, 536 Isopteropodine, 83,114, 125,141 Ligudent ine , 537 Isosophoridine, 537 Ligularia hrachyphylla, 537 Isoreserpiline, 167, 546 Liqularia dentata, 537 Isorhynchophylline, 83,93,94, 103, 124, Liqularia macrophylla, 537 128,154 Ligularine, 537 Isorotundifoline, 83,93,94,104,124,128 Limonia acidissima, 535 Isorubijervine, 19 Lindelofidine, 538 Isorubijervosine, 19 Liparia parva, 538 Isospecionoxeine, 83, 93, 94, 106, 124, Liparia sphaerica, 538 Liparw loeselii, 538 133 Isothebenine Rearrangement, 417 Liriodendron tulipifera, 227 N-Isovalerylhistamine, 526 Liriodenine, 225,226,511,543,544,552
SUBJECT INDEX
Litsea glutinosa, 228 Litsea haytae, 228 Litsea zeylanica, 538 Lobelia species, 538 Lobeline, 515 Lolium perenne, 538 Lonchocarpus speciosus, 515 Longistrobine, 540 Loroguine, 562 Lotusine, 544 Lucidioline, 351, 358 Luciduline, 349, 350, 370 Lunaria annua, 539 Lunaria biennis, 539 Lunarine, 519, 539 Lupanine, 532, 537, 538, 539 Lupinine, 539 Lupinus hispanicus, 539 Lupinus paniculatus, 539 Lycobergine, 351 Lycocernuine, 352 Lycoclavine, 351 Lycodine, 349, 352 Lycodoline, 351, 354 Lyconnotine, 349 Lycopecurine, 350, 362 Lycopodine, 349, 350, 354, 390, 396 Lycopodium alopecuroides, 348, 350 Lycopodium alpinum, 350 Lycopodium annotinum, 351 Lycopodium carolinianurn, 352 Lycopodium cernuurn, 353 Lycopodium clavatum, 351 Lycopodium inundatum, 350, 353 Lycopodium lucidulurn, 348, 350 Lycopodium selago, 350 Lycopodium serraturn, 348, 350 Lycopodium tristachyum, 397 Lycopodium volubile, 350 Lycoserine, 352 Lycoserramine, 351 Lycothunine, 350 Lysergic amide, 512 Lysicamine, 225, 229 Lysichiton camtschatcense, 228 Lythramine, 539 Lythrancine-I,II,III,IV, 539 Lythrancipine-I,II,III, 539 Lythranidine, 539 Lythranine, 539 Lythrum anceps, 539
605
M Mackinlaya klossii, 539 Mackinlaya macrosciadea, 539 Macralstonine, 168 Macroline, 175 Macrorhamnus faralaotra, 520 Macrorine, 540 Macrorungia longistrobus, 540 Magnoflorine, 560 Magnolia coco, 228, 541 Magnolia grandifiva, 228 Magnolia kachirachirai, 236 Magnolia pumila, 541 Mahanimbicine, 544 Mahonia aquifolium, 541 Majdine, 83, 93, 117, 141 Majorexine, 109 Malacocarpus crithmifolius, 541 Malaxis grandifolia, 541 Mammillaria prismatica, 512 Mammillaria sulcata, 5 12 Matrine, 536 Maytenus ovatus, 541 Maytine, 541 Maytol, 542 Maytoline, 541 Melanthioidine, 268, 288, 297, 314 Melicope confusa, 542 Melodinus scandens, 542 Melodorum punctulatum, 543 Meloscandinone, 542 Menispermum dauricum, 543 Merendera jolantae, 543 Merendera raddeana, 543 Merenderin, 543 Meroquinene, 187 Mesembranol, 555 Mesembrenol, 555 Mesembrenone, 555 Mesembrine, 543, 555 6-Methoxydictamnine, 534 10-Methoxydihydrocorynantheol,546 4-Methoxy-1-methyl-2-quinolone,535 4-Methoxyphenethylamine, 527 2-Methoxypyrazine, 55 1 N-Methylalataphylline, 5 13 0-Methylandrocymbine, 277, 305, 319 0-Methylatheroline, 235 N-Methylbrevicarine, 517 N-Methylbuxene-M, 66
606
SUBJECT INDEX
0-Methylcoclaurine, 544 Mucuna mutisiana, 544 N-Methylcorydaldine, 560 Murraya koenigii, 544 0 -Methylcorypalline, 544 Multifloramine, 271, 281 N-Methylcrotsparinine, 522 Myosmine, 517 N-Methylcytisine, 515, 536, 557, 561 0-Methyldauricine, 520 N N-Methyl-3,4-dimethoxy-j3-phenethylamine, 512 2,6-Naphthyridine, 511 1,2-Methylenedioxy-l0,1 l-dimethoxyNeferine, 544 oxoaporphine, 225, 252 Nectandra pichurium, 544 1,2-Methylenedioxy-10-methoxyoxoNelumbo nucifera, 544 aporphine, 225, 251 Neoevonhe, 529 N-Methylisosalsoline, 534 N-Methyl-4-methoxy-j3-phenethylamine, Neo-evonymine, 529 Neolitsia sericea, 228 512 Neonauclea schlechterei, 126 N-Methylmorpholine, 517 Neothiobinupharidine, 545 0-Methylmoschatoline, 262 Nervogenic acid, 538 4-Methyl-2,6-naphthyridine, 511 Nicotine, 517 N-Methylphenethylamine, 527 Nigella damascena, 544 1-Methylpiperidine N-oxide, 563 2-Methyl-1,2,3,4-tetrahydro-j3-~arboline, Nitidine, 530 Nobiline, 525, 526 550 Norargemonine, 529 N,-Methyltetrahydroharman, 514, 557 Norcinnamolaurine , 518 N-Methylthalidaline, 560 Norisoboldine, 538 N-Methyltyramine, 512 Nornicotine, 517 Michelalbine, 5 11, 543 N-Nornuciferine, 544 Michelea alba, 228 0-Nornuciferine, 544 Michelea champaca, 228 N-Norprotosinomenine, 527 Michelea compressa, 228 Norsecurinine, 429, 489 Michelia lanuginosa, 233 Nuciferine, 520, 544 Milliamine A, 530 Nuphur luteum, 545 Milliamine B, 530 Mitraciliatine, 125, 135 Mitragyna africana, I26 0 Mitragyna ciliata, 126 Mitragyna diversifolia, 126 a-Obscurine, 352 Mitragyna hirsuta, 92, 126 p-Obscurine, 352 Mitragyna inermw, 93, 123, 126 Ochrobirine, 546 Mitragyna javanica, 92, 119, 126 Ochrosia vieillardii, 546 Mitragyna macrophylla, 126 Ocotea macropoda, 244 Mitragyna parvifolia, 92, 123, 126, 168 Olea europaea, 182 Mitragyna rotundifolia, 123, 126 Oncinotis inandensis, 546 Mitragyna speciosa, 93, 126 Oriza japonica, 546 Mitragyna stipulosa, 123, 126 Ottonia vahlii, 546 Mitragynine, 83, 109, 125, 135 Ourouparine, 123, 146 Mitragynol, 94 Oxindole Alkaloids,-IR-spectra, 96 Mitrajavine, 123, 126, 141, 145 Oxindole Alkaloids,-PMR-spectra, 97 Mitrephora species, 552 Oxindole Alkaloids,-UV-spectra, 95 Mitraphylline, 83, 93, 113, 125, 137 Oxopurpureine, 225, 245 Mitrinermine, 94 Oxoushinsuine, 51I Moschatoline, 225, 231 13-Oxycryptopine, 547
SUBJECT INDEX
P Pachycarpine, 557, 561 Pallidine, 421, 521 Palmatine, 512 Palmeria arfakania, 546 Palmeria fengeriana, 546 Palmeria gracilis, 547 Papaver orientale, 246 Papaver somniferum, 547 Paracynoglossum imeretinum, 547 Parflumine, 532 Paucine, 549 Pauridiantha callicarpoides, 547 Pauridianthine, 547 Pauridianthinine, 547 Paynantheine, 125, 134 Pedicularis olgae, 548 Pediculine, 564 Peduncularine, 512 Pegamine, 548 Peganine, 507 Peganidine, 548 Peganum crithmqolium, 541 Peganum harmala, 548 Pelletierine, 395 Penecillium concavo-rugulosum, 549 Pentaclethra macrophylla, 549 Peripentadenia mearsii, 549 Perlolyrine, 538 Perriera madagascariemk, 549 Phakelia flabellata, 549 Phakellin, 549 Phalaenopsine, 536 Phalaenopsis cornu-cervi, 549 Phallaris tuberosa, 550 Phelline billardieri, 550 Phelline comosa, 272, 550 Phenethylisoquinoline, 266 Phenylacetamide, 543 Phyllanthidine, 426, 478, 488 Phyllanthine, 428, 481 Phyllanthus discoides, 427, 429, 452, 481, 488 Phyllobates aurotaenia, 551 Phyllochrysine, 428, 452 Picralinal, 168 Picraline, 158 Picramicine, 161 Picrinine, 158 Piperovatine, 546
607
Piper ovatum, 546 Piper trichostachyon, 551 P i s u m sativum, 551 Plasmodium falciparum, 220 Platydesmine, 526 Pleiocarpamine, 168 Polyalthia nitidissima, 228, 552 Pontevedrine, 225, 249, 533 Poranthera corymbosa, 551 Porantherine, 551 Preakuammicine, 157 Priestleya eliptica, 551 Protopine, 512,514,520,521,522,529,532 Pronuciferine, 544 Protostemonine, 552 Protosinomenine, 527 Pseudobaleabuxine-F, 68 Pseudocinchona africana, 107 Pseudoepi-isoelaecarpiline,326, 337 Pseudoselagine, 351 Pseuduvaria grandifolia, 228 Pseuduvaria species, 552 Pfelia trifoliata, 553 Pterogyne nitens, 553 Pteropodine, 83, 114, 125, 141 Ptelefoline, 553 Pterogynidine, 553 Pterogynine, 553 Purpureine, 245
Q Quebrachidine, 169 Quinamine, 209 Quinidine, 184, 194, 220 Quinidinone, 204 Quinine, 184, 194, 210, 220 Quininone, 204 Quinotoxine, 183, 193
R Rauniticine, 83, 116, 142 Rauvanine, 83, 113, 137 Rauvoxine, 83, 93, 115, 141 Rauvoxinine, 83, 93, 115, 141 Rauwoljia vomitoria, 93 Ravenia spectabilis, 536 Ravenoline, 536
608
SUBJECT INDEX
Regulovasine, 549 Reticuline, 511, 518, 538, 547 Remerine, 544 Rhazine, 168 Reserpiline, 142, 167 Rhombifoline, 561 Rhynchociline, 83, 93, 94, 105, 124, 128 Rhyncophylline, 83, 93, 94, 103, 124, 128, 154 Rhynchopyllol, 134 Ribalinidine, 553 Ricinidine, 562 Roemeria refracta, 228 Rotundifoline, 83, 93, 94, 104, 124, 128 Roxburghine, 123, 148 Roxburghine-A, 126 Roxburghine-B, 126, 154 Roxburghine-C, 126 Roxburghine-D, 126, 154 Roxburghine-E, 126, 154 Rubijervine, 19 Ruta graveolens, 553
S Sanguinarine, 512, 514, 520, 532 Salutaridine, 547 Santiaguine, 507 Sceletium joubertii, 553 Sceletium namquense, 554 Sceletium strictum, 554, 555 Sceletium tortuosum, 555 Schefferomitra subaequalis, 228, 552 Schelhammera pedunculata, 271 Schelhammericine, 272, 282 Schelhammeridine, 273, 282 Schelhammerine, 271, 282 Scopolamine, 555 Scopolia tangutica, 555 Scoulerine, 522 Scutia buxifolia, 555 Scutianine, 555 Secoyohimbane Oxindoles, 94 Securinega durissima, 429 Securinega fluggeoides, 429 Securinega suflruticosa, 427, 429 Securinega virosa, 429, 477 Securinine, 426, 428, 496 Securinol A, 428, 484 Securinol B, 428, 484
Securinol C, 428, 484 Securitinine, 428, 477 Selagine, 349, 352 Sendaverine, 520, 522 Senecio ledebourii, 537 Serotonine, 536, 556 Serpentine, 559 Serratanidine, 351, 365 Serratanine, 350 Serratidine, 350, 356 Serratine, 351, 365 Serratinidine, 352, 346 Serratinine, 349, 351, 365 Sessiflorine, 510 Sewarine, 159 Shepherdia argentea, 556 Shepherdia canadensis, 556 Shepherdine, 556 Sibara virginica, 556 Simiba bicolor, 525 Sinoacutine, 421, 521 Sinomeninone, 416 Skimmia foremanni, 556 Skimmia japonica, 556 Skimmianine, 525, 534, 535, 542 Skythanthines, 556 Skythanthus acutus, 556 Solanidanine, 1, 18 Solanidine, 19 Solanum khasianum, 557 Solasodine, 557 Solenopsis saevissima, 557 Sophora griffcthri, 557 Sparsiflorine, 522 Sparteine, 538, 539, 561 Spathiostemon javensis, 557 Speciociliatine, 125, 135 Speciofoline, 83, 94, 108 Speciogynine, 125, 135 Specionoxeine, 83, 93, 94, 106, 124, 133 Speciophylline, 83, 93, 114, 125, 141 Speciosine, 557 Spherophysine, 558 Spireine, 558 Spireae japonica, 558 Stemofoline, 558 Stemona japonica, 558 Stemonine, 552 Steparine, 541 Stephania abyssinica, 234 Stephazine, 543
609
SUBJECT INDEX
Stepholidine, 543 Stipulatine, 94 Strychnos camptoneura, 559 Strychnos nux-vomica, 559 Suffruticodine, 426,428,488 Suffruticonine, 426,428,489 Symphytum aspersum, 559
2,9,10-Trimethoxyoxoaporphine, 225, 250 Tropococaine, 549 Tropine, 555 Tropine 3,4,5-trimethoxycinnamate,528 Tryptophan, 536 Tylocrebrine, 562 Tylophora asthmatica, 562 Tylophorine, 562 Tylophorinidine, 562
T Tarenine, 559 Tarenna bipindensis, 559 Taspine, 536,560 Tetrahydroalstonine, 126,142,168 Tetrahydrocoptisine, 518 Tetrahydroharmol, 556 Tetrahydropalmatine, 522 Tetrahydrosecurinine, 439,449 Tetrahydrothalifendine, 560 1,2,9,10-Tetramethyoxynoraporphine, 552 1,2,9,10-Tetramethoxyoxoaporphine, 225,
235 1,2,10,11 -Tetramethoxyoxoaporphine, 225,250 Tetrastemma solheidii, 563 Thalflavine, 560 Thalicarpine, 560 Thalicmine, 560 Thalicminine, 225,242,560 Thalicsimidine, 561 Thalictricine, 561 Thalictrum fendleri, 560 Thalictrum jlavum, 560 Thalictrum minus, 242,560 Thalictrum simplex, 242,560 Thalmethine, 560 Thermopsamine, 561 Thermopsine, 561 Thermopsis alternijlora, 561 Thermopsis lanceolata, 561 Thermopsis montana, 561 Tienmulilmine, 32 Tigloylcyclovirobuxeine-B, 39 Tiliacora racemosa, 562 Tiliacorydine, 562 Timonius kaniensis, 562 Tortuosamine, 555 Trewia nudiJora, 562 Trichonine, 551 1,2,10-Trimethoxyoxoaporphine,225,252
U Uncaria cordata, 126 Uncaria gambir, 93,124,126,168 Uncaria kawakamii, 126 Uncaria ovalijolia, 126 Uncaria sclerophylla, 126 Uncarine-A, 125 Uncarine-B, 125 Uncarine-C, 125,141 Uncarine-D, 125 Uncarine-E, 125,141 Uncarine-F, 83,93,114,141 Urechites karwinsky, 562 Urophyllum callicarpoides, 547 Uvariopsine, 563 Uvariopsis solheidii, 563
v 0-Vanilloycyclovirobuxine-D,46 Vallesiachotamine, 150 Vanda cristata, 563 Vandopsis longicaulw, 563 Vasicoline, 507,508 Venalstonidine, 168 Venalstonine, 168 Venenatine, 169 Venesperine, 168 Veracintine, 30 Veralinine, 27 Veralkamine, 24 Veralobine, 19 Veralozidine, 20,23 Veralozine, 20 Veralozinine, 20,33 Veramarine, 17 Veramine, 28 Verarine, 10
610 Veratramine, 13 Veratranine, 1, 5 Veratrobasine, 5 Veratrum album, 17 Ve'eratrumcalifornicum, 17 Veratrum grandijlorum, 23 Verazine, 20 Verbascine, 563 Verbasine, 563 Veronamine, 560 Vepris ampody, 563 Verbascum nobile, 563 Villalstonine, 177 Vinca elegantissima, 93 Vinca erecta, 94, 119 Vinca herbacea, 93, 138 Vinca major, 93 Vinca pubescens, 93 Vinca rosea, 93, 157, 168 Vincsmajine, 168
SUBJECT INDEX
Vincoside, 152 Vineridine, 94, 119 Vinerine, 94, 119 Vinine, 93 Viroallosecurinine, 429, 477 Virosins, 429 Virosecurinine, 427, 464, 496
X Xanthofagarine, 530 Xylopia brasiliensis, 235
Z Zanthoxylum senegalense, 530 Zanthoxylum macrophyllum, 530
